CN112898208B - Phenylpyrimidine amine antitumor compound and preparation method and application thereof - Google Patents
Phenylpyrimidine amine antitumor compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, relates to a compound with a specific chemical structure and anti-tumor activity, and in particular relates to a phenylpyrimidinamine compound as well as a preparation method and application thereof. The structural general formula of the phenylpyrimidinamine compound is as follows:
Description
Technical Field
The invention belongs to the technical field of medicines, relates to a compound with a specific chemical structure and anti-tumor activity, and in particular relates to a phenylpyrimidinamine anti-tumor compound and a preparation method and application thereof.
Background
Malignant melanoma is skin cancer with the strongest invasion capacity and the highest metastasis capacity, and experiments prove that the natural apoptosis rate of the malignant melanoma is obviously lower than that of other tumors. Although melanoma accounts for only 5% of skin cancers, 80% of skin cancer deaths are associated with melanoma.
Experiments prove that the endothelin B receptor is malignantThe increase in expression in melanoma cells is significant, and when endothelin 1, endothelin 3 and endothelin B receptor bind, various biological effects are produced that contribute to proliferation and invasion, such as down-regulation of E-cadherin and related connexin expression, up-regulation of N-cadherin expression, gap connexin Cx43 phosphorylation, α v β 3 Integrins, alpha 2 β 1 Integrin, matrix metalloproteinase 2 matrix, metalloproteinase 9 expression are increased, as well as downstream focal adhesion kinase pathway and extracellular signal-regulated kinase 1/2 signaling pathway activation. Moreover, these biological effects are significantly inhibited by endothelin receptor B antagonists, thereby inhibiting the proliferation and metastatic capacity of malignant tumors. And the phenotype and genotype analysis of the malignant melanoma cells identifies the endothelin B receptor as a tumor marker, so that the endothelial cell becomes a potential target for treating malignant melanoma.
There are many non-peptide endothelin receptor antagonists at present, but they are mainly used for the treatment of hypertension. Such as bosentan for treating pulmonary arterial hypertension of WHO grade II-IV, macitentan for treating pulmonary arterial hypertension, and tizosentan for research use and treatment of congestive heart failure, liver disease and heart disease.
According to the optimization of the public parent nucleus of the endothelin B receptor antagonist, the part connected with the pyrimidine ring is directly extracted so as to obtain the novel compound with better anti-tumor activity, and no report on related structures is seen in the prior art.
Disclosure of Invention
In view of the problems existing in the prior art, the invention aims to provide a phenylpyrimidinamine compound, a preparation method and application thereof, and the prepared compound shows good results in-vitro antitumor activity test and can be used for preparing antitumor drugs.
In order to achieve the above purpose, the present invention adopts the following technical scheme.
A phenylpyrimidinamine compound having the structural formula I:
general formula I
Wherein: the R group is a hydrogen atom, a 2-position monosubstituted fluorine atom, or a 3-position and 4-position monosubstituted methyl, fluorine atom, chlorine atom and bromine atom.
Further, the phenylpyrimidinamine compound, the compound with the general formula I or pharmaceutically acceptable salt, hydrate or solvate thereof has a structure selected from any one of the following:
6-chloro-5- (2-methoxyphenoxy) -2-phenylpyrimidin-4-amine (A1);
6-chloro-2- (2-fluorophenyl) -5- (2-methoxyphenoxy) pyrimidin-4-amine (A2);
6-chloro-2- (3-fluorophenyl) -5- (2-methoxyphenoxy) pyrimidin-4-amine (A3);
6-chloro-2- (4-fluorophenyl) -5- (2-methoxyphenoxy) pyrimidin-4-amine (A4);
6-chloro-5- (2-methoxyphenoxy) -2- (m-tolyl) pyrimidin-4-amine (A5);
6-chloro-5- (2-methoxyphenoxy) -2- (p-tolyl) pyrimidin-4-amine (A6);
6-chloro-2- (3-chlorophenyl) -5- (2-methoxyphenoxy) pyrimidin-4-amine (A7);
6-chloro-2- (4-chlorophenyl) -5- (2-methoxyphenoxy) pyrimidin-4-amine (A8);
2- (3-bromophenyl) -6-chloro-5- (2-methoxyphenoxy) pyrimidin-4-amine (A9);
2- (4-bromophenyl) -6-chloro-5- (2-methoxyphenoxy) pyrimidin-4-amine (A10).
