CN101417995A - Phenoxy pyrimidine derivates and its production and use - Google Patents
Phenoxy pyrimidine derivates and its production and use Download PDFInfo
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- CN101417995A CN101417995A CNA2008102443085A CN200810244308A CN101417995A CN 101417995 A CN101417995 A CN 101417995A CN A2008102443085 A CNA2008102443085 A CN A2008102443085A CN 200810244308 A CN200810244308 A CN 200810244308A CN 101417995 A CN101417995 A CN 101417995A
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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Abstract
The invention discloses a kind of phenoxy pyrimidine derivates and its production and use, its name is called: N-[4-methyl-3-[4-(3-pyridyl)-2-2-pyrimidinyl oxy]-phenyl]-3-(4-methylpiperazine methyl)-benzamide, chemical formulation is as above; With 4-methyl-3-[4-(3-pyridyl)-2-2-pyrimidinyl oxy]-aniline is one of main raw material prepared in reaction above-claimed cpd; The compound that obtains has the obvious suppression effect to tumour cell, and compound of the present invention reaches the scope of 1.5～20 μ M to the half-inhibition concentration of leukemia, liver cancer, cancer of the stomach, mammary cancer and ovarian cancer cell propagation.
Description
Technical field
The present invention relates to a kind of phenoxy pyrimidine derivates, and the preparation method of this compound and pharmaceutical applications thereof, this compound has the effect that suppresses tyrosine protein kinase.
Background technology
The patent No. is that 01138070.5 Chinese patent discloses a class 2-phenoxy pyrimidine derivates, and their chemical structure is expressed as follows:
Wherein,
X is oxygen, sulphur, secondary amino or carbonyl;
Y is carbonyl, oxygen, sulphur or secondary amino;
R
1, R
8Be the hexa-atomic aromatic nucleus or the hexa-atomic aromatic heterocycle of hexa-atomic aromatic nucleus or hexa-atomic aromatic heterocycle and replacement, described substituting group comprises hydrogen, halogen, C
1-C
3Alkyl or C
1-C
3Alkoxyl group, hydroxyl, amino and nitro;
R
2, R
3, R
5, R
6, R
7Be hydrogen, halogen, C
1-C
6Alkyl, C
3-C
15Cycloalkyl, C
1-C
6The hexa-member heterocycle that alkyl replaces;
R
4Be hydrogen, halogen, hydroxyl, C
1-C
6Alkoxyl group or C
1-C
6Alkyl;
R
9Be selected from hydrogen, oxygen, sulphur, methyne, secondary amino, C
1-C
6Alkyl or-Z-R
10
Wherein Z represents oxygen, sulphur, methyne, secondary amino or C
1-C
6Alkyl;
R
10Be hydrogen, halogen, C
1-C
6Alkyl, C
3-C
15Cycloalkyl, C
1-C
6The hexa-member heterocycle that alkyl replaces.
This compounds of above-mentioned general formula definition is the inhibitor of protein kinase and modification thereof, and is inhibited to the Abl tyrosine protein kinase, and in addition, the phenoxy pyrimidine analog derivative also may the generation effect by suppressing other protein kinase such as Threonine.
This compounds of above-mentioned general formula definition can be used for treatment and prevents proliferative disease and existing medicine is produced chemical sproof disease, as cancer and inflammation class disease, also can be used for treating nerve degeneration kind disease such as senile dementia, cardiovascular disorder, viral infection and fungal infection in addition.
The embodiment of above-mentioned patent discloses the restraining effect test data of 18 kinds of compounds to the Abl tyrosine protein kinase, the result show 18 kinds of compounds of tool to the Abl tyrosine protein kinase according to their half-inhibition concentration (IC arranged obviously and very strong restraining effect
50) in the scope of 0.025-2.0 μ M.
Though the compound in the foregoing invention has obviously and very strong restraining effect the tyrosine protein kinase aspect, in this patent documentation, these compounds suppress the activity not checking as yet of tumor cell proliferation, the unknown of actual therapeutic purposes.Unexpected is that in the experiment of the tumor cell proliferation that after this contriver carries out, they do not demonstrate stronger restraining effect.Therefore, in using the actual procedure of this series compound as medicine, it is stronger to seek to suppress effect, and the compound of suitable suitability for industrialized production.
