CN103059030A - Pyrimidine compound with effect of adhesion kinase inhibition and preparation method and application thereof - Google Patents
Pyrimidine compound with effect of adhesion kinase inhibition and preparation method and application thereof Download PDFInfo
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- CN103059030A CN103059030A CN2012105919329A CN201210591932A CN103059030A CN 103059030 A CN103059030 A CN 103059030A CN 2012105919329 A CN2012105919329 A CN 2012105919329A CN 201210591932 A CN201210591932 A CN 201210591932A CN 103059030 A CN103059030 A CN 103059030A
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- -1 Pyrimidine compound Chemical class 0.000 title claims abstract description 23
- 230000000694 effects Effects 0.000 title abstract description 24
- 230000005764 inhibitory process Effects 0.000 title abstract description 12
- 238000002360 preparation method Methods 0.000 title abstract description 10
- 108091000080 Phosphotransferase Proteins 0.000 title 1
- 102000020233 phosphotransferase Human genes 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 68
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 7
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims abstract description 7
- 125000001246 bromo group Chemical group Br* 0.000 claims abstract description 6
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 5
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 12
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- 239000002253 acid Substances 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
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- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 2
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 210000004881 tumor cell Anatomy 0.000 abstract description 8
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- 102000016621 Focal Adhesion Protein-Tyrosine Kinases Human genes 0.000 description 11
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Abstract
The invention provides a pyrimidine compound, and the structure of the pyrimidine compound is shown in the following formulas (I) and (II), wherein R is substituted phenyl or substituted pyridyl; R1 is -NO2, -Br, -COOH or -OCH3; n is an integer of 1-3; X is -Br or CI; and R8, R9 and R10 are identical or different -H, -OCH3, -COOMe, -Br, -COOEt, -CH2COOMe, -NO2 or (CH2)1-4OH. The pyrimidine compound provided by the invention has an effect of FAK inhibition, can effectively enter tumor cells, has a good effect of inhibiting the tumor cells and can be better detained. The invention also provides a preparation method of the compound and the application of the compound to the preparation of preparing a tumor inhibitor.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to the field of radiopharmaceutical chemistry, and especially relates to a series of pyrimidine derivatives with focal adhesion kinase inhibition effect.
Background
Focal Adhesion Kinase (FAK) is an non-receptor tyrosine protein Kinase[1]It was identified in 1992 as a hyperphosphorylated protein associated with the oncogene v-src, located in the integrin-rich focal adhesion region of normal cells. FAK is an important intracellular scaffold protein and severalThe key molecules of the signal path have important effects on cell survival, proliferation, migration and invasion[2-7]. FAK plays a very important role in the process of tumor occurrence and development, so that FAK can be used as a marker molecule for judging whether tumor invasion exists and predicting the prognosis of malignant tumors, and FAK can be an effective target for tumor treatment and can be a new target for tumor diagnosis and treatment. Therefore, FAK has great potential to play a role in the specific diagnosis of tumors, targeted molecular therapy, and prognostic evaluation of tumors. Currently, the main FAK inhibitors are TAC544 and TAE226 from Nowa, PF-562,271 and PF-573,228 from Perey, GSK2256098 from Kurarin Schke, Y15 from Sigma and CFAK-C4 from Curefaktor[8]。
The current inspection methods commonly used for diagnosing malignant tumors have certain limitations, false positives, poor specificity or low sensitivity; b-mode ultrasound, CT, nuclear magnetic resonance examination, and the like are based on morphological changes of diseases, and it is difficult to provide diagnostic information when there is no structural morphological change at an early stage of canceration. The most outstanding advantages of radionuclide-labeled compound imaging and targeted molecular therapy are the advantages of functional imaging and targeted molecular therapy, and the radionuclide-labeled compound imaging and targeted molecular therapy has unique advantages in reflecting biochemical processes such as blood flow, receptor density and activity, metabolism, functional change and the like of organs or tissues, and is one of the most advanced technologies for clinical diagnosis and treatment of diseases at present.
Based on the above background, there is a need to develop a FAK inhibitor that can be labeled with a radionuclide, which has a greater promoting effect in tumor molecular imaging agents and radioimmunotherapy of malignant tumors.
Disclosure of Invention
One object of the present invention is: the pyrimidine compound with the FAK inhibition effect can effectively enter tumor cells, has a good inhibition effect on the tumor cells and can be well retained.
Another object of the invention is: provides pharmaceutically acceptable salts of the pyrimidine compounds.
Yet another object of the present invention is: provides a preparation method of the pyrimidine compound.
Yet another object of the present invention is: provides the application of the pyrimidine compound.
The above object of the present invention is achieved by the following technical solutions:
provides a pyrimidine compound, the structure of which is shown as the following formula (I):
wherein R is substituted phenyl or substituted pyridyl; r1is-NO2-Br, -COOH or-OCH3(ii) a n is an integer of 1 to 3.
In a preferred embodiment of the present invention, R in formula (I) is a substituted phenyl group, n =1, and the structure thereof is represented by formula (I-1):
wherein R is2、R3、R4And R5Are identical or different-H, -COOMe, Br-COPh or (CH)2)1-4OH。
Among the compounds represented by the above formula (I-1) of the present invention, further preferred compounds include:
in another preferred embodiment of the present invention, R in formula (I) is a substituted pyridyl group, n =1, and the structure thereof is represented by formula (I-2):
wherein R is6And R7Taking same or different-H, -COOMe, -Br, -NO2Or (CH)2)1-4OH。
Among the compounds represented by the above formula (I-2), a further preferred compound is compound 3, which has the following structure:
the invention also provides a pyrimidine compound, the structure of which is shown as the following formula (II):
wherein X is-Br or Cl; r1is-NO2-Br, -COOH or-OCH3(ii) a n is an integer of 1 to 3; r8、R9And R10Are identical or different-H, -OCH3、-COOMe、-Br、-COOEt、-CH2COOMe、-NO2Or (CH)2)1-4OH。
In still another preferred embodiment of the present invention, X in the formula (II) is Br, R1is-COOH or-OCH, R8、R9And R10Are identical or different-H, -OCH3-Br or-COOEt.
Among the compounds represented by the above formula (II) of the present invention, the following compounds are further preferred:
compound 4, structure as follows:
compound 6, structure is as follows:
compound 7, structure as follows:
compound 8, structure as follows:
compound 9, structure as follows:
compound 11, structure as follows:
compound 12, structure as follows:
compound 13, structure as follows:
compound 14, structure as follows:
the invention also provides a preparation method of the compound.
Wherein the preparation method of the compound shown in the formula (I-1) comprises the following steps:
as shown in the following synthetic scheme, 10mmol of 2-chloro-7H-pyrrolo [2,3-d ]]And pyrimidine, 30mmol of anhydrous potassium phosphate, a small amount of CuI and trans-1, 2-cyclohexanediamine and 10ml of dioxane were added to a three-necked flask, and then 12mmol of Compound A were slowly added thereto at 110 ℃ and N2Stirring and refluxing for 5h under protection. Detecting the reaction with TLC plate, filtering the solid after the reaction is finished, washing the solid with a small amount of dioxane for 3 times, and adding saturated NaHCO3The solution, organic phase was washed with 3 × 10mL of saturated brine, dried over anhydrous MgSO4, filtered, spin dried dioxane, washed with developing solvent ethyl acetate: petroleum ether =1: 10-1: passing through silica gel column to obtain light white solid B. And adding the compound B, the compound C, concentrated hydrochloric acid and n-butyl alcohol into the digestion tank, sealing, and reacting at 140 ℃ for 24 hours. Pouring the reaction solution into a 100ml flask, adding 50ml of water, adjusting the pH to be 6-7 with saturated sodium carbonate solution, extracting with 3 × 50ml of ethyl acetate, collecting the organic phase, spin-drying the ethyl acetate to obtain a solid, washing the solid with water for 3 times, washing the solid with n-hexane for 3 times, filtering, collecting a filter cake, and developing with ethyl acetate: petroleum ether =1: 10-1: passing through silica gel column to obtain compound D. Namely, the compound represented by the formula (I-1) of the present invention. The synthetic route is as follows, wherein each substituent of R1-R5 is defined as the same as the above:
the process for producing the compound represented by the formula (I-2) of the present invention can be carried out by referring to the process for producing the compound represented by the formula (I-1) described above.
The preparation method of the compound shown in the formula (II) comprises the following steps:
as shown in the following scheme, 10mmol of B ', 12mmol of Compound A', 30mmol of potassium carbonate, 25ml of isopropanol and 25ml of water were stirred at room temperature overnight. Detecting the reaction by using a thin-layer chromatography plate, filtering the solid after the reaction is finished, washing the solid for 3 times by using a small amount of ethanol, collecting the solid, putting the solid into a beaker, adding 25ml of water, stirring at a constant temperature, and filtering to obtain a compound E. Dissolving 10mmol of the compound E in dioxane, adding the compound C, 15mmol of p-toluenesulfonic acid and a small amount of DMF, and stirring at 100 ℃ for reaction overnight. The reaction was checked on a thin layer chromatography plate, the reaction was complete, the solid was filtered and washed 3 times with a small amount of ethyl acetate to give a grey solid. Adding 20ml of water, extracting by using 3X 10ml of ethyl acetate, collecting an organic phase, and spin-drying to obtain a compound F, namely the compound shown as the formula (II) in the invention. The synthetic route is as follows, wherein each substituent is defined as the same as the former:
all the raw material compounds and preparations used in the preparation method are the existing products.
The invention also provides pharmaceutically acceptable salts of the pyrimidine compounds.
The salt is an addition salt formed by the pyrimidine compound and acid, and the acid can be hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid or arginine.
The addition salts of the compounds of the present invention can be prepared by using the above-mentioned various acids and the compounds of the present invention as raw materials and by conventional methods.
The addition salt formed by the pyrimidine compound and the acid can be used for preparing medicines with different dosage forms according to different physicochemical properties.
The invention also provides application of the compound in preparing a tumor cell inhibitor.
Preliminary cytotoxicity experiments and radionuclide labeling experiments show that the compound has obvious FAK inhibition effect and good inhibition effect on tumor cells; the result of a biodistribution experiment shows that the compound can effectively enter tumor cells and can be well retained.