But not limited to the above compounds, as long as the structural formula of the compounds satisfies the general formula, are all within the scope of the present invention.
The preparation method of the phenylpyrimidinamine compound specifically comprises the following steps.
Step 1, putting 1 time of diethyl malonate, 1.05 times of NBS and a proper amount of chloroform into a reaction bottle, adding a trace amount of concentrated sulfuric acid as a catalyst, and reacting for 10-12 hours at 50 ℃; monitoring the reaction progress by thin layer chromatography, washing the reaction solution with saturated sodium sulfite solution for multiple times after the reaction is finished, washing the reaction solution with saturated sodium chloride solution for multiple times, drying the reaction solution with anhydrous sodium sulfate, and then evaporating the solvent under reduced pressure to obtain diethyl 2-bromomalonate as colorless transparent liquid.
Step 2, putting 1 time of diethyl 2-bromomalonate, 1 time of guaiacol, 1.5 times of potassium carbonate and a proper amount of acetonitrile into a reaction bottle, reacting for 10-12 hours at 80 ℃, and monitoring the reaction progress by thin layer chromatography; after the reaction is finished, the reaction solution is filtered, the filter cake is washed by acetonitrile solution, the filter cake is filtered again, the obtained filtrate is combined, the solvent is distilled off under reduced pressure, and the diethyl 2- (2-methoxyphenoxy) malonate is black liquid.
Step 3, putting 1 time of R-substituted benzonitrile, 0.6 time of sodium methoxide and a proper amount of methanol into a reaction bottle, and reacting for 16 hours at room temperature; adding 1.8 times of ammonium chloride, continuing to react at room temperature for 10-12h, and monitoring the reaction progress by thin layer chromatography; after the reaction is finished, decompressing and distilling out the solvent to obtain white solid; dissolving the solid with a proper amount of ethanol solvent, carrying out ultrasonic treatment, carrying out suction filtration, collecting filtrate, and evaporating the solvent under reduced pressure to obtain R-substituted benzamidine hydrochloride as a white solid.
Step 4, cutting 1.5 times of metal sodium into strips, slowly adding the strips into a reaction bottle containing a proper amount of methanol at a low temperature for reaction for 0.5h, then adding 1.3 times of diethyl 2- (2-methoxyphenoxy) malonate and 1 time of R-substituted benzamidine hydrochloride for reaction for 18h at room temperature, monitoring the reaction process by thin layer chromatography, decompressing and distilling off the solvent after the reaction is finished, then adding sodium hydroxide solution, suction filtering, regulating the pH value of the filtrate to be acidic by using hydrochloric acid, precipitating a large amount of solid, suction filtering, and drying a filter cake to obtain 5- (2-methoxyphenoxy) -2- (R-substituted phenyl) pyrimidine-4, 6-diol as light yellow solid.
Step 5, adding 5- (2-methoxyphenoxy) -2- (R-substituted phenyl) pyrimidine-4, 6-diol and a proper amount of phosphorus oxychloride into a reaction bottle, and reacting for 48 hours at 100 ℃; after the reaction is finished, slowly pouring the reaction solution into ice water, precipitating solid, suction filtering, and drying a filter cake to obtain 4, 6-dichloro-5- (2-methoxyphenoxy) -2- (R-substituted phenyl) pyrimidine which is a black solid.
Step 6, placing 1 time of 4, 6-dichloro-5- (2-methoxyphenoxy) -2- (R-substituted phenyl) pyrimidine, 1 time of ammonium chloride, 2 times of potassium carbonate and a proper amount of DMF into a reaction bottle, reacting for 10-12 hours at 80 ℃, and monitoring the reaction progress by thin-layer chromatography; after the reaction, slowly pouring the reaction solution into water to precipitate solid, suction filtering, drying a filter cake, removing impurities by using a column chromatography, and recrystallizing by using isopropanol/water to obtain 6-chloro-2- (R-substituted phenyl) -5- (2-methoxyphenoxy) pyrimidine-4-amine as a white solid.