Summary of the invention
The object of the invention provides a kind of phenoxy pyrimidine derivates, effect obvious more and intensive inhibition tyrosine protein kinase is provided, thereby utilizes this compound to suppress the medicine of growth of tumour cell; Another object of the present invention provides the preparation method of this compound, and optimal preparation technology makes this compound be fit to industrial production.
For achieving the above object, the technical solution used in the present invention is: a kind of phenoxy pyrimidine derivates, its name is called: N-[4-methyl-3-[4-(3-pyridyl)-2-2-pyrimidinyl oxy]-phenyl]-3-(4-methylpiperazine methyl)-benzamide; Its chemical formulation is as follows:
Except that the compound that the present invention directly describes, also in protection scope of the present invention, the medicinal salt that the present invention relates to compound comprises and mineral acid, organic acid or mineral alkali, the formed various salt of organic bases the medicinal salt of this compound.
The example of acid-salt has acetate, adipic acid salt, alginate, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, Citrate trianion, camphorate, the camphor iodate, cyclopentyl propionate, two gluconates, dodecane sulfonate, metilsulfate, ethyl sulfonate, formate, fumarate, gluceptate, glycerophosphate, glycollate,-sulfinate, enanthate, caproate, hydrochloride, hydrobromate, hydriodate, 2-hydroxyethyl sulfonate, lactic acid salt, malate, malonate, naphthalenesulfonate, the Nicotine hydrochlorate, nitrate, oxalate, palmitate, pectate, persulphate, 3-phenylpropionic acid salt, phosphoric acid salt, picrate, pivalate, isopropyl acid salt, salicylate, succinate, vitriol, tartrate, thiocyanate-, tosylate and undecane hydrochlorate; The example of basic salt then has basic metal (as sodium, potassium) salt, alkaline divalent metal (as magnesium) salt, ammonia salt and contains the alkylamine salt of 1-4 carbon atoms.
Phenoxy pyrimidine derivates of the present invention, its salt or medicinal precursor can with can be as medicinal carrier combinations patent medicine preparation.
Described phenoxy pyrimidine derivates, its salt or medicinal precursor can act on protein kinase and modification thereof, the catalysis of regulation and control and change protein kinase and modification thereof.
Wherein protein kinase that is acted on and modification thereof can be tyrosine protein kinase and modification thereof, comprise acceptor class tyrosine protein kinase and modification thereof and non-acceptor class tyrosine protein kinase and modification thereof.The tyrosine protein kinase of acceptor class and modification thereof comprise 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-acceptor class tyrosine protein kinase and modification thereof comprise Abl, Src, Frk, Btk, Csk, MAP, P38, ZAP70, Fes/Fps, Fak, Jak, ArkYes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.
Described protein kinase and modification thereof can be serine/threonine protein kitase and modification thereof also, comprise CDK2, MAP, P38, Raf and PKC.
Give the above-mentioned compound of human body effective dose, can be used for treating the disease relevant with protein kinase and modification thereof with prevention.
The compound that the present invention relates to can be via the carrier of medicinal to the human body administration, and these pharmaceutical carriers comprise ion exchange resin; aluminum oxide; aluminum stearate; Yelkin TTS; serum protein (as the human serum albumin); cushion is (as phosphoric acid salt; glycine; Sorbic Acid; potassium sorbate etc.); the glyceride of fractional saturation vegetables oil; the mixture of water and salt or ionogen are (as protamine sulfate; Sodium phosphate dibasic; potassium hydrogen phosphate; sodium-chlor etc.); zinc salt; colloidal silica gel; the trimerization Magnesium Silicate q-agent; polyvinylpyrrolidone; cellulose family; the polyethylene glyceryl alcohol; the carboxylic acid methyl sodium cellulosate; poly-acylate; wax class and lanolin etc.
The compound that the present invention relates to can be by different approaches to the human body administration, and that concrete route of administration comprises is oral, parenteral administration, oral cavity suction, administration through skin, rectal administration, intranasal administration, sublingual administration, cheek administration, vagina administration and by the administration of the property implanted container; That parenteral administration is included in again is subcutaneous, in the intravenously, intramuscular, intraarticular, synovial membrane chamber, in the breastbone, in the sheath, in the liver, in the damage location and intracranial injection or infiltration.
The compound that the present invention relates to can be made into different formulations and is used for the human body administration, concrete formulation has aqueous solution injection, oily suspension injection, oral capsule, oral tablet, oral aqueous solution, oral administration mixed suspension, rectal suppository, eye drop, eye ointment, skin with sprays, oral spray, oral cavity aerosol, nasal mist and nasal aerosol etc., also to comprise the sustained release dosage of these different dosage forms and the preparation of sustained release speed and dosage with ointment, dermatological cream, skin simultaneously.
