CN101417995B

CN101417995B - Phenoxy pyrimidine derivates and preparation method and use thereof

Info

Publication number: CN101417995B
Application number: CN2008102443085A
Authority: CN
Inventors: 陈依军
Original assignee: Individual
Current assignee: Nanjing Biotica Pharmaceutical Co
Priority date: 2008-11-21
Filing date: 2008-11-21
Publication date: 2012-06-06
Anticipated expiration: 2028-11-21
Also published as: WO2010057418A1; CN101417995A

Abstract

The invention discloses a phenoxy pyrimidine derivative, a method for preparing the same and application thereof. The name of the derivative is N-[4-methyl-3-[4-(3-pyridyl)-2-pyrimidineoxy]-phenyl]-3-(4-methylpiperazinemethyl)-benzamide, and the chemical formula is expressed as below; the compound is prepared by using 4-methyl-3-[4-(3-pyridyl)-2-pyrimidineoxy]-aniline as one of main raw materials through reaction; and the obtained compound can obviously inhibit tumor cells. The inhibition concentration of the compound to half of the cell proliferation of leukemia, liver cancer, stomach cancer, mammary cancer and ovarian cancer reaches a range of between 1.5 and 20 mu M.

Description

Phenoxy pyrimidine derivatives, preparation method and application thereof

Technical Field

The invention relates to a phenoxyl pyrimidine derivative, a preparation method and a pharmaceutical application thereof, and the phenoxyl pyrimidine derivative has the effect of inhibiting tyrosine protein kinase.

Background

Chinese patent No. 01138070.5 discloses a class of 2-phenoxypyrimidine derivatives, whose chemical structure is represented as follows:

wherein,

x is oxygen, sulfur, secondary amino or carbonyl;

y is carbonyl, oxygen, sulfur or secondary amino;

R₁、R₈is a six-membered aromatic ring or a six-membered aromatic heterocyclic ring and a substituted six-membered aromatic ring or a six-membered aromaticAromatic heterocyclic ring, the substituent group comprises hydrogen, halogen and C₁-C₃Alkyl or C₁-C₃Alkoxy, hydroxy, amino and nitro of (a);

R₂、R₃、R₅、R₆、R₇is hydrogen, halogen, C₁-C₆Alkyl radical, C₃-C₁₅Cycloalkyl radical, C₁-C₆An alkyl-substituted six-membered heterocyclic ring;

R₄is hydrogen, halogen, hydroxy, C₁-C₆Alkoxy or C₁-C₆Alkyl groups of (a);

R₉selected from hydrogen, oxygen, sulfur, methine, secondary amino, C₁-C₆Alkyl or-Z-R₁₀；

Wherein Z represents oxygen, sulfur, methine, a secondary amino group or C₁-C₆Alkyl groups of (a);

R₁₀is hydrogen, halogen, C₁-C₆Alkyl of (C)₃-C₁₅Cycloalkyl radical, C₁-C₆An alkyl-substituted six-membered heterocyclic ring.

The compounds defined by the general formula are inhibitors of protein kinases and variants thereof, have inhibitory effects on Abl tyrosine protein kinases, and in addition, phenoxypyrimidine derivatives may also have effects by inhibiting other protein kinases such as threonine.

The compounds defined by the general formula can be used for treating and preventing proliferative diseases and diseases which generate drug resistance to the existing drugs, such as cancers and inflammatory diseases, and can also be used for treating neurodegenerative diseases, such as senile dementia, cardiovascular diseases, viral infection and mould infection.

The examples of the above patent disclose the data of 18 compounds for the inhibition test of Abl tyrosine protein kinase, and the results show that 18 compounds have obvious and strong inhibition effect on Abl tyrosine protein kinase, and theyHalf maximal Inhibitory Concentration (IC)₅₀) In the range of 0.025-2.0. mu.M.