A pharmaceutical composition comprises the phenylpyrimidinamine compound, a pharmaceutically acceptable salt, hydrate or solvate thereof and a pharmaceutically acceptable carrier.
The phenylpyrimidinamine compound or pharmaceutically acceptable salt, hydrate or solvate thereof or the application of the pharmaceutical composition in preparing antitumor drugs.
Further, the tumor is malignant melanoma.
Further, the dosage form of the medicament is a pharmaceutically acceptable dosage form.
Further, the dosage of the drug is a pharmaceutically acceptable dosage.
The invention also includes prodrugs of the compounds of the invention. Prodrugs of the compounds of the present invention are derivatives of formula I which are converted under physiological conditions (e.g., by metabolism, solvolysis or otherwise) to the corresponding biologically active form. The pharmaceutical compositions of the present invention may be formulated into a number of dosage forms including, but not limited to, injections, tablets, capsules, powders, and the like.
Compared with the prior art, the invention has the following beneficial effects.
The phenylpyrimidinamine compound provided by the invention shows good results in-vitro antitumor activity test, has a certain inhibitory activity on human malignant melanoma cells, can be used for preparing antitumor drugs, and opens up a new way for developing antitumor drugs with endothelin receptors as new targets. The preparation method provided by the invention is simple and feasible, has higher yield and is easy for mass production.
Detailed Description
The invention is further illustrated below in connection with specific examples which are intended to be illustrative only and in no way limit the scope of the invention.
A phenylpyrimidinamine compound having the structural formula I:
general formula I
Wherein: the R group is a hydrogen atom, a 2-position monosubstituted fluorine atom, or a 3-position and 4-position monosubstituted methyl, fluorine atom, chlorine atom and bromine atom.
Example 16 preparation of chloro-5- (2-methoxyphenoxy) -2-phenylpyrimidin-4-amine (A1).
Preparation of diethyl 2-bromomalonate.
Diethyl malonate (30.00 g,187.30 mmol), NBS (35.00 g,196.67 mmol) and 100ml of chloroform were put into a 250ml flask, and two drops of concentrated sulfuric acid were added as a catalyst. The reaction was carried out at 50℃for 12h and the progress of the reaction was monitored by thin layer chromatography. After the completion of the reaction, the reaction solution was washed with a saturated sodium sulfite solution, then with a saturated sodium chloride solution, and then the reaction solution was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 43.65g of a colorless transparent liquid product, yield 97.48%.
Preparation of diethyl 2- (2-methoxyphenoxy) malonate.
Diethyl 2-bromomalonate (43.65 g,182.59 mmol), guaiacol (22.67 g,182.59 mmol), potassium carbonate (35.33 g,255.62 mmol) and 100ml acetonitrile were put into a 250ml flask, reacted at 80℃for 13 hours, and the progress of the reaction was monitored by thin layer chromatography. After the reaction, the reaction solution was suction-filtered, the filter cake was washed with acetonitrile, suction-filtered again, the filtrates were combined, and the solvent was distilled off under reduced pressure to obtain 45.27g of a black liquid product, yield 87.83%.
c. Preparation of benzamidine hydrochloride.
Benzonitrile (10.00 g,96.97 mmol), sodium methoxide (3.14 g,58.18 mmol) and 100ml methanol were placed in a 250ml flask and reacted at room temperature for 16h, ammonium chloride (9.34 g,174.55 mmol) was added, the reaction was continued at room temperature for 12h, and the progress of the reaction was monitored by thin layer chromatography. After the reaction was completed, the solvent was distilled off under reduced pressure, then the solid was dispersed with ethanol, sonicated, suction-filtered, the filtrate was collected, and the solvent was distilled off under reduced pressure to obtain 15.02g of a white solid product, yield 98.88%.
