CN112807310B - Application of 2, 4-diamino substituted-5-methylpyrimidine micromolecule compound - Google Patents
Application of 2, 4-diamino substituted-5-methylpyrimidine micromolecule compound Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention discloses application of a 2, 4-diamino substituted-5-methylpyrimidine small molecular compound, wherein the 2, 4-diamino substituted-5-methylpyrimidine small molecular compound has high inhibition activity on PDGFR alpha and PDGFR beta kinase, and has weaker inhibition activity on other kinases, so that the 2, 4-diamino substituted-5-methylpyrimidine small molecular compound has high selectivity and can be used as a potential drug for resisting tumors or relieving wet macular degeneration or uveitis of ophthalmic diseases.
Description
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to an application of a 2, 4-diamino substituted-5-methylpyrimidine micromolecule compound.
Background
Platelet-derived growth factor receptors (PDGFRs) share two subtypes, PDGFR α and PDGFR β, which play important roles in the growth, development, vascularization, and tissue wound repair of organisms. Under normal physiological conditions, the PDGFRs signaling pathway is generally quiescent in adults, except during development and during tissue wound repair. PDGFRs overexpression, gene mutation and gene rearrangement result in abnormal activation of PDGFRs-mediated signaling pathways and a range of diseases such as fibrotic diseases, tumors and various ophthalmic diseases, such as wet macular degeneration (AMD) and uveitis, and thus PDGFRs have become important drug targets for treating these diseases.
The currently reported selective inhibitors for PDGFRs comprise imatinib, CP-673451 and the like, and the inhibitors generally have the defects of poor kinase inhibition activity, large toxic and side effects caused by multi-target inhibition, easy drug resistance and the like. Therefore, there is a need to provide a class of inhibitors that selectively inhibit pdgfra or pdgfrp, and that doubly target pdgfra and pdgfrp, so as to provide a research basis for precise targeted medicine.
Disclosure of Invention
Through experiments, the inventor of the invention discovers a selective PDGFRs inhibitor, and the inhibitor can effectively relieve tumors with high PDGFRs gene expression and various ophthalmic diseases.
The technical scheme of the invention is as follows:
the application of the 2, 4-diamino substituted-5-methylpyrimidine small molecular compound is used for preparing PDGFRs inhibitors;
the 2, 4-diamino substituted-5-methylpyrimidine micromolecule compound is one of a compound shown in a formula (I), a salt thereof, a solvate thereof and a prodrug thereof;
preferably, the PDGFRs inhibitor can effectively inhibit PDGFR alpha and PDGFR beta, but has weak inhibitory activity on other kinases.
Preferably, the pyrimidine small molecular compound is used for preparing antitumor drugs.
Preferably, the antitumor drug is used for inhibiting osteosarcoma cells.
Preferably, the pyrimidine small-molecule compound is used for preparing a medicament for treating ophthalmic diseases.
Preferably, the medicament is used for inhibiting the vascular proliferation of the fundus oculi, and further relieving the ophthalmic diseases of wet macular degeneration or uveitis.
Compared with the prior art, the invention has the beneficial effects that:
(1) the 2, 4-diamino substituted-5-methylpyrimidine small molecular compound has high inhibition activity on PDGFR alpha and PDGFR beta kinase, and has medium or weak inhibition activity on other kinases, so the compound has high selectivity;
(2) the 2, 4-diamino substituted-5-methylpyrimidine micromolecule compound has better anti-osteosarcoma effect and is a potential anti-tumor drug;
(3) the 2, 4-diamino substituted-5-methylpyrimidine micromolecule compound can effectively inhibit the fundus vascular proliferation, and further relieve the ophthalmic diseases of wet macular degeneration or uveitis.
