Dronedarone derivative with broad-spectrum anticancer activity as well as preparation method and application of dronedarone derivative

Abstract

The invention relates to the field of medicinal chemistry, in particular to dronedarone derivatives with broad-spectrum anticancer activity and a preparation method and application thereof. The invention designs and synthesizes a dronedarone derivative, and the derivative has broad-spectrum anticancer activity and shows good treatment potential for resisting cancers such as gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, cervical cancer and ampulla cancer. The derivative has remarkable anti-tumor cell proliferation activity, the effect of the derivative is better than that of a clinical drug fluorouracil, and the derivative can be used for preparing novel anti-tumor drugs and has wide application prospects.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a class of dronedarone derivatives with broad-spectrum anticancer activity, and a preparation method and use thereof. Background Art

[0002] Cancer is a heterogeneous group of malignant diseases caused by genetic mutations. Its core characteristics are abnormal cell proliferation and invasion of surrounding tissues. Cancer has become the second leading cause of death worldwide, posing a serious threat to human life and health while placing a significant economic burden on healthcare systems. Current treatments for cancer primarily include surgery, chemotherapy, and radiotherapy.

[0003] Chemotherapy is a systemic treatment method that uses chemical drugs to interfere with the proliferation process of cancer cells. However, problems such as drug resistance and toxic side effects often occur in the later stages of treatment. It is very necessary to find new anti-cancer drugs. "New uses for old drugs" is to reveal new therapeutic indications or molecular targets for marketed drugs through systematic scientific research. This strategy has shown significant potential in the field of cancer treatment: first, previous drugs already have complete safety assessment data and clinical application basis, which can significantly shorten the research and development cycle and reduce the risk of conversion; second, some traditional drugs (such as non-steroidal anti-inflammatory drugs aspirin and biguanide hypoglycemic drugs metformin) have been shown to exert anti-cancer effects through mechanisms such as regulating tumor cell metabolism and inhibiting angiogenesis. This innovative research paradigm not only provides cancer patients with diversified treatment options, but also promotes the innovation of drug development models and translational medicine research directions.

[0004] Methods for repurposing old drugs include computational prediction, phenotypic screening, and clinical data mining. Among these, phenotypic screening is a classic approach for discovering anti-cancer drugs. Phenotypic screening screens potential drugs by observing the effects of compounds on the phenotypes of cells or organisms, without requiring prior knowledge of their target. It is a simple and efficient method for discovering anti-cancer drugs.

[0005] The present invention screens existing clinical drugs for anticancer activity through phenotypic screening and finds that dronedarone, a drug for the clinical treatment of arrhythmias, has potential anticancer activity. Medicinal chemistry methods are then used to derivatize and structurally modify dronedarone to obtain a series of derivatives. Activity tests reveal that these derivatives have superior anticancer activity compared to dronedarone and the clinical anticancer drug fluorouracil. Summary of the Invention

[0006] The present invention aims to provide a dronedarone derivative having broad-spectrum anticancer activity. Specifically, the present invention includes the following contents:

[0007] In a first aspect, the present invention provides a dronedarone derivative having broad-spectrum anticancer activity, wherein the structural formula of the derivative is shown in the following formula (I):

[0008]

[0009] wherein M is selected from CR'; R' is selected from H, halogen, carbonyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkoxycarbonyl, substituted or unsubstituted C1-C6 acylamino, substituted or unsubstituted C1-C 10 alkyl;

[0010] R is selected from substituted or unsubstituted C6-C 12 Aryl or heteroaryl, substituted or unsubstituted 3-12 membered cycloalkyl or heterocyclic group, substituted or unsubstituted C2-C6 alkenyl;

[0011] The substitution refers to the substitution of one or more hydrogen atoms on the group by a substituent selected from the group consisting of a halogen atom, a carbonyl group, a carboxyl group, a hydroxyl group, an amino group, a nitro group, a cyano group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a C1-C6 alkoxycarbonyl group, a C1-C6 acylamino group, a C1-C6 alkyl ... 10 Alkyl C6-C 10 Aryl, five-membered heteroaryl, six-membered heteroaryl, or C1-C 10 Alkyl, C6-C 10 aryl or five-membered or six-membered heteroaryl.

[0012] Preferably, the structural formula of the derivative is shown in the following formula (II):

[0013]

[0014] Preferably, R is selected from substituted or unsubstituted phenyl, substituted or unsubstituted benzo 5-6 membered heterocyclic group, substituted or unsubstituted 3-12 membered cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted vinyl group.

