CN111518078B - Aminopyridine-containing pyrimidine compound and application thereof - Google Patents
Aminopyridine-containing pyrimidine compound and application thereof Download PDFInfo
- Publication number
- CN111518078B CN111518078B CN202010480122.0A CN202010480122A CN111518078B CN 111518078 B CN111518078 B CN 111518078B CN 202010480122 A CN202010480122 A CN 202010480122A CN 111518078 B CN111518078 B CN 111518078B
- Authority
- CN
- China
- Prior art keywords
- aminopyridine
- compound
- organic phase
- ethyl acetate
- containing pyrimidine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a pyrimidine compound containing aminopyridine,the chemical structure of the compound is shown below. The compound has obvious inhibition effect on human cervical cancer cells HeLa, human prostate cancer cells PC-3, human colon cancer cells HCT116 and human breast cancer cells MDA-MB-231, and can be used for preparing antitumor drugs.
Description
Technical Field
The invention relates to a heterocyclic compound, in particular to a pyrimidine compound containing aminopyridine heterocycle, which has anti-tumor activity and is suitable for preparing anti-tumor drugs.
Background
Malignant tumors are a serious disease seriously harming human health, surpass cardiovascular diseases at present, become the diseases with the highest global mortality rate, and overcoming the malignant tumors is still a great challenge in modern medicine. In recent years, with the progress of research on cellular carcinogenesis, various basic life activity mechanisms in malignant tumor cells, such as signal transduction, cycle regulation, apoptosis induction, and angiogenesis, have been elucidated. However, although clinically used antitumor drugs have a certain curative effect, the problems of poor selectivity, large toxic and side effects, easy occurrence of drug resistance and the like still exist, so that the search for efficient, high-selectivity and low-toxicity broad-spectrum anticancer drugs is the main direction for the development of the current anticancer drugs.
The pyrimidine derivatives are important heterocyclic compounds, and the compounds containing pyrimidine structures often have wide biological activities of cancer resistance, inflammation resistance, bacteria resistance and the like. The compounds become a hotspot of research of researchers in the pharmaceutical field, and particularly are applied to antitumor drugs, such as: the antineoplastic drugs available on the market in recent years, such as tigiokoxa, imatinib, bemacillin and palbociclib, contain pyrimidine structural fragments. Example 7 of the patent application publication No. WO 03/018022a1 discloses A3- [4- (5-tert-butylisoxazol-3-ylamino) -pyrimidin-2-ylamino ] phenylsulfonylamine compound having an inhibitory effect on the protein kinase CDK1-4, having an effect on treating colon cancer, lung cancer and cervical cancer. However, the effect of the compounds on inhibiting the proliferation of cervical cancer, prostate cancer, colon cancer or breast cancer cells is still not ideal.
Disclosure of Invention
The invention aims to solve the technical problem of providing a pyrimidine compound containing aminopyridine heterocycle, which has obvious inhibition effect on human cervical cancer cells HeLa, human prostate cancer cells PC-3, human colon cancer cells HCT116 and human breast cancer cells MDA-MB-231.
The scheme for solving the technical problems is as follows:
an aminopyridine-containing pyrimidine compound has the following chemical structure:
the aminopyridine-containing pyrimidine compound is specifically named as N2- (4-aminosulfonylphenyl) -N4- (pyridin-2-yl) -2, 4-diaminopyrimidine.