Detailed Description
Example 1: synthesis of target Compound
The synthetic route is as follows:
the specific synthesis method comprises the following steps:
(1) 2, 4-dichloro-5-methylpyrimidine (2.0mmol) and N, N-Diisopropylethylamine (DIPEA) (516.96mg, 4mmol) were dissolved in DMF (4mL) and cooled to 0 ℃. To the mixture was added dropwise 6-aminoindazole (266.3mg, 2mmol) dissolved in DMF (2 mL). The reaction mixture was stirred at 0 ℃ for about 1 hour. Next, the ice bath was removed, the reaction mixture was stirred at room temperature and monitored by TLC, the resulting mixture was extracted with EtOAc (3X 25mL), washed with saturated brine and over anhydrous Na 2 SO 4 Dried and concentrated to obtain an intermediate product by silica gel column chromatography. Mixing with dichloromethane: methanol 16: eluent 1, the intermediate product is obtained as yellow solid.
(2) The intermediate product of step (1) (259.7mg, 1mmol) and 4- (4-methylpiperazine) aniline (191.27mg, 1mmol) were dissolved in 4ml of methanol, and TFA (148.56 μ L, 2mmol) was added, warmed to 80 ℃, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, and the resulting mixture was adjusted to neutral with saturated sodium hydrogencarbonate, extracted with ethyl acetate (3X 25mL), washed with saturated brine, and then washed with anhydrous Na 2 SO 4 Drying and concentrating, and obtaining the product through silica gel column chromatography.
The structure and characterization data for the compounds are as follows:
N 4 - (1H-indazol-6-yl) -5-methyl-N 2 - (3- (4-methylpiperazin-1-yl) phenyl) pyrimidine-2, 4-diamine
Yellow solid, 63.5% yield. 1 H NMR(500MHz,DMSO-d 6 )δ12.83(s,1H),8.79(s,1H),8.38(s,1H),7.97(s,1H),7.91(s,1H),7.82(s,1H),7.64(d,J＝10.3Hz,1H),7.40(d,J＝8.6Hz,1H),7.29(s,1H),7.17(d,J＝7.9Hz,1H),6.92(t,J＝7.9Hz,1H),6.40(d,J＝8.0Hz,1H),5.75(s,1H),2.89(s,4H),2.24(s,4H),2.13(s,6H). 13 C NMR(126MHz,DMSO-d 6 )δ159.18,158.18,155.68,151.27,141.79,138.04,133.23,128.59,119.80,119.04,117.21,109.64,108.10,105.94,105.47,101.78,54.28,47.96,45.47,13.51；ESI-MS m/z:415.3(M﹢H) ﹢ .
Example 2: synthesis of comparative Compound IV-1
(1) 2, 4-dichloro-5-methoxypyrimidine (2mmol) and N, N-Diisopropylethylamine (DIPEA) (516.96mg, 4mmol) were dissolved in DMF (4mL) and cooled to 0 ℃. To the mixture was added 6-aminoindazole (266.3mg, 2mmol) dissolved in DMF (2mL) dropwise. The reaction mixture was stirred at 0 ℃ for about 1 hour. Next, the ice bath was removed, the reaction mixture was stirred at room temperature and monitored by TLC, the resulting mixture was extracted with EtOAc (3X 25mL), washed with saturated brine and over anhydrous Na 2 SO 4 Dried and concentrated to obtain an intermediate compound by silica gel column chromatography.
(2) The intermediate compound (1mmol) and 4- (4-methylpiperazine) aniline (191.27mg, 1mmol) were dissolved in methanol (4ml), trifluoroacetic acid (TFA) (148.56 μ L, 2mmol) was added, the temperature was raised to 80 ℃ and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, and the resulting mixture was adjusted to neutral pH with saturated sodium hydrogencarbonate, extracted with ethyl acetate (3X 25mL), washed with saturated brine, and then washed with anhydrous Na 2 SO 4 Dried and concentrated, and purified by silica gel column chromatography to give comparative compound IV-1.