Although the compounds of the invention have obvious and strong inhibition effect on tyrosine protein kinase, the activity of the compounds for inhibiting tumor cell proliferation is not verified in the patent literature, and the actual therapeutic application is unknown. Unexpectedly, they did not show strong inhibition in the experiments of tumor cell proliferation conducted by the inventors thereafter. Therefore, in the practical process of applying the series of compounds as therapeutic drugs, compounds which have stronger inhibitory effect and are suitable for industrial production are required.

Disclosure of Invention

The invention aims to provide a phenoxyl pyrimidine derivative, which provides more obvious and strong effect of inhibiting tyrosine protein kinase, thereby utilizing the compound to prepare a medicament for inhibiting the growth of tumor cells; the invention also aims to provide a preparation method of the compound, and optimize the preparation process, so that the compound is suitable for industrial production.

In order to achieve the purpose, the invention adopts the technical scheme that: a phenoxypyrimidine derivative, having the name: n- [ 4-methyl-3- [4- (3-pyridyl) -2-pyrimidinyloxy ] -phenyl ] -3- (4-methylpiperazinemethyl) -benzamide; the chemical formula is shown as follows:

in addition to the compounds described directly in the present invention, the pharmaceutically acceptable salts of the compounds are also within the scope of the present invention, and the present invention relates to the pharmaceutically acceptable salts of the compounds including various salts formed with inorganic acids, organic acids or inorganic bases and organic bases.

Examples of acidic salts are acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphoriodate, cyclopentylpropionate, digluconate, dodecanesulfonate, methylsulfonate, ethylsulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, sulfinate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, malate, malonate, naphthalenesulfonate, nicotinate, nitrate, oxalate, palmitate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, isopropionate, salicylate, succinate, sulfate, tartrate, thiocyanate, Tosylate and undecanoate salts; examples of the alkaline salts are alkali metal (e.g., sodium, potassium) salts, alkaline divalent metal (e.g., magnesium) salts, ammonia salts, and alkylamine salts having 1 to 4 carbon atoms.

The phenoxypyrimidine derivatives, salts or medicinal precursors thereof can be combined with a carrier which can be used as a medicine to form a medicinal preparation.

The phenoxyl pyrimidine derivative, the salt or the medicinal precursor thereof can act on the protein kinase and the variant thereof, and regulate and change the catalytic function of the protein kinase and the variant thereof.

The protein kinase and its variant acted on can be tyrosine protein kinase and its variant, including receptor tyrosine protein kinase and its variant and non-receptor tyrosine protein kinase and its variant. Receptor tyrosine protein kinases and variants thereof include PDGFR α, PDGFR β, EGF, HER2, HER3, HER4, IR, IGF-IR, IRR, CSFIR, C-kit, C-fms, Flk-IR, Flk-4, KDR/Flk-1, Flt-1, FGFR-1R, FGFR-2R, FGFR-3R and FGFR-4R; non-receptor tyrosine-like protein kinases and variants thereof include Abl, Src, Frk, Btk, Csk, MAP, P38, ZAP70, Fes/Fps, Fak, Jak, ArkYes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.

The protein kinase and variants thereof may also be serine/threonine protein kinases and variants thereof, including CDK2, MAP, P38, Raf, and PKC.

The compounds described above are administered to humans in effective amounts for the treatment and prevention of diseases associated with protein kinases and variants thereof.

The compounds of the present invention can be administered to the human body via pharmaceutically acceptable carriers, which include ion exchange resins, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffers (e.g., phosphates, glycine, sorbic acid, potassium sorbate, etc.), glycerolipids of partially saturated vegetable oils, mixtures of water and salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, etc.), zinc salts, colloidal silica gel, magnesium trisilicate, polyvinyl pyrrolidone, celluloses, polyvinyl glycerol, sodium carboxymethylcellulose, polyimides, waxes, lanolin, and the like.