The compound that the present invention relates to is when being used for human body and treating with preventing disease, used dosage is subjected to influence of various factors, these factors comprise age, body weight, healthy state, sex, race, food habits, administration time, the frequency of urinating reach whether use other medicines, or the like.
The compound that the present invention relates to has special pharmacologically active, and particularly tyrosine protein kinase acid and modification thereof work its activity by the arrestin kinases.In being background technology one joint of 01138070.5 Chinese patent, the patent No. set forth all kinds of diseases relevant with the activity of protein kinase, the present invention is by the activity of arrestin kinases and modification thereof, effective especially for proliferative disease, can also solve the existing resistance problem of present clinical use medicine simultaneously.
Compound of the present invention thus is specially adapted to treatment and prevents following various diseases:
Occur in the solid malignant tumour of following position and tissue: mammary gland, ovary, colon, liver, courage, lung, stomach, prostate gland, pancreas, throat, bladder, brain, skin etc.;
Lymphocytic type blood class tumour: acute lymphoblastic type blood disease, acute lymphoblast type leukemia, B cellular type leukemia, T cellular type leukemia, He Jiejin lymphomas, non_hodgkin lymphoma, trichoblast lymphoma and Burkett lymphomas;
Medullary cell type blood class tumour: acute medullary cell type leukemia, chronic medullary cell type leukemia, hypoplastic bone marrow disease and promyelocyte type leukemia;
Other also comprises and occurs in unify tumour in the peripheral nervous system of central nervous system;
Because the regulation and control of tyrosine protein kinase cellular function and proliferation of cells and breeding play important effect, compound of the present invention may have treatment and prophylactic effect to any disease that influences cell function regulation and control and hyperplasia, and these diseases comprise inflammation, neural deterioration disease, virus infection and fungal infection etc.
The preparation method of compound of the present invention can select any in following two kinds, and method one may further comprise the steps:
(1) chloride of 3-chloromethyl benzoic acid is obtained the 3-chloromethyl benzoic acid chlorides, be dissolved in the solvent, add diisopropylethylamine then;
(2) solution of compd A is added in the solution of step (1) gained and make it reaction, add N methyl piperazine again, stirring reaction; The molecular formula of described compd A is:
(3) remove and to desolvate, add the solution of strong base-weak acid salt, then through extraction, dry, filter, concentrate, separation and purification obtains target product; The molecular formula of target product is:
In the technique scheme, the preparation method of compd A is that 01138070.5 Chinese patent is open in the patent No..
Optimized technical scheme may further comprise the steps: the amount of substance with the 3-chloromethyl benzoic acid is 1 part;
(1) chloride of 1 part of 3-chloromethyl benzoic acid is obtained the 3-chloromethyl benzoic acid chlorides, its molecular formula is as follows:
The 3-chloromethyl benzoic acid chlorides is dissolved in solvent orange 2 A, adds 1.5～3 parts of diisopropylethylamine then, and mixing solutions is cooled to-50～-80 ℃;
Described solvent orange 2 A is selected from: tetrahydrofuran (THF), methyl alcohol, ethanol, Virahol, acetone, propyl carbinol or the bigger organic solvent of ethyl acetate isopolarity;
(2) 1～2 part of compd A is dissolved in solvent B, this solution is added step (1) gained solution, after 5～60 minutes, be warming up to 0-25 ℃; Be incubated after 2-5 hours, add 1～2 part of N methyl piperazine, stirring reaction is 5～20 hours under the room temperature;
The molecular formula of described compd A is:
Described solvent B is selected from: tetrahydrofuran (THF) and N, the mixture of dinethylformamide, tetrahydrofuran (THF) and other and water-insoluble organic solvent comprise the mixture of methylene dichloride, trichloromethane, MTBE, ethyl acetate, propyl carbinol, benzene, toluene, BEHP, normal hexane, hexanaphthene, DMSO or sherwood oil;
(3) remove and to desolvate, add the solution of strong base-weak acid salt, then through extraction, dry, filter, concentrate, separation and purification obtains target product; The molecular formula of target product is:
Described weak base is selected from: sodium bicarbonate, saleratus, Sodium phosphate dibasic, dipotassium hydrogen phosphate, SODIUM PHOSPHATE, MONOBASIC, potassium primary phosphate, dimethylamine, Trimethylamine 99 or triethylamine; Be preferably massfraction and be 2%～20% sodium hydrogen carbonate solution.
