CN112876418A

CN112876418A - Acetamide derivative and application thereof in antitumor and antitumor drug preparation

Info

Publication number: CN112876418A
Application number: CN202011603449.9A
Authority: CN
Inventors: 王茂磊; 刘涛
Original assignee: Individual
Current assignee: Individual
Priority date: 2020-12-30
Filing date: 2020-12-30
Publication date: 2021-06-01

Abstract

The invention belongs to the field of medicines, and relates to an acetamide derivative and application thereof in antitumor and antitumor drug preparation. The structural formula of the acetamide derivative is shown as the formula I:

pharmacological research shows that the compound prepared by the invention can effectively degrade PARP1 protein, inhibit tumor cell proliferation and induce tumor cell apoptosis, thereby having the effects of resisting tumors and preparing related antitumor drugs.

Description

Acetamide derivative and application thereof in antitumor and antitumor drug preparation

Technical Field

The invention belongs to the field of medicines, and relates to an acetamide derivative and application thereof in antitumor and antitumor drug preparation.

Background

Poly (A-ribose) diphosphate polymerase (PARP) is a monomeric protease that is widely found in the nucleus of most eukaryotic cells. First discovered by Chambon in 1963. Over the last 50 years, researchers have also made clearer insights into the composition and function of the PARP enzyme family. During poly ADP glycosylation, PARP enzymes are involved in certain processes, regulating cell death, cell cycle progression, gene transcription, intracellular DNA repair, and the like. It has been found that there are at least 18 members of the PARP family, which have some homology. The classification into 4 classes based on the differences in the domains of these enzymes includes NDA damage-dependent, e.g., PARP1-3, PARPs, which bind to damaged DNA by binding to the DNA binding domain; tankyrases containing ankyrin repetitive structural domains, including Tankyrase-1 and Tankyrase-2; the CCCH type PARPs including PARP-7, PARP-12, PARP-13, which comprise a zinc finger domain binding to RNA and WWE (Trp-Trp-Glu) domain having PAR binding activity; macroscopic PARPs, exclusively monoadenosyl-diphosphate ribosyl-transferase (mono-ADP-ribosyltransferase). PARP1 and PARP2 are two main classes of enzymes in the PARP family, among which PARP1 performs more than 90% of functions and the substrate selectivity is different.

Apoptosis is an important life phenomenon in multicellular organisms and can be divided into apoptosis presentation and 2 continuous processes implemented by apoptosis. The significance of PARP as an essential factor in the implementation of apoptosis has been demonstrated in a number of experiments. Subsequent research shows that poly ADP ribosylation occurs in early apoptosis stage, and that cleavage hydrolysis of PARP protease occurs in the middle apoptosis stage, and the role of PARP enzyme in apoptosis process is converted to have important significance for apoptosis.

PARP inhibitors are currently an effective means for treating cancer, and are the focus and focus of the development of antitumor drugs. Studies show that the PARP enzyme inhibitor can regulate the generation of apoptosis, and the zinc ion can inhibit DNA fragmentation induced by tumor chemotherapeutic drug VP-16 by preventing poly adenosine diphosphate ribosylation reaction and is considered as the characteristic change of apoptosis. Currently, 4 PARP inhibitors have been approved for clinical use, and show good antitumor effects both in combination and in single use. There are also molecules undergoing clinical trials and it is believed that many more effective inhibitors will be used clinically in the near future.