[0015] Preferably, the substitution is selected from alkyl substitution, alkoxy substitution, halogen substitution, haloalkyl substitution, and aryl substitution.

[0016] Preferably, the substitution is C 1-4 Alkyl substitution, methoxy substitution, halogen substitution, trifluoromethyl substitution, trifluoromethoxy substitution, nitro substitution, phenyl substitution.

[0017] Preferably, R is selected from 4-chloro substituted phenyl, 4-trifluoromethyl substituted phenyl, 4-methoxy substituted phenyl, 4-nitro substituted phenyl, 4-trifluoromethoxy substituted phenyl, 3-fluoro substituted phenyl, 3-methyl substituted phenyl, vinyl phenyl, methylenedioxyphenyl, furan, morpholine, 2-chloropyridine, and cyclopropane.

[0018] Preferably, the structural formula of the derivative is any one of the following formulas (1) to (13):

[0019]

[0020]

[0021] In a second aspect, the present invention provides the use of the derivatives described in the first aspect in the following applications:

[0022] Application in the preparation of anti-tumor drugs;

[0023] Application in the preparation of drugs for treating autoimmune diseases;

[0024] Application in the preparation of drugs for treating inflammation;

[0025] Application in the preparation of drugs for treating Alzheimer's disease.

[0026] Preferably, the tumor includes gastric cancer, liver cancer, pancreatic cancer, colorectal cancer and ampullary cancer.

[0027] Preferably, the derivative is added with a pharmaceutically acceptable salt excipient to prepare any pharmaceutically acceptable dosage form.

[0028] Preferably, the dosage forms include tablets, injections, granules, and suspensions.

[0029] The beneficial effects of the present invention are as follows: the present invention provides a dronedarone derivative, and the dronedarone exhibits significant anti-tumor cell proliferation activity; pharmacodynamic experiments show that the compounds involved in the present invention can be used as therapeutic drugs for tumors, autoimmune diseases, inflammation or Alzheimer's disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 The results of dronedarone derivatives inhibiting tumor cell colony formation;

[0031] Figure 2 Dronedarone derivatives inhibit the migration of tumor cells;

[0032] Figure 3 Hoechst33258 staining experimental results;

[0033] Figure 4 Annexin V-FITC / PI staining experimental results. DETAILED DESCRIPTION

[0034] Taking compound 1 (Route I) as an example, the preparation method of the compound of the present invention is as follows:

[0035] It should be noted that the specific embodiments included below are for illustration purposes only and should not be construed as limiting the scope of the present invention. In addition, it should be understood that after reading the contents of the present invention, those skilled in the art may make various changes or modifications to the present invention, and such equivalent forms also fall within the scope defined by the appended claims.

[0036] The synthetic route of compound 1 is shown in Route 1:

[0037]

[0038] In route I: a is 4-chlorobenzoyl chloride, N,N-diisopropylethylamine, 4-dimethylaminopyridine, dichloromethane, and room temperature.

[0039] 5-FU and dronedarone were purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.; liver cancer cell line HepG-2, cervical cancer cell line Hela, gastric cancer cell line HGC27, colorectal cancer cell line HT29, and pancreatic cancer cell line PANC-1 were from the American ATCC Biological Standard Resource Center; ampullary cancer cell line DPC-X1 was from the First Hospital of Lanzhou University.

[0040] Example 1 Synthesis of Dronedarone Derivatives

[0041] 1. Synthesis of N-(2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl)-4-chloro-N-(methylsulfonyl)benzamide (Compound 1)

[0042]

[0043] To a 250 mL round-bottom flask, add dronedarone (1 g), 4-dimethylaminopyridine (50 mg), dichloromethane (100 mL), NN-diisopropylethylamine (1 mL), and 4-chlorobenzoyl chloride (0.3 g). Stir the reaction mixture at room temperature for 6 hours, monitoring the reaction by TLC. Add 40 mL of water, extract with ethyl acetate, and rotary evaporation to obtain a crude yellow solid. Column chromatography (developing solvent: CH2Cl2:MeOH = 40:1) yields 80%. 1H NMR (400MHz, DMSO-d6) δ7.73(d,J=8.5Hz,2H),7.64(d,J=8.8Hz,1H),7.51(d,J=8.6 Hz,2H),7.45–7.36(m,4H),7.06(d,J=8.6Hz,2H),4.20(s,2H),3.54(s,3H),3.22(s ,2H),3.06(s,4H),2.78(t,J=7.5Hz,2H),2.20(s,2H),1.63(p,J=7.5Hz,6H),1.33( p,J=7.4Hz,4H),1.22(q,J=7.4Hz,2H),0.90(t,J=7.3Hz,6H),0.79(t,J=7.3Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ189.05,169.60,165.75,162.86,153.00,136.87,133.06,132.57,131.96,131.25,131.11,128.9 0,127.67,123.43,116.72,114.90,112.32,65.86,52.15,49.18,40.99,29.80,27.60,25.43,22.15,19.98,14.07,13.88.