The compound can be administrated to human bodies by different routes, and the specific administration routes comprise oral administration, parenteral administration, oral inhalation, transdermal administration, rectal administration, nasal administration, sublingual administration, buccal administration, vaginal administration and administration through an implanted container; parenteral administration in turn includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infiltration.

The compound can be prepared into different dosage forms for human body administration, and the specific dosage forms comprise aqueous solution injection, oily suspension injection, oral capsules, oral tablets, oral aqueous solution, oral suspension, rectal suppository, eye drops, eye ointment, skin cream, skin spray, oral aerosol, nasal spray, nasal aerosol and the like, and also comprise sustained release agents and preparations for controlling release speed and dosage of the different dosage forms.

The dosage of the compound of the present invention used for the treatment and prevention of diseases in human body is influenced by various factors including age, body weight, health condition, sex, race, eating habit, administration time, frequency of urination and whether other drugs are used, etc.

The compounds of the present invention have specific pharmacological activities which are effected by inhibition of protein kinases, particularly tyrosine protein kinases and variants thereof. Various diseases related to the activity of protein kinases have been described in the background section of the chinese patent No. 01138070.5, and the present invention is particularly effective for proliferative diseases by inhibiting the activity of protein kinases and variants thereof, while also solving the problem of drug resistance existing in currently clinically used drugs.

The compounds of the invention are therefore particularly suitable for the treatment and prophylaxis of the following diseases:

solid malignancies that occur in the following sites and tissues: breast, ovary, colon, liver, gallbladder, lung, stomach, prostate, pancreas, throat, bladder, brain, skin, etc.;

lymphocytic blood-based tumors: acute lymphocytic, acute primitive lymphocytic, B-cell, T-cell, hodgkin's, non-hodgkin's, hairy cell, and Burkett's lymphomas;

bone marrow cell type blood-based tumor: acute myeloid leukemia, chronic myeloid leukemia, myelodysplasia and promyelocytic leukemia;

others also include tumors occurring within the central and peripheral nervous systems;

since tyrosine protein kinase plays an important role in the regulation of cell function and the proliferation and reproduction of cells, the compounds of the present invention may have therapeutic and prophylactic effects on any diseases affecting the regulation of cell function and the proliferation of cells, including inflammation, neurodegenerative diseases, viral infection, fungal infection, etc.

The preparation method of the compound of the invention can select any one of the following two, and the first method comprises the following steps:

(1) acylating chlorination of 3-chloromethylbenzoic acid to obtain 3-chloromethylbenzoyl chloride, dissolving in solvent, and adding diisopropylethylamine;

(2) adding the solution of the compound A into the solution obtained in the step (1) for reaction, adding N-methylpiperazine, and stirring for reaction; the molecular formula of the compound A is as follows:

(3) removing the solvent, adding a solution of strong base and weak acid salt, and then extracting, drying, filtering, concentrating, separating and purifying to obtain a target product; the molecular formula of the target product is:

in the above technical scheme, the preparation method of compound a is disclosed in chinese patent No. 01138070.5.

The preferable technical scheme comprises the following steps: 1 part of 3-chloromethylbenzoic acid;

(1) acylating chlorination of 1 part of 3-chloromethylbenzoic acid to give 3-chloromethylbenzoyl chloride of the formula:

dissolving 3-chloromethylbenzoyl chloride in a solvent A, then adding 1.5-3 parts of diisopropylethylamine, and cooling the mixed solution to-50-80 ℃;

the solvent A is selected from: organic solvents with larger polarity such as tetrahydrofuran, methanol, ethanol, isopropanol, acetone, n-butanol or ethyl acetate;