In the clinical application of PARP inhibitors, several problems are accompanied, and most importantly, the long-term use of PARP is liable to cause the generation of tumor drug resistance, thereby reducing the curative effect. How to generate drug resistance and overcome and improve the drug resistance problem needs to be solved, and secondly, the half-life period of the PARP inhibitor is short, and the PARP inhibitor needs to be frequently administered. In the treatment process, the long-term intake of a large amount of PARP inhibitors not only has the killing effect on tumor cells, but also has a certain killing effect on normal cells. More refined treatment schemes are required to be set for different patients to delay and avoid the generation of drug resistance. It is therefore of particular importance to further develop PARP inhibitors and new protocols for the treatment of tumors. The compound prepared by the invention can effectively degrade PARP1 protein, inhibit tumor cell proliferation and induce tumor cell apoptosis, thereby having the effects of resisting tumors and preparing related antitumor drugs. In order to obtain a brand new compound which can be used for resisting tumors and preparing related anti-tumor drugs, and the prior art does not have reports of related structures.

Disclosure of Invention

In view of the above problems, the present invention aims to provide a preparation method and an application of acetamide derivatives, which have good antitumor activity and can be used for preparing antitumor drugs and antitumor drugs. In order to achieve the purpose, the invention adopts the following technical scheme.

An acetamide derivative, which has the following structural formula I:

R＝*CH₃、

another objective of the invention is to provide a synthetic route of acetamide derivative formula I:

further, the synthesis method of each step in the synthesis route is as follows:

1) in a proper solvent, 1- (2, 4-dichloro-5-nitrophenyl) ethan-1-one is taken as a raw material to react to obtain 1- (5-amino-2, 4-dichlorophenyl) ethan-1-one (a compound shown in a structural formula 2);

2) taking 2-chloro-N- (3, 4-dimethoxyphenethyl) acetamide as a raw material, and reacting to obtain 2- ((5-acetyl-2, 4-dichlorophenyl) amino) -N- (3, 4-dimethoxyphenethyl) acetamide (a compound shown in a structural formula 3);

3) taking 2- ((5-acetyl-2, 4-dichlorophenyl) amino) -N- (3, 4-dimethoxyphenethyl) acetamide as a raw material, and reacting to obtain 2- ((5-acetyl-2-chloro-4- ((5-methyl-1H-pyrazol-3-yl) amino) phenyl) amino) -N- (3, 4-dimethoxyphenethyl) acetamide (a compound shown in a structural formula 4);

4) taking 2- ((5-acetyl-2-chloro-4- ((5-methyl-1H-pyrazol-3-yl) amino) phenyl) amino) -N- (3, 4-dimethoxyphenethyl) acetamide and a corresponding secondary amine derivative as raw materials, and reacting to obtain a final product.

Of partial compounds¹H-NMR (400MHz) and¹³C-NMR (125MHz) was as follows:

intermediate 1 (compound of formula 2):¹H-NMR(400MHz,CDCl₃)δ:2.62(s,3H), 3.97(s,2H),7.01(s,1H),7.50(s,1H).¹³C-NMR(125MHz,CDCl₃)δ:28.30,114.97, 120.24,126.16,131.43,136.63,143.34,199.53；

intermediate 2 (compound of formula 3):¹H-NMR(400MHz,CDCl₃)δ:2.60(t,2H), 2.62(s,3H),3.37(t,2H),3.75(s,3H),3.77(s,2H),3.83(s,3H),4.11(s,1H),5.55(s,1H), 6.60(d,1H),6.74(s,1H),6.79(d,1H),6.98(s,1H),7.60(s,1H).¹³C-NMR(125MHz, CDCl₃)δ:28.30,35.88,41.98,43.47,56.83,113.55,113.87,115.52,122.42,122.82, 131.80,132.05,132.91,138.01,144.28,147.86,150.28,169.19,199.53；

intermediate 3 (compound of formula 4):¹H-NMR(400MHz,CDCl₃)δ:1.81(s,3H), 2.60(t,2H),2.62(s,3H),3.37(t,2H),3.75(s,3H),3.77(s,2H),3.83(s,3H),5.10(s,1H), 5.71(s,1H),6.23(s,1H),6.60(d,1H),6.74(s,1H),6.79(d,1H),7.00(s,1H),7.43(s, 1H).¹³C-NMR(125MHz,CDCl₃)δ:12.99,28.30,35.88,41.98,43.47,56.83,89.46, 113.55,113.87,114.57,122.42,123.10,127.74,127.88,132.91,135.59,139.20, 139.43,147.86,148.45,150.28,169.19,205.70；