Preparation of 5- (2-methoxyphenoxy) -2-phenylpyrimidine-4, 6-diol.
Solid sodium (3.31 g,143.86 mmol) was cut into strips, slowly added in a cold trap to a 250ml flask containing 100ml methanol, reacted for 0.5h, then diethyl 2- (2-methoxyphenoxy) malonate (35.20 g,124.68 mmol) and benzamidine hydrochloride (15.02 g,95.91 mmol) were added, reacted at room temperature for 18h, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is finished, the solvent is distilled off under reduced pressure, then sodium hydroxide solution with the pH value of 9.0 is added to dissolve the solid, suction filtration is carried out, the pH value of the filtrate is regulated to 3.0 by using dilute hydrochloric acid, a large amount of solid is separated out, suction filtration is carried out, the filter cake is dried, and 14.88g of light yellow solid is obtained, and the yield is 50.00%.
e.4 preparation of 6-dichloro-5- (2-methoxyphenoxy) -2-phenylpyrimidine.
5- (2-methoxyphenoxy) -2-phenylpyrimidine-4, 6-diol (14.88 g,47.95 mmol) and 50ml phosphorus oxychloride were added to a 250ml flask and reacted at 100℃for 48h. After the reaction, the reaction solution was slowly poured into ice water to precipitate a black solid, which was suction-filtered and the cake was dried to obtain 15.21g of a black solid with a yield of 91.35%.
Preparation of f.6-chloro-5- (2-methoxyphenoxy) -2-phenylpyrimidin-4-amine.
4, 6-dichloro-5- (2-methoxyphenoxy) -2-phenylpyrimidine (15.21 g,43.81 mmol), ammonium chloride (2.34 g,43.81 mmol), potassium carbonate (12.11 g,87.62 mmol) and 100ml DMF were placed in a 250ml flask and reacted at 80℃for 12h, followed by thin layer chromatography to monitor the progress of the reaction. After the reaction is finished, the reaction solution is poured into water to precipitate solid, and the solid is filtered by suction, and the filter cake is dried. Purification by column chromatography followed by recrystallization from isopropanol/water gave 3.26g of a white solid product in 23.78% yield.
1 H NMR(500MHz,DMSO-d 6 )δ8.28–8.23(m,2H),7.50(d,J＝4.9Hz,3H),7.34(s,2H),7.12(d,J＝8.0Hz,1H),7.04(t,J＝7.7Hz,1H),6.84(t,J＝7.7Hz,1H),6.65(d,J＝8.1Hz,1H),3.86(s,3H)。
Example 26 preparation of chloro-2- (2-fluorophenyl) -5- (2-methoxyphenoxy) pyrimidin-4-amine (A2).
Diethyl malonate was used as starting material, diethyl 2- (2-methoxyphenoxy) malonate was prepared according to the procedure of example 1a,1b, and 2-fluorobenzonitrile was further used as starting material, 4, 6-dichloro-2- (2-fluorophenyl) -5- (2-methoxyphenoxy) pyrimidine was prepared according to the procedure of example 1c,1d,1e, 6-chloro-2- (2-fluorophenyl) -5- (2-methoxyphenoxy) pyrimidin-4-amine (A2) was prepared according to the procedure of example 1f as a white solid, yield: 22.17%.
1 H NMR(500MHz,DMSO-d 6 )δ7.91(t,J＝7.8Hz,1H),7.57–7.20(m,5H),7.13(d,J＝8.1Hz,1H),7.05(t,J＝7.7Hz,1H),6.86(t,J＝7.7Hz,1H),6.65(d,J＝8.0Hz,1H),3.86(s,3H)。
Example 3 6 preparation of chloro-2- (3-fluorophenyl) -5- (2-methoxyphenoxy) pyrimidin-4-amine (A3).