The reaction process of method one can be expressed as follows:
Method two comprises following concrete steps:
(1) 3-(4-methylpiperazine methyl)-Benzoyl chloride is dissolved in the solvent, stirs adding compd A down, react;
The molecular formula of described compd A is:
(2) remove and to desolvate, add the solution of strong base-weak acid salt, through extraction, dry, filter, concentrate, after the separation and purification, obtain target product, the molecular formula of target product is:
Optimized technical scheme may further comprise the steps:
(1) in amount of substance, 1 part of 3-(4-methylpiperazine methyl)-Benzoyl chloride is dissolved in the solvent, stir 1～2 part of compd A of adding down, reacted 1～10 hour;
The molecular formula of described compd A is:
Described solvent is selected from alkali organic solvent such as pyridine, dimethylamine, Trimethylamine 99 or triethylamine;
(2) remove and to desolvate, add the solution of strong base-weak acid salt, through extraction, dry, filter, concentrate, after the separation and purification, obtain target product, the molecular formula of target product is:
Described weak base is selected from: sodium bicarbonate, saleratus, Sodium phosphate dibasic, dipotassium hydrogen phosphate, SODIUM PHOSPHATE, MONOBASIC, potassium primary phosphate, dimethylamine, Trimethylamine 99 or triethylamine; Be preferably massfraction and be 2%～20% sodium hydrogen carbonate solution.
The reaction process of method two can be expressed as follows:
The preparation method of the 3-described in the method two (4-methylpiperazine methyl)-Benzoyl chloride may further comprise the steps:
Amount of substance with the 3-bromomethyl-benzoic acid methyl ester is 1 part;
(1) gets 1 part of 3-bromomethyl-benzoic acid methyl ester, 1.2 parts of N methyl piperazines and 1.5～2 parts of triethylamines and be dissolved in toluene, reflux 10 hours; Cooling is filtered, and concentrates and obtains 3-(4-methylpiperazine methyl)-methyl benzoate;
(2) 3-(4-methylpiperazine methyl)-methyl benzoate is dissolved in the methyl alcohol, drips massfraction then and be the methanol solution of 10% sodium hydroxide, stir alcoholysis under the room temperature, regulate pH to 7～8 then, filter and obtain 3-(4-methylpiperazine methyl)-phenylformic acid;
(3) 3-(4-methylpiperazine methyl)-phenylformic acid chloride is obtained 3-(4-methylpiperazine methyl)-Benzoyl chloride.
The process of above-mentioned preparation 3-(4-methylpiperazine methyl)-Benzoyl chloride can be expressed as:
Can be among the present invention with target product
The preparation salify, for example: target product is dissolved in the methyl alcohol, adds the methanol solution of 10% hydrochloric acid then, removing desolvates promptly gets the hydrochloride of these product.Other salt also can prepare according to ordinary method.
Because the technique scheme utilization, the present invention compared with prior art has following advantage:
1. compound of the present invention has good inhibition effect to tumour cell, and restraining effect is used half-inhibition concentration (IC usually
50) represent that compound of the present invention is to the cell strain half-inhibition concentration (IC of leukemia, liver cancer, cancer of the stomach, mammary cancer and ovarian cancer
50) reach the scope of 1.5～20 μ M; Comparatively speaking, disclosed compound in patent 01138070.5 is though have stronger restraining effect, poor effect aspect the inhibition tumor cell proliferation, its IC on Abl protein kinase level
50Value is all greater than 50 μ M.
2. the invention provides 2 kinds of methods that prepare target compound, the productive rate of method one is 38%, and the productive rate of method two is 60%, can take all factors into consideration the factors such as being easy to get property, environmental pollution, input-output ratio of raw material in the practical application and select synthetic route.
3. compound of the present invention when suppressing tumor cell proliferation, the selectivity height, side effect is little.