product 1:¹H-NMR(400MHz,CDCl₃)δ:1.16(s,1H),1.81(s,3H),2.20(s,3H), 2.34(t,4H),2.59(t,2H),2.61(s,3H),3.36(t,2H),3.43(t,4H),3.74(s,3H),3.76(s,2H), 3.82(s,3H),4.84(s,1H),5.67(s,1H),6.38(s,1H),6.58(d,1H),6.72(s,1H),6.77(d, 1H),6.86(s,1H).¹³C-NMR(125MHz,CDCl₃)δ:12.99,28.30,35.88,41.98,43.47, 46.06,50.76,52.65,56.83,89.46,111.84,113.55,113.87,117.73,122.23,122.42, 123.30,132.91,139.20,142.71,145.69,147.86,148.45,150.28,169.19,205.70。

the acetamide derivative disclosed by the invention can effectively degrade PARP1 protein, inhibit tumor cell proliferation and induce tumor cell apoptosis, and has obvious anti-tumor activity. The acetamide derivative has positive significance in resisting tumors and can be further studied.

The prepared anti-tumor medicine or the pharmaceutically acceptable salt or solvate thereof is applied to development of anti-tumor medicines, and further, the tumor is fallopian tube cancer, colorectal cancer, prostate cancer or esophageal cancer. .

Compared with the prior art, the invention has the following beneficial effects:

the compound of the invention has good anti-tumor effect. Further, it can be seen from the research results provided by the present invention that: the compound can effectively degrade PARP1 protein, inhibit tumor cell proliferation, induce tumor cell apoptosis and has obvious antitumor activity.

In conclusion, the acetamide derivative has good development prospect when used for preparing antitumor drugs.

Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.

Drawings

FIG. 1: the influence of the compound obtained by the invention on the proliferation of tumor cells.

FIG. 2: the effect of the compound obtained by the invention on the degradation of PARP1 protein in tumor cells.

Detailed Description

The following synthetic examples, biological test results, are used to further illustrate the invention, but are not meant to limit the invention.

Synthesis examples

Example 1 preparation of product 1 (Compound represented by chemical formula 5)

The synthetic route is

(1) Synthesis of intermediate 1- (5-amino-2, 4-dichlorophenyl) ethan-1-one (compound shown in structural formula 2)

In an autoclave, 1- (2, 4-dichloro-5-nitrophenyl) ethan-1-one (compound of formula 1) (9.13g, 0.039mol) was dissolved in methanol (175mL), to which was added Raney nickel (1g) and hydrogenated at 70psi for 2.5 hours. After the hydrogenation reaction was completed, the reaction mixture was filtered and the solvent was distilled off. Off-white crystals were obtained, 7.06g, with a yield of 88.7%.

¹H-NMR(400MHz,CDCl₃)δ:2.62(s,3H),3.97(s,2H),7.01(s,1H),7.50(s,1H). ¹³C-NMR(125MHz,CDCl₃)δ:28.30,114.97,120.24,126.16,131.43,136.63, 143.34,199.53.LC-MS(ESI,pos,ion)m/z:204[M+H]。

(2) Synthesis of intermediate 2- ((5-acetyl-2, 4-dichlorophenyl) amino) -N- (3, 4-dimethoxyphenethyl) acetamide (compound represented by structural formula 3):

1- (5-amino-2, 4-dichlorophenyl) ethan-1-one (compound of formula 2) (6.73g, 0.033mol), 2-chloro-N- (3, 4-dimethoxyphenethyl) acetamide (10.57g, 0.041mol), sodium iodide (6.00g, 0.040mol) and potassium carbonate (9.26g, 0.067mol) were suspended in DMF (200mL) and stirred at 50 ℃ for 80 hours. The solvent was distilled off, and the crude product was dissolved in water (400mL) and extracted with dichloromethane (4X 200 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography (silica gel 60,400g, solvent: EA: acetone ═ 1: 1). A yellow powder, 11.16g, was obtained in 79.5% yield. TLC solvent: EA: MeOH: 10: 1.