The aminopyridine-containing pyrimidine compound is prepared by the following method:
(1) dissolving 2-aminopyridine in tetrahydrofuran, adding 2 mol times of sodium hydride according to the molar weight of the 2-aminopyridine, reacting for 30 minutes at room temperature, adding 1.1 mol times of 2, 4-dichloropyrimidine according to the molar weight of the 2-aminopyridine, continuously reacting for 24 hours at room temperature, adjusting the pH of a reaction solution to be neutral by using dilute hydrochloric acid, adding ethyl acetate for extraction, taking an organic phase, drying the organic phase by using anhydrous sodium sulfate, performing desolventization, and performing column chromatography separation and purification to obtain 2-chloro-N- (pyridine-2-) pyrimidine-4-amine;
the chemical reaction formula of the step (1) is as follows:
(2) dissolving the 2-chloro-N- (pyridine-2-) pyrimidine-4-amine obtained in the step (1) and 1.2 times of 4-aminophenylsulfonamide in mole in ethylene glycol monomethyl ether, reacting for 20 hours at 120 ℃ under the catalysis of hydrochloric acid, extracting a reaction solution by using ethyl acetate, drying an organic phase by using anhydrous sodium sulfate, desolventizing, and separating and purifying by column chromatography to obtain the aminopyridine-containing pyrimidine compound;
the chemical reaction formula of the step (2) is as follows:
the process route of the method for synthesizing the aminopyridine-containing pyrimidine compounds is as follows:
the aminopyridine-containing pyrimidine compound has obvious inhibition effect on human cervical cancer cells HeLa, human prostate cancer cells PC-3, human colon cancer cells HCT116 and human breast cancer cells MDA-MB-231, and can be used for preparing antitumor drugs.
Drawings
FIG. 1 is a hydrogen spectrum of nuclear magnetic resonance of aminopyridine-containing pyrimidine compounds of the invention.
FIG. 2 is a carbon spectrum diagram of nuclear magnetic resonance of aminopyridine-containing pyrimidine compounds of the invention.
Detailed Description
Example 1 (Synthesis of the aminopyridine-containing pyrimidines)
(1) Synthesizing an intermediate 2-chloro-N- (pyridine-2-) pyrimidine-4-amine:
adding 2.0mmol of 2-aminopyridine into 15mL of anhydrous tetrahydrofuran, adding 4.0mmol of sodium hydride while stirring at room temperature, reacting for 30 minutes, adding 2.2mmol of 2, 4-dichloropyrimidine, continuing to stir at room temperature for 24 hours, detecting by TLC, after the reaction is finished, dropwise adding dilute hydrochloric acid into the reaction liquid to adjust the pH to be neutral, pouring the reaction liquid into 100mL of water, extracting with ethyl acetate (100mL multiplied by 3), standing for liquid separation, washing an organic phase with saturated saline (80mL multiplied by 3), drying with anhydrous sodium sulfate, performing suction filtration, removing the ethyl acetate under reduced pressure to obtain a white solid, and adding petroleum ether: performing column chromatography on ethyl acetate to obtain 0.165 g of white solid powder with the yield of 40 percent; the white solid powder obtained by column chromatography is identified by a nuclear magnetic resonance hydrogen spectrum method, and the result shows that the white solid powder is 2-chloro-N- (pyridine-2-) pyrimidine-4-amine, and the structural formula of the white solid powder is shown in the specification
(2) Synthesis of aminopyridine-containing pyrimidines
Adding 1.0mmol of the intermediate 2-chloro-N- (pyridine-2-) pyrimidine-4-amine in the step (1), 1.2mmol of 4-aminophenylsulfonamide and 0.1mL of hydrochloric acid into 5mL of ethylene glycol monomethyl ether, heating to 120 ℃ for reaction for 15-20 hours, detecting by TLC, pouring the reaction liquid into 100mL of water after the reaction is finished, extracting by using ethyl acetate (100mL multiplied by 3), standing for liquid separation, washing an organic phase by using saturated saline solution (80mL multiplied by 3), drying by using anhydrous sodium sulfate, carrying out suction filtration, removing the ethyl acetate under reduced pressure to obtain a white solid, and adding petroleum ether: column chromatography on ethyl acetate afforded 0.205 g of a white solid powder, mp 251.6-252.2 ℃.
The obtained white solid is identified by nuclear magnetic resonance spectrum and high-resolution mass spectrum, and the identification result is as follows:1H NMR(400MHz,DMSO-d6)δ:7.03(t,J＝5.8Hz,2H,ArH),7.17(s,2H,NH2),7.75(dd,J1＝8.4Hz,J2＝19.6Hz,3H,ArH),7.95–8.01(m,3H,ArH),8.20(d,J＝6.0Hz,1H,ArH),8.32(d,J＝4.4Hz,1H,ArH),9.68(s,1H,NH),9.99(s,1H,NH).13C NMR(100MHz,DMSO-d6)δ:159.96,159.36,157.33,153.59,148.12,144.39,138.21,136.13,126.84,118.29,118.02,113.96,100.94.HRMS(ESI)m/z:calcd for C15H14N6O2S[M+H]+343.0977 found to be N, found 343.0970 found to be a white solid2- (4-aminosulfonylphenyl) -N4- (pyridin-2-yl) -2, 4-diaminopyrimidine (IV) of the formula
The yield of the process described in this example was calculated to be 60%.
