CN101245061A - 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 the class protein with tyrosine kinase activity of strict control in vivo, γ-phosphate on their energy 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 a class ATP, though the ATP of PTK combines the homology that the territory has height in conjunction with the territory with the ATP of serine/threonine protein kitase, miazines still has very big selectivity as ptk inhibitor.In the anilino compounds, the derivative of 3 bit substituents has stronger inhibition activity (Zhou Yiming, Sun Liguang than the derivative 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 for the treatment of chronic myeloid leukemia CML and gastrointestinal stromal knurl GISTs of lead compound exploitation with the 2-aniline pyrimidine as Novartis Co.,Ltd, it combines by competitive inhibition ATP and tyrosine protein kinase Abl-Bcr's, specific prevention Abl-Bcr autophosphorylation, influence cell signalling, suppress the propagation of tumour cell.
NO (nitrogen protoxide) is important messenger molecule and an effector molecule 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 the reparation of apoptosis and prevention DNA; Aspect immunity system, NO mediation scavenger cell is to outside the performance cytotoxicity 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 suppresses the expression of proto-oncogene, may 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 release of NO is still the emphasis of research.
Comprise the anilino-pyrimidine derivative example that has analog structure with this invention in the following patent: EP 0564409, WO066613, WO099187, US 0248918.
Summary of the invention
N-(5-amino-2-methyl phenyl)-4-(3-the pyridyl)-2-pyrimidinamine derivatives that the object of the present invention is to provide a class to have 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
Or
R
2Be selected from: the straight or branched alkane 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-chain paraffin of carbonatoms 2-10; The branched paraffin 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-chain paraffin, and carbonatoms is 3 or 5 branched paraffin, 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-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] benzamide
4-[(6-nitre oxygen base hexyloxy) methyl-]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] benzamide
4-[(2-nitre oxygen base propoxy-) methyl-]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] benzamide
4-[[(4-nitre oxygen ylmethyl)] phenoxymethyl-]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] benzamide
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 this area routine the salifying method preparation.
Can make composition with acceptable carrier on anticancer active constituent compound that comprises the general formula (I) for the treatment of significant quantity and the pharmaceutics among the present invention.Composition can this area routine the preparation of preparation means.
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 invention provides following technical scheme:
The synthetic route of lead compound N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE (A) is as follows, referring to [US5521184 and Zolt á n Szak á cs, Szabolcs B é ni, Zolt á n Varga, L á szlo _ rfi, Gy_rgy 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, it is the alcohols that nitric ether replaces, can be by corresponding diol at acetate, diacetyl oxide obtains by nitric acid nitrating under existing, specifically referring to [George N.Ziakas, Eleni A.Rekka, Antonios M.Gavalas, Phaedra T.Eleftheriou, Karyofillis C.Tsiakitzis and Panos N.Kourounakis.Nitric oxide releasingderivatives of tolfenamic acid with anti-inflammatory activity and safe gastrointestinal profile[J] .Bioorgganic ﹠amp; Medicinal Chemistry, 2005,13:6485-6492.]
Compound I
1-17Synthetic: alcohols that nitric ether replaces or phenolic compound and halogenated acetic acids are in inert solvent, esterification takes place in the presence of the DMAP of DCC (dicyclohexylcarbodiimide) 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 (tetrahydrofuran (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-chain paraffin of carbonatoms 2-10, the branched paraffin of carbonatoms 3-6.
Compound I
15-17
Compound I
18-33Synthetic: N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE is through to monochloromethyl benzoyl halogen acidylate, and alcohols or the phenolic compound that replaces with nitric ether in the presence of phase-transfer catalyst etherification reaction takes place again.Phase-transfer catalyst wherein is preferably quaternary ammonium salt, more preferably TBAB (Tetrabutyl amonium bromide); Halogenated methyl benzoyl halogen is preferably chloromethyl benzoic acid chlorides wherein.
Compound I
18-33, R represents the straight-chain paraffin of carbonatoms 2-10, the branched paraffin of carbonatoms 3-6, or corresponding phenolic.