(2) dissolving 1-2 parts of a compound A in a solvent B, adding the solution into the solution obtained in the step (1), and after 5-60 minutes, heating to 0-25 ℃; after preserving heat for 2-5 hours, adding 1-2 parts of N-methylpiperazine, and stirring and reacting for 5-20 hours at room temperature;

the molecular formula of the compound A is as follows:

the solvent B is selected from: mixtures of tetrahydrofuran and N, N-dimethylformamide, mixtures of tetrahydrofuran and other water-insoluble organic solvents including dichloromethane, chloroform, MTBE, ethyl acetate, N-butanol, benzene, toluene, BEHP, N-hexane, cyclohexane, DMSO or petroleum ether;

the weak base is selected from: sodium hydrogen carbonate, potassium hydrogen carbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, dimethylamine, trimethylamine, or triethylamine; preferably sodium bicarbonate solution with the mass fraction of 2 to 20 percent.

The reaction process of method one can be represented as follows:

the second method comprises the following specific steps:

(1) dissolving 3- (4-methylpiperazinomethyl) -benzoyl chloride in a solvent, adding a compound A under stirring, and reacting;

the molecular formula of the compound A is as follows:

(2) removing the solvent, adding a solution of strong base and weak acid salt, extracting, drying, filtering, concentrating, separating and purifying to obtain a target product, wherein the molecular formula of the target product is as follows:

the preferable technical scheme comprises the following steps:

(1) dissolving 1 part of 3- (4-methylpiperazinomethyl) -benzoyl chloride in a solvent according to the mass amount, adding 1-2 parts of compound A under stirring, and reacting for 1-10 hours;

the molecular formula of the compound A is as follows:

the solvent is selected from alkaline organic solvents such as pyridine, dimethylamine, trimethylamine or triethylamine and the like;

The reaction process of method two can be represented as follows:

the preparation method of the 3- (4-methylpiperazinemethyl) -benzoyl chloride in the second method comprises the following steps:

1 part of 3-bromomethyl benzoate;

(1) dissolving 1 part of methyl 3-bromomethylbenzoate, 1.2 parts of N-methylpiperazine and 1.5-2 parts of triethylamine in toluene, and heating and refluxing for 10 hours; cooling, filtering and concentrating to obtain 3- (4-methylpiperazine methyl) -methyl benzoate;

(2) dissolving 3- (4-methylpiperazinomethyl) -methyl benzoate in methanol, then dropwise adding a methanol solution of sodium hydroxide with the mass fraction of 10%, stirring and alcoholyzing at room temperature, then adjusting the pH value to 7-8, and filtering to obtain 3- (4-methylpiperazinomethyl) -benzoic acid;

(3) the acyl chloride of 3- (4-methylpiperazinomethyl) -benzoic acid is chlorinated to obtain 3- (4-methylpiperazinomethyl) -benzoyl chloride.

The above process for preparing 3- (4-methylpiperazinomethyl) -benzoyl chloride can be represented as follows:

in the invention, the target product can be prepared

Salt formation is prepared, for example: dissolving the target product in methanol, adding 10% hydrochloric acid in methanol, and removing solvent to obtain hydrochloride. Other salts may also be prepared according to conventional methods.

Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:

1. the compound of the invention has good inhibition effect on tumor cells, and the inhibition effect is usually half Inhibition Concentration (IC)₅₀) The half Inhibitory Concentration (IC) of the compound of the invention on cell lines of leukemia, liver cancer, gastric cancer, breast cancer and ovarian cancer₅₀) Reaching the range of 1.5-20 mu M; in contrast, the compound disclosed in patent 01138070.5, although having a strong inhibitory effect on the Abl protein kinase level, is not effective in inhibiting tumor cell proliferation, and its IC is poor₅₀The values were all greater than 50. mu.M.

2. The invention provides 2 a method for preparing a target compound, wherein the yield of the method I is 38%, the yield of the method II is 60%, and in practical application, factors such as availability of raw materials, environmental pollution, input-output ratio and the like can be comprehensively considered to select a synthetic route.