The structure and characterization data for comparative compound IV-1 are as follows:
N 4 - (1H-indazol-6-yl) -5-methoxy-N 2 - (4- (4-methylpiperazin-1-yl) phenyl) pyrimidine-2, 4-diamine
1 H NMR(400MHz,DMSO-d 6 )δ8.77(s,1H),8.65(s,1H),7.96(s,2H),7.83(s,1H),7.65(d,J＝8.7Hz,1H),7.55-7.53(m,3H),6.79(d,J＝9.0Hz,2H),3.86(s,3H),3.01(s,4H),2.45(s,4H),2.22(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ154.60,152.26,145.77,138.16,137.40,134.87,134.48,133.77,120.40,119.79,119.69,119.52,117.10,116.54,101.56,57.42,55.25,49.61,46.27。
Example 3: synthesis of comparative Compound IV-2
(1) 2, 4-dichloro-4-methylpyrimidine (2mmol) and N, N-Diisopropylethylamine (DIPEA) (516.96mg, 4mmol) were dissolved in DMF (4mL) and cooled to 0 ℃. To the mixture was added 6-aminoindazole (266.3mg, 2mmol) dissolved in DMF (2mL) dropwise. The reaction mixture was stirred at 0 ℃ for about 1 hour. Next, the ice bath was removed, the reaction mixture was stirred at room temperature and monitored by TLC, the resulting mixture was extracted with EtOAc (3X 25mL), washed with saturated brine and over anhydrous Na 2 SO 4 Dried and concentrated to obtain an intermediate compound by silica gel column chromatography.
(2) The intermediate compound (1mmol) and 4- (4-methylpiperazine) aniline (191.27mg, 1mmol) were dissolved in methanol (4ml), trifluoroacetic acid (TFA) (148.56 μ L, 2mmol) was added, the temperature was raised to 80 ℃ and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, and the resulting mixture was adjusted to neutral pH with saturated sodium hydrogencarbonate, extracted with ethyl acetate (3X 25mL), washed with saturated brine, and then washed with anhydrous Na 2 SO 4 Dried and concentrated, and purified by silica gel column chromatography to give comparative compound IV-2.
Example 4: synthesis of comparative Compound IV-3
(1) 2, 4-dichloro-5-methylpyrimidine (2mmol) and N, N-Diisopropylethylamine (DIPEA) (516.96mg, 4mmol) were dissolved in DMF (4mL) and cooled to 0 ℃. To the mixture was added 5-aminoindazole (2mmol) dissolved in DMF (2mL) dropwise. The reaction mixture was brought to 0 deg.CStirred for about 1 hour. Next, the ice bath was removed, the reaction mixture was stirred at room temperature, and the reaction was monitored by TLC. After completion of the reaction, the resulting mixture was extracted with EtOAc (3X 25mL), washed with saturated brine, and then dried over anhydrous Na 2 SO 4 Drying and concentrating, and obtaining an intermediate through silica gel column chromatography.
Intermediate (1mmol) and 4- (4-methylpiperazine) aniline (191.27mg, 1mmol) were dissolved in methanol (4ml), TFA (148.56 μ L, 2mmol) was added, the temperature was raised to 80 ℃ and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, and the resulting mixture was adjusted to neutral with saturated sodium hydrogencarbonate, extracted with ethyl acetate (3X 25mL), washed with saturated brine, and then washed with anhydrous Na 2 SO 4 Drying and concentrating, and performing silica gel column chromatography to obtain the final product IV-3.
N 4 - (1H-indazol-5-yl) -5-methyl-N 2 - (4- (4-methylpiperazin-1-yl) phenyl) pyrimidine-2, 4-diamine
Yellow oil,63.5％yield. 1 H NMR(500MHz,DMSO-d 6 )δ8.80(s,1H),8.76(d,J＝3.5Hz,1H),8.56(s,1H),8.50(s,1H),8.12(d,J＝8.0Hz,1H),8.04(dd,J＝9.0,2.0Hz,1H),7.96–7.89(m,3H),7.48(d,J＝8.5Hz,2H),6.78(d,J＝9.0Hz,1H),3.06–3.00(m,4H),2.48–2.43(m,4H),2.23(s,2H),2.16(s,3H). 13 C NMR(126MHz,DMSO-d 6 )δ158.89,158.64,156.12,148.42,145.85,144.42,138.08,135.19,133.13,128.64,128.28,125.73,121.23,120.85,116.54,115.85,105.27,54.73,48.98,45.76,13.48；ESI-MS m/z:414.3(M﹢H) ﹢
EXAMPLE 5 Synthesis of comparative Compound IV-4
(1) 2, 4-dichloro-5-methylpyrimidine (2mmol) and N, N-Diisopropylethylamine (DIPEA) (516.96mg, 4mmol) were dissolved in DMF (4mL) and cooled to 0 ℃. To the mixture was added dropwise 6-aminoindazole (266.3mg, 2mmol) dissolved in DMF (2 mL). The reaction mixture was stirred at 0 ℃ for about 1 hour. Next, the ice bath was removed and the reaction mixture was placed inStirring at room temperature and monitoring the reaction by TLC, the resulting mixture was extracted with EtOAc (3X 25mL), washed with saturated brine, over anhydrous Na 2 SO 4 Dried and concentrated to obtain an intermediate compound by silica gel column chromatography.
