Isatin-containing thiazolo [3, 2-a] pyrimidine derivative as well as preparation method and application thereof

Abstract

The invention provides a novel 7-methyl-3-oxo-2-(2-oxoindoline-3-subunit)-6-ethoxyformyl-5-aryl-2, 3-dihydro-5H-thiazolo [3, 2-a] pyrimidine derivative as shown in a formula (I), and in the formula (I), a substituent group R is H, C1-6 alkyl, F, Cl, Br, I, alkoxy, hydroxyl, nitrile group, nitro, carboxyl, amino or sulfonic acid group. The 7-methyl-3-oxo-2-(2-oxoindoline-3-subunit)-6-ethoxyformyl-5-aryl-2, 3-dihydro-5H-thiazolo [3, 2-a] pyrimidine derivative disclosed by the invention has certain inhibitory activity on tumor cells, the synthesis method of the 7-methyl-3-oxo-2-(2-oxoindoline-3-subunit)-6-ethoxyformyl-5-aryl-2, 3-dihydro-5H-thiazolo [3, 2-a] pyrimidine derivative is simple, and the materials are easy to obtain. The compound can be used for preparing anti-tumor drugs. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of drugs. Specifically, it relates to a 7-methyl-3-oxo-2-(2-oxoindoline-3-ylidene)-6-ethoxycarbonyl-5-aryl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine derivative, a preparation method thereof, and an application as an anti-cancer drug. Background Art

[0002] Cancer has become the largest category of non-communicable diseases threatening human health and life. Currently, the main methods for treating cancer are radiotherapy and chemotherapy. Therefore, the research and development of anti-cancer drugs have always been a hot topic of concern for chemists and pharmacologists. Searching for anti-cancer drugs with high efficiency, high selectivity, and low toxicity and side effects is one of the main directions in drug research and development.

[0003] Dihydropyrimidine derivatives are nitrogen-containing heterocyclic compounds widely present in nature and the human body. They have attracted 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-cancer, anti-hypertensive, analgesic, anti-inflammatory, anti-tuberculosis, anti-HIV, and antibacterial. For example, dimethylenastron (a cyclohexanone-fused dihydropyrimidine compound) reported by Gartner M. has good anti-tumor activity (hemBioChem, 2005, 6, 1173 - 1177), and Raltegravir (a dihydropyrimidine compound containing 1,3,4-oxadiazole) reported by Summa, V. et al. has good HIV activity (J. Med. Chem. 2008, 51, 5843). Given the importance of dihydropyrimidine compounds in organic synthesis and drug synthesis, the synthesis and activity research of such compounds have attracted great interest.

[0004] Isatin (also known as: Isatin), an indole compound, is a natural marine antibiotic derived from marine organisms such as lobsters and is essential for their survival. It has various biological activities such as antibacterial, anti-inflammatory, and anti-tumor, and is a good potential drug to be developed. It has now been confirmed that the effective anti-tumor component of Qingdai, which plays a major role in the traditional Chinese medicine Danggui Longhui Pills, is an Isatin derivative, indirubin. This compound has a significant inhibitory effect on chronic myeloid leukemia (CML) and is also a unique type I anti-cancer new drug in China. Therefore, designing and synthesizing new dihydropyrimidine derivatives containing Isatin for anti-tumor drugs has important theoretical and practical significance. Summary of the Invention

[0005] The object of the present invention is to provide a novel 7-methyl-3-oxo-2-(2-oxoindoline-3-ylidene)-6-ethoxycarbonyl-5-aryl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine derivative.

[0006] The object of the present invention also lies in providing a preparation method of a 7-methyl-3-oxo-2-(2-oxoindoline-3-ylidene)-6-ethoxycarbonyl-5-aryl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine derivative.

[0007] The object of the present invention also lies in providing the application of the above-mentioned 7-methyl-3-oxo-2-(2-oxoindoline-3-ylidene)-6-ethoxycarbonyl-5-aryl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine derivative in the preparation of anti-tumor drugs.