[0044] 2. Synthesis of N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]-1-benzofuran-5-yl}-N-(methylsulfonyl)furan-2-carboxamide (Compound 2)

[0045]

[0046] The preparation was carried out according to a synthetic method similar to that in Example 1, except that furoyl chloride was used instead of 4-chlorobenzoyl chloride as the raw material, and the other steps were the same as those in Example 1.

[0047] 1H NMR (400MHz, DMSO-d6) δ7.89(s,1H),7.79(d,J=8.7Hz,1H),7.73(d,J=8.5Hz,2H),7.48(dd,J=8.7 ,2.3Hz,1H),7.40(d,J=2.2Hz,1H),6.96(d,J=8.5Hz,2H),6.52(dd,J=3.7,1.7Hz,1H),6.07(d,J=3 .6Hz,1H),4.12(d,J=6.0Hz,2H),3.56(s,3H),2.84(t,J=7.5Hz,2H),2.67(s,2H),2.33(s,2H),1. 94(s,2H),1.69(p,J=7.4Hz,2H),1.43(s,4H),1.28(p,J=7.4Hz,8H),0.83(dt,J=10.6,7.3Hz,9H). 13 C NMR(101MHz,DMSO-d6)δ189.12,165.72,163.10,158.58,153.57,148.36,145.21,132.01,131.91,131.07,127.93,127.43,123.4 1,120.73,116.85,114.71,112.88,112.61,66.10,53.22,49.72,41.72,29.88,27.61,27.04,26.38,22.17,20.25,14.24,13.91.

[0048] 3. Synthesis of N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]-1-benzofuran-5-yl}-N-(methylsulfonyl)-3-phenylacrylamide (Compound 3)

[0049]

[0050] The preparation was carried out according to a synthetic method similar to that in Example 1, except that cinnamoyl chloride was used instead of 4-chlorobenzoyl chloride as the raw material in the first step, and the other steps were the same as those in Example 1.

[0051] 1H NMR (400MHz, DMSO-d6) δ7.82(d,J=8.7Hz,1H),7.77(d,J=8.6Hz,2H),7.71(d,J=15.5Hz,1H),7.51(d,J= 8.1Hz,2H),7.45(dd,J=8.7,2.2Hz,1H),7.40–7.33(m,4H),6.84(d,J=8.8Hz,2H),6.27(d,J=15.6Hz,1H ),3.90(t,J=6.0Hz,2H),3.57(s,3H),2.85(t,J=7.6Hz,2H),2.44(t,J=6.7Hz,2H),2.31(t,J=6.9Hz,4H ), 1.72(dp,J=22.6,7.6,6.9Hz,4H), 1.26(ddd,J=22.4,15.0,7.5Hz,10H), 0.81(dt,J=10.7,7.2Hz,9H). 13 C NMR (101MHz, DMSO-d6) δ189.13,166.15,165.53,163.28,153.53,145.46,134.20,132.03,131.34,131.26,130.90,129.47,128.96,128.2 0,127.39,123.36,118.35,116.96,114.56,112.70,66.21,53.75,49 .92,42.04,29.94,29.52,27.61,26.90,22.18,20.52,14.37,13.90.

[0052] 4. Synthesis of N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]-1-benzofuran-5-yl}-N-(methylsulfonyl)-4-(trifluoromethyl)benzamide (Compound 4)

[0053]

[0054] The preparation was carried out according to a synthetic method similar to that in Example 1, except that 4-trifluoromethylbenzoyl chloride was used instead of 4-chlorobenzoyl chloride as the raw material, and the other steps were the same as in Example 1.