The tumor cells take liver cancer cells as an example, and among 14 compounds synthesized at present, 5 compounds have been tested to have the inhibition effect on the growth of HepG2 liver cancer cells. 4 compounds have a better cytotoxic effect: the compound No. 1 has a strong growth inhibition effect on HepG2 liver cancer cells, the growth of more than 80% of the cells can be inhibited when the concentration is 1umol, and the experimental result is wrong probably caused by operation and other reasons due to the data of 5umol concentration in a figure; the compound No. 3 has stronger growth inhibition effect on HepG2 liver cancer cells only under the concentration of 10umol, and has no obvious effect on other concentrations; the compound No. 5 has obvious inhibition effect on HepG2 liver cancer cells in 2umol, can inhibit the growth of about 40 percent of cells, and can inhibit the growth of more than 90 percent of cells in 5 umol; the compound No. 13 has growth inhibition effect on cells within the range of 5-50umol, and has good dose-effect relationship.
Drawings
FIG. 1 shows the effect of different concentrations of Compound 1 in the present invention on the growth of HepG2 liver cancer cells.
FIG. 2 shows the effect of different concentrations of Compound 3 in the present invention on the growth of HepG2 liver cancer cells.
FIG. 3 shows the effect of different concentrations of Compound 5 on the growth of HepG2 liver cancer cells.
FIG. 4 shows the effect of different concentrations of Compound 13 on the growth of HepG2 liver cancer cells.
Detailed Description
Example 1
The synthesis of compound 1, the synthetic route is as follows:
the method comprises the following specific steps:
1.5g (10mmol) 2-chloro-7H-pyrrolo [2,3-d]And pyrimidine, 3g of potassium phosphate anhydrous, a small amount of CuI and trans-1, 2-cyclohexanediamine with 10ml of dioxane were added to a three-necked flask, and then 3.2g (12mmol) of 3-bromobenzone were slowly added at 110 ℃ under N2Stirring and refluxing for 5h under protection. Detecting the reaction with TLC plate, filtering the solid after the reaction is finished, washing the solid with a small amount of dioxane for 3 times, and adding saturated NaHCO3The solution, organic phase was washed with 3 × 10mL of saturated brine, dried over anhydrous MgSO4, filtered, spin dried dioxane, washed with developing solvent ethyl acetate: petroleum ether =1: 10-1: passing through silica gel column 2 to obtain light white solid A with yield of 75.5%. The compound A300mg, parabromoaniline 600mg, concentrated hydrochloric acid 3ml and n-butanol 4ml are added into a digestion tank, and after sealing, the reaction is carried out for 24 hours at 140 ℃. Pouring the reaction solution into a 100ml flask, adding 50ml of water, adjusting the pH to be 6-7 with saturated sodium carbonate solution, extracting with 3 × 50ml of ethyl acetate, collecting the organic phase, spin-drying the ethyl acetate to obtain a solid, washing the solid with water for 3 times, washing the solid with n-hexane for 3 times, filtering, collecting a filter cake, and developing with ethyl acetate: petroleum ether =1: 10-1: 1, passing through a silica gel column to obtain 130mg of solid, namely the compound 1 of the invention. Nuclear magnetic spectrum: 6.7785(s,1H), 7.4534(d,2H), 7.6146(t,2H), 7.7279(t,1H), 7.8269(m,5H), 7.9714(d,2H), 8.1716(d,2H), 8.8671(s,1H), 9.7563(s, 1H).
Example 2
The synthesis of compound 2, the synthetic route is as follows:
the specific synthesis steps comprise:
adding 3.5g of 2, 5-dibromobenzoic acid and 20ml of methanol into a 100ml single-neck bottle, slowly adding 10ml of concentrated sulfuric acid under stirring at room temperature, stirring for 10 minutes after the concentrated sulfuric acid is added, starting heating and refluxing, reacting for 8 hours, detecting the reaction by using a thin layer chromatography plate, after the reaction is finished, spin-drying excessive methanol, adding 50ml of water, and filtering to obtain a white solid, wherein the yield is more than 85%. 1.5g (10mmol) 2-chloro-7H-pyrrolo [2,3-d]And pyrimidine, 3g of anhydrous potassium phosphate, a small amount of CuI and trans-1, 2-cyclohexanediamine were added to a three-necked flask with 10ml of dioxane, 3.0g of 2, 5-dibromobenzoic acid methyl ester was added, and stirring was carried out at 110 ℃ under reflux for 6 hours. Detecting the reaction with TLC plate, filtering the solid after the reaction is finished, washing the solid with a small amount of dioxane for 3 times, and adding saturated NaHCO3The solution, organic phase was washed with 3 × 10mL of saturated brine, dried over anhydrous MgSO4, filtered, spin dried dioxane, washed with developing solvent ethyl acetate: petroleum ether =1: 10-1: 1, passing through a silica gel column to finally obtain a light white solid with the yield of 75.5 percent. The digestion tank was charged with 300mg g of Compound B, 500mg of anisidine, 3ml of concentrated hydrochloric acid and 4ml of n-butanol, and after sealing, the reaction was carried out overnight at 140 ℃. Pouring the reaction solution into a 100ml flask, adding 50ml of water, adjusting the pH to be 6-7 by using a saturated sodium carbonate solution, extracting by using 3 x 50ml of ethyl acetate, collecting an organic phase, carrying out spin-drying on the ethyl acetate to obtain a solid, washing the solid by using water for 3 times, washing the solid by using normal hexane for 3 times, filtering, collecting a filter cake, and using a developing agent of ethyl acetate: petroleum ether =1: 10-1: 1, passing through a silica gel column, and finally isolating to obtain 79mg of a product, namely the compound 2 of the invention. Nuclear magnetic spectrum: 3.812(s,3H), 3.970(s,3H), 6.675(t,1H), 6.93(q,2H), 7.261(d,1H), 7.378(m,2H), 7.585(d,1H), 8.167(q,2H), 8.272(t,1H), 8.376(t,1H), 8.600(m, 1H).
Example 3
The synthesis of compound 3, the synthetic route is as follows:
the specific synthesis steps comprise:
1.5g (10mmol) 2-chloro-7H-pyrrolo [2,3-d]And pyrimidine, 3g of anhydrous potassium phosphate, a small amount of CuI and trans-1, 2-cyclohexanediamine were added to a three-necked flask with 10ml of dioxane, and then 4.5g of 2, 5-dibromopyridine was slowly added thereto, and stirred at 110 ℃ under reflux for 5 hours. Detecting the reaction with TLC plate, filtering the solid after the reaction is finished, washing the solid with a small amount of dioxane for 3 times, and adding saturated NaHCO3The solution, organic phase was washed with 3 × 10mL of saturated brine, dried over anhydrous MgSO4, filtered, spin dried dioxane, washed with developing solvent ethyl acetate: petroleum ether =1: 10-1: passing through silica gel column to obtain light white solid 950 mg. The digestion tank was charged with Compound C300mg, anisidine 600mg, concentrated hydrochloric acid 3ml, and n-butanol 4ml, sealed, and reacted at 140 ℃ overnight. Pouring the reaction solution into a 100ml flask, adding 50ml of water, adjusting the pH to be 6-7 by using a saturated sodium carbonate solution, extracting by using 3 x 50ml of ethyl acetate, collecting an organic phase, carrying out spin-drying on the ethyl acetate to obtain a solid, washing the solid by using water for 3 times, washing the solid by using normal hexane for 3 times, filtering, collecting a filter cake, and using a developing agent of ethyl acetate: petroleum ether =1: 10-1: 1, passing through a silica gel column to obtain 70mg of solid, namely the compound 3 of the invention. Nuclear magnetic spectrum: 6.617(d,4H), 6.944(t,2H), 7.528(d,2H), 7.903(d,1H), 8.115(s,3H), 8.528(d,2H), 8.565(s,1H), 8.622(s, 1H).
Example 4
The synthesis of compound 4 is as follows:
the specific synthesis steps comprise:
3g (22mmol) of 5-bromo-2, 4-dichloropyrimidine, 4.0g of aniline, 4.0g of potassium carbonate, 30ml of water and 30ml of isopropanol were placed in a 100ml three-necked flask and stirred at room temperature overnight. Detecting the reaction by using a thin-layer chromatography plate, filtering the solid after the reaction is finished, washing the solid for 3 times by using a small amount of ethanol, collecting the solid, putting the solid into a 100ml beaker, adding 50ml of water, stirring at a warm temperature, filtering, finally obtaining a white solid, and drying the solid, wherein the yield is more than 90%. Dissolve light 1g of yellow solid with 50ml of dioxane, add 2.5g of 3,4, 5-trimethoxyaniline, 1.5g of p-toluenesulfonic acid, a small amount of DMF, and stir at 100 ℃ for reaction overnight. The reaction was checked on a thin layer chromatography plate, the reaction was complete, the solid was filtered and washed 3 times with a small amount of ethyl acetate. Spin-dry to give an off-white solid, add 30ml of water and extract with 3X 10ml of ethyl acetate, collect the organic phase and spin-dry to give an off-white solid. With developing solvent ethyl acetate: petroleum ether =1: passing through silica gel column 2 to obtain off-white solid, compound 4 of the present invention, in 67.7% yield. Nuclear magnetic spectrum: 1.433(t,3H), 3.758(s,6H), 3.849(s,3H), 4.445(m,2H), 6.776(s,2H), 7.084(t,1H), 7.262(d,1H), 7.436(t,1H), 8.071(d,1H), 8.207(s,1H), 8.743(d,1H), and 8.764(s, 1H).
Example 5
The synthesis of compound 5, the synthetic route is as follows:
the specific synthesis steps comprise:
1) 3g (22mmol) of 5-bromo-2, 4-dichloropyrimidine, 4.5g (35 mmol) of anisidine, 4.0g of potassium carbonate, 30ml of water and 30ml of isopropanol were put in a 100ml three-necked flask and stirred at room temperature overnight. Detecting the reaction by using a thin-layer chromatography plate, filtering the solid after the reaction is finished, washing the solid for 3 times by using a small amount of ethanol, collecting the solid, putting the solid into a 100ml beaker, adding 50ml of water, stirring at a warm temperature, filtering, finally obtaining a light yellow solid, drying the solid, and ensuring the yield to be more than 90%.
2) 1g of the pale yellow solid obtained in step 1) was dissolved in 50ml of dioxane, and 2.5g of 3,4, 5-trimethoxyaniline, 1.5g of p-toluenesulfonic acid and a small amount of DMF were added thereto, and the mixture was stirred at 100 ℃ for reaction overnight. The reaction was checked on a thin layer chromatography plate, the reaction was complete, the solid was filtered and washed 3 times with a small amount of ethyl acetate. Spin-dry to give a pale yellow solid, add 30ml of water and extract with 3X 10ml of ethyl acetate, collect the organic phase and spin-dry to give a pale yellow solid. With developing solvent ethyl acetate: petroleum ether =1: passing through silica gel column 2 to obtain off-white solid, compound 5 of the present invention, in 56.7% yield. Nuclear magnetic spectrum: 3.658(s,5H), 3.813(5H, m), 6.728(s,2H), 6.884(d,2H), 7.212(s,1H), 7.409(d,2H), and 8.053(s, 1H).
Example 6
The synthesis of compound 6, the synthetic route is as follows:
the specific synthesis steps comprise:
1.5g of the pale yellow solid obtained in step 1) of example 5 was dissolved in 50ml of dioxane, and 2.1g of 3, 4-dimethoxyaniline, 1.5g of p-toluenesulfonic acid, a small amount of DMF, and the reaction was stirred at 100 ℃ overnight. The reaction was checked on a thin layer chromatography plate, after the reaction was complete, the solid was filtered and washed 3 times with a small amount of ethyl acetate to give a dark red solid. Passing through silica gel column with developing agent dichloromethane finally gives light white solid, i.e. compound 6 of the present invention, with 85.2% yield. Nuclear magnetic spectrum: 3.600(s,3H), 3.77(s,3H), 6.70(s,3H), 6.81(d,1H), 6.91(t,3H), 7.02(s,1H), 7.08(d,1H), 7.19(s,1H), 7.36(t,2H), 8.02(s, 1H).
Example 7
The synthesis of compound 7, the synthetic route is as follows:
the specific synthesis steps comprise:
1.5g of the pale yellow solid obtained in step 1) of example 5 was dissolved in 50ml of dioxane, and 1.5g of anisidine, 1.5g of p-toluenesulfonic acid and a small amount of DMF were added thereto, and the mixture was stirred at 100 ℃ for reaction overnight. The reaction was checked on a thin layer chromatography plate, after the reaction was complete, the solid was filtered and washed 3 times with a small amount of ethyl acetate to give a dark red solid. 20ml of water are added and extracted with 3X 10ml of ethyl acetate, the organic phase is collected and dried by spinning to give a pale red solid. With developing solvent ethyl acetate: petroleum ether =1: 2, passing through a silica gel column to finally obtain a milky white solid, namely the compound 7 of the invention, with the yield of 78.1 percent. Nuclear magnetic spectrum: 3.816(q,5H), 6.811(t,2H), 6.896(q,2H), 7.114(s,1H), 7.368(q,2H), 7.425(m,2H), and 8.025(s, 1H).
Example 8
The synthesis of compound 8, the synthetic route is as follows:
the specific synthesis steps comprise:
2.5g of anthranilic acid was dissolved in 50ml of dioxane, and 1g of pale yellow solid obtained in step 1) of example 5, 1.5g of p-toluenesulfonic acid and a small amount of DMF were added thereto, and the mixture was stirred at 100 ℃ for reaction overnight. The reaction was checked on a thin layer chromatography plate, the reaction was complete, the solid was filtered and washed 3 times with a small amount of ethyl acetate to give a grey solid. 20ml of water are added and extracted with 3X 10ml of ethyl acetate, the organic phase is collected and dried by spinning to give a pale yellow solid, compound 8 according to the invention, in 71.5% yield. Nuclear magnetic spectrum: 3.771(s,3H), 6.922(s,2H), 7.214(q,2H), 7.466(q,3H), 7.933(s,1H), 8.048(s,1H), 8.199(s,1H), 8.542(s,1H), 9.438(s, 1H).
Example 9
The synthesis of compound 9, the synthetic route is as follows:
the specific synthesis steps comprise:
1) 16g of ethyl m-aminobenzoate was added with 5-bromo-2, 4-dichloropyrimidine (15 g), potassium carbonate (30 g), isopropanol (80 ml) and water (80 ml), and the mixture was stirred at room temperature overnight. Detecting the reaction by using a thin-layer chromatography plate, filtering the solid after the reaction is finished, washing the solid for 3 times by using a small amount of ethanol, collecting the solid, putting the solid into a 250ml beaker, adding 150ml of water, stirring at a constant temperature, filtering, finally obtaining a light yellow solid, drying the solid, and ensuring the yield to be more than 90%.
2) 2g of the pale yellow solid obtained in step 1) was dissolved in 50ml of dioxane, and 3.0g of anisidine, 1.5g of p-toluenesulfonic acid and a small amount of DMF were added thereto, and the mixture was stirred at 100 ℃ for reaction overnight. The reaction was checked on a thin layer chromatography plate, the reaction was complete, the solid was filtered and washed 3 times with a small amount of ethyl acetate to give a grey solid. 20ml of water are added and extracted with 3X 10ml of ethyl acetate, the organic phase is collected and dried by spinning to give a pale grey solid, compound 9 according to the invention, in 81.5% yield. Nuclear magnetic spectrum: 1.37(s,3H), 3.79(s,3H), 4.37(s,2H), 6.81(s,2H), 7.26(t,1H), 7.39(q,3H), 7.83(s,1H), 7.90(s,1H), 7.91(s,1H), 7.92(s, 1H).
Example 10
The synthesis of compound 10, the synthetic route is as follows:
the specific synthesis steps comprise:
2g of the pale yellow solid obtained in step 1) of example 9 was dissolved in 50ml of dioxane, and 3.5g of 3, 4-dimethoxyaniline, 1.5g of p-toluenesulfonic acid, a small amount of DMF, and the reaction was stirred at 100 ℃ overnight. The reaction was checked on a thin layer chromatography plate, the reaction was complete, the solid was filtered and washed 3 times with a small amount of ethyl acetate to give a dark grey solid. The solid was washed 3 times with a small amount of ethyl acetate, 20ml of water was added and extracted with 3X 10ml of ethyl acetate, the organic phase was collected and dried by spinning to give a pale grey solid, compound 10 of the invention, in 83.6% yield. Nuclear magnetic spectrum: 1.379(t,3H), 3.704(s,3H), 3.868(s,3H), 4.368(t,2H), 6.781(m,1H), 6.986(s,1H), 7.045(q,1H), 7.261(s,1H), 7.398(q,1H), 7.823(t,1H), 7.922(s,1H), 7.945(s,1H), 8.113(s, 1H).
Example 11
The synthesis of compound 11, the synthetic route is as follows:
the specific synthesis steps comprise:
2g of the pale yellow solid obtained in step 1) of example 9 was dissolved in 50ml of dioxane, and 3, 4-dimethoxyaniline (2.5 g), p-toluenesulfonic acid (1.5 g), a small amount of DMF (N-dimethylformamide) and stirred at 100 ℃ overnight. The reaction was checked on a thin layer chromatography plate, after the reaction was complete, the solid was filtered and washed 3 times with a small amount of ethyl acetate to give a pale yellow solid. And the solid was washed 3 times with a small amount of ethyl acetate, 20ml of water was added, and extracted with 3 × 10ml of ethyl acetate, and the organic phase was collected and spin-dried to obtain a pale yellow solid, compound 11 of the present invention, in 65.6% yield. Nuclear magnetic spectrum: 1.372(s,3H), 3.668(s,5H), 3.824(d,3H), 4.365(t,2H), 6.715(s,2H), 7.395(t,3H), 7.874(q,1H), 7.944(d,1H), 8.029(s,1H), 8.095(s, 1H).
Example 12
The synthesis of compound 12, the synthetic route is as follows:
the specific synthesis steps comprise:
1) adding 15g of p-aminobenzoic acid and 100g of absolute ethyl alcohol into a 250ml three-neck flask, stirring at room temperature, slowly dropwise adding 16g of concentrated sulfuric acid, stirring for 10min after dropwise adding of the concentrated sulfuric acid, heating to reflux, reacting overnight, detecting the reaction by using a thin-layer chromatography plate, and after the reaction is finished, clarifying the reaction solution from turbidity. Removing excessive methanol under reduced pressure, adding ethyl acetate and saturated sodium bicarbonate water solution, adjusting pH to 8-9, separating to obtain organic phase, adding small amount of ethyl acetate into water phase for back extraction, combining organic phases, adding anhydrous magnesium sulfate for drying, filtering, and spin drying to obtain white solid ethyl p-aminobenzoate.
2) 16g of ethyl p-aminobenzoate obtained in step 1), 15g of 5-bromo-2, 4-dichloropyrimidine, 30g of potassium carbonate, 80ml of isopropanol and 80ml of water were added, and the mixture was stirred at room temperature overnight. Detecting the reaction by using a thin-layer chromatography plate, filtering the solid after the reaction is finished, washing the solid for 3 times by using a small amount of ethanol, collecting the solid, putting the solid into a 250ml beaker, adding 150ml of water, stirring at a constant temperature, filtering, finally obtaining a light yellow solid, drying the solid, and ensuring the yield to be more than 90%.
3) Taking 2.1g of the light yellow solid obtained in the step 2), dissolving in 50ml of dioxane, adding 2.5g of 3,4, 5-trimethoxyaniline, 1.5g of p-toluenesulfonic acid and a small amount of DMF, and stirring at 100 ℃ for reacting overnight. The reaction was checked on a thin layer chromatography plate, the reaction was complete, the solid was filtered and washed 3 times with a small amount of ethyl acetate to give a grey solid. 20ml of water are added and the mixture is extracted with 3X 10ml of ethyl acetate, the organic phase is collected and dried by spinning to give a pale white solid, compound 12 according to the invention, in 62.4% yield. Nuclear magnetic spectrum: 1.318(s,3H), 3.575(s,4H), 4.290(d,2H), 6.969(t,2H), 7.870(s,4H), 8.310(s,1H), 8.871(s,1H), 9.300(s, 1H).
Example 13
The synthesis of compound 13, the synthetic route is as follows:
the specific synthesis steps comprise:
1) 1.5g (22mmol) of 5-bromo-2, 4-dichloropyrimidine, 2g (35 mmol) of m-bromoaniline, 2g of potassium carbonate, 20ml of water and 20ml of isopropanol were placed in a 100ml three-necked flask and stirred at room temperature overnight. Detecting the reaction by using a TLC plate, filtering the solid after the reaction is finished, washing the solid for 3 times by using a small amount of ethanol, collecting the solid, putting the solid into a 100ml beaker, adding 50ml of water, stirring at a warm temperature, filtering, finally obtaining light yellow solid, drying the solid, and ensuring the yield to be more than 90%.
2) 1g of the pale yellow solid obtained in step 1) was dissolved in 50ml of dioxane, and 1.8g of anisidine, 1.5g of p-toluenesulfonic acid and a small amount of DMF were added thereto, and the mixture was stirred at 100 ℃ for reaction overnight. The reaction was checked on a thin layer chromatography plate, the reaction was complete, the solid was filtered and washed 3 times with a small amount of ethyl acetate. Spin-dry to give a yellow solid, add 30ml of water and extract with 3X 10ml of ethyl acetate, collect the organic phase and spin-dry to give a yellow solid. With developing solvent ethyl acetate: petroleum ether =1: passing through silica gel column 2 to obtain light yellow solid, i.e. the compound 13 of the invention, with the yield of 45.5%. Nuclear magnetic spectrum: 3.824(s,3H), 6.874(d,2H), 7.138(t,1H), 7.260(m,1H), 7.374(s,2H), 7.436(t,4H), and 8.107(d, 1H).
Example 14
The synthesis of compound 14, the synthetic route is as follows:
the specific synthesis steps comprise:
1g of the pale yellow solid obtained in step 1) of example 13 was dissolved in 50ml of dioxane, and 3,4, 5-trimethoxyaniline, 1g of p-toluenesulfonic acid, a small amount of DMF, and the mixture was stirred at 50 ℃ overnight. The reaction was checked on a thin layer chromatography plate, the reaction was complete, the solid was filtered and washed 3 times with a small amount of ethyl acetate. Spin-dry to give a dark yellow solid, add 20ml of water and extract with 3X 10ml of ethyl acetate, collect the organic phase and spin-dry to give a yellow solid. With developing solvent ethyl acetate: petroleum ether =1: 2, passing through a silica gel column to finally obtain a yellow solid, namely the compound 14 of the invention, with the yield of 68.5 percent. Nuclear magnetic spectrum: 3.655(s,3H), 3,767(d,3H), 6.665(d,2H), 7.192(s,1H), 7.383(s,1H), 8.061(s, 1H).
Example 15
The hydrochloride of the compound 1 is synthesized by the following steps: 10mmol of the compound 1 prepared in example 1 was dissolved in 10ml of tetrahydrofuran, dried hydrogen chloride was introduced, reaction was carried out at room temperature for 2h, a white solid was precipitated, and recrystallization was carried out with 20ml of diethyl ether to obtain the pure hydrochloride of the compound 1. Nuclear magnetic spectrum data: 6.7785(s,1H);7.4534(d,2H);7.6146(t,2H);7.7279(t,1H);7.8269(m,5H);7.9714(d,2H);8.1716(d,2H);8.8671(s,1H);9.7563(s, 1H).
Example 16
The sulfate of compound 1 is synthesized by the following steps: dissolving 10mmol of the compound 1 prepared in example 1 in 10ml of ethanol, adding 10mmol of sulfuric acid into the solution, heating and refluxing at 100 ℃, slowly cooling to room temperature, keeping for 1-2h from 75 ℃ to room temperature until the solution is clear, and precipitating white solid, namely sulfate of the compound 1, which is recorded as compound 16, and nuclear magnetic spectrum data: 6.7785(s,1H);7.4534(d,2H);7.6146(t,2H);7.7279(t,1H);7.8269(m,5H);7.9714(d,2H);8.1716(d,2H);8.8671(s,1H);9.7563(s, 1H).
Example 17
Hydrochloride of compound 2, the synthesis procedure is as follows: 10mmol of the compound 2 prepared in example 2 was dissolved in 10ml of tetrahydrofuran, dried hydrogen chloride was introduced, reaction was carried out at room temperature for 2h, a white solid was precipitated, and recrystallization was carried out with 20ml of diethyl ether to obtain the pure hydrochloride of the compound 2.
Example 18
The sulfate of compound 2 is synthesized by the following steps: dissolving 10mmol of the compound 2 prepared in example 2 in 15ml of ethanol, adding 10mmol of sulfuric acid into the solution, heating and refluxing at 100 ℃, slowly cooling to room temperature, maintaining for 1-1.5h from 75 ℃ to room temperature until the solution is clear, and precipitating white solid which is the sulfate of the compound 2.