[0008] The above object of the present invention is achieved by the following solutions: A 7-methyl-3-oxo-2-(2-oxoindoline-3-ylidene)-6-ethoxycarbonyl-5-aryl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine derivative, whose chemical structural formula is shown as formula I:

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

[0010] A preparation method of a 7-methyl-3-oxo-2-(2-oxoindoline-3-ylidene)-6-ethoxycarbonyl-5-aryl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine derivative, and the general reaction formula is:

[0011] The specific steps are as follows: (1) Take thiourea and sulfamic acid and dissolve them in absolute ethanol. Dropwise add ethyl acetoacetate. After the solid in the reaction flask is completely dissolved, add aromatic aldehyde. The reaction temperature is 80 °C, and reflux for about 10 h. Track the reaction process by TLC. After the reaction is completed, a large amount of white solid precipitates in the reaction solution. Filter while it is hot, and the filter residue is recrystallized with ethanol to obtain the intermediate 4-methyl-6-aryl-5-acetyl-2-mercapto-1,6-dihydropyrimidine 1; (2) Weigh intermediate 1 and dissolve it in tetrahydrofuran, then slowly dropwise add chloroacetyl chloride, and reflux the reaction at 70 °C. A solid gradually precipitates in the reaction flask, and the reaction progress is tracked by TLC. After the reaction is completed, a large amount of yellow solid appears in the reaction solution. Filter by suction, and recrystallize the filter residue with ethanol to obtain intermediate 7-methyl-3-oxo-6-ethoxycarbonyl-5-aryl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine 2; (3) Dissolve intermediate 2 in glacial acetic acid, then add sodium acetate and isatin, and reflux the reaction at 100 °C. The reaction progress is tracked by TLC. After the reaction is completed, a large amount of red solid appears in the reaction solution. Filter by suction, and then recrystallize with ethanol to obtain the target product (Z)-7-methyl-3-oxo-2-(2-oxoindolin-3-ylidene)-6-ethoxycarbonyl-5-aryl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine 3.

[0012] Preferably, the catalyst described in step (1) is sulfamic acid, and the reaction temperature is 80 °C.

[0013] Preferably, the reflux temperature described in step (2) is 70 °C.

[0014] Preferably, the base described in step (3) is sodium acetate, acetic acid is used as the solvent, and the reflux temperature is 100 °C.

[0015] Use of the 7-methyl-3-oxo-2-(2-oxoindolin-3-ylidene)-6-ethoxycarbonyl-5-aryl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine derivative in the preparation of anti-tumor drugs.

[0016] The dosage form of the anti-tumor drug is tablet, pill, capsule, injection, suspension or emulsion.

[0017] Advantages of the present invention: Through experiments, it is proved that the 7-methyl-3-oxo-2-(2-oxoindolin-3-ylidene)-6-ethoxycarbonyl-5-aryl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine derivative of the present invention has good inhibitory activity against tumor cells. It can be used to prepare drugs for inhibiting tumor cells. And the synthesis method is simple, the materials are easy to obtain, and the yield is high, providing a new development route for solving anti-tumor drugs. Detailed implementation manners

[0018] To better understand the present invention, examples for preparing the 7-methyl-3-oxo-2-(2-oxoindolin-3-ylidene)-6-ethoxycarbonyl-5-aryl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine derivative are given below. The present invention includes but is not limited to this preparation method.

[0019] Example 1: Synthesis of (Z)-7-methyl-3-oxo-2-(2-oxoindolin-3-ylidene)-6-ethoxycarbonyl-5-p-tolyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine (3a).

[0020] Weigh 3 mmol of sulfamic acid and 15 mmol of thiourea, dissolve them in 10 mL of absolute ethanol, and then slowly add 12 mmol of ethyl acetoacetate dropwise at 50 °C. After all the solids in the reaction flask are dissolved, add p-tolualdehyde (10 mmol) to it. Reflux the reaction at 80 °C, and monitor the reaction progress by TLC. After the reaction is completely finished, a large amount of white solid appears in the reaction flask. Filter while it is hot, and then recrystallize with ethanol to obtain the intermediate 6-methyl-5-ethoxycarbonyl-4-p-tolyl-2-thioxo-1,2,3,4-tetrahydropyrimidine 1.

[0021] Dissolve 4 mmol of intermediate 1 in 5 mL of tetrahydrofuran, and then slowly add 6 mmol of chloroacetyl chloride dropwise to it. Heat and reflux at 70 °C, and a solid gradually precipitates in the reaction flask. Monitor the reaction progress by TLC. After the reaction is finished, a large amount of yellow solid appears in the reaction solution. Filter by suction, and recrystallize the filter residue with ethanol to obtain the intermediate 7-methyl-3-oxo-6-ethoxycarbonyl-5-p-tolyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine 2.