3. The compound has high selectivity and small side effect when inhibiting the proliferation of tumor cells.

Detailed Description

The invention is further described below with reference to the following examples:

the first embodiment is as follows: the preparation of 4-methyl-3- [4- (3-pyridyl) -2-pyrimidinyloxy ] -aniline can be seen in Chinese patent 01138070.5; the synthetic route is as follows:

(1) preparation of 3-dimethylamino-1- (3-pyridinyl) -2-propen-1-one:

3-acetylpyridine (181.5 g, 1.5 mol) and N, N-dimethylformamide dimethyl hemiacetal (178.5, 1.5 mol) were added to a reaction flask, and the mixture was dissolved in 500 ml of N, N-dimethylformamide and heated to 120 ℃ and 130 ℃ and stirred for 4 hours;

the solvent was removed and the residue was recrystallized from ether to yield a white pale yellow crystal: 252 grams. Yield: 95 percent. Melting point: 81-82 ℃.

MS ES+m/z＝1FF(MH⁺)。

H-NMR(400MHz，CDCl₃) And (3) analysis results:

ppm：9.08(d，1H，J＝2.9Hz)；8.6F(dd，1H，J＝1.8，4.9Hz)；8.19(dt，1H，J＝2.0，1.9，8.0Hz)；7.84(d，1H，J＝12.3Hz)；7.33(m，1H)；5.68(d，1H，J＝12.3Hz)；3.18(s，3H)；2.95(s，3H)。

(2) preparation of 2-methylthio-4- (3-pyridyl) pyrimidine:

dissolving metal sodium (18.4 g, 0.8 mol) in 500 ml of absolute ethyl alcohol, adding thiourea (76.1 g, 1 mol) and 176 g (1 mol) of 3-dimethylamino-1- (3-pyridyl) -2-propen-1-one, heating and refluxing for 6 hours, adding 1L of water, adjusting pH to be approximately equal to 5 by glacial acetic acid, heating and refluxing for about 15 minutes, then cooling to room temperature, filtering, and drying to obtain a white solid (about 140 g) for later use.

The white solid was taken, dissolved in 500 ml of 1N NaOH solution and cooled to about 0 ℃. Slowly adding methyl iodide under stirring, maintaining stirring for 15 min, filtering to obtain a solid, pulping with water, washing, draining, drying, and recrystallizing with ethanol. The product (yellow) is obtained: 119 g (yield: 58.6%). Melting point: 140 ℃ and 142 ℃.

MS ES+m/Z＝204(MH+)。

H-NMR(400MHz，CDCl₃) And (3) analysis results:

ppm：9.28(d，1H，J＝2.3Hz)；8.74(dd，1H，J＝1.5，4.8Hz)；8.61(d，1H，J＝5.3Hz)；8.42(m，1H)；7.45(m，1H)；7.41(d，1H，J＝5.3Hz)；2.65(s，3H)。

(3) preparation of 2-methionyl-4- (3-pyridyl) -pyrimidine:

dissolving 2-methylthio-4- (3-pyridyl) pyrimidine (50 g, 0.24 mol) in 250 ml of a methanol-water (7: 3) mixed solution, adding potassium metabisulfite (3X 60g) in batches under stirring, then stirring at room temperature for 3 hours until the reaction solution is light yellow, and drying to obtain a product: 48 g (yield: 85%). Melting point: 120-122 ℃.

MS ES+m/Z＝236(MH+)。

H-NMR(400MHz，CDCl₃) And (4) analyzing results:

δppm：9.34(dd，1H，J＝0.8，2.4Hz)；9.01(d，1H，J＝5.3Hz)；8.82(dd，1H，J＝1.6，4.7Hz)；8.54(dd，1H，J＝1.6，2.4Hz)；7.99(d，1H，)＝5.3Hz)；7.52(m，1H)；3.45(S，3H)。

(4) preparation of N-tert-butoxycarbonyl-3-hydroxy-4-methylaniline:

3-hydroxy-4-methylaniline (25 g, 0.203 mol) was dissolved in 400 ml of ethyl acetate, followed by stirring of low-valent dibutoxy carbonate (47 ml, 0.203 mol). Stirring was continued at room temperature for 24 hours. Washed with 10% sodium bicarbonate, water, dried, concentrated, and chromatographed (ethyl acetate: ethane: 1/5) to give a white solid: 43 g (yield: 95%). Melting point: 118 ℃ and 120 ℃.