[0055] 1H NMR (400MHz, DMSO-d6) δ7.71–7.66(m,6H),7.63(d,J=9.3Hz,1H),7.46(dd,J=6.0,2.2Hz,2H),7.01(d,J=8.8Hz,2H),4.13(t,J=6.1Hz,2H),3.59(s ,3H),2.75(t,J=7.6Hz,2H),2.34(t,J=7.0Hz,4H),1.84(p,J=6.3Hz,2H) ,1.61(p,J=7.6Hz,2H),1.41–1.11(m,12H),0.78(dt,J=14.6,7.3Hz,9H). 13 C NMR(101MHz,DMSO-d6)δ189.02,169.28,165.50,163.37,153.07,138.45,132.18,131.92,130.89,129.74,127.76,125.68,125.65,1 25.31,123.59,122.60,116.76,114.79,112.29,66.43,53.70,49.98,41.19,29.76,29.42,27.60,26.90,22.12,20.50,14.34,13.81.

[0056] 5. Synthesis of N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]-1-benzofuran-5-yl}-N-(methylsulfonyl)cyclopropanecarboxamide (Compound 5)

[0057]

[0058] The preparation was carried out according to a synthetic method similar to that in Example 1, except that cyclopropanecarbonyl chloride was used instead of 4-chlorobenzoyl chloride as the raw material, and the other steps were the same as in Example 1.

[0059] 1 H NMR (400MHz, DMSO-d6) δ7.80(d,J=9.0Hz,3H),7.47(d,J=9.0Hz,2H),7.05(d,J=8.6Hz,2H),4.12(t,J=6.1Hz,2H),3.50(s,3H), 2.82(t,J=7.5Hz,2H),2.37(s,4H),1.85(s,2H),1.67(p,J=7.4Hz,2H),1.44–1.14(m,12H),0.90(s,2H),0.81(q,J=7.0Hz,12H). 13C NMR (101MHz, DMSO-d6) δ189.27,174.39,165.49,163.33,153.46,132.03,131.92,131.03,128.22,127.32,123.23,116. 87,114.82,112.72,66.34,53.64,49.92,41.98,29.85,29.39,27.66,26.84,22.11,20.46,15.03,14.35,13.86,10.52.

[0060] 6. Synthesis of N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]-1-benzofuran-5-yl}-N-(methylsulfonyl)-4-methoxybenzamide (Compound 6)

[0061]

[0062] The preparation was carried out according to a synthetic method similar to that in Example 1, except that 4-chlorobenzoyl chloride was replaced by 4-methoxybenzoyl chloride as a raw material, and the other steps were the same as those in Example 1.

[0063] 1 H NMR (400MHz, DMSO-d6) δ7.71(d,J=8.5Hz,2H),7.66(d,J=8.7Hz,1H),7.51(d,J=8.8Hz,2H),7 .42(dd,J=8.8,2.3Hz,1H),7.31(d,J=2.2Hz,1H),7.02(d,J=8.5Hz,2H),6.86(d,J=8.8Hz,2H ),4.16(t,J=6.0Hz,2H),3.72(s,3H),3.46(s,3H),2.80(t,J=7.5Hz,2H),2.67(s,2H),2.33( s,2H),1.99(s,2H),1.64(p,J=7.5Hz,2H),1.59–1.08(m,12H),0.82(dt,J=23.9,6.7Hz,9H). 13C NMR(101MHz,DMSO-d6)δ189.04,170.13,165.80,163.09,162.59,152.87,133.36,132.15,131.95,131.08,127.63,127.42,125.57,1 22.96,116.74,114.82,114.14,112.36,66.10,55.88,53.09,49.73,40.53,29.85,29.19,27.58,25.45,22.15,20.24,14.23,13.88.

[0064] 7. Synthesis of N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]-1-benzofuran-5-yl}-N-(methylsulfonyl)-6-chloropyridine-3-carboxamide (Compound 7)

[0065]

[0066] The preparation was carried out according to a synthetic method similar to that in Example 1, except that 6-chloronicotinoyl chloride was used instead of 4-chlorobenzoyl chloride as the raw material, and the other steps were the same as in Example 1.