[0022] Dissolve 1 mmol of intermediate 2 in 5 mL of glacial acetic acid, then add 1.5 mmol of sodium acetate and 1.3 mmol of isatin, and heat and reflux at 100 °C. Monitor the reaction progress by TLC. After the reaction is finished, a large amount of red solid appears in the reaction solution. Filter by suction, and recrystallize the filter residue with ethanol to obtain the red solid target product (Z)-7-methyl-3-oxo-2-(2-oxoindolin-3-ylidene)-6-ethoxycarbonyl-5-p-tolyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine. Yield: 78%.

[0023] 1 HNMR(400 MHz, DMSO-d6)δ11.24(s, 1H), 8.63 (d, J = 7.6 Hz, 1H), 7.35(t, J = 7.6 Hz, 1H), 7.17 (dd, J = 22.8,8 Hz, 4H), 7.02 (t, J = 8 Hz, 1H),6.91 (d, J = 8 Hz, 1H), 6.00 (s, 1H), 4.05 (q, J = 6.8 Hz, 2H), 2.39 (s, 3H),2.23 (s, 3H), 1.14 (t, J = 7.2 Hz, 3H);13 CNMR (100 MHz, DMSO-d6) δ 168.87, 165.30, 164.56, 157.63, 150.82, 144.07, 138.47, 137.45, 133.04, 129.71, 129.10, 128.18, 128.03, 127.16, 122.51, 120.31, 111.02, 110.18, 60.72, 55.21, 22.82, 21.16, 14.36; ESI MS m / z: 460 (M+H) + . Example 2: Synthesis of (Z)-7-methyl-3-oxo-2-(2-oxoindoline-3-ylidene)-6-ethoxycarbonyl-5-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine (3b).

[0024] The preparation method of this example is the same as that of Example 1 except that benzaldehyde is used instead of p-tolualdehyde, and finally the target compound of red solid is obtained, yield: 75%.

[0025] 1 HNMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 8.61 (d, J = 7.6 Hz, 1H), 7.37–7.28 (m, 6H), 7.01 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.03 (s, 1H), 4.09 – 4.01 (m, 2H), 2.39 (s, 3H), 1.13 (t, J = 7.2 Hz, 3H); 13 CNMR (100MHz, DMSO-d6) δ 168.83, 165.25, 164.52, 157.71, 151.02, 144.07, 140.33, 133.02, 129.16, 129.02, 128.98, 128.16, 128.13, 127.21, 122.49, 120.29, 110.99, 110.05, 60.72, 55.47, 22.85, 14.33; ESI MS m / z: 446 (M+H) + . ESI MS m / z: 446 (M+H) + . Example 4: Synthesis of (Z)-7-methyl-3-oxo-2-(2-oxoindolin-3-ylidene)-6-ethoxycarbonyl-5-(3-chlorophenyl)-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine (3c).

[0026] The preparation method of this example is the same as that of Example 1 except that m-chlorobenzaldehyde is used instead of p-tolualdehyde. Finally, the target compound as a red solid is obtained, with a yield of 76%.

[0027] 1 HNMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 8.64 (d, J = 7.9 Hz, 1H), 7.42–7.36 (m, 4H), 7.29 (d, J = 6.8 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 6.05 (s, 1H), 4.14 – 4.00 (m, 2H), 2.41 (s, 3H), 1.14 (t, J = 7.2 Hz, 3H); 13CNMR (100 MHz, DMSO-d6) δ 168.83, 165.06, 164.55, 157.89, 151.57, 144.10, 142.50, 133.46, 133.08, 131.20, 129.05, 128.89, 128.29, 128.16, 127.31, 126.91, 122.52, 120.29, 111.02, 109.35, 60.80, 55.12, 22.97, 14.30. ESI MS m / z: 480 (M+H)+. Example 5: Synthesis of (Z)-7-methyl-3-oxo-2-(2-oxoindolin-3-ylidene)-6-ethoxycarbonyl-5-(2-bromophenyl)-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine (3d).

[0028] The preparation method of this example is the same as that of Example 1 except that o-bromobenzaldehyde is used instead of p-tolualdehyde. Finally, the target compound as a red solid is obtained, with a yield of 58%.