MS ES+m/Z＝224(MH+)；

H-NMR(400Hz，CDCl₃) And (3) analysis results:

δppm：7.11(br，1H)；6.98(m，1H)；6.62(m，1H)；6.62(m，1H)；6.41(m，1H)；5.03(S，1H)；2.18(s，3H)；1.52(m，9H)。

(5) preparation of N-tert-butoxycarbonyl-4-methyl-3- [4- (3-pyridyl) -2-pyrimidinyloxy ] -aniline:

N-tert-Butoxycarbonyl-3-hydroxy-4-methylaniline (8.6 g, 39 mmol) was dissolved in 50 ml of anhydrous N, N-dimethylformamide, and 60% sodium hydride (4.6 g, 115 mmol) was added in portions at 0 ℃ with stirring. After stirring for 1 hour, 2-methionyl-4- (3-pyridyl) -pyrimidine (9.5 g, 40 mmol) was added. After 30 minutes, the reaction mixture was allowed to warm to room temperature and stirred overnight, the pH of the reaction mixture was adjusted to approximately 7 with 10% citric acid, and a solid precipitated. The mixture was poured into 500 ml of ice water, stirred, filtered and washed thoroughly with water. The solid was dissolved in dichloromethane, dried, filtered and concentrated. Obtaining a product: 12 g (yield: 80%). Melting point: 164 ℃ and 165 ℃.

MS ES+m/Z＝379(MH⁺)。

H-NMR(400MHz，CDCl₃) And (4) analyzing results:

δppm：9.22(dd，1H，J＝0.8，2.3Hz)；8.72(dd，1H，J＝1.5，4.6Hz)；8.61(d，1H，J＝5.1Hz)；8.36(m，1H)；7.46(d，1H，J＝5.1Hz)；7.42(m，1H)；7.37(br，1H)；7.19(d，1H，J＝8.3Hz)；7.08(m，1H)；6.58(br，1H)；2.15(S，3H)；1.49(S，9H)。

(6) preparation of 4-methyl-3- [4- (3-pyridyl) -2-pyrimidinyloxy ] -aniline:

N-tert-Butoxycarbonyl-4-methyl-3- [4- (3-pyridyl) -2-pyrimidinyloxy ] -aniline (11.5 g, 30 mmol) was dissolved in 30 ml of dichloromethane, followed by the addition of trifluoroacetic acid (20 ml) at 0 ℃. The reaction was then stirred at room temperature overnight. After the reaction is finished, adjusting the pH value to be approximately equal to 8 by using 10 percent sodium bicarbonate, separating out an organic phase, drying, filtering and concentrating. Recrystallizing the residue by using dichloromethane/diethyl ether to obtain a product: 8.0 g (yield: 94%). Melting point: 157 ℃ and 159 ℃.

MS ES+m/Z＝279(MHz)。

H-NMR(400Hz，CDCl₃) And (4) analyzing results:

δppm：9.23(d，1H，J＝2.3Hz)；8.73(dd，1H，J＝1.5，4.7Hz)；8.62(d，1H，J＝5.3Hz)；8.37(m，1H)；7.46(d，1H，J＝5.3Hz)；7.43(m，1H)；7.08(d，1H，J＝8.0Hz)；6.52-6.57(m，2H)；2.07(S，3H)。

example two: preparation of N- [ 4-methyl-3- [4- (3-pyridyl) -2-pyrimidinyloxy ] -phenyl ] -3- (4-methylpiperazinomethyl) -benzamide

3-Chloromethylbenzoic acid (1.84 g, 10.8 mmol) and thionyl chloride (8ml) were added to a bottle, and the mixture was heated to 70 ℃ and stirred for 3 hours. The remaining thionyl chloride was removed under reduced pressure. The residue was removed with toluene. The residue was then dissolved in anhydrous tetrahydrofuran (15 ml) and diisopropylethylamine (1.88 ml, 21.6 mmol) was added. The mixture was cooled to-78 ℃ and a solution of 4-methyl-3- [4- (3-pyridyl) -2-pyrimidinyloxy ] -aniline (3g, 10.8 mmol) in tetrahydrofuran and N, N-dimethylformamide (. about.10 ml) was added. After 10 minutes, the temperature was raised to 0 ℃ and after two hours, N-methylpiperazine (1.08 g, 10.8 mmol) was added. The mixture was then stirred at room temperature overnight. The solvent was removed under reduced pressure, 10% sodium bicarbonate was added, and extraction was performed with dichloromethane. The combined organic phases were dried, filtered and concentrated. The residue was purified by column chromatography. Obtaining a product: 2.0 g (38% yield). Melting point: 215 to 218 ℃.

MS ES+m/z＝495(MH⁺)。

H-NMR(400MHz，CDCl₃) And (4) analyzing results:

δppm：9.22(d，1H，J＝2.3Hz)；8.72(dd，1H，J＝1.6，4.9Hz)；8.62(d，1H，J＝5.1Hz)；8.35-8.38(m，1H)；8.00(br，1H)；7.68-7.81(m，3H)；7.39-7.50(m，5H)；3.55(s，2H)；2.42(b r，8H)；2.28(s，3H)；2.20(s，3H)。

example three: preparation of N- [ 4-methyl-3- [4- (3-pyridyl) -2-pyrimidinyloxy ] -phenyl ] -3- (4-methylpiperazinomethyl) -benzamide

(1) Preparation of methyl 3- (4-methylpiperazinomethyl) -benzoate:

to a bottle were added methyl 3-bromomethylbenzoate (10 g, 44 mmol), N-methylpiperazine (5.2 g, 52 mmol) and triethylamine (10 ml), toluene (100 ml). The mixture was heated to reflux (10 hours). Cooling, filtering and concentrating. The residue was chromatographed (dichloromethane/methanol 20/1) to give the product: 8g (yield: 73%).

MS ES+m/z＝249(MH⁺)。

H-NMR(400MHz，CDCl₃)：δppm：7.92-7.98(m，2H)；7.36-7.55(m，2H)；3.92(m，3H)；3.55(s，2H)；2.47(br，8H)；2.28(s，3H)。

(2) Preparation of 3- (4-methylpiperazinylmethyl) -benzoic acid:

methyl 3- (4-methylpiperazinomethyl) -benzoate (7 g, 28 mmol) was dissolved in 40 ml of methanol, and then a 10% sodium hydroxide solution in methanol (30 ml) was added dropwise. Stirring at room temperature until no raw material is obtained. The pH value is adjusted to be approximately equal to 7-8 by 36 percent hydrochloric acid to generate solid, and the solid is cooled and filtered. The mother liquor was concentrated to dryness. Obtaining a product: 6.1g (yield: 93%).

MS ES+m/z＝235(MH⁺)。

H-NMR(400MHz，DMSO-cl₆)：δppm：7.85(s，1H)；7.80(m，1H)；7.36-7.45(m，2H)；3.49(s，2H)；2.36(br，8H)；2.16(s，3H)。

(3) Preparation of 3- (4-methylpiperazinylmethyl) -benzoyl chloride:

to a bottle was added 3- (4-methylpiperazinomethyl) -benzoic acid (5 g, 21 mmol) and thionyl chloride (50 ml). Heated to reflux for 4 hours. The remaining thionyl chloride was removed under reduced pressure. Obtaining 3- (4-methyl piperazine methyl) -benzoyl chloride;