Diethyl malonate was used as a starting material, diethyl 2- (2-methoxyphenoxy) malonate was prepared according to the procedure of example 1a,1b, and 3-fluorobenzonitrile was further used as a starting material, 4, 6-dichloro-2- (3-fluorophenyl) -5- (2-methoxyphenoxy) pyrimidine was prepared according to the procedure of example 1c,1d,1e, 6-chloro-2- (3-fluorophenyl) -5- (2-methoxyphenoxy) pyrimidin-4-amine (A3) was prepared according to the procedure of example 1f as a pale yellow solid, yield: 23.52%.
1 H NMR(500MHz,DMSO-d 6 )δ8.09(d,J＝7.8Hz,1H),7.95(d,J＝9.5Hz,1H),7.71–7.23(m,4H),7.12(d,J＝8.1Hz,1H),7.04(t,J＝7.7Hz,1H),6.84(t,J＝7.6Hz,1H),6.66(d,J＝8.0Hz,1H),3.86(s,3H)。
Example 4 6 preparation of chloro-2- (4-fluorophenyl) -5- (2-methoxyphenoxy) pyrimidin-4-amine (A4).
Diethyl malonate was used as starting material, diethyl 2- (2-methoxyphenoxy) malonate was prepared according to the procedure of example 1a,1b, 4, 6-dichloro-2- (4-fluorophenyl) -5- (2-methoxyphenoxy) pyrimidine was prepared according to the procedure of example 1c,1d,1e from 4-fluorobenzonitrile, 6-chloro-2- (4-fluorophenyl) -5- (2-methoxyphenoxy) pyrimidin-4-amine (A4) was prepared according to the procedure of example 1f as a pale yellow solid, yield: 24.17%.
1 H NMR(500MHz,DMSO-d 6 )δ8.28(t,2H),7.38(s,2H),7.32(t,J＝8.3Hz,2H),7.12(d,J＝8.1Hz,1H),7.04(t,J＝7.7Hz,1H),6.83(t,J＝7.7Hz,1H),6.65(d,J＝8.0Hz,1H),3.86(s,3H)。
Example 5 6 preparation of chloro-5- (2-methoxyphenoxy) -2- (m-tolyl) pyrimidin-4-amine (A5).
Diethyl malonate was used as a starting material, diethyl 2- (2-methoxyphenoxy) malonate was prepared according to the steps of example 1a,1b, 3-methylbenzonitrile was further used as a starting material, 4, 6-dichloro-5- (2-methoxyphenoxy) -2- (m-tolyl) pyrimidine was prepared according to the steps of example 1c,1d,1e, and 6-chloro-5- (2-methoxyphenoxy) -2- (m-tolyl) pyrimidin-4-amine (A5) was prepared according to the step of example 1f as a pale yellow solid with a yield of 23.28%.
1 H NMR(500MHz,DMSO-d 6 )δ8.08(s,1H),8.04(d,J＝7.6Hz,1H),7.53–7.20(m,4H),7.12(d,J＝8.1Hz,1H),7.04(t,J＝7.7Hz,1H),6.84(t,J＝7.7Hz,1H),6.64(d,J＝8.0Hz,1H),3.86(s,3H),2.39(s,3H)。
Example 6 6 preparation of chloro-5- (2-methoxyphenoxy) -2- (p-tolyl) pyrimidin-4-amine (A6).
Diethyl malonate was used as a starting material, diethyl 2- (2-methoxyphenoxy) malonate was prepared according to the procedure of example 1a,1b, 4, 6-dichloro-5- (2-methoxyphenoxy) -2- (p-tolyl) pyrimidine was prepared according to the procedure of example 1c,1d,1e from 4-methylbenzonitrile, and 6-chloro-5- (2-methoxyphenoxy) -2- (p-tolyl) pyrimidin-4-amine (A6) was prepared according to the procedure of example 1f as a white solid with a yield of 24.43%.
1 H NMR(500MHz,DMSO-d 6 )δ8.15(d,J＝7.7Hz,2H),7.49–7.19(m,4H),7.12(d,J＝8.1Hz,1H),7.03(t,J＝7.7Hz,1H),6.83(t,J＝7.7Hz,1H),6.64(d,J＝8.0Hz,1H),3.86(s,3H),2.37(s,3H)。
Example 7 6 preparation of chloro-2- (3-chlorophenyl) -5- (2-methoxyphenoxy) pyrimidin-4-amine (A7).