Example 2 (anti-tumor Activity study)
The in vitro antitumor activity of the compounds of the invention was demonstrated using the following assay. These effects indicate that the compounds of the present invention are useful in the treatment of cancer, particularly solid tumors such as cervical, prostate, colon and breast cancer. The specific test method is as follows:
detection of aminopyridine-containing pyrimidine Compound (IV) prepared in example 1 by MTT methodIn vitro antitumor activity. Cells were collected in log phase and cell suspension concentration was adjusted at 4X 103-5×103one/mL of the cells were inoculated in a 96-well plate and incubated for 12-24 h. After the cells adhere to the wall, drugs with different concentrations are added, 6 concentration gradients of 0.3, 1, 3, 10, 30 and 100 mu mol/l are set, and each concentration is 4 multiple wells. Placing at 37 ℃ and 5% CO2And an incubator for starting time-lapse culture. After 48h of dosing, the 96-well plate was removed, 20. mu.L of 5mg/mL MTT solution was added to each well, and incubation was continued at 37 ℃ for 4 h. Then, the supernatant in the wells was carefully aspirated, 150. mu.L of DMSO was added to each well, and the mixture was shaken for 10min to dissolve the crystals. The absorbance (OD) of each well was measured on an enzyme linked immunosorbent assay (ELISA) using a 570nm wavelength. Finally, data statistics were performed, in which the OD value (570nm) was taken as the ordinate and the treatment time was taken as the abscissa, to thereby plot the effect of the drug on the inhibition of cell growth. The inhibition rate was calculated as (1-addition group OD value/control group OD value) × 100% according to the following formula. Half maximal inhibitory IC was calculated using GraphPad Prism software50。
The results of the measured activities are shown in table 1:
TABLE 1 antitumor Activity of the object Compound (IV)
Positive control and control (5-fluorouracil) were compared to sample IV, respectively, with P <0.001
The positive control in the above table is the compound 3- [4- (5-tert-butylisoxazol-3-ylamino) -pyrimidin-2-ylamino ] phenylsulfonyl-amine disclosed in example 7 of the patent application publication No. WO 03/018022a1, the synthetic route and method for this compound is as follows:
adding 2.0mmol of 5-tert-butylisoxazol-3-amine into 15mL of anhydrous tetrahydrofuran, adding 4.0mmol of sodium hydride while stirring at room temperature, reacting for 30 minutes, adding 2.2mmol of 2, 4-dichloropyrimidine, continuing to stir at room temperature for reacting for 24 hours, detecting by TLC, after the reaction is finished, dropwise adding dilute hydrochloric acid into the reaction liquid to adjust the pH to be neutral, pouring the reaction liquid into 100mL of water, extracting with ethyl acetate (100mL x 3), separating, standing, washing an organic phase with saturated saline (80mL x 3), drying with anhydrous sodium sulfate, performing suction filtration, removing the ethyl acetate under reduced pressure to obtain a white solid, and adding petroleum ether: column chromatography with ethyl acetate afforded 0.120 g of a white solid powder. Adding 1mmol of the intermediate VI and 1mmol of 3-aminophenylsulfonamide into 5mL of ethylene glycol monomethyl ether, heating to 120 ℃ for reaction for 15 hours, pouring the reaction solution into 100mL of water after the reaction is finished, extracting by using ethyl acetate (100mL multiplied by 3), standing for separating liquid, washing an organic phase by using saturated saline solution (80mL multiplied by 3), drying by using anhydrous sodium sulfate, filtering by suction, removing the ethyl acetate by reducing pressure to obtain a white solid, and adding the solid by using petroleum ether: column chromatography on ethyl acetate afforded 0.132 g of a white solid powder.