¹H-NMR(400MHz,CDCl₃)δ:2.60(t,2H),2.62(s,3H),3.37(t,2H),3.75(s,3H), 3.77(s,2H),3.83(s,3H),4.11(s,1H),5.55(s,1H),6.60(d,1H),6.74(s,1H),6.79(d, 1H),6.98(s,1H),7.60(s,1H).¹³C-NMR(125MHz,CDCl₃)δ:28.30,35.88,41.98, 43.47,56.83,113.55,113.87,115.52,122.42,122.82,131.80,132.05,132.91,138.01, 144.28,147.86,150.28,169.19,199.53.LC-MS(ESI,pos,ion)m/z:425[M+H]。

(3) Synthesis of intermediate 2- ((5-acetyl-2-chloro-4- ((5-methyl-1H-pyrazol-3-yl) amino) phenyl) amino) -N- (3, 4-dimethoxyphenethyl) acetamide (compound of formula 4):

2- ((5-acetyl-2, 4-dichlorophenyl) amino) -N- (3, 4-dimethoxyphenethyl) acetamide (compound represented by formula 3) (10.63g, 0.025mol) was dissolved in anhydrous DMF (25mL), then 5-methyl-2-aminopyrazole (2.67g, 0.0275mol), sodium iodide (4.50g, 0.03mol) and Diisopropylethylamine (DIPEA) (4.96mL, 0.03mol) were added, the solution was heated to 100 ℃ overnight, then cooled to room temperature, diluted with ethyl acetate (200mL), washed with a saturated sodium bicarbonate solution (3X 200mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel with 0% to 4% methanol/dichloromethane as eluent to give a yellow powdered solid, 11.02g, 90.7% yield.

¹H-NMR(400MHz,CDCl₃)δ:1.81(s,3H),2.60(t,2H),2.62(s,3H),3.37(t,2H), 3.75(s,3H),3.77(s,2H),3.83(s,3H),5.10(s,1H),5.71(s,1H),6.23(s,1H),6.60(d, 1H),6.74(s,1H),6.79(d,1H),7.00(s,1H),7.43(s,1H).¹³C-NMR(125MHz,CDCl₃) δ:12.99,28.30,35.88,41.98,43.47,56.83,89.46,113.55,113.87,114.57,122.42, 123.10,127.74,127.88,132.91,135.59,139.20,139.43,147.86,148.45,150.28, 169.19,205.70.LC-MS(ESI,pos,ion)m/z:486[M+H]。

(4) Synthesis of 2- ((5-acetyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) -2- (4-methylpiperazin-1-yl) phenyl) amino) -N- (3, 4-methoxyphenethyl) acetamide (compound of formula 5):

2- ((5-acetyl-2-chloro-4- ((5-methyl-1H-pyrazol-3-yl) amino) phenyl) amino) -N- (3, 4-dimethoxyphenethyl) acetamide (compound represented by structural formula 4) (9.72g, 0.02mol) was dissolved in anhydrous dioxane (20mL), then N-methylpiperazine (2.20g, 0.022mol), 4-Dimethylaminopyridine (DMAP) (0.122g, 0.001mol) and Diisopropylethylamine (DIPEA) (3.97mL, 0.024mol) were added, then the solution was refluxed for 8 hours, cooled to room temperature, then concentrated under reduced pressure, and the resulting crude product was purified by flash chromatography on silica gel with an eluent of 0% to 10% methanol/dichloromethane to give a pale yellow solid, 9.92g, yield 90.2%.