(4) the 3- (4-methylpiperazinomethyl) -benzoyl chloride obtained in step (3) was dissolved in 50 ml of pyridine, and 4-methyl-3- [4- (3-pyridyl) -2-pyrimidinyloxy ] -aniline (3g, 10.8 mmol) was added with stirring. The reaction was carried out at room temperature for 5 hours. The pyridine was removed by concentration under reduced pressure. 5% sodium bicarbonate solution (. about.10 ml) was added and extracted with dichloromethane (3X 20 ml). The combined organic layers were dried, filtered and concentrated. The residue was purified by column chromatography (chloroform/methanol 20/1). Obtaining a product: 3.2 g (yield: 60%).

Example four: preparation of hydrochloride salt:

2 g of N- [ 4-methyl-3- [4- (3-pyridyl) -2-pyrimidinyloxy ] -phenyl ] -3- (4-methylpiperazinomethyl) -benzamide was dissolved in methanol (5 ml), and about 2 ml of a 10% hydrochloric acid solution in methanol was added to remove the solvent to obtain the hydrochloride of the product.

Experimental example five: in vitro tumor cell inhibiting effect

Different kinds of tumor cells were cultured in RPMI1640 medium or high-sugar DMEM medium containing 10% calf serum at 37 ℃ in a 5% carbon dioxide incubator for 24 hours.

N- [ 4-methyl-3- [4- (3-pyridyl) -2-pyrimidinyloxy]-phenyl radical]-3- (4-methylpiperazinomethyl) -benzamide was dissolved with dimethyl sulfoxide and then diluted with serum-free culture broth. Adding the diluted medicinal solution into culture well containing tumor cells to final concentration of 0.1-100 μ M, culturing for 72 hr, and detecting death number of tumor cells by MTT method to obtain semi-concentration Inhibitory Concentration (IC) of the compound on different tumor cells₅₀)。

In order to compare the inhibition effect of the compound of the present invention and the compound of Chinese patent No. 01138070.5 on tumor cell lines, the inhibition effect of the compounds obtained in example two and example sixteen of the existing patents was tested, which are respectively:

(comparative example 1) and

(comparative 2).

The following table 1 shows the inhibition of some tumor cell lines by different compounds:

TABLE 1 results of half-concentration inhibition of tumor cell lines by different compounds

Tumor species

Leukemia (leukemia)

Liver cancer

Stomach cancer

Breast cancer

Ovarian cancer

Compound (I)

Tumor strain

K562

U937

HL60

SMMS-7721

BGC-231

MCF-7

HO-8910

The invention

IC₅₀

1.5μM

7.5μM

20μM

5μM

2.5μM

7.5μM

10μM

Comparative example 1

IC₅₀

76μM

＞100μM

Comparative example 2

IC₅₀

82μM

＞100μM

Claims

1. A phenoxypyrimidine derivative, having the name: n- [ 4-methyl-3- [4- (3-pyridyl) -2-pyrimidinyloxy ] -phenyl ] -3- (4-methylpiperazinemethyl) -benzamide; the chemical formula is shown as follows:

2. a process for preparing a compound according to claim 1, comprising the steps of:

3. a process for the preparation of a compound according to claim 1, characterized by the following specific steps:

the molecular formula of the compound A is as follows:

4. a medicament for inhibiting the growth of tumor cells, comprising: the compound of claim 1 as an active ingredient.

5. Use of a compound according to claim 1 for the manufacture of a medicament for inhibiting tumor cell growth.

6. Use of a compound according to claim 5 for the manufacture of a medicament for inhibiting tumor cell growth, wherein: the tumor is selected from leukemia, hepatocarcinoma, gastric cancer, breast cancer and ovarian cancer.

7. A medicament for inhibiting the growth of tumor cells, comprising: a pharmaceutically acceptable salt of the compound of claim 1 as an active ingredient.