And identifying the obtained white solid by adopting a nuclear magnetic resonance spectrum, wherein the identification result is as follows: 1H NMR (400MHz, DMSO-d6) delta 1.28(s,9H,3 XCH 3),6.53(d, J ═ 5.2Hz,1H, ArH),6.64(s,1H, ArH),7.16(s,2H, NH)2),7.68(s,1H,ArH),7.71(s,1H,ArH),7.88(s,1H,ArH),7.92(s,1H,ArH),8.13(d,J＝5.6Hz,1H,ArH),9.12(s,1H,NH),10.14(s,1H,NH).13C NMR(100MHz,DMSO-d6)δ:180.11,160.00,159.48,159.18,157.82,152.96,136.84,132.78,99.17,98.20,94.06,28.73.
From the above identification results, it was found that the obtained white solid was 3- [4- (5-tert-butylisoxazol-3-ylamino) -pyrimidin-2-ylamino ] -pyrimidine]Phenylsulfonyl amine (VII) having the formula
The yield of the process described in this example was calculated to be 34%.
The in vitro experiment results show that the aminopyridine-containing pyrimidine compound (IV) has stronger inhibition effects on four human tumor cells, namely HeLa, MDA-MB-231, HCT116 and PC-3, and the effects are obviously superior to the inhibition activities of a positive control and a control drug.
Claims (4)
1. An aminopyridine-containing pyrimidine compound, which has the chemical structure as shown in the specification:
2. an aminopyridine-containing pyrimidine according to claim 1, wherein the compound is prepared by:
(1) dissolving 2-aminopyridine in tetrahydrofuran, adding 2 mol times of sodium hydride according to the molar weight of the 2-aminopyridine, reacting at room temperature for 30 minutes, adding 1.1 mol times of 2, 4-dichloropyrimidine according to the molar weight of the 2-aminopyridine, continuously reacting at room temperature for 24 hours, adjusting the pH of a reaction solution to be neutral by using dilute hydrochloric acid, adding ethyl acetate for extraction, taking an organic phase, drying the organic phase by using anhydrous sodium sulfate, performing desolventization, and performing column chromatography separation and purification to obtain 2-chloro-N-pyrimidin-4-yl) -pyridin-2-ylamine;
(2) dissolving the (2-chloropyrimidin-4-yl) -pyridin-2-ylamine obtained in the step (1) and 1.2 molar times of sulfanilamide of the (2-chloropyrimidin-4-yl) -pyridin-2-ylamine in ethylene glycol monomethyl ether, reacting for 20 hours at 120 ℃ under the catalysis of hydrochloric acid, extracting a reaction solution by using ethyl acetate, drying an organic phase by using anhydrous sodium sulfate, desolventizing, and separating and purifying by column chromatography to obtain the aminopyridine-containing pyrimidine compound.