[0067] 1 H NMR(400MHz,DMSO-d6)δ8.50(d,J=2.4Hz,1H),7.91(dd,J=8.3,2.5Hz,1H),7.6 8(dd,J=14.1,8.9Hz,3H),7.53–7.44(m,3H),7.05(d,J=8.5Hz,2H),4.16(t,J=6 .0Hz,2H),3.59(s,3H),2.77(t,J=7.6Hz,2H),2.67(s,2H),2.33(s,2H),1.97( s,2H),1.63(p,J=7.5Hz,2H),1.55–1.08(m,12H),0.81(dt,J=22.8,7.2Hz,9H). 13 C NMR(101MHz,DMSO-d6)δ188.96,167.58,165.63,163.20,153.13,152.71,150.06,139.93,132.09,131.97,130.98,130.14,127.85,1 27.73,124.45,123.81,116.78,114.85,112.43,66.14,53.13,49.76,41.31,29.80,29.18,27.94,27.57,22.14,20.26,14.24,13.86.

[0068] 8. Synthesis of N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]-1-benzofuran-5-yl}-N-(methylsulfonyl)benzo[d][1,3]dioxolane-5-carboxamide (Compound 8)

[0069]

[0070] The preparation was carried out according to a synthetic method similar to that in Example 1, except that piperonyl chloride was used instead of 4-chlorobenzoyl chloride as the raw material, and the other steps were the same as in Example 1.

[0071] 1 H NMR (400MHz, DMSO-d6) δ7.68 (dd, J=17.1, 8.7Hz, 3H), 7.44 (dd, J=8.7, 2.3Hz, 1H), 7. 30(d,J=2.2Hz,1H),7.12(d,J=8.2Hz,1H),7.08–6.99(m,3H),6.86(d,J=8.2Hz,1H),6 .04(s,2H),4.14(t,J=6.1Hz,2H),3.45(s,3H),2.80(t,J=7.6Hz,2H),2.68(s,2H),2. 37(s,2H),1.90(s,2H),1.64(p,J=7.4Hz,2H),1.53–1.09(m,12H),0.88–0.75(m,9H). 13 CNMR(101MHz,DMSO-d6)δ187.80,168.74,164.63,162.10,151.71,149.73,146.41,132.05,130.81,129.79,126.46,126.25,126.22,124.55,1 21.80,115.60,113.66,111.21,108.31,107.29,101.40,65.10,52.26, 48.66,39.32,28.72,28.36,27.91,26.37,21.00,19.21,13.13,12.72.

[0072] 9. Synthesis of N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]-1-benzofuran-5-yl}-N-(methylsulfonyl)-4-nitrobenzamide (Compound 9)

[0073]

[0074] The preparation was carried out according to a synthetic method similar to that of Example 1, except that 4-nitrobenzoyl chloride was used instead of 4-chlorobenzoyl chloride as a raw material, and the other steps were the same as those of Example 1.

[0075] 1 H NMR(400MHz,DMSO-d6)δ8.11(d,J=8.6Hz,2H),7.73(dd,J=19.0,8.5Hz,4H),7. 62(d,J=8.5Hz,1H),7.48(d,J=8.6Hz,2H),7.03(d,J=8.5Hz,2H),4.15(t,J=6. 1Hz,2H),3.61(s,3H),2.74(t,J=7.6Hz,2H),2.64(s,2H),2.34(s,2H),1.91(s ,2H),1.60(p,J=7.5Hz,2H),1.49–1.06(m,12H),0.79(dt,J=25.4,7.3Hz,9H). 13 C NMR(101MHz,DMSO-d6)δ188.98,169.26,165.59,163.29,153.01,150.49,133.27,132.50,131.90,131.65,130.93,127.69,123.42,1 21.51,120.81,118.95,116.77,114.77,112.29,66.32,53.54,49.91,41.01,29.79,29.05,27.56,26.49,22.09,20.41,14.28,13.81.

[0076] 10. Synthesis of N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]-1-benzofuran-5-yl}-N-(methylsulfonyl)-4-(trifluoromethoxy)benzamide (Compound 10)

[0077]

[0078] The preparation was carried out according to a synthetic method similar to that in Example 1, except that 4-trifluoromethoxybenzoyl chloride was used instead of 4-chlorobenzoyl chloride as a raw material, and the other steps were the same as those in Example 1.