[0029] 1HNMR(400 MHz, DMSO-d6) δ 11.23 (s, 1H), 8.57 (d, J = 8 Hz, 1H), 7.58 (d, J = 8 Hz, 1H), 7.39 – 7.38 (m, 2H), 7.34 (td, J = 7.6, 0.4 Hz, 1H), 7.23 – 7.19 (m, 1H), 7.02 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 8 Hz, 1H), 6.33 (d, J = 0.8 Hz, 1H), 4.03 (q, J = 7.2 Hz, 2H), 2.35 (s, 3H), 1.09 (t, J = 6.8 Hz, 3H); 13CNMR (100 MHz, DMSO-d6) δ 168.89, 165.16, 164.54, 157.53, 150.84, 144.02, 138.90, 133.56, 132.99, 131.80, 130.74, 128.79, 128.75, 128.03, 126.95, 123.50, 122.51, 120.27, 111.01, 109.26, 60.64, 55.94, 22.88, 14.43. ESI MS m / z: 524 (M+H)+. Example 6: Synthesis of (Z)-7-methyl-3-oxo-2-(2-oxoindolin-3-ylidene)-6-ethoxycarbonyl-5-(2-chlorophenyl)-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine (3e).

[0030] The preparation method of this example was the same as that of Example 1 except that o-chlorobenzaldehyde was used instead of p-tolualdehyde, and finally the target compound as a red solid was obtained with a yield of 55%.

[0031] 1 HNMR(400 MHz, DMSO- d 6 ) δ 11.23 (s, 1H), 8.56 (d, J J = 7.6 Hz, 1H), 7.41(dd, J J = 7.6, 1.6 Hz, 2H), 7.36 – 7.28 (m, 3H), 7.01 (td, J J = 8, 0.8 Hz, 1H),6.90 (d, J= 8 Hz, 1H), 6.34 (d, J = 1.2 Hz, 1H), 4.02 (q, J = 6.4 Hz, 2H),2.35 (d, J = 0.8 Hz, 3H), 1.09 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, DMSO- d 6 ) δ 168.86, 165.13, 164.46, 157.52, 151.12, 144.03, 137.25, 133.25, 132.99, 131.72, 130.58, 130.21, 128.72, 128.12, 128.04, 127.02, 122.50, 120.26, 111.00, 108.87, 60.67, 53.89, 22.90, 14.33. ESI MS m / z: 480 (M+H) + . Example 8: Synthesis of (Z)-7-methyl-3-oxo-2-(2-oxoindolin-3-ylidene)-6-ethoxycarbonyl-5-(3-fluorophenyl)-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine (3f).

[0032] The preparation method of this example is the same as that of Example 1 except that 3-fluorobenzaldehyde is used instead of p-tolualdehyde, and finally the target compound is obtained as a red solid, with a yield of 71%.

[0033] 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.25 (s, 1H), 8.61 (d, J = 8 Hz, 1H), 7.43–7.38 (m, 1H), 7.34 (td, J = 7.6, 0.8 Hz, 1H), 7.17–7.11 (m, 3H), 7.03–6.99 (m, 1H), 6.90 (d, J = 8 Hz, 1H), 6.03 (s, 1H), 4.12–4.00 (m, 2H), 2.40(s, 3H), 1.13 (t, J= 7.2 Hz, 3H); 13 C NMR (100 MHz, DMSO- d 6 ) δ 168.83, 165.12, 164.55, 162.36 (d, J = 243.1 Hz), 157.82, 151.49, 144.09, 142.80 (d, J = 6.5 Hz), 133.08, 131.29 (d, J = 8.1 Hz), 128.92, 128.16, 127.28, 124.22, 122.52, 120.28, 115.96 (d, J = 20.8 Hz), 115.28 (d, J = 21.8 Hz), 111.02, 109.41, 60.79, 55.04, 22.94, 14.32. ESI MS m / z: 464 (M+H) + . Example 9:( Z )-7-Methyl-3-oxo-2-(2-oxoindoline-3-ylidene)-6-ethoxycarbonyl-5-(4-chlorophenyl)-2,3-dihydro-5 H -thiazolo[3,2-a]pyrimidine (3g) synthesis: The preparation method of this example is the same as that of Example 1 except that p-chlorobenzaldehyde is used instead of p-tolualdehyde, and finally the red solid target compound is obtained, yield: 81%.