3. Use of aminopyridine-containing pyrimidines of claim 1 or 2 in the preparation of antitumor medicaments.
4. The use of claim 3, wherein the neoplasm is cervical cancer, prostate cancer, colon cancer or breast cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010480122.0A CN111518078B (en) | 2020-05-30 | 2020-05-30 | Aminopyridine-containing pyrimidine compound and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010480122.0A CN111518078B (en) | 2020-05-30 | 2020-05-30 | Aminopyridine-containing pyrimidine compound and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111518078A CN111518078A (en) | 2020-08-11 |
| CN111518078B true CN111518078B (en) | 2021-02-26 |
Family
ID=71911487
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010480122.0A Expired - Fee Related CN111518078B (en) | 2020-05-30 | 2020-05-30 | Aminopyridine-containing pyrimidine compound and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111518078B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101151258A (en) * | 2005-03-10 | 2008-03-26 | 拜尔药品公司 | Pyrimidine derivatives for treatment of hyperproliferative disorders |
| CN109438365A (en) * | 2018-12-06 | 2019-03-08 | 华南师范大学 | N- (3- ((4- trifluoromethyl) -2- pyrimidine radicals) aminophenyl) -2,6- difluorobenzenesulfonamide derivative |
| CN110256465A (en) * | 2019-07-13 | 2019-09-20 | 南方医科大学 | A kind of 2,4- di-amino-pyrimidine and its application containing dihydropyran and thiazole |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7115617B2 (en) * | 2001-08-22 | 2006-10-03 | Amgen Inc. | Amino-substituted pyrimidinyl derivatives and methods of use |
-
2020
- 2020-05-30 CN CN202010480122.0A patent/CN111518078B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101151258A (en) * | 2005-03-10 | 2008-03-26 | 拜尔药品公司 | Pyrimidine derivatives for treatment of hyperproliferative disorders |
| CN109438365A (en) * | 2018-12-06 | 2019-03-08 | 华南师范大学 | N- (3- ((4- trifluoromethyl) -2- pyrimidine radicals) aminophenyl) -2,6- difluorobenzenesulfonamide derivative |
| CN110256465A (en) * | 2019-07-13 | 2019-09-20 | 南方医科大学 | A kind of 2,4- di-amino-pyrimidine and its application containing dihydropyran and thiazole |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111518078A (en) | 2020-08-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103275018B (en) | 4-[the chloro-4-substituted anilinic of 3-]-6-substituted formyl amino-quinazoline compound and Synthesis and applications | |
| CN109438365B (en) | N- (3- ((4-trifluoromethyl) -2-pyrimidinyl) aminophenyl) -2, 6-difluorobenzenesulfonamide derivative | |
| CN113061138A (en) | Triazole [5,4-d ] pyrimidone tricyclic compound and preparation method and application thereof | |
| CN110041310B (en) | Preparation method and application of imatinib derivative | |
| CN112125911A (en) | CDK9 inhibitor and preparation method and application thereof | |
| CN104072493A (en) | Naphthalimide compound containing 2-mercaptobenzothiazole and triazole heterocycle, preparation method and application thereof | |
| JP7101781B2 (en) | Salt morphology as an Akt inhibitor and its crystalline morphology | |
| CN109053592B (en) | 1- (2, 5-dimethoxyphenyl) -3- (substituted pyrimidine-4-yl) urea compound and preparation and application thereof | |
| CN111518078B (en) | Aminopyridine-containing pyrimidine compound and application thereof | |
| CN110437156B (en) | Paeonol dihydropyrimidinone derivative, preparation method and application thereof | |
| CN109053594B (en) | 1- (3, 5-dimethoxyphenyl) -3- (substituted pyrimidine-4-yl) urea compound and preparation and application thereof | |
| CN113461661B (en) | 6- (pyridin-3-yl) quinazoline-4 (3H) -ketone derivative and preparation and application thereof | |
| CN115477639B (en) | Polysubstituted pyrimidine compound with FGFR1 as target point, and preparation method and application thereof | |
| CN113563340B (en) | Matrine pyrimidine derivative and preparation method and application thereof | |
| CN106045980A (en) | Quinazoline derivative and preparation method thereof | |
| CN110078706B (en) | Imatinib derivative and preparation method and application thereof | |
| CN113956234B (en) | N-phenyl substituted 1H-indazole-3-amine compound, preparation thereof and application of antitumor activity | |
| CN110156672B (en) | Preparation method of semicarbazide compound and application of prepared compound | |
| CN103254143B (en) | 4-[4-(2-diethylin kharophen) anilino]-6-substituted quinazoline compounds and Synthesis and applications | |
| CN110194741B (en) | 4-benzoyl piperazine-3-nitro-1, 8-naphthalimide derivative and preparation method and application thereof | |
| CN109020883B (en) | 3-cyano-2-aminopyridine derivative and preparation method and application thereof | |
| CN110746398A (en) | 4-heterocyclic substituted quinazoline derivative and preparation method and application thereof | |
| CN103242321A (en) | Benzylpiperazine compound and anti-tumor application thereof | |
| CN103724260A (en) | Benzamide derivative and preparation method and application thereof | |
| CN103804303A (en) | Epidermal growth factor receptor (EGFR) small-molecule inhibitor pyrimidine derivative as well as preparation method and use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20210226 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |