Dithiazolinone-containing dihydropyrimidine derivative as well as preparation method and application thereof

Abstract

The invention provides a dihydropyrimidine derivative containing bithiazolinone, the chemical structural formula of the dihydropyrimidine derivative is as shown in formula (I), in the formula (I), substituent R is H, C1-6 alkyl, F, Cl, Br, I, alkoxy, hydroxyl, nitrile group, nitryl, carboxyl, ester group, amino or sulfonic acid group. The bithiazolinone-containing dihydropyrimidine derivative has certain inhibitory activity on tumor cells, the synthesis method is simple, materials are easy to obtain, and the bithiazolinone-containing dihydropyrimidine derivative can be used for preparing antitumor drugs. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a 7-methyl-6-(1-(4-oxothiazol-2-yl)hydrazine)ethyl)-5-aryl-5H-thiazolo[3,2-α]pyrimidin-3(2H)-one derivative, a preparation method thereof, and an application thereof as an anti-tumor drug. Background Art

[0002] Cancer has become the most threatening non-communicable disease to human health and life. Currently, the main methods for treating cancer are radiotherapy and chemotherapy. Therefore, the research and development of anticancer drugs has always been a hot topic for chemists and pharmacists. Finding highly effective, highly selective and low-toxic anticancer drugs is one of the main directions of drug research and development.

[0003] Dihydropyrimidine derivatives are important heterocyclic compounds widely found in nature. They have aroused great interest due to their unique chemical, physiological and pharmacological activities. More and more studies have shown that dihydropyrimidine compounds have biological activities such as anti-tumor, anti-AIDS, anti-inflammatory, analgesic, bactericidal, and anti-hyperglycemic. For example, fluorastrol (a dihydropyrimidine compound containing o-difluorobenzoyl) reported by HYK Kaan et al. has good anti-tumor activity (J. Med. Chem. 2010, 53, 5676-5683), and a dihydropyrimidine derivative containing formamide reported by BNNaidu et al. has good anti-HIV activity (Bioorg. Med. Chem. Lett., 2015, 25, 717-720). In view of the importance of dihydropyrimidine compounds in organic synthesis and drug synthesis, the synthesis and activity research of this type of compounds has aroused great interest.

[0004] Thiazolinone is a class of five-membered heterocyclic compounds containing nitrogen and sulfur atoms. The good biological activity of thiazolinone compounds has been widely used in medicine and pesticides, such as anti-diabetic, anti-inflammatory, bactericidal and anti-tumor activities. S.Cascioferro et al. reported that a thiazolinone compound containing benzothiazole has good antibacterial activity (J.Med.Chem.2020,63,7923-7956). In 2012, D.Havrylyuk et al. reported that Isatin derivatives containing thiazolinone have good antitumor activity. Its GI 50 0.071 μM (inhibits NCI-60 cells) (J.Med.Chem.

[0005] 2012, 55, 8630-8641). Therefore, the design and synthesis of new dihydropyrimidine derivatives containing thiazolinone skeleton for use as anti-tumor drugs has important theoretical and practical significance. Summary of the invention

[0006] The purpose of the present invention is to provide a dihydropyrimidine derivative containing a bisthiazolinone; the purpose of the present invention is also to provide a method for preparing a dihydropyrimidine derivative containing a bisthiazolinone. In addition, the purpose of the present invention is also to provide the use of the above-mentioned dihydropyrimidine derivative containing a bisthiazolinone in the preparation of anti-tumor drugs.

[0007] To achieve the above object, the technical solution adopted by the present invention is: a dihydropyrimidine derivative containing a bis-thiazolinone, the chemical structure of which is shown in formula (I):

[0008]

[0009] In formula (I), the substituent R is H, C 1-6 The invention further comprises an alkyl group, a F group, a Cl group, a Br group, an I group, an alkoxy group, a hydroxy group, a nitrile group, a nitro group, a carboxyl group, an ester group, an amino group or a sulfonic acid group.

[0010] A method for preparing a dihydropyrimidine derivative containing bithiazolinone, the general reaction formula is:

[0011]

[0012] The specific steps are as follows:

[0013] (1) Dissolve thiourea and aminosulfonic acid in anhydrous ethanol. When the temperature of the reaction system rises to 50°C, add acetylacetone dropwise. When the solid in the reaction bottle is completely dissolved, add aromatic aldehyde. After reacting for 10 minutes, raise the temperature of the reaction system to 80°C and reflux for about 10 hours. After the reaction is completed, a large amount of solid precipitates in the reaction solution. Filter while hot, wash the filter residue with hot ethanol, and obtain the intermediate product 4-methyl-6-aryl-5-acetyl-2-mercapto-1,6-dihydropyrimidine 1 by column chromatography.

[0014] (2) The intermediate product 1 and thiosemicarbazide are dissolved in anhydrous ethanol, stirred evenly at room temperature, hydrochloric acid is added dropwise, and the reaction system is heated to 65° C. and refluxed for reaction; the reaction progress is tracked by thin layer chromatography, and after the reaction is completed, a solid is precipitated, which is filtered while hot, and the residue is recrystallized from ethanol to obtain the intermediate product 1-(4-methyl-6-aryl-2-mercapto-1,6-dihydropyrimidin-5-yl) ethyl ketone thiosemicarbazide 2;

[0015] (3) Weigh the intermediate product 2 and triethylamine and dissolve them in ethanol. Then, ethyl bromoacetate is added dropwise, and then the temperature of the reaction system is raised to 80°C. TLC is used to track the progress of the reaction. After the reaction is completed, a large amount of solid is precipitated in the reaction bottle. The solid is filtered while hot, and the residue is recrystallized from ethanol to obtain the target compound 7-methyl-6-(1-(4-oxothiazol-2-yl)hydrazine)ethyl)-5-aryl-5H-thiazolo[3,2-α]pyrimidin-3(2H)-one (i.e., a dihydropyrimidine derivative containing a bithiazolinone).

[0016] Preferably, the acid catalyst in step (1) is aminosulfonic acid, and the reaction temperature is 80°C.

[0017] Preferably, the acid catalyst in step (2) is concentrated hydrochloric acid, and the reflux temperature is 65°C.

[0018] Preferably, the base in step (3) is triethylamine and the reaction temperature is 80°C.

[0019] The application of the dihydropyrimidine derivative containing bithiazolinone in the preparation of anti-tumor drugs.

[0020] The dosage form of the anti-tumor drug is tablet, pill, capsule, injection, suspension or emulsion.

[0021] Beneficial effects of the present invention: Experiments have shown that the 7-methyl-6-(1-(4-oxothiazol-2-yl)hydrazine)ethyl)-5-aryl-5H-thiazolo[3,2-α]pyrimidin-3(2H)-one derivatives of the present invention have good inhibitory activity on tumor cells. They can be used to prepare drugs that inhibit tumor cells. In addition, the synthesis method is simple, the materials are easily available, and the yield is high, which provides a new development approach for solving the problem of anti-tumor drugs. DETAILED DESCRIPTION

[0022] In order to better understand the present invention, an example of preparing 7-methyl-6-(1-(4-oxothiazol-2-yl)hydrazine)ethyl)-5-aryl-5H-thiazolo[3,2-α]pyrimidin-3(2H)-one derivatives (i.e., dihydropyrimidine derivatives containing bithiazolinone) is now given. The present invention includes but is not limited to this preparation method.

[0023] Example 1: Synthesis of 7-methyl-6-(1-(4-oxothiazol-2-yl)hydrazide)ethyl)-5-phenyl-5H-thiazolo[3,2-α]pyrimidin-3(2H)-one (3a).

[0024] 20mmol thiourea and 17mmol aminosulfonic acid were dissolved in 10mL anhydrous ethanol. When the temperature of the reaction system rose to 50°C, 17mmol acetylacetone was added dropwise. When the solid in the reaction bottle was completely dissolved, aromatic aldehyde was added. After 10 minutes of reaction, the temperature of the reaction system was raised to 80°C and refluxed for about 10 hours. After the reaction was completed, a large amount of solid precipitated in the reaction solution, which was filtered while hot, and the filter residue was washed with hot ethanol. The intermediate product 4-methyl-6-phenyl-5-acetyl-2-mercapto-1,6-dihydropyrimidine 1 was obtained by column chromatography.

[0025] 4.0 mmol of intermediate product 1 and 5.0 mmol of thiosemicarbazide were dissolved in anhydrous ethanol, stirred evenly at room temperature, and 1.0 mL of concentrated hydrochloric acid was added dropwise, and the reaction system was heated to 65°C for reflux reaction. The reaction process was tracked by thin layer chromatography. After the reaction was completed, a solid was precipitated and filtered while hot. The residue was recrystallized from ethanol to obtain the intermediate product 1-(4-methyl-6-phenyl-2-mercapto-1,6-dihydropyrimidin-5-yl) ethyl ketone thiosemicarbazide 2

[0026] Weigh 1mmol of intermediate product 2 and 1mmol of triethylamine and dissolve them in 5ml of ethanol, then drop 3.0mmol of ethyl bromoacetate, and then raise the temperature of the reaction system to 80°C. TLC tracks the progress of the reaction. After the reaction is completed, a large amount of solid precipitates in the reaction bottle, which is filtered while hot. The filter residue is recrystallized from ethanol to obtain the target compound 7-methyl-6-(1-(4-oxothiazol-2-yl)hydrazine)ethyl)-5-phenyl-5H-thiazolo[3,2-α]pyrimidin-3(2H)-one. Its chemical structure is shown in formula (3a), and the yield is 68%.

[0027]

[0028] 1 HNMR(500MHz, (CD3)2SO) δ7.44(t,J=7.5Hz,2H),7.35(t,J=7.5Hz,1H),7.21(d,J=7.5Hz,2H),5. 74(s,1H),4.19(d,J=17.0Hz,1H),4.09(d,J=17.0Hz,2H),3.83(s,2H),2.21(s,3H),1.41(s,3H). 13 C NMR (125MHz, CDCl3) δ188.32,179.60,170.87,161.21,155.17,136.70,129. 452,128.54,125.68,81.71,56.53,50.28,38.08,31.64,24.99,14.52; ESIMS m / z:400(M+H) + .

[0029] Example 2: Synthesis of 7-methyl-6-(1-(4-oxothiazol-2-yl)hydrazide)ethyl)-5-(p-chlorophenyl)-5H-thiazolo[3,2-α]pyrimidin-3(2H)-one (3b).

[0030] The preparation method of this example is the same as that of Example 1 except that p-chloroaniline is used instead of aniline. Finally, a light yellow solid 7-methyl-6-(1-(4-oxothiazol-2-yl)hydrazine)ethyl)-5-p-chlorophenyl-5H-thiazolo[3,2-α]pyrimidin-3(2H)-one is obtained. Its chemical structure is shown in Formula (3b). The yield is 65%.

[0031]

[0032] 1 H NMR(500MHz,(CD3)2SO)δ7.51(d,J=8.5Hz,2H),7.26(d,J=8.5Hz,2H),5.74(s,1H),4 .17(d,J=17.0Hz,1H),4.08(d,J=17.0Hz,2H),3.83(s,2H),2.21(s,3H),1.45(s,3H). 13 C NMR (125MHz, CDCl3) δ188.32,179.66,170.85,161.04,155.01,135.88,133. 19,129.43,127.818,81.65,56.25,49.79,38.09,31.69,25.01,14.52;ESIMS m / z:434(M+H) + .

[0033] Example 3: Synthesis of 7-methyl-6-(1-(4-oxothiazol-2-yl)hydrazide)ethyl)-5-p-hydroxyphenyl-5H-thiazolo[3,2-α]pyrimidin-3(2H)-one (3c).

[0034] The preparation method of this embodiment is the same as that of Example 1 except that p-hydroxyaniline is used instead of aniline. Finally, a light yellow solid 7-methyl-6-(1-(4-oxothiazol-2-yl)hydrazine)ethyl)-5-p-hydroxyphenyl-5H-thiazolo[3,2-α]pyrimidin-3(2H)-one is obtained. Its chemical structure is shown in Formula (3c). The yield is 62%.

[0035]

[0036] 1H NMR(500MHz,(CD3)2SO)δ9.59(s,1H),6.98(d,J=8.5Hz,2H),6.78(d,J=8.5Hz,2H),5.63(s,1H),4 .16(d,J=17.0Hz,1H),4.06(d,J=17.0Hz,1H),4.01(s,1H),3.82(s,2H),2.17(s,3H),1.45(s,3H). 13 C NMR (125MHz, CDCl3) δ187.83,179.06,170.28,160.81,156.97,154.69,126. 30,126.10,115.59,81.29,56.24,49.47,37.56,31.10,24.51,13.99;ESIMS m / z:416(M+H) + .

[0037] Example 4: Synthesis of 7-methyl-6-(1-(4-oxothiazol-2-yl)hydrazide)ethyl)-5-p-methoxyphenyl-5H-thiazolo[3,2-α]pyrimidin-3(2H)-one (3d).

[0038] The preparation method of this example is the same as that of Example 1 except that p-methoxyaniline is used instead of aniline. Finally, a light yellow solid 7-methyl-6-(1-(4-oxothiazol-2-yl)hydrazine)ethyl)-5-p-methoxyphenyl-5H-thiazolo[3,2-α]pyrimidin-3(2H)-one is obtained. Its chemical structure is shown in Formula (3d). The yield is 58%.

[0039]

[0040] 1 H NMR(500MHz, (CD3)2SO) δ7.12(d,J=9.0Hz,2H),6.98(d,J=8.5Hz,2H),5.68(s,1H),4.16(d,J=17. 0Hz,1H),4.07(d,J=17.0Hz,1H),4.05(s,1H),3.83(s,2H),3.76(s,3H),2.19(s,3H),1.45(s,3H). 13 C NMR (125MHz, CDCl3) δ188.33,179.58,170.80,161.27,159.29,155.17,128.40, 126.91,114.76,81.75,56.64,55.65,49.89,38.07,31.61,25.07,14.51;ESIMS m / z:430(M+H)+ .

[0041] Example 5: Synthesis of 7-methyl-6-(1-(4-oxothiazol-2-yl)hydrazide)ethyl)-5-m-bromophenyl-5H-thiazolo[3,2-α]pyrimidin-3(2H)-one (3e).

[0042] The preparation method of this example is the same as that of Example 1 except that p-bromoaniline is used instead of aniline. Finally, a brownish yellow solid 7-methyl-6-(1-(4-oxothiazol-2-yl)hydrazine)ethyl)-5-m-bromophenyl-5H-thiazolo[3,2-α]pyrimidin-3(2H)-one is obtained. Its chemical structure is shown in Formula (3e). The yield is 56%.

[0043]

[0044] 1 H NMR(500MHz,(CD3)2SO)δ7.64(s,1H),7.56(d,J=8.0Hz,1H),7.39(t,J=8.0Hz,1H),5.75(s,1H),4 .20(d,J=17.0Hz,1H),4.11(s,1H),4.07(d,J=17.0Hz,1H),3.83(s,2H),2.21(s,3H),1.47(s,3H). 13 C NMR (125MHz, CDCl3) δ188.31,179.67,170.85,160.98,155.07,139.64,131.62,131. 49,129.30,124.34,122.88,81.61,56.24,49.71,38.10,31.68,25.08,14.48; ESIMS m / z:478(M+H) + .

[0045] Example 6: Synthesis of 7-methyl-6-(1-(4-oxothiazol-2-yl)hydrazide)ethyl)-5-p-tolyl-5H-thiazolo[3,2-α]pyrimidin-3(2H)-one (3f).

[0046] The preparation method of this embodiment is the same as that of Example 1 except that p-toluidine is used instead of aniline, and finally a light yellow solid 7-methyl-6-(1-(4-oxothiazol-2-yl)hydrazine)ethyl)-5-p-tolyl-5H-thiazolo[3,2-α]pyrimidin-3(2H)-one is obtained. Its chemical structure is shown in Formula (3f) and the yield is 70%.

[0047]

[0048] 1 H NMR(500MHz, (CD3)2SO) δ7.23(d,J=8.0Hz,2H),7.08(d,J=8.5Hz,2H),5.69(s,1H),4.17(d, J=17.0Hz,1H),4.07(d,J=17.0Hz,2H),3.83(s,2H),2.30(s,3H),2.20(s,3H),1.43(s,3H). 13 C NMR (125MHz, CDCl3) δ188.31,179.58,170.82,161.26,155.15,137.82,133.7 5,129.97,125.5881.72,56.55,50.15,38.07,31.61,25.07,21.06,14.51;ESI MS m / z:414(M+H) + .

[0049] Example 7: Synthesis of 7-methyl-6-(1-(4-oxothiazol-2-yl)hydrazide)ethyl)-5-o-fluorophenyl-5H-thiazolo[3,2-α]pyrimidin-3(2H)-one (3 g).

[0050] The preparation method of this embodiment is the same as that of Example 1 except that o-fluoroaniline is used instead of aniline. Finally, a light yellow solid 7-methyl-6-(1-(4-oxothiazol-2-yl)hydrazine)ethyl)-5-o-fluorophenyl-5H-thiazolo[3,2-α]pyrimidin-3(2H)-one is obtained. Its chemical structure is shown in Formula (3g). The yield is 67%.

[0051]

[0052] 1 H NMR(500MHz,(CD3)2SO)δ7.48-7.43(m,1H),7.36(t,J=8.5Hz,1H),7.27(t,J=7.5Hz,1H),6.96(t,J=7.5Hz,1H), 5.73(s,1H),4.13(d,J=17.0Hz,1H),4.03(d,J=17.0Hz,1H),3.99(s,1H),3.84(s,2H),2.18(s,3H),1.57(s,3H). 13C NMR (125MHz, CDCl3) δ188.32, 179.51, 170.76, 160.22, 159.50 (J = 243.8Hz), 155.01, 131.14 (J = 7.5Hz), 126. 55,125.48,124.38(J=12.5Hz),116.90(J=20.0Hz),81.53,54.55,45.88,38.11,31.55,25.36,14.42; ESIMS m / z:418(M+H) + .

[0053] Example 8: Synthesis of 7-methyl-6-(1-(4-oxothiazol-2-yl)hydrazide)ethyl)-5-p-hydroxyphenyl-5H-thiazolo[3,2-α]pyrimidin-3(2H)-one (3h).

[0054] The preparation method of this embodiment is the same as that of Example 1 except that p-hydroxyaniline is used instead of aniline, and finally a light yellow solid 7-methyl-6-(1-(4-oxothiazol-2-yl)hydrazine)ethyl)-5-p-hydroxyphenyl-5H-thiazolo[3,2-α]pyrimidin-3(2H)-one is obtained. Its chemical structure is shown in Formula (3h) and the yield is 55%.

[0055]

[0056] 1 H NMR(500MHz, (CD3)2SO) δ9.65(s,1H),7.21(t,J=8.0Hz,1H),6.72(d,J=8.0Hz,1H),6.62(d,J=8.0Hz,1H),6.58(s,1 H),5.63(s,1H),4.14(d,J=17.0Hz,1H),4.08(d,J=17.0Hz,1H),4.03(s,1H),3.83(s,2H),2.18(s,3H),1.48(s,3H). 13 C NMR (125MHz, CDCl3) δ187.83,179.06,170.28,160.81,156.97,154.69,126. 30,126.10,115.59,81.29,56.24,49.47,37.56,31.10,24.51,13.99;ESIMS m / z:416(M+H) + .

[0057] Example 9: Synthesis of 7-methyl-6-(1-(4-oxothiazol-2-yl)hydrazide)ethyl)-5-(p-fluorophenyl)-5H-thiazolo[3,2-α]pyrimidin-3(2H)-one (3i).

[0058] The preparation method of this embodiment is the same as that of Example 1 except that p-fluoroaniline is used instead of aniline. Finally, a light yellow solid 7-methyl-6-(1-(4-oxothiazol-2-yl)hydrazine)ethyl)-5-p-fluorophenyl-5H-thiazolo[3,2-α]pyrimidin-3(2H)-one is obtained. Its chemical structure is shown in Formula (3i). The yield is 71%.

[0059]

[0060] 1 H NMR (500MHz, (CD3)2SO) δ7.29-7.27(m,4H),5.74(s,1H),4.17(d,J=17.0Hz,1H),4.09-4.06(m,2H),3.83(s,2H),2.20(s,3H),1.44(s,3H). 13 C NMR (125MHz, CDCl3) δ188.32, 179.65, 170.85, 162.10 (J = 243.8Hz), 161.09, 155.07, 132.90 (J = 2.5Hz), 127 .94(J=7.5Hz),116.32(J=21.25Hz),81.68,56.45,49.76,38.08,31.67,25.04,14.51; ESIMSm / z:418(M+H) + .

[0061] Example 10: Synthesis of 7-methyl-6-(1-(4-oxothiazol-2-yl)hydrazide)ethyl)-5-m-fluorophenyl-5H-thiazolo[3,2-α]pyrimidin-3(2H)-one (3j).

[0062] The preparation method of this embodiment is the same as that of Example 1 except that m-fluoroaniline is used instead of aniline. Finally, a light yellow solid 7-methyl-6-(1-(4-oxothiazol-2-yl)hydrazine)ethyl)-5-m-fluorophenyl-5H-thiazolo[3,2-α]pyrimidin-3(2H)-one is obtained. Its chemical structure is shown in Formula (3j). The yield is 73%.

[0063]

[0064] 1HNMR(500MHz,(CD3)2SO)δ7.51-7.46(m,1H),7.23-7.19(m,2H),6.97(d,J=8.0Hz,1H),5.75(s,1H), 4.22(d,J=17.0Hz,1H),4.13(s,1H),4.07(d,J=17.0Hz,1H),3.83(s,2H),2.21(s,3H),1.45(s,3H). 13 C NMR (125MHz, CDCl3) δ188.32, 179.69, 170.89, 162.91 (J=243.8Hz), 160.99, 155.01, 139.75 (J=7.5Hz), 131.53 (J= 8.75Hz), 121.45, 115.58 (J = 20.0Hz), 113.42 (J = 22.5Hz), 81.66, 56.24, 49.82, 38.09, 31.69, 25.00, 14.48; ESIMS m / z:418(M+H) + .

[0065] Example 11: Synthesis of 7-methyl-6-(1-(4-oxothiazol-2-yl)hydrazide)ethyl)-5-m-chlorophenyl-5H-thiazolo[3,2-α]pyrimidin-3(2H)-one (3k).

[0066] The preparation method of this embodiment is the same as that of Example 1 except that m-chloroaniline is used instead of aniline. Finally, a yellow solid 7-methyl-6-(1-(4-oxothiazol-2-yl)hydrazine)ethyl)-5-m-chlorophenyl-5H-thiazolo[3,2-α]pyrimidin-3(2H)-one is obtained. Its chemical structure is shown in Formula (3k). The yield is 78%.

[0067]

[0068] 1 H NMR(500MHz,(CD3)2SO)δ7.49-7.42(m,3H),7.06(d,J=7.5Hz,1H),5.75(s,1H),4.20(d,J =17.0Hz,1H),4.12(s,1H),4.08(d,J=17.0Hz,2H),3.83(s,2H),2.21(s,3H),1.46(s,3H). 13C NMR (125MHz, CDCl3) δ188.31,179.68,170.87,160.98,155.02,139.43,134.32,131. 27,128.71,126.41,124.01,81.62,56.22,49.78,38.10,31.69,25.07,14.48;ESIMS m / z:434(M+H) + .

[0069] The present invention is further described in detail below through activity test examples.

[0070] The anticancer activity of the synthesized target product 7-methyl-6-(1-(4-oxothiazol-2-yl)hydrazino)ethyl)-5-aryl-5H-thiazolo[3,2-α]pyrimidin-3(2H)-one was tested by MTT method. Human MM231 (breast cancer cells), HepG2 (liver cancer cells) and RKO803 (colon cancer cells) were used as test materials. Collect logarithmic phase cells, digest the cells with trypsin, adjust the cell suspension concentration to 2×104 / mL, dispense into 96-well plates, add 200μL to each well; incubate at 5% CO2, 37℃ for half a day until the cell monolayer covers the bottom of the well, add samples of different concentrations, 100μl to each well, set up 3 parallel wells; incubate at 5% CO2, 37℃ for four days, observe under an inverted microscope; add 20μl MTT solution (5mg / ml, i.e. 0.5% MTT) to each well, continue to culture for 4h, if the drug can react with MTT, centrifuge first and then discard the culture medium, carefully rinse with PBS 2-3 times, then add the culture medium containing MTT, terminate the culture, carefully aspirate the culture medium in the well; add 180μl dimethyl sulfoxide to each well, place on a shaker and oscillate at low speed for 10min to fully dissolve the crystals. Measure the absorbance of each well at a wavelength of 550nm on an enzyme-linked immunosorbent assay. With reference to the control (without sample, the sample was replaced by the solvent in which it was dissolved, and other conditions were exactly the same), the inhibition rate IC50 was calculated. The test results are shown in Table 1.