[0079] 1H NMR(400MHz, DMSO-d6)δ7.72–7.59(m,5H),7.45(dd,J=8.7,2.2Hz,1H),7.39( d,J=2.2Hz,1H),7.30(d,J=8.3Hz,2H),7.00(d,J=8.9Hz,2H),4.13(t,J=6.1H z,2H),3.55(s,3H),2.77(t,J=7.5Hz,2H),2.60(s,2H),2.43(s,2H),1.88(s, 2H),1.61(p,J=7.5Hz,2H),1.45–1.07(m,12H),0.78(dt,J=17.2,7.3Hz,9H). 13 C NMR(101MHz,DMSO-d6)δ188.98,169.26,165.59,163.29,153.01,150.49,133.27,132.50,131.90,131.65,130.93,127.69,123.42,1 21.51,120.81,118.95,116.77,114.77,112.29,66.32,53.54,49.91,41.01,29.79,29.05,27.56,26.49,22.09,20.41,14.28,13.81.

[0080] 11. Synthesis of N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]-1-benzofuran-5-yl}-N-(methylsulfonyl)morpholine-4-carboxamide (Compound 11)

[0081]

[0082] The preparation was carried out according to a synthetic method similar to that in Example 1, except that 4-morpholinecarbonyl chloride was used instead of 4-chlorobenzoyl chloride as the raw material, and the other steps were the same as in 1.

[0083] 1 H NMR (400MHz, DMSO-d6) δ7.78(dd,J=8.7,3.7Hz,3H),7.40(d,J=10.3Hz,2H),7.04(d,J=8.4Hz,2H),4.11(t,J=6.1Hz,2H),3.35(s ,8H),3.17(s,3H),2.83(t,J=7.4Hz,2H),2.35(s,4H),1.84(s,2H),1.67(p,J=7.5Hz,2H),1.53–1.06(m,12H),0.84–0.76(m,9H). 13C NMR (101MHz, DMSO-d6) δ189.21,165.76,163.33,154.55,152.80,133.02,132.00,131.02,128.05,124.98,120.42,116. 91,114.80,112.71,66.40,65.97,53.69,49.98,45.64,38.63,29.85,29.43,27.63,26.91,22.12,20.49,14.36,13.87.

[0084] 12. Synthesis of N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]-1-benzofuran-5-yl}-N-(methylsulfonyl)-3-fluorobenzamide (Compound 12)

[0085]

[0086] The preparation was carried out according to a synthetic method similar to that in Example 1, except that 3-fluorobenzoyl chloride was substituted for 4-chlorobenzoyl chloride as the raw material, and the other steps were the same as those in Example 1.

[0087] 1 H NMR (400MHz, DMSO-d6) δ7.69(d,J=8.5Hz,2H),7.64(d,J=8.8Hz,1H),7.47(dd,J=8 .7,2.2Hz,1H),7.40–7.29(m,4H),7.27–7.19(m,1H),7.02(d,J=8.6Hz,2H),4.14( t,J=6.1Hz,2H),3.55(s,3H),2.77(t,J=7.6Hz,2H),2.59(s,2H),2.42(s,2H),1.8 8(s,2H),1.62(p,J=7.5Hz,2H),1.50–1.10(m,12H),0.79(dt,J=14.2,7.3Hz,9H). 13 C NMR(101MHz,DMSO-d6)δ188.94,169.18,165.58,163.33,160.50,153.00,132.45,131.92,131.00,130.91,127.76,127.64,125.22,123.4 4,118.86,116.74,116.06,115.82,114.79,112.26,66.31,53.56,49 .90,41.01,29.82,29.07,27.54,26.63,22.14,20.43,14.31,13.85.

[0088] 13. Synthesis of N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]-1-benzofuran-5-yl}-N-(methylsulfonyl)-3-methylbenzamide (Compound 13)

[0089]

[0090] The preparation was carried out according to a synthetic method similar to that in Example 1, except that 4-chlorobenzoyl chloride was replaced by 3-methylbenzoyl chloride as the raw material in the third step, and the other steps were the same as in Example 1.

[0091] 1 H NMR (400MHz, DMSO-d6) δ7.68(d,J=8.4Hz,2H),7.63(d,J=8.7Hz,1H),7.44(d,J=8.8Hz,1 H),7.35(d,J=19.8Hz,2H),7.25(d,J=6.4Hz,1H),7.18(d,J=7.4Hz,2H),7.00(d,J=8.4Hz ,2H),4.13(t,J=6.1Hz,2H),3.51(s,3H),2.76(t,J=7.4Hz,2H),2.58(s,2H),2.41(s,2H) ,2.21(s,3H),1.88(s,2H),1.61(p,J=7.4Hz,2H),1.50–1.09(m,12H),0.84–0.74(m,9H). 13 C NMR(101MHz,DMSO-d6)δ188.99,170.72,165.56,163.28,152.93,138.15,134.04,132.93,132.90,131.90,130.94,129.90,128.48,127.74,1 27.58,126.44,123.18,116.73,114.78,112.21,66.32,53.57,49.91, 40.81,29.82,29.19,27.57,26.51,22.13,21.12,20.44,14.32,13.85.