(2) The intermediate compound (1mmol) and 4- (piperazinyl) aniline (191.27mg, 1mmol) were dissolved in methanol (4ml), trifluoroacetic acid (TFA) (148.56. mu.L, 2mmol) was added, the temperature was raised to 80 ℃ and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, and the resulting mixture was adjusted to neutral pH with saturated sodium hydrogencarbonate, extracted with ethyl acetate (3X 25mL), washed with saturated brine, and then washed with anhydrous Na 2 SO 4 Dried and concentrated, and purified by silica gel column chromatography to give comparative compound IV-4.
N 4 -(1H-indazol-6-yl)-5-methyl-N 2 -(4-(piperazin-1-yl)phenyl)pyrimidine-2,4-diamine
N 4 - (1H-indazol-6-yl) -5-methyl-N 2 - (4- (piperazin-1-yl) phenyl) -pyrimidine-2, 4-diamine
Yellow solid,29.4％yield. 1 H NMR(500MHz,DMSO-d 6 )δ12.93(s,1H),8.93(s,1H),8.55(s,1H),8.01(s,1H),7.84(d,J＝18.5Hz,2H),7.69(d,J＝8.5Hz,1H),7.50(d,J＝9.0Hz,2H),7.41(d,J＝8.0Hz,1H),6.73(d,J＝8.5Hz,2H),3.74–3.67(m,4H),3.01–2.92(m,4H),2.13(s,3H). 13 C NMR(126MHz,DMSO-d 6 )δ159.84,156.85,152.41,146.01,140.31,137.43,133.25,132.61,120.52,119.89,119.51,117.78,115.57,105.57,103.16,66.11,49.26,13.41；ESI-MS m/z:401.2(M﹢H) ﹢ .
Example 6: kinase inhibition assay for compounds
The experimental method is a Caliper Mobility Shift Assay, and the method is a detection platform taking the Mobility detection technology of the microfluidic chip technology as the core. The experimental steps are as follows: the preparation was carried out in 1.25 Xkinase reaction buffer (62.5mmol/L HEPES, pH 7.5; 0.001875% Brij-35; 12.5mmol/L MgCl) 2 (ii) a 2.5mM DTT) and kinase reaction stop solution (100mmol/L HEPES, pH 7.5; 0.015% Brij-35; 0.2% Coating Reagent # 3); mu.l of a 2.5 Xkinase solution (kinase in 1.25 Xkinase reaction buffer) was added to 5. mu.l of a 5 Xconcentration solution of the compound (dissolved in DMSO, diluted 10-fold with water), incubated at room temperature for 10min, then 10. mu.l of a 2.5 Xsubstrate peptide solution (FAM-labeled peptide and ATP in 1.25 Xkinase reaction buffer) was added, and after a specified time at 28 ℃ 25. mu.l of a kinase reaction stop solution was added. Data were collected by testing on a Caliper with a (max-conversion)/(max-min) 100 inhibition of kinase activity. "max" is DMSO control without compound addition and "min" is low control. Determination of IC 50 Each sample was plated with 2 replicate wells of 10 dilutions, 3 replicates.
Chemical structures of the compounds of Table 1 and the inhibition ratios of PDGFR alpha and PDGFR beta kinase at 100nM concentration (%)
TABLE 2 IC of inhibition of the relevant kinases by the Compound I of interest 50 Value of
The results show that the target compound I obtained in example 1 can effectively inhibit kinases PDGFR alpha and PDGFR beta, and the inhibitory activity of the comparative compounds IV-1, IV-2, IV-3 and IV-4 with slightly changed structures is obviously reduced. Meanwhile, it can be seen that the target compound I obtained in example 1 has relatively weak inhibitory activity against other kinases, indicating good kinase selectivity.
EXAMPLE 7 inhibition of osteosarcoma cells by active Compounds
The osteosarcoma cells in log phase were seeded in 96-well plates at a cell concentration of 1500 cells/well by the MTT method, 200. mu.L of cell suspension per well, and cultured for 6 h. Preparing the samples into solutions with 0.5,2.5,5,10,25 mu mol/L and 5 concentration gradients, arranging 5 multiple holes for each sample, and culturing in an incubator48h(37℃，5％CO 2 ) Adding 20 mu L of MTT (3- (4, 5-dimethylthiazole-2) -2, 5-diphenyl tetrazolium bromide) into each well, continuously culturing for 4h, removing the culture solution by suction, adding 200 mu L of DMSO into each well, shaking and dissolving for 10min, measuring the OD value of each well at 490nM by using a multifunctional microplate reader, and calculating the inhibition rate. IC50 value calculation method: the IC50 values for the samples were calculated by curve fitting using GraphPad Prism software to obtain a function.
TABLE 3 MTT assay for inhibitory Activity of Compound I of interest against four osteosarcoma cells (IC50)
The result shows that the active compound I has strong activity of inhibiting the proliferation of four osteosarcoma cell strains relative to three positive medicaments. Shows that the medicament has excellent anti-osteosarcoma effect.
EXAMPLE 8 test of the inhibitory Activity of active Compound I on two human neovascular cells
The inhibitory activity of the objective compound on two kinds of retinal cells was measured by the same MTT method as in example 7.
TABLE 4 MTT assay for inhibitory Activity of active Compounds on two human-based neovascular cells (IC50)
The result shows that the active compound I has strong activity of inhibiting human immortalized human brain microvascular endothelial cells (HCMEC/D3) and human brain perivascular cells (HBVP) relative to positive drugs, and almost has no inhibitory activity to human normal retinal cell ARPE-19 at low concentration, which shows that the active compound can effectively inhibit fundus blood vessel hyperplasia, further relieve the ophthalmic diseases of wet macular degeneration or uveitis, and has low toxicity.
Claims (6)
1. The application of the 2, 4-diamino substituted-5-methylpyrimidine micromolecule compound is characterized in that the 2, 4-diamino substituted-5-methylpyrimidine micromolecule compound is used for preparing antitumor drugs;
the 2, 4-diamino substituted-5-methylpyrimidine micromolecule compound is one of a compound shown in a formula (I) and a salt thereof;
the antitumor drug is used for inhibiting osteosarcoma cells.
2. The use of claim 1, wherein the 2, 4-diamino substituted-5-methylpyrimidine small molecule compound is used as a PDGFRs inhibitor.
3. The use of claim 2, wherein the PDGFRs inhibitor inhibits pdgfra and pdgfrp with high potency but with poor inhibitory activity against other kinases.
4. The application of the 2, 4-diamino substituted-5-methylpyrimidine micromolecule compound is characterized in that the 2, 4-diamino substituted-5-methylpyrimidine micromolecule compound is used for preparing the medicine for treating ophthalmic diseases;
the 2, 4-diamino substituted-5-methylpyrimidine micromolecule compound is one of a compound shown in a formula (I) and a salt thereof;
the medicine is used for inhibiting the vascular proliferation of the fundus oculi, and further relieving the ophthalmic diseases of wet macular degeneration or uveitis.
5. The use of claim 4, wherein the 2, 4-diamino substituted-5-methylpyrimidine small molecule compound is used as a PDGFRs inhibitor.
6. The use of claim 5, wherein the PDGFRs inhibitor inhibits PDGFRs and PDGFRs with high potency but with poor inhibitory activity against other kinases.
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