[0034] 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.22 (s, 1H), 8.60 (d, J = 8 Hz, 1H), 7.41 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 8.4 Hz, 3H), 7.02 (t, J = 7.6 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.01 (s, 1H), 4.08 – 4.00 (m, 2H), 2.39 (s, 3H), 1.13 (t, J= 7.2 Hz, 3H); 13 13C NMR (100 MHz, DMSO- d 6 ) δ 168.84, 165.13, 164.55, 157.77, 151.40, 144.07, 139.15, 133.62, 133.11, 130.21, 129.16, 128.94, 128.15, 127.26, 122.53, 120.26, 111.05, 109.54, 60.82, 54.92, 22.92, 14.33. ESI MS m / z: 480 (M+H) + . Example 10: ( Z )-7-Methyl-3-oxo-2-(2-oxoindolin-3-ylidene)-6-ethoxycarbonyl-5-(3-hydroxyphenyl)-2,3-dihydro-5 H -thiazolo[3,2-a]pyrimidine (3H): The preparation method of this example was the same as that of Example 1 except that m-hydroxybenzaldehyde was used instead of p-tolualdehyde. Finally, the target compound as a red solid was obtained with a yield of 65%.

[0035] 1 1H NMR (400 MHz, DMSO- d 6 ) δ 11.26 (s, 1H), 9.54 (s, 1H), 8.64 (d, J J =7.2 Hz, 1H), 7.35 (t, J J = 6.4 Hz, 1H), 7.12 (t, J J = 7.6 Hz, 1H), 7.03 (t, J J =7.2 Hz, 1H), 6.91 (d, J J = 7.2 Hz, 1H), 6.72 (d, J J = 12 Hz, 2H), 6.65 (d, J J =7.6 Hz, 1H), 5.95 (s, 1H), 4.08– 4.07 (m, 2H), 2.38 (s, 3H), 1.16 (t, J J = 6.8Hz, 3H); 13 13C NMR (100 MHz, DMSO- d6 ) δ 168.89, 165.35, 164.56, 157.95, 157.75, 150.69, 144.09, 141.61, 133.08, 130.21, 129.07, 128.20, 127.23, 122.55, 120.33, 118.56, 116.01, 114.62, 111.05, 110.21, 60.78, 56.49, 22.81, 14.37. ESI MS m / z: 462 (M+H) + . Example 11: Synthesis of (Z)-7-methyl-3-oxo-2-(2-oxoindoline-3-ylidene)-6-ethoxycarbonyl-5-(2-fluorophenyl)-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine (3i): The preparation method of this example is the same as that of Example 1 except that o-fluorobenzaldehyde is used instead of p-tolualdehyde, and finally a red solid target compound is obtained with a yield of 79%.

[0036] 1 HNMR (400 MHz, DMSO- d 6 ) δ 11.23 (s, 1H), 8.58 (d, J = 8 Hz, 1H), 7.38–7.31 (m, 3H), 7.20 – 7.15 (m, 2H), 7.01 (t, J = 8 Hz, 1H), 6.89 (d, J = 8Hz, 1H), 6.23 (s, 1H), 4.06 – 3.98 (m, 2H), 2.38 (s, 3H), 1.11 (t, J = 7.2Hz, 3H); 13 CNMR (100 MHz, DMSO- d 6 ) δ 168.82, 165.04, 164.39, 160.23 (d, J =248.1 Hz), 157.51, 151.59, 144.05, 133.00, 131.17 (d, J = 8.3 Hz), 130.74 (d, J= 2.6 Hz), 128.79, 128.10, 127.30 (d, J = 13.0 Hz), 127.15, 125.22 (d, J = 2.8 Hz), 122.50, 120.26, 116.05 (d, J = 21.4 Hz), 110.98, 108.54, 60.69, 50.34, 22.93, 14.19. ESI MS m / z: 464 (M+H) + . The present invention will be further described in detail below through examples of activity experiments.