Embodiment
Below in conjunction with embodiment the present invention is further described:
Embodiment one: 4-methyl-3-[4-(3-pyridyl)-2-2-pyrimidinyl oxy]-preparation of aniline, its preparation process can be referring to Chinese patent 01138070.5; Synthetic route is as follows:
(1) preparation of 3-dimethylamino-1-(3-pyridyl)-2-propylene-1-ketone:
Add 3-acetylpyridine (181.5 grams, 1.5 moles) and N in reaction flask, dinethylformamide dimethyl hemiacetal (178.5,1.5 moles) is dissolved in 500 milliliters of N with this mixture, in the dinethylformamide and be heated to 120-130 ℃ and stirred 4 hours;
Remove and desolvate, residuum ether recrystallization obtains a white light yellow crystal: 252 grams.Productive rate: 95%.Fusing point: 81-82 ℃.
MS?ES+m/z＝1FF(MH
+)。
H-NMR (400MHz, CDCl
3) analytical results:
δ
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 group-4-(3-pyridyl) pyrimidine:
With sodium Metal 99.5 (18.4 grams, 0.8 mole) be dissolved in 500 milliliters of dehydrated alcohols, add thiocarbamide (76.1 grams, 1 mole) and 176 gram (1 mole) 3-dimethylamino-1-(3-pyridyl)-2-propylene-1-ketone, heating reflux reaction 6 hours, add 1 premium on currency, transfer PH ≈ 5 with Glacial acetic acid again, about 15 minutes of reflux is cooled to room temperature then, filter, dry that a white solid (about 140 grams) is stand-by.
Get above-mentioned white solid, be dissolved in 500 milliliters of 1N NaOH solution, be cooled to about 0 ℃.Stir and slowly to add methyl iodide down, keep and stirred 15 minutes, filter a solid, the water washing of fully pulling an oar is drained, drying is used ethyl alcohol recrystallization.Get product (yellow): 119 gram (productive rates: 58.6%).Fusing point: 140-142 ℃.
MS?ES+m/Z＝204(MH+)。
H-NMR (400MHz, CDCl
3) analytical results:
δ
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-first sulfonyl-4-(3-pyridyl)-pyrimidine:
With 2-methylthio group-4-(3-pyridyl) pyrimidine (50 grams, 0.24 mole) be dissolved in the mixed solution of 250 ml methanol-water (7: 3), add inclined to one side two potassium sulfites (3 * 60g) down in stirring in batches, at room temperature stirred then 3 hours, it is faint yellow that reaction solution is, drying gets product: 48 gram (productive rates: 85%).Fusing point: 120-122 ℃.
MS?ES+m/Z＝236(MH+)。
H-NMR (400MHz, CDCl
3) interpretation of result:
δ?ppm：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 the special fourth oxygen of N-carbonyl acyl group-3-hydroxy-4-methyl aniline:
3-hydroxy-4-methyl aniline (25 grams, 0.203 mole) is dissolved in 400 milliliters of ethyl acetate, stirs down two tert-butoxy carbonic ethers (47 milliliters, 0.203 mole) at a low price then.Continue under the room temperature to stir 24 hours.Use 10% sodium bicarbonate, water washs respectively, and drying concentrates, column chromatography (ethyl acetate: ethane=1/5) get white solid: 43 gram (productive rates: 95%).Fusing point: 118-120 ℃.
MS?ES+m/Z＝224(MH+)；
H-NMR (400Hz, CDCl
3) analytical results:
δ?ppm：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) the special fourth oxygen of N-carbonyl acyl group-4-methyl-3-[4-(3-pyridyl)-2-2-pyrimidinyl oxy]-preparation of aniline:
The special fourth oxygen of N-carbonyl acyl group-3-hydroxy-4-methyl aniline (8.6 grams, 39 mmoles) is dissolved in 50 milliliters of anhydrous N, in the dinethylformamide, adds 60% sodium hydride (4.6 grams, 115 mmoles) in 0 ℃ of gradation under stirring.Stir after 1 hour, add 2-first sulfonyl-4-(3-pyridyl)-pyrimidine (9.5 grams, 40 mmoles).Naturally be warming up to room temperature after 30 minutes and keep to stir and spend the night, reaction solution transfers to PH ≈ 7. with 10% citric acid and separates out solid.This mixture is poured in 500 milliliters of frozen water, stirred, filter the water thorough washing.Solid dissolves with methylene dichloride, and drying is filtered, and concentrates.Get product: 12 gram (productive rates: 80%).Fusing point: 164-165 ℃.