[0092] Example 2 Anti-tumor cell proliferation activity of dronedarone derivatives

[0093] In this example, the MTT assay was used to evaluate the antiproliferative activity of compounds 1-13 prepared in Example 1 of the present invention against HepG-2, a hepatoma cell line, Hela, a cervical cancer cell line, HGC27, a colorectal cancer cell line, HT29, a pancreatic cancer cell line, PANC-1, and a ampullary cancer cell line, DPC-X1, using 5-FU and dronedarone as positive controls. Other compounds of the present invention exhibited similar antiproliferative effects as compounds 1-13, but the compounds of the present invention should not be construed as exhibiting only the following beneficial effects.

[0094] The test steps for anti-tumor cell proliferation activity are as follows: digest and collect tumor cells in the logarithmic growth phase, seed them in a 96-well culture plate at a cell density of 8000 cells / well, add 100 μL of complete culture medium containing 10% fetal bovine serum to each well, place the culture plate in an incubator (37°C, 5% CO2) and incubate for about 24 hours, then remove the culture medium and replace it with culture medium containing different concentrations of the compound and continue incubating for 48 hours. Then, add 10 μL of MTT to each well of the culture plate, place the culture plate in an incubator (37°C, 5% CO2) and continue incubating for 3-4 hours. Finally, use a multifunctional microplate reader to measure the absorbance (OD) value at a wavelength of 490 nm to calculate the half-maximal inhibitory concentration (IC) 50 As shown in Table 1, the dronedarone derivatives of the present invention exhibit significant anti-tumor cell proliferation activity, and the anti-proliferative activity is superior to that of clinical drugs fluorouracil and dronedarone.

[0095] Table 1 Anti-tumor cell proliferation activity of dronedarone derivatives

[0096]

[0097] Example 3 Dronedarone derivatives inhibit the colony formation of tumor cells

[0098] This example uses compound 4 prepared in Example 1 as an example to evaluate the anti-tumor cell proliferation activity of the synthesized series of compounds using a cell cloning assay. Other compounds in the present invention have similar anti-proliferative effects as compound 4, but it should not be construed that the compounds of the present invention only have the following beneficial effects.

[0099] The cell cloning assay was performed as follows: HT29 cells were cultured in medium-sized culture dishes. When the cells reached 70% growth, they were digested as described above to prepare a cell suspension. Cells were then seeded in 24-well plates at a density of 500 cells / well in 500 μL of total culture medium. The inoculated plates were then placed in a cell culture incubator and incubated for approximately 24 hours. The old culture medium was then discarded, and culture medium containing various concentrations of T0 was added for a further 8-10 days. The complete culture medium containing various concentrations of Compound 4 was replaced every 48 hours. Once the cells reached an appropriate density, the old culture medium was discarded, and the cells were washed twice with 1× PBS. The cells were then fixed with 500 μL of 4% paraformaldehyde for approximately 40 minutes. The fixative was then aspirated, and the 24-well plates were washed again with 1× PBS. The plates were then stained with 0.1% crystal violet for 30 minutes. After the crystal violet solution was recovered, the plates were washed three times with 1× PBS, air-dried, and photographed.

[0100] The results are as follows Figure 1 As shown, the dronedarone derivatives of the present invention can significantly inhibit the colony formation of colorectal cancer cells.

[0101] Example 4 Dronedarone derivatives inhibit tumor cell migration

[0102] This example uses compound 4 prepared in Example 1 as an example to evaluate the anti-tumor cell proliferation activity of the synthesized series of compounds using a cell scratch assay. Other compounds in the present invention have similar anti-proliferative effects to the compounds listed below, but should not be construed as limiting the compounds of the present invention to having only the following beneficial effects.