Embodiment
Below further set forth the present invention by 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 (promyelocyticleukemia), PC-3 (prostate), HT-29 (colon), DU 145 (colon) is made into suspension with RPMI1640 nutrient solution (Gibco-BRL), add 10% through heat-killed foetal calf serum (FCS, Gibco), 100IU/ml penicillin 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 hole flat boards (CONING), the dull and stereotyped reader (Dynatech MR5000) of automatization spectrophotometric.
Medicine: according to the I of embodiment 1～5 method preparation
1～I
5, Gleevec
Experimental technique:
In every hole of 96 hole flat boards, add 0.1mL and contain the suspension 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 liquor, every hole adds 150 μ l DMSO, jolting 15 minutes, dull and stereotyped by the dull and stereotyped reader of automatization spectrophotometric, measure the optical density(OD) (OD) in each hole in 540nm wavelength place.Do not add optical density(OD) that test-compound records product in contrast 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 IC
50Value.(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 results are shown in Table 1 to marrow sexual cell leukemia cell line.
| Examplex | IC 50(μg/ml) | ||||
| HL-60 | K562 | DU-145 | HT-29 | PC-3 | |
| I 1 | 8.34 | 7.24 | 41.45 | 22.54 | 14.51 |
| I 6 | 3.51 | 4.23 | 14.54 | 35.67 | 10.45 |
| I 11 | 5.65 | 7.15 | 76.56 | 25.34 | 24.25 |
| I 15 | 4.76 | 3.98 | 55.78 | 19.05 | 16.75 |
| I 26 | 8.88 | 10.56 | 43.56 | 43.44 | 18.69 |
| I 32 | 5.02 | 4.98 | 30.26 | 3.79 | 13.42 |
The IC of table 1 test-compound in each JEG-3
50(μ g/ml)
Conclusion:
From the antitumour activity test-results as can be seen, 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 cell strains, illustrate 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 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 ethylene glycol (2.48g 40mmol) is dissolved in the 100ml ethyl acetate, add successively concentrated nitric acid (4.36g, 45mmol), Glacial acetic acid 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, the Anhydrous potassium carbonate drying, concentrate the yellow oily crude product.Column chromatography (ethyl 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 in batches DCC (2.74g, 13.30mmol) and the DMAP of catalytic amount.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 (ethyl 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 tetrahydrofuran (THF) and to stir 20 minutes, add 2-nitre oxygen monobromoethane acetic ester (1.34g, 5.88mmol) and the TBAB of catalytic amount refluxed 5 hours, filter, saturated sodium bicarbonate is washed, anhydrous sodium sulfate drying, concentrate, ethyl 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-NMRδ(ppm)：9.3(d，1H，J＝1.81，NH)，8.7(m，2H)，8.4(m，2H，)，7.5(dd，1H ，J 1＝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-pyridine)-2-pyrimidine] amino]-phenyl] acetate-own ester (I of 6-nitre oxygen base
5)
With reference to example 1 preparation method, by 1, the 6-hexylene glycol is that starting raw material prepares N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] acetate-own ester of 6-nitre oxygen base, yield: 58.64%, 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-NMRδ(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 (I
9)
With reference to example 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-propylene glycol (3.04g 40mmol) is dissolved in the 100ml ethyl acetate, add successively concentrated nitric acid (873g, 80mmol), Glacial acetic acid 20ml, acetic anhydride 20ml stirred overnight at room temperature.10% sodium bicarbonate aqueous solution flushing is near neutral, the saturated common salt washing, the Anhydrous potassium carbonate drying, concentrate the yellow oily crude product.Column chromatography (ethyl 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 in batches DCC (2.06g, 10mmol) and the DMAP of catalytic amount.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 (ethyl 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 tetrahydrofuran (THF), stirred 20 minutes, add bromoacetic acid-2-nitre oxygen base propyl ester (1.42g, 5.88mmol) and the TBAB of catalytic amount refluxed 6 hours, filter, saturated sodium bicarbonate is washed, anhydrous sodium sulfate drying, concentrate ethyl 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-NMRδ(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＝820)，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 (I
12) with reference to example 5, by 1, the 2-butyleneglycol is that starting raw material is prepared into yield: 45.56%, 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-NMRδ(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, adds DCC (0.84g after the stirring and dissolving, 4.08mmol) and the DMAP of catalytic amount, adding bromoacetic acid under the ice bath (0.86g, 6.18mmol), stirring at room 3 hours, filter, concentrate the back and add the 50ml ethyl acetate, 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 tetrahydrofuran (THF), stirring and dissolving is with 2-bromoacetic acid-3-nitre oxygen methyl phenyl ester (1.96g, 3.46mmol) and the TBAB of catalytic amount add wherein, reflux 12 hours is filtered, and column chromatography gets 1.42g, yield: 64.84%, mp:156.7-158.6 ℃
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] benzamide (I
18) 4-chloromethyl-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] benzamide
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 tetrahydrofuran (THF) and stirred 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%.