¹H-NMR(400MHz,CDCl₃)δ:1.16(s,1H),1.81(s,3H),2.20(s,3H),2.34(t,4H), 2.59(t,2H),2.61(s,3H),3.36(t,2H),3.43(t,4H),3.74(s,3H),3.76(s,2H),3.82(s,3H), 4.84(s,1H),5.67(s,1H),6.38(s,1H),6.58(d,1H),6.72(s,1H),6.77(d,1H),6.86(s, 1H).¹³C-NMR(125MHz,CDCl₃)δ:12.99,28.30,35.88,41.98,43.47,46.06,50.76, 52.65,56.83,89.46,111.84,113.55,113.87,117.73,122.23,122.42,123.30,132.91, 139.20,142.71,145.69,147.86,148.45,150.28,169.19,205.70.LC-MS(ESI,pos,ion) m/z:550[M+H]。

Example 2 preparation of product 2 (Compound represented by chemical formula 6)

The synthetic route is as follows:

(1) synthesis of 2- ((5-acetyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) -2- (4-phenylpiperazin-1-yl) phenyl) amino) -N- (3, 4-methoxyphenethyl) acetamide (compound of formula 6):

2- ((5-acetyl-2-chloro-4- ((5-methyl-1H-pyrazol-3-yl) amino) phenyl) amino) -N- (3, 4-dimethoxyphenethyl) acetamide (compound represented by structural formula 4) (9.72g, 0.02mol) was dissolved in anhydrous dioxane (20mL), then N-phenylpiperazine (3.57g, 0.022mol), 4-Dimethylaminopyridine (DMAP) (0.122g, 0.001mol) and Diisopropylethylamine (DIPEA) (3.97mL, 0.024mol) were added, then the solution was refluxed for 8 hours, cooled to room temperature, then concentrated under reduced pressure, and the resulting crude product was purified by flash chromatography on silica gel with an eluent of 0% to 10% methanol/dichloromethane to give a yellow solid, 10.8g, 88% yield.

¹H-NMR(400MHz,CDCl₃)δ:2.24(s,3H),2.64(s,3H),2.67(t,2H),3.18(s,8H), 3.31(m,2H),3.77(d,2H),3.84(d,6H),3.99(t,1H),6.13(s,1H),6.61-6.66(m,3H), 6.69(s,1H),6.78(d,1H),6.85-6.93(m,4H),7.25(t,2H),7.80(s,1H),13.70(s,1H). ¹³C-NMR(125MHz,CDCl₃)δ:12.49,27.84,34.40,41.11,43.12,47.62,55.99, 92.12,108.37,112.56,116.31,117.25,117.80,122.64,126.70,128.47,129.41, 131.21,135.23,139.68,141.58,148.08,149.47,151.72,169.56, 202.98.LC-MS(ESI,pos,ion)m/z:612[M+H]。

Example 3 preparation of product 3 (Compound represented by chemical formula 7)

The synthetic route is as follows:

(1) synthesis of 2- ((5-acetyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) -2- (4- (4-methoxyphenyl) piperazin-1-yl) phenyl) amino) -N- (3, 4-methoxyphenethyl) acetamide (compound represented by structural formula 7)

2- ((5-acetyl-2-chloro-4- ((5-methyl-1H-pyrazol-3-yl) amino) phenyl) amino) -N- (3, 4-dimethoxyphenethyl) acetamide (compound represented by structural formula 4) (9.72g, 0.02mol) was dissolved in anhydrous dioxane (20mL), N- (4-methoxyphenyl) piperazine (4.23g, 0.022mol), 4-Dimethylaminopyridine (DMAP) (0.122g, 0.001mol) and Diisopropylethylamine (DIPEA) (3.97mL, 0.024mol) were added, the solution was stirred under reflux for 8 hours, cooled to room temperature, then concentrated under reduced pressure, and the resulting crude product was purified by flash silica gel chromatography with an eluent of 0% to 10% methanol/dichloromethane, this gave a pale yellow solid, 11.7g, 91.5% yield.