MS?ES+m/Z＝379(MH
+)。
H-NMR (400MHz, CDCl
3) interpretation of result:
δ?ppm：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) 4-methyl-3-[4-(3-pyridyl)-2-2-pyrimidinyl oxy]-preparation of aniline:
With the special fourth oxygen of N-carbonyl acyl group-4-methyl-3-[4-(3-pyridyl)-2-2-pyrimidinyl oxy]-aniline (11.5 grams, 30 mmoles) is dissolved in 30 milliliters of methylene dichloride, adds trifluoroacetic acid (20 milliliters) in 0 ℃ then.Reaction is at room temperature stirred and is spent the night then.After question response finishes, transfer PH ≈ 8. to tell organic phase with 10% sodium bicarbonate, drying is filtered, and concentrates.Residuum gets product: 8.0 gram (productive rates: 94%) with methylene dichloride/ether recrystallization.Fusing point: 157-159 ℃.
MS?ES+m/Z＝279(MHz)。
H-NMR (400Hz, CDCl
3) interpretation of result:
δ?ppm：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)。
Embodiment two: N-[4-methyl-3-[4-(3-pyridyl)-2-2-pyrimidinyl oxy]-phenyl]-preparation of 3-(4-methylpiperazine methyl)-benzamide
In bottle, add 3-chloromethyl benzoic acid (1.84 grams, 10.8 mmoles) and thionyl chloride (8ml), be heated to 70 ℃ and stirred 3 hours.Remaining thionyl chloride reduces pressure away.Remaining removes with toluene.Then residuum is dissolved in anhydrous tetrahydro furan (15 milliliters), adds diisopropylethylamine (1.88 milliliters, 21.6 mmoles).This mixture is cooled to-78 ℃, adds 4-methyl-3-[4-(3-pyridyl)-2-2-pyrimidinyl oxy]-tetrahydrofuran (THF) and the N of aniline (3g, 10.8 mmoles), the solution of dinethylformamide (～10 milliliters).After 10 minutes, rise to 0 ℃, after two hours, add N methyl piperazine (1.08 grams, 10.8 mmoles).This mixed solution at room temperature stirs subsequently and spends the night.Decompression removes down and desolvates, and adds 10% sodium bicarbonate, uses dichloromethane extraction.Merge organic phase, drying is filtered, and concentrates.Residuum uses column chromatography purifying.Get product: 2.0 grams (productive rate 38%).Fusing point: 215～218 ℃.
MS?ES+m/z＝495(MH
+)。
H-NMR (400MHz, CDCl
3) interpretation of result:
δ?ppm：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(br，8H)；2.28(s，3H)；2.20(s，3H)。
Embodiment three: N-[4-methyl-3-[4-(3-pyridyl)-2-2-pyrimidinyl oxy]-phenyl]-preparation of 3-(4-methylpiperazine methyl)-benzamide
(1) preparation of 3-(4-methylpiperazine methyl)-methyl benzoate:
In bottle, add 3-bromomethyl-benzoic acid methyl ester (10 grams, 44 mmoles), N methyl piperazine (5.2 grams, 52 mmoles) and triethylamine (10 milliliters), toluene (100 milliliters).Heat this mixture to reflux (10 hours).Cooling is filtered, and concentrates.Residuum gets product: 8g (productive rate: 73%) with column chromatography (methylene chloride=20/1).
MS?ES+m/z＝249(MH
+)。
H-NMR(400MHz，CDCl
3)：δ?ppm：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) 3-(4-methylpiperazine methyl)-benzoic preparation:
Get 3-(4-methylpiperazine methyl)-methyl benzoate (7 grams, 28 mmoles) and be dissolved in 40 ml methanol, drip the methanol solution (30 milliliters) of 10% sodium hydroxide then.Be stirred to no raw material under the room temperature.Transfer pH ≈ 7-8 with 36% hydrochloric acid, generate solid, cold filtration.Mother liquor is concentrated into dried.Get product: 6.1g (productive rate: 93%).
MS?ES+m/z＝235(MH
+)。
H-NMR(400MHz，DMSO-cl
6)：δ?ppm：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-methylpiperazine methyl)-Benzoyl chloride:
In bottle, add 3-(4-methylpiperazine methyl)-phenylformic acid (5 grams, 21 mmoles) and thionyl chloride (50 milliliters).Reflux 4 hours.Remaining thionyl chloride is removed in decompression.Get 3-(4-methylpiperazine methyl)-Benzoyl chloride;
(4) step (3) gained 3-(4-methylpiperazine methyl)-Benzoyl chloride is dissolved in 50 milliliters of pyridines, stirs adding 4-methyl-3-[4-(3-pyridyl)-2-2-pyrimidinyl oxy down]-aniline (3 grams, 10.8 mmoles).Room temperature reaction 5 hours.Concentrating under reduced pressure is removed pyridine.Add 5% sodium hydrogen carbonate solution (～10 milliliters), and with dichloromethane extraction (3 * 20 milliliters).Merge organic layer, drying is filtered, and concentrates.Residuum column chromatography purification (chloroform/methanol=20/1).Get product: 3.2 gram (productive rates: 60%).