Diethyl malonate was used as a starting material, diethyl 2- (2-methoxyphenoxy) malonate was prepared according to the procedure of example 1a,1b, and 3-chlorobenzonitrile was further used as a starting material, 4, 6-dichloro-2- (3-chlorophenyl) -5- (2-methoxyphenoxy) pyrimidine was prepared according to the procedure of example 1c,1d,1e, and 6-chloro-2- (3-chlorophenyl) -5- (2-methoxyphenoxy) pyrimidin-4-amine (A7) was prepared according to the procedure of example 1f, as a pale yellow solid, yield 25.83%.
1 H NMR(500MHz,DMSO-d 6 )δ8.23(s,1H),8.18(d,J＝7.6Hz,1H),7.76–7.18(m,4H),7.12(d,J＝7.9Hz,1H),7.04(t,J＝7.7Hz,1H),6.83(t,J＝7.6Hz,1H),6.66(d,J＝8.0Hz,1H),3.86(s,3H)。
Example 86 preparation of chloro-2- (4-chlorophenyl) -5- (2-methoxyphenoxy) pyrimidin-4-amine (A8).
Diethyl malonate was used as a raw material, diethyl 2- (2-methoxyphenoxy) malonate was prepared according to the steps of example 1a and 1b, 4, 6-dichloro-2- (4-chlorophenyl) -5- (2-methoxyphenoxy) pyrimidine was prepared according to the steps of example 1c,1d and 1e from 4-chlorobenzonitrile, and 6-chloro-2- (4-chlorophenyl) -5- (2-methoxyphenoxy) pyrimidin-4-amine (A8) was prepared according to the step of example 1f as a pale yellow solid with a yield of 25.16%.
1 H NMR(500MHz,DMSO-d 6 )δ8.25(d,J＝8.1Hz,2H),7.56(d,J＝8.1Hz,2H),7.40(s,2H),7.12(d,J＝8.0Hz,1H),7.04(t,J＝7.7Hz,1H),6.83(t,J＝7.7Hz,1H),6.66(d,J＝8.0Hz,1H),3.86(s,3H)。
Example 9 2 preparation of- (3-bromophenyl) -6-chloro-5- (2-methoxyphenoxy) pyrimidin-4-amine (A9).
Diethyl malonate was used as a starting material, diethyl 2- (2-methoxyphenoxy) malonate was prepared according to the steps of example 1a,1b, and 3-bromoxynil was used as a starting material, 2- (3-bromophenyl) -4, 6-dichloro-5- (2-methoxyphenoxy) pyrimidine was prepared according to the steps of example 1c,1d,1e, and 2- (3-bromophenyl) -6-chloro-5- (2-methoxyphenoxy) pyrimidin-4-amine (A9) was prepared according to the step of example 1f, as a white solid, with a yield of 28.86%.
1 H NMR(500MHz,DMSO-d 6 )δ8.39(s,1H),8.22(d,J＝7.7Hz,1H),7.82–7.18(m,4H),7.12(d,J＝8.1Hz,1H),7.04(t,J＝7.7Hz,1H),6.83(t,J＝7.7Hz,1H),6.66(d,J＝8.0Hz,1H),3.86(s,3H)。
Example 10 preparation of 2- (4-bromophenyl) -6-chloro-5- (2-methoxyphenoxy) pyrimidin-4-amine (A10).
Diethyl malonate was used as a starting material, diethyl 2- (2-methoxyphenoxy) malonate was prepared according to the procedure of example 1a,1b, and 2- (4-bromophenyl) -4, 6-dichloro-5- (2-methoxyphenoxy) pyrimidine was prepared according to the procedure of example 1c,1d,1e from 4-bromoxynil, 2- (4-bromophenyl) -6-chloro-5- (2-methoxyphenoxy) pyrimidin-4-amine (a 10) was prepared according to the procedure of example 1f, as a white solid, yield 27.61%.
1 H NMR(500MHz,DMSO-d 6 )δ8.17(d,J＝7.0Hz,2H),7.70(d,J＝7.0Hz,2H),7.43(s,2H),7.12(d,J＝8.0Hz,1H),7.04(t,J＝7.1Hz,1H),6.82(t,J＝7.5Hz,1H),6.65(d,J＝8.0Hz,1H),3.85(s,3H)。
Example 11 inhibition of tumor cell proliferation experiments.
The compounds of the present invention were tested for tumor cell proliferation inhibition using conventional MTT methods.
Culturing tumor cells: the cell lines were selected from SK-MEL-28 (human skin malignant melanoma cells) and A375 (human melanoma cells), and cultured in a culture medium of DMEM+10% FBS+double antibody (penicillin 100 units/mL, streptomycin 100. Mu.g/mL).
Sample preparation: after dissolution in DMSO (Merck), PBS (-) was added to make a 1000. Mu.g/mL solution or homogeneous suspension, which was then diluted with DMSO-containing PBS (-). The final concentrations were respectively: 80. Mu.M, 8. Mu.M, 0.8. Mu.M, 0.08. Mu.M, 008. Mu.M. Ambrisentan was used as a control with imatinib.
Test method for inhibition of cell proliferation: the addition concentration of each well of the 96-well plate is 4-5 multiplied by 10 4 mu.L of each/mL cell suspension was incubated at 37℃with 5% CO 2 The incubator. After 24 hours, add sample solution and pair respectivelyThe reference liquid, 10. Mu.L/well, was provided with double wells, 37℃and 5% CO 2 The reaction was carried out for 24 hours. 5mg/mL MTT (3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazole Weng Xiuhua) solution 15 mu L is added into each hole, after 4 hours of action, solution DMSO is added into each hole, 100 mu L/hole is placed into an incubator, after dissolution, the OD value at 490nm is measured by using an MK-2 full-automatic enzyme label instrument, and the inhibition rate is calculated.
The experimental results are shown in Table 1.
TABLE 1 IC50 values of in vitro proliferation inhibiting activity of samples on human tumor cells.
The experimental data show that although the phenylpyrimidinamine compounds provided by the invention have larger antitumor activity difference, part of the compounds have excellent in-vitro antitumor activity, so that the compounds are worthy of intensive research, and a new way is opened up for developing antitumor drugs with endothelin receptors as new targets.
Claims (7)
1. A phenylpyrimidinamine compound or a pharmaceutically acceptable salt thereof, characterized in that the compound has the structural formula I:
general formula I
Wherein: the R group is hydrogen atom, or 3-position monosubstituted methyl, chlorine atom, bromine atom, or 4-position monosubstituted fluorine atom, chlorine atom, bromine atom.
2. The phenylpyrimidinamine compound, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the structure of said compound is selected from any one of the following:
6-chloro-5- (2-methoxyphenoxy) -2-phenylpyrimidin-4-amine;
6-chloro-2- (4-fluorophenyl) -5- (2-methoxyphenoxy) pyrimidin-4-amine;
6-chloro-5- (2-methoxyphenoxy) -2- (m-tolyl) pyrimidin-4-amine;
6-chloro-2- (3-chlorophenyl) -5- (2-methoxyphenoxy) pyrimidin-4-amine;
6-chloro-2- (4-chlorophenyl) -5- (2-methoxyphenoxy) pyrimidin-4-amine;
2- (3-bromophenyl) -6-chloro-5- (2-methoxyphenoxy) pyrimidin-4-amine;
2- (4-bromophenyl) -6-chloro-5- (2-methoxyphenoxy) pyrimidin-4-amine.