Cytotoxicity test
The experimental method comprises the following steps:
HepG2 cells which are in good growth state and in logarithmic growth phase are taken and paved in a 96-well plate and divided into a PBS negative control group and an additive group. Wherein the medicine adding group comprises (0.1,0.2,0.5,1,2,5,10,20,50,100,200,500umol/L)12 different dosage groups, and each group comprises 4 compound holes. Giving an experimental dry prognosis, at a volume fraction of 5% CO2Continuously culturing for 24h in a cell culture box with constant humidity at 37 ℃, discarding old culture solution, adding 100 mu l of sterile PBS and 10 mu l of CCK-8 reagent into each hole, slightly shaking for 10min, placing in an incubator with 37 ℃ for continuously culturing for 4h, then discarding culture medium, observing the growth state of cells under a microscope, finally detecting the ultraviolet absorbance value of each hole at 450nm by using an enzyme-labeling instrument, and detecting the change of cell viability after an intervention factor is given. Cell viability was calculated according to the formula: cell viability (T/C%) = (stem cell group OD/non-stem cell group OD) × 100.
Summary of experimental results:
among 14 compounds synthesized by the present invention, 5 compounds have been tested to have inhibition effect on the growth of HepG2 liver cancer cells, and 4 compounds have better cytotoxicity effect: the compound No. 1 has a strong growth inhibition effect on HepG2 liver cancer cells, can inhibit the growth of more than 80% of the cells at the concentration of 1umol, and can cause error experimental results due to operation and other reasons (shown in figure 1) when the concentration of 5umol is used as data; the compound No. 3 has stronger growth inhibition effect on HepG2 liver cancer cells under the concentration of 10umol (shown in figure 2); the compound No. 5 has obvious inhibition effect on HepG2 liver cancer cells in 2umol, can inhibit the growth of about 40 percent of cells, and can inhibit the growth of more than 90 percent of cells in 5umol (shown in figure 3); the compound No. 13 has growth inhibition effect on cells within the range of 5-50umol, and has good dose-effect relationship (shown in figure 4).
Claims (10)
1. A pyrimidine compound has a structure shown in the following formula (I):
wherein R is substituted phenyl or substituted pyridyl; r1is-NO2-Br, -COOH or-OCH3(ii) a n is an integer of 1 to 3.
2. A pyrimidine compound according to claim 1, wherein R in formula (I) is a substituted phenyl group, n =1, and has the structure shown in formula (I-1):
wherein R is2、R3、R4And R5Are identical or different-H, -COOMe, Br, -COPh or (CH)2)1-4OH。
3. A pyrimidine compound according to claim 2, wherein the compound of formula (I-1) has the following structure, denoted as compound 1:
4. a pyrimidine compound according to claim 2, wherein the compound of formula (I-1) has the following structure, denoted as compound 2:
5. a pyrimidine compound as claimed in claim 1, wherein R in formula (I) is a substituted pyridyl group, n =1, and has the structure shown in formula (I-2):
wherein R is6And R7Taking same or different-H, -COOMe, -Br, -NO2Or (CH)2)1-4OH。
6. A pyrimidine compound according to claim 5, wherein the compound of formula (I-2) has the following structure, denoted as compound 3:
7. a pyrimidine compound, the structure of which is shown as the following formula (II):
wherein X is-Br or Cl; r1is-NO2-Br, -COOH or-OCH3(ii) a n is an integer of 1 to 3; r8、R9And R10Are identical or different-H, -OCH3、-COOMe、-Br、-COOEt、-CH2COOMe、-NO2Or (CH)2)1-4OH。
8. A pyrimidine compound according to claim 7, wherein X in formula (II) is Br and R is1is-COOH or-OCH, R8、R9And R10Are identical or different-H, -OCH3-Br or-COOEt.
9. A pyrimidine compound according to claim 7, wherein the compound of formula (II) is any one of the following compounds:
compound 4, structure as follows:
compound 5, structure is as follows:
compound 6, structure is as follows:
compound 7, structure as follows:
compound 8, structure as follows:
compound 9, structure as follows:
compound 10, structure as follows:
compound 11, structure as follows:
compound 12, structure as follows:
compound 13, structure as follows:
or,
compound 14, structure as follows:
10. a pyrimidine compound of claim 1 or 7, wherein the acid addition salt is selected from the group consisting of: the acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid or arginine.
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| US11529350B2 (en) | 2019-07-03 | 2022-12-20 | Sumitomo Pharma Oncology, Inc. | Tyrosine kinase non-receptor 1 (TNK1) inhibitors and uses thereof |
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| CN114716385A (en) * | 2022-04-08 | 2022-07-08 | 北京师范大学 | Compound of targeting focal adhesion kinase, preparation method and application |
| CN114716385B (en) * | 2022-04-08 | 2024-03-12 | 北京师范大学 | Compound of targeted focal adhesion kinase, preparation method and application |
| CN114957248A (en) * | 2022-05-09 | 2022-08-30 | 南开大学 | Pyrrolopyrimidine compound, and preparation method, pharmaceutical composition and application thereof |
| CN114957248B (en) * | 2022-05-09 | 2023-12-29 | 南开大学 | Pyrrolo pyrimidine compound and preparation method, pharmaceutical composition and application thereof |
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