Embodiment four: the preparation of hydrochloride:
Get N-[4-methyl-3-[4-(3-pyridyl)-2-2-pyrimidinyl oxy]-phenyl]-3-(4-methylpiperazine methyl)-benzamide 2 grams are dissolved in the methyl alcohol (5 milliliters), add about 2 milliliters of the methanol solution of 10% hydrochloric acid then, remove desolvate the hydrochloride of these product.
Experimental example five: extracorporeal suppression tumor cell effect
Different types of tumour cell with the RPMI1640 substratum or the high sugared DMEM culture medium culturing that contain 10% calf serum, was grown 24 hours in 37 ℃ and 5% CO2gas incubator.
N-[4-methyl-3-[4-(3-pyridyl)-2-2-pyrimidinyl oxy]-phenyl]-3-(4-methylpiperazine methyl)-benzamide is first with the methyl-sulphoxide dissolving, and then dilute with the nutrient solution that does not contain serum.Drug solution after the dilution add in the culture hole that contains tumour cell to ultimate density be 0.1-100 μ M. after cultivating 72 hours, detect the death of neoplastic cells number with the MTT method, thereby meter weighs up the half dense inhibition concentration (IC of this compound to different tumour cells
50).
Be the restraining effect of the compound of 01138070.5 Chinese patent for compound more of the present invention and the patent No., test its restraining effect, be respectively with embodiment two and embodiment 16 gained compounds in the existing patent to tumor cell line:
Following table 1 is the restraining effect of different compounds to the part tumor cell line:
The different compounds of table 1 are to half dense inhibition concentration result of tumor cell line
| The knurl kind | Leukemia | Leukemia | Leukemia | Liver cancer | Cancer of the stomach | Mammary cancer | Ovarian cancer | |
| Compound | The knurl strain | K562 | U937 | HL60 | SMMS-7721 | BGC-231 | MCF-7 | HO-8910 |
| The present invention | IC 50 | 1.5μM | 7.5μM | 20μM | 5μM | 2.5μM | 7.5μM | 10μM |
| Contrast 1 | IC 50 | 76μM | >100μM | >100μM | >100μM | >100μM | >100μM | >100μM |
| Contrast 2 | IC 50 | 82μM | >100μM | >100μM | >100μM | >100μM | >100μM | >100μM |
Claims (9)
1. phenoxy pyrimidine derivates, its name is called: N-[4-methyl-3-[4-(3-pyridyl)-2-2-pyrimidinyl oxy]-phenyl]-3-(4-methylpiperazine methyl)-benzamide; Its chemical formulation is as follows:
2. method for preparing the described compound of claim 1 is characterized in that may further comprise the steps:
(1) chloride of 3-chloromethyl benzoic acid is obtained the 3-chloromethyl benzoic acid chlorides, be dissolved in the solvent, add diisopropylethylamine then;
(2) solution of compd A is added in the solution of step (1) gained and make it reaction, add N methyl piperazine again, stirring reaction; The molecular formula of described compd A is:
(3) remove and to desolvate, add the solution of strong base-weak acid salt, then through extraction, dry, filter, concentrate, separation and purification obtains target product; The molecular formula of target product is:
3. method for preparing the described compound of claim 1 is characterized in that comprising following concrete steps:
(1) 3-(4-methylpiperazine methyl)-Benzoyl chloride is dissolved in the solvent, stirs adding compd A down, react;
The molecular formula of described compd A is:
(2) remove and to desolvate, add the solution of strong base-weak acid salt, through extraction, dry, filter, concentrate, after the separation and purification, obtain target product, the molecular formula of target product is:
4. one kind is suppressed the medicine that tumour cell increases, and it is characterized in that: with the described compound of claim 1 is active ingredient.
5. the application of the described compound of claim 1 in the medicine that preparation inhibition tumour cell increases.
6. according to the described a kind of medicine that tumour cell increases that suppresses of claim 5, it is characterized in that: described tumour comprises leukemia, liver cancer, cancer of the stomach, mammary cancer and ovarian cancer.
7. the described compound of claim 1 acts on protein kinase and modification thereof in preparation, plays regulation and control and changes application in the medicine of catalysis of protein kinase and modification thereof.
8. the described application of compound of claim 7, it is characterized in that: described protein kinase and modification thereof are tyrosine protein kinase and modification thereof.
9. one kind is suppressed the medicine that tumour cell increases, and it is characterized in that: the medicinal salt with the described compound of claim 1 is active ingredient.
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| PCT/CN2009/074933 WO2010057418A1 (en) | 2008-11-21 | 2009-11-13 | A phenoxypyrimidine derivative, its preparation method and the use thereof |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010057418A1 (en) * | 2008-11-21 | 2010-05-27 | Chen Yijun | A phenoxypyrimidine derivative, its preparation method and the use thereof |
| CN102212057A (en) * | 2011-04-13 | 2011-10-12 | 合肥工业大学 | Carboxylic acid non-steroidal anti-inflammatory agent derivative and preparation method and application thereof |
| CN102225925A (en) * | 2011-04-13 | 2011-10-26 | 合肥工业大学 | Compound with activity for resisting chronic cell leukemia and preparation method thereof |
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| CN103893182A (en) * | 2014-03-27 | 2014-07-02 | 中国药科大学 | SET protein small-molecule inhibitor and application thereof |
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| CN116120261A (en) * | 2022-11-30 | 2023-05-16 | 浙大宁波理工学院 | Preparation method of 3- [ (4-sulfadiazine-1-yl) methyl ] benzoic acid compound |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0022438D0 (en) * | 2000-09-13 | 2000-11-01 | Novartis Ag | Organic Compounds |
| US20030176443A1 (en) * | 2001-05-16 | 2003-09-18 | Matthias Stein-Gerlach | Pyridylpyrimidine derivatives as effective compounds against prion diseases |
| CN1181062C (en) * | 2001-12-28 | 2004-12-22 | 陈依军 | 2-phenoxy pyrimidine derivative and its use in treating disease |
| GB0201508D0 (en) * | 2002-01-23 | 2002-03-13 | Novartis Ag | Organic compounds |
| CN101417995B (en) * | 2008-11-21 | 2012-06-06 | 陈依军 | Phenoxy pyrimidine derivates and preparation method and use thereof |
-
2008
- 2008-11-21 CN CN2008102443085A patent/CN101417995B/en not_active Expired - Fee Related
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010057418A1 (en) * | 2008-11-21 | 2010-05-27 | Chen Yijun | A phenoxypyrimidine derivative, its preparation method and the use thereof |
| CN102212057A (en) * | 2011-04-13 | 2011-10-12 | 合肥工业大学 | Carboxylic acid non-steroidal anti-inflammatory agent derivative and preparation method and application thereof |
| CN102225925A (en) * | 2011-04-13 | 2011-10-26 | 合肥工业大学 | Compound with activity for resisting chronic cell leukemia and preparation method thereof |
| CN102212057B (en) * | 2011-04-13 | 2013-11-27 | 合肥工业大学 | Carboxylic acid non-steroidal anti-inflammatory agent derivative and preparation method and application thereof |
| CN103351381A (en) * | 2013-07-26 | 2013-10-16 | 天津法莫西医药科技有限公司 | Preparation method of imatinib and mesylate of imatinib |
| CN103351381B (en) * | 2013-07-26 | 2014-10-22 | 天津法莫西医药科技有限公司 | Preparation method of imatinib and mesylate of imatinib |
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| CN105237518A (en) * | 2015-09-11 | 2016-01-13 | 中国药科大学 | 4-heterocycle substituted pyrimidine compound and uses thereof |
| CN105237518B (en) * | 2015-09-11 | 2018-04-24 | 中国药科大学 | 4- heterocyclic substituted pyrimidines and application thereof |
| CN116120261A (en) * | 2022-11-30 | 2023-05-16 | 浙大宁波理工学院 | Preparation method of 3- [ (4-sulfadiazine-1-yl) methyl ] benzoic acid compound |
| CN116120261B (en) * | 2022-11-30 | 2024-01-23 | 浙大宁波理工学院 | Preparation method of 3- [ (4-sulfadiazine-1-yl) methyl ] benzoic acid compound |
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| WO2010057418A1 (en) | 2010-05-27 |
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