4-chloromethyl-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] (0.86g, 2mmol), (0.32g 2.99mmol) joins in the toluene benzamide, 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 extracts with toluene, merge organic layer, use dilute hydrochloric acid successively, saturated sodium bicarbonate and saturated common salt water washing, anhydrous sodium sulfate drying, remove 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-NMRδ(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] benzamide (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] benzamide (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] benzamide (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. general formula (I) compound and pharmacy acceptable salt thereof:
R
1For
Or
R
2Be selected from: the straight or branched alkane of carbonatoms 2-10, o, m, p-(CH
2)
m-Ph-(CH
2)
n-, m=0-6 wherein, n=1-4.
2. the described general formula of claim 1 (I) compound, R
2Be selected from: the straight-chain paraffin of carbonatoms 2-10; The branched paraffin of carbonatoms 3-6; O, m, p-(CH
2)
m-Ph-(CH
2)
n-, m=0-2 wherein, n=1-3.
3. the described general formula of claim 2 (I) compound, R
2Be selected from: the straight-chain paraffin of carbonatoms 2,5,10, the branched paraffin of carbonatoms 3,5, o, m, p-Ph-CH
2-.
4. the described general formula of claim 1 (I) compound, 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-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] benzamide,
4-[(6-nitre oxygen base hexyloxy) methyl-]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] benzamide,
4-[(2-nitre oxygen base propoxy-) methyl-]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] benzamide,
4-[[(4-nitre oxygen ylmethyl)] phenoxymethyl-]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] benzamide.
5. the preparation method of each described general formula (I) compound of claim 1-4 may further comprise the steps:
1) R
1For
The time general formula (I) compound:
(1) esterification takes place in the alcohol compound and the halogenated acetic acids of nitric ether replacement in the presence of dicyclohexylcarbodiimide,
(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 general formula (I) compound:
(1) N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE is through to halogenated methyl benzoyl halogen acidylate,
(2) etherification reaction takes place in the alcohol compound with the nitric ether replacement in the presence of phase-transfer catalyst.
According in the claim 1-4 item each general formula (I) compound and add the composition that acceptable carrier is made on the pharmaceutics.
7. the application of each general 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 general 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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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012022217A1 (en) * | 2010-08-20 | 2012-02-23 | 成都地奥制药集团有限公司 | N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)phenyl]benzamide derivatives, a preparation method and use for synthesis of imatinib thereof |
| CN104292210A (en) * | 2013-07-15 | 2015-01-21 | 天津药物研究院 | Pyridine-containing nitric oxide donor compound and preparation method and use thereof |
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|---|---|---|---|---|
| TW225528B (en) * | 1992-04-03 | 1994-06-21 | Ciba Geigy Ag | |
| GB0201508D0 (en) * | 2002-01-23 | 2002-03-13 | Novartis Ag | Organic compounds |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012022217A1 (en) * | 2010-08-20 | 2012-02-23 | 成都地奥制药集团有限公司 | N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)phenyl]benzamide derivatives, a preparation method and use for synthesis of imatinib thereof |
| CN102372690A (en) * | 2010-08-20 | 2012-03-14 | 成都地奥制药集团有限公司 | Intermediate for synthesizing imatinib and application of intermediate in imatinib synthesis |
| CN102372690B (en) * | 2010-08-20 | 2014-05-28 | 成都地奥制药集团有限公司 | Intermediate for synthesizing imatinib and application of intermediate in imatinib synthesis |
| CN104292210A (en) * | 2013-07-15 | 2015-01-21 | 天津药物研究院 | Pyridine-containing nitric oxide donor compound and preparation method and use thereof |
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