¹H-NMR(400MHz,CDCl₃)δ:2.24(s,3H),2.64(s,3H),2.67(t,2H),3.13(s,8H), 3.31(m,2H),3.77(d,2H),3.85(d,9H),3.99(t,1H),6.13(s,1H),6.61(m,1H),6.65(m, 2H),6.69(s,1H),6.78(d,1H),6.90(s,1H),7.06(d,2H),7.25(d,2H),7.80(s,1H), 13.70(s,1H).¹³C-NMR(125MHz,CDCl₃)δ:12.49,27.84,34.40,41.11,43.12, 47.62,55.40,56.04,92.12,108.37,112.81,115.43,117.32,122.64,126.70, 128.47,131.21,135.23,139.68,141.58,148.36,149.62,154.23,169.56,202.98. LC-MS(ESI,pos,ion)m/z:642[M+H]。

Example 4 preparation of product 4 (Compound represented by chemical formula 8)

The synthetic route is as follows:

(1) synthesis of 2- ((5-acetyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) -2-benzylpiperazin-1-yl) phenyl) amino) -N- (3, 4-methoxyphenethyl) acetamide (compound represented by structural formula 8)

2- ((5-acetyl-2-chloro-4- ((5-methyl-1H-pyrazol-3-yl) amino) phenyl) amino) -N- (3, 4-dimethoxyphenethyl) acetamide (compound represented by structural formula 4) (9.72g, 0.02mol) was dissolved in anhydrous dioxane (20mL), then N-benzylpiperazine (3.88g, 0.022mol), 4-Dimethylaminopyridine (DMAP) (0.122g, 0.001mol) and Diisopropylethylamine (DIPEA) (3.97mL, 0.024mol) were added, then the solution was refluxed for 8 hours, cooled to room temperature, then concentrated under reduced pressure, and the resulting crude product was purified by flash chromatography on silica gel with an eluent of 0% to 10% methanol/dichloromethane to give a yellow solid, 11.1g, 88.6% yield.

¹H-NMR(400MHz,CDCl₃)δ:2.22(s,3H),2.64(s,3H),2.67(t,2H), 3.12-3.22(m,4H),3.26-3.33(m,6H),3.76-3.79(m,4H),3.84(d,6H),3.99(t,1H,) 6.13(s,1H),6.61(d,1H),6.65(t,2H),6.69(s,1H),6.79(d,1H),6.90(s,1H),7.28(m, 5H),7.80(s,1H),13.50(s,1H).¹³C-NMR(125MHz,CDCl₃)δ:12.49,27.84,34.40, 41.11,43.12,50.49,52.49,56.04,63.14,92.12,108.37,112.56,117.25,122.64, 126.70,127.41,128.64,131.21,135.23,138.27,139.68,141.58,148.08,149.62, 169.56,202.98.LC-MS(ESI,pos,ion)m/z:626[M+H]。

Test example 1 inhibitory Effect of the obtained Compound on PARP1 enzyme

The inhibition effect of the compound on PARP1 enzyme on molecular level is determined by enzyme linked immunosorbent assay (ELISA). AZD2281 was used as a positive control, and the experiment was performed using 1 μ M dilution, 6 concentration gradients on PARP1 enzyme, triplicate. Based on the results, the IC is calculated₅₀The value is obtained.

Table 1 inhibition of PARP1 enzyme by the resulting compounds.

Remarking: value is IC₅₀，nM，Mean±SD

The above results show that the compounds obtained by the present invention all have inhibitory effect on PARP1 enzyme, wherein compound 1, compound 2 and compound 3 are all stronger than positive control AZD 2281. It is noted that Compound 3 is most potent and IC₅₀Values below 1 nM.