[0037] Using the MTT method, an anti-cancer activity experiment was carried out on the synthesized target product 7-methyl-3-oxo-2-(2-oxoindoline-3-ylidene)-6-ethoxycarbonyl-5-aryl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine. Human H1975 (human lung adenocarcinoma cells), RT4 (human bladder transitional cell papilloma cells), T24 (human bladder transitional cell carcinoma cells) and MCF10A (human normal mammary epithelial cells) were used as test materials. Logarithmic-phase cells were collected, digested with trypsin, and the cell suspension concentration was adjusted to 2×10 4 cells / mL, dispensed into 96-well plates, 200 μL was added to each well; incubated at 5% CO2 and 37 °C for half a day until the cell monolayer covered the bottom of the well, different concentrations of the sample were added, 100 μl to each well, and 3 parallel wells were set; then incubated at 5% CO2 and 37 °C for four days, and observed under an inverted microscope; 20 μl of MTT solution (5 mg / ml, i.e., 0.5% MTT) was added to each well, and the culture was continued for 4 h. If the drug could react with MTT, the culture medium could be centrifuged and discarded first, carefully rinsed 2-3 times with PBS, and then the culture medium containing MTT was added to terminate the culture, and the culture medium in the well was carefully aspirated; 180 μl of dimethyl sulfoxide was added to each well, and shaken on a shaker at low speed for 10 min to fully dissolve the crystals. The absorbance of each well was measured at a wavelength of 550 nm using an enzyme-linked immunosorbent assay detector. Referring to the control (without the sample, the sample was replaced with the solvent that dissolved it, and other conditions were exactly the same), the inhibition rate IC 50 was calculated, and the test results are shown in Table 1.

[0038] Table 1 Anti-tumor activity of 7-methyl-3-oxo-2-(2-oxoindoline-3-ylidene)-6-ethoxycarbonyl-5-aryl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine derivatives

[0039] As can be seen from Table 1, 7-methyl-3-oxo-2-(2-oxoindolin-3-ylidene)-6-ethoxycarbonyl-5-aryl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine derivatives have antitumor activity. Among them, compounds 3f and 3i have good inhibitory effects on both H1975 (human lung adenocarcinoma cells) and RT4 (human bladder transitional cell papilloma cells), and their IC50 values are both less than that of the positive control 5-Fu (5-fluorouracil). Compounds 3a, 3b, 3f and 3i have good inhibitory effects on T24 (human bladder transitional cell carcinoma cells), and their IC50 values are all less than that of the positive control 5-Fu. At the same time, we also selected compounds 3f and 3i, which have good inhibitory effects on H1975, RT4 and T24, for normal cell experiments. As can be seen from Table 1, their effects on normal cells are weak, showing good selectivity.

Claims

1. A thiazolo[3,2-a]pyrimidine derivative containing isatin, and its chemical structural formula is shown as formula (I):

2. In formula (I), the substituent R is H, C 1-6 alkyl, F, Cl, Br, I, alkoxy, hydroxy, nitrile, nitro, carboxyl, amino or sulfonic acid group.

3. A method for preparing an isatin thiazolo[3,2-a]pyrimidine derivative as described in claim 1, characterized in that The steps are as follows: (1) Take thiourea and sulfamic acid and dissolve them in absolute ethanol. Slowly add ethyl acetoacetate dropwise. After the solid in the reaction flask is completely dissolved, add aromatic aldehyde. The reaction temperature is 80 °C, and reflux for about 10 h. Track the reaction process by TLC. After the reaction is completed, a large amount of white solid precipitates in the reaction solution. Filter while it is hot, and the filter residue is recrystallized with ethanol to obtain intermediate 4-methyl-6-aryl-5-acetyl-2-mercapto-1,6-dihydropyrimidine 1; (2) Weigh intermediate 1 and dissolve it in tetrahydrofuran, then slowly add chloroacetyl chloride dropwise, and reflux at 70 °C. A solid gradually precipitates in the reaction flask. Track the reaction process by TLC. After the reaction is completed, a large amount of yellow solid appears in the reaction solution. Filter by suction, and the filter residue is recrystallized with ethanol to obtain intermediate 7-methyl-3-oxo-6-ethoxycarbonyl-5-aryl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine 2; (3) Dissolve intermediate 2 in glacial acetic acid, then add sodium acetate and isatin, and reflux at 100 °C. Track the reaction process by TLC. After the reaction is completed, a large amount of red solid appears in the reaction solution. Filter by suction, and then recrystallize with ethanol to obtain the target product (Z)-7-methyl-3-oxo-2-(2-oxoindolin-3-ylidene)-6-ethoxycarbonyl-5-aryl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine 3.

4. Use of the isatin-containing thiazolo[3,2-a]pyrimidine derivative prepared by the method according to claim 2 in the preparation of anti-tumor drugs.

5. Use of the isatin thiazolo[3,2-a]pyrimidine derivative according to claim 3 in the preparation of an anti-tumor drug, characterized in that The dosage form of the anti-tumor drug is tablet, pill, capsule, injection, suspension or emulsion.

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