3. The method for preparing the phenylpyrimidinamine compound according to claim 1, comprising the steps of:
step 1, putting 1 time of diethyl malonate, 1.05 times of NBS and a proper amount of chloroform into a reaction bottle, adding a trace amount of concentrated sulfuric acid as a catalyst, and reacting for 10-12 hours at 50 ℃; monitoring the reaction progress by thin layer chromatography, washing the reaction liquid for a plurality of times by using a saturated sodium sulfite solution after the reaction is finished, washing the reaction liquid for a plurality of times by using a saturated sodium chloride solution, drying the reaction liquid by using anhydrous sodium sulfate, and then evaporating the solvent under reduced pressure to obtain diethyl 2-bromomalonate which is colorless and transparent liquid;
step 2, putting 1 time of diethyl 2-bromomalonate, 1 time of guaiacol, 1.5 times of potassium carbonate and a proper amount of acetonitrile into a reaction bottle, reacting for 10-12 hours at 80 ℃, and monitoring the reaction progress by thin layer chromatography; after the reaction is finished, carrying out suction filtration on the reaction solution, washing a filter cake with acetonitrile solution, carrying out suction filtration again, combining obtained filtrate, and evaporating solvent under reduced pressure to obtain diethyl 2- (2-methoxyphenoxy) malonate which is black liquid;
step 3, putting 1 time of R-substituted benzonitrile, 0.6 time of sodium methoxide and a proper amount of methanol into a reaction bottle, and reacting for 16 hours at room temperature; adding 1.8 times of ammonium chloride, continuing to react at room temperature for 10-12h, and monitoring the reaction progress by thin layer chromatography; after the reaction is finished, decompressing and distilling out the solvent to obtain white solid; dissolving the solid with a proper amount of ethanol solvent, performing ultrasonic treatment, performing suction filtration, collecting filtrate, and evaporating the solvent under reduced pressure to obtain R-substituted benzamidine hydrochloride which is a white solid;
step 4, cutting 1.5 times of metal sodium into strips, slowly adding the strips into a reaction bottle containing a proper amount of methanol at a low temperature for reaction for 0.5h, then adding 1.3 times of diethyl 2- (2-methoxyphenoxy) malonate and 1 time of R-substituted benzamidine hydrochloride for reaction for 18h at room temperature, monitoring the reaction process by thin layer chromatography, decompressing and distilling off the solvent after the reaction is finished, then adding sodium hydroxide solution, suction-filtering, regulating the pH value of the filtrate to be acidic by using hydrochloric acid, precipitating a large amount of solid, suction-filtering, and drying a filter cake to obtain 5- (2-methoxyphenoxy) -2- (R-substituted phenyl) pyrimidine-4, 6-diol as light yellow solid;
step 5, adding 5- (2-methoxyphenoxy) -2- (R-substituted phenyl) pyrimidine-4, 6-diol and a proper amount of phosphorus oxychloride into a reaction bottle, and reacting for 48 hours at 100 ℃; after the reaction is finished, slowly pouring the reaction solution into ice water, precipitating solid, carrying out suction filtration, and drying a filter cake to obtain 4, 6-dichloro-5- (2-methoxyphenoxy) -2- (R-substituted phenyl) pyrimidine which is a black solid;
step 6, placing 1 time of 4, 6-dichloro-5- (2-methoxyphenoxy) -2- (R-substituted phenyl) pyrimidine, 1 time of ammonium chloride, 2 times of potassium carbonate and a proper amount of DMF into a reaction bottle, reacting for 10-12 hours at 80 ℃, and monitoring the reaction progress by thin-layer chromatography; after the reaction, slowly pouring the reaction solution into water to precipitate solid, suction filtering, drying a filter cake, removing impurities by using a column chromatography, and recrystallizing by using isopropanol/water to obtain 6-chloro-2- (R-substituted phenyl) -5- (2-methoxyphenoxy) pyrimidine-4-amine as a white solid.
4. A pharmaceutical composition comprising the phenylpyrimidinamine compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
5. Use of a phenylpyrimidinamine compound according to claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 4 for the manufacture of a medicament for the treatment of malignant melanoma.
6. The use of claim 5, wherein the pharmaceutical dosage form is a pharmaceutically acceptable dosage form.
7. The use of claim 5, wherein the dose of the medicament is a pharmaceutically acceptable dose.
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