Test example 2 proliferation inhibitory Effect of the obtained Compound on human mammary tumor cells

The BRCA 1-deficient human breast tumor cell MDA-MB-436 is cultured, and the proliferation growth inhibition effect and the degree of the obtained compound are compared by adopting a CCK-8 method. The proliferation inhibitory effect of the compound obtained in the present invention on MDA-MB-436 cells was evaluated using AZD2281 as a positive control. In the experiment, the highest final concentration of 10 μ M, 10 times diluted downwards, 7 concentration gradients, 7 days of cell treatment, three times of repetition, calculation of its IC₅₀The values, results are shown in FIG. 1. The results show that the compounds obtained by the invention all have inhibitory effect on cell proliferation of MDA-MB-436, wherein the compound 3 has the strongest effect and IC₅₀The value below 10nM is far superior to the inhibition of the positive control.

Test example 3 degradation of PARP1 enzyme by the obtained Compound

The degradation of PARP1 enzyme by the resulting compounds was determined by western blotting. Cultured MDA-MB-436 cells were trypsinized and transferred to 6-well plates (1X 10)⁶Cells/well). After continued overnight incubation, the compounds of example 3 were treated with the cells at the working concentration of 100 nM. After 24 and 48 hours of treatment, cells were harvested. After the cultured cells were harvested, they were lysed using Whole Cell Lysates (WCL), centrifuged, added with sample buffer and boiled, subjected to SDS-PAGE, after which proteins were transferred to PVDF membrane, after 5% BSA blocking, primary antibody (PARP1) and internal reference protein (GAPDH)) were incubated overnight, washed with HPR-labeled secondary antibody and incubated at room temperature for two hours, and after washing, Enhanced chemiluminescence detection (ECL) detection system was performed, the results are shown in FIG. 2. The results show that the compound obtained by the invention can be used for treating cells for 24 hours, and the obvious PARP1 protein degradation effect can be observed, and the degradation effect is strongest at 48 hours.

The compound prepared by the invention has positive significance in tumor treatment, effectively degrades PARP1 protein, inhibits tumor cell proliferation, induces tumor cell apoptosis, and provides a new research idea for research and development of antitumor drugs.

Claims

1. An acetamide derivative, the chemical structure general formula of which is shown in formula I,

in the formula: r ═ CH₃、

2. The acetamide derivative of claim 1, formula I, wherein the synthesis route is as follows:

3. the process for preparing acetamide derivatives of claim 1, comprising the steps of:

(1) in a proper solvent, 1- (2, 4-dichloro-5-nitrophenyl) ethan-1-one is used as a raw material to react to obtain 1- (5-amino-2, 4-dichlorophenyl) ethan-1-one (an intermediate 1);

(2) taking 2-chloro-N- (3, 4-dimethoxyphenethyl) acetamide as a raw material, and reacting to obtain 2- ((5-acetyl-2, 4-dichlorophenyl) amino) -N- (3, 4-dimethoxyphenethyl) acetamide (an intermediate 2);

(3) taking 2- ((5-acetyl-2, 4-dichlorophenyl) amino) -N- (3, 4-dimethoxyphenethyl) acetamide as a raw material, and reacting to obtain 2- ((5-acetyl-2-chloro-4- ((5-methyl-1H-pyrazol-3-yl) amino) phenyl) amino) -N- (3, 4-dimethoxyphenethyl) acetamide (intermediate 3);

(4) taking 2- ((5-acetyl-2-chloro-4- ((5-methyl-1H-pyrazol-3-yl) amino) phenyl) amino) -N- (3, 4-dimethoxyphenethyl) acetamide and a corresponding secondary amine derivative as raw materials, and reacting to obtain a final product.

4. The process according to claim 3, wherein the solvent used in the synthesis step (1) is preferably methanol.

5. The acetamide derivative according to claim 1 for use in antitumor applications.

6. The use according to claim 5, characterized in that the compounds obtained according to the invention are used in medicaments against tumors and for the preparation of related antitumor medicaments.