[0071] Table 1 Antitumor activity of 7-methyl-6-(1-(4-oxothiazol-2-yl)hydrazide)ethyl)-7-methyl-5-aryl-5H-thiazolo[3,2-α]pyrimidin-3(2H)-one derivatives

[0072]

[0073] Note: ND means IC50 value was not measured

[0074] As can be seen from Table 1, 7-methyl-6-(1-(4-oxothiazol-2-yl)hydrazide)ethyl)-7-methyl-5-aryl-5H-thiazolo[3,2-α]pyrimidin-3(2H)-one derivatives have anti-tumor activity, among which compounds 3g, 3h, 3i and 3j have good inhibitory effects on MM231, HepG2 and RKO803 cells, and their IC 50 The values ​​were all lower than the positive control 5-Fu (5-fluorouracil). At the same time, we also selected compounds 3g, 3i and 3j that have good inhibitory effects on MM-231, HepG2 and RKO803 for normal cell (MCF10A) experiments. From Table 1, we can see that their effects on normal cells are weak and they all show good selectivity.

Claims

1. A dihydropyrimidine derivative containing a bisthiazolinone, characterized in that: Its chemical structure is shown in formula (I): In formula (I), the substituent R is H, C 1-6 The invention further comprises an alkyl group, a F group, a Cl group, a Br group, an I group, an alkoxy group, a hydroxy group, a nitrile group, a nitro group, a carboxyl group, an ester group, an amino group or a sulfonic acid group.

2. A method for preparing a dihydropyrimidine derivative containing a bithiazolinone as claimed in claim 1, characterized in that: The steps include: (1) Dissolve thiourea and aminosulfonic acid in anhydrous ethanol, and when the temperature of the reaction system rises to 50° C., add acetylacetone dropwise. When the solid is completely dissolved, add aromatic aldehyde. After sufficient reaction, raise the temperature of the reaction system to 80° C. After the reflux reaction is completed, a large amount of solid precipitates in the reaction solution, which is filtered while hot, and the filter residue is washed with hot ethanol. The intermediate product 4-methyl-6-aryl-5-acetyl-2-mercapto-1,6-dihydropyrimidine 1 is obtained by column chromatography; (2) The intermediate product 1 and thiosemicarbazide are dissolved in anhydrous ethanol, stirred evenly at room temperature, concentrated hydrochloric acid is added dropwise, the reaction system is heated to 65°C for reflux reaction, and the reaction progress is tracked by thin layer chromatography. After the reaction is completed, a solid is precipitated, which is filtered while hot, and the residue is recrystallized from ethanol to obtain the intermediate product 1-(4-methyl-6-aryl-2-mercapto-1,6-dihydropyrimidin-5-yl) ethyl ketone thiosemicarbazide 2; (3) The intermediate product 2 and triethylamine were weighed and dissolved in ethanol, and then ethyl bromoacetate was added dropwise. The temperature of the reaction system was then raised to 80°C. The reaction progress was tracked by TLC. After the reaction was completed, a large amount of solid was precipitated in the reaction bottle. The solid was filtered while hot, and the residue was recrystallized from ethanol to obtain the target compound 7-methyl-6-(1-(4-oxothiazol-2-yl)hydrazine)ethyl)-5-aryl-5H-thiazolo[3,2-α]pyrimidin-3(2H)-one 4, i.e., a dihydropyrimidine derivative containing bithiazolinone.

3. Use of the dihydropyrimidine derivative containing bithiazolinone prepared by the method of claim 2 in the preparation of antitumor drugs.

4. The use of the dihydropyrimidine derivative containing bithiazolinone according to claim 3 in the preparation of anti-tumor drugs, characterized in that The dosage form of the anti-tumor drug is tablet, pill, capsule, injection, suspension or emulsion.

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