[0103] The steps of the cell scratch test are as follows: First, use a marker pen to draw horizontal lines evenly on the back of a 6-well plate, approximately every 0.5 to 1 cm, across the wells, and at least 5 lines per well; then, remove colon cancer HT29 cells in the logarithmic growth phase, discard the old culture medium, wash the cells twice with 1× PBS, and then digest them with trypsin to make a single cell suspension, and use 3×10 5 The cells were inoculated at a density of 100 cells / well in a 6-well culture plate. The inoculation principle was that the fusion rate reached 90% after overnight, and the final total volume of culture medium per well was 2 mL; then cultured in a 37°C, 5% CO2 incubator for 24 hours. The next day, a 10 μL pipette tip was used to scratch the 6-well plate lid perpendicular to the horizontal line on the back. The pipette tip could not be tilted during the entire operation. After the scratching, the cells were washed 3 times with PBS to remove the scratched cell debris. Wipe off the marker horizontal scratches on the back of the 6-well plate. Serum-free culture medium and serum-free culture medium containing different concentrations of compound 4 were then added, and photos were taken under a microscope. Finally, the images were processed and the results were analyzed.

[0104] The results are as follows Figure 2As shown, the dronedarone derivatives of the present invention can significantly inhibit the migration of cancer cells.

[0105] Example 5 Dronedarone derivatives promote apoptosis of tumor cells

[0106] This example uses Compound 4 prepared in Example 1 as an example to evaluate the tumor cell apoptosis-promoting activity of the synthesized series of compounds using Hoechst 33258 staining and Annexin V-FITC / PI staining. Other compounds in the present invention exhibit similar tumor cell apoptosis-promoting effects as the compounds listed below, but this should not be construed as limiting the compounds of the present invention to the following beneficial effects.

[0107] The Hoechst 33258 staining test procedure is as follows: HT29 cells were cultured in a cell culture dish. When the cells grew to 80%, the cells were digested as described above and prepared into a cell suspension. 4 The cells were seeded at a density of 1000 μL / well in a 12-well plate with a total culture medium of 1000 μL. The inoculated culture plate was then placed in a cell culture incubator and cultured for about 24 hours. The old culture medium was then discarded and culture medium containing different concentrations of compound 4 was added and incubated for another 48 hours. The old culture medium was discarded and the cells were washed three times with 1× PBS solution. A 50 μg / mL Hoechst 33258 solution was prepared with 1× PBS solution. 500 μL of Hoechst 33258 staining solution was added to each well of the 12-well plate and incubated in a cell culture incubator for another 30 minutes. The cells were washed three times with 1× PBS solution and immediately observed under an inverted fluorescence microscope. The nuclear staining of apoptotic cells was enhanced, the fluorescence was brighter, and the cells appeared as round, condensed, or clumpy structures.

[0108] The results are as follows Figure 3 As shown, the dronedarone derivatives of the present invention can significantly promote the apoptosis of cancer cells.

[0109] Annexin V-FITC / PI staining test steps are as follows: HT29 cells were cultured in a cell culture dish. When the cells grew to 80%, the cells were digested as described above to prepare a cell suspension. Then, 4×10 4Cells were seeded at a density of 1000 μL of culture medium per well in a 12-well plate. The plate was then placed in a cell culture incubator and incubated for approximately 24 hours. The old culture medium was then discarded and culture medium containing various concentrations of Compound 4 was added for a further 48 hours. The culture medium from the 6-well plate was transferred to a 5 mL centrifuge tube. The cells were washed with 1 mL of PBS and the wash solution was collected in a 10 mL centrifuge tube. The cells were digested with EDTA-free trypsin for 2 minutes. The collected culture medium was added to the cells and mixed thoroughly. The supernatant was discarded at 1500 rpm for 5 minutes, and 1 mL of pre-chilled PBS was added to resuspend the cells. The cells were then collected by centrifugation. The supernatant was discarded, and 100 μL of PBS was added and mixed thoroughly. The cell suspension was transferred to a 5 mL flow cytometry tube and 5 μL of Annexin V-FITC staining solution was added. After mixing, the suspension was incubated at room temperature in the dark for 5 minutes. Before detection, 5 μL of propidium iodide (PI) solution was added, followed by 400 μL of PBS and mixed thoroughly. Flow cytometry analysis was performed immediately.

[0110] The results are as follows Figure 4 As shown, the dronedarone derivatives of the present invention can significantly promote the apoptosis of cancer cells.

[0111] In summary, the dronedarone derivatives prepared by the present invention have anti-colorectal cancer, pancreatic cancer, cervical cancer, gastric cancer, liver cancer, and ampullary cancer activities, and can be used as potential broad-spectrum anticancer drugs. Moreover, the dronedarone derivatives have good selectivity for colon cancer cells, can inhibit the proliferation and migration of colon cancer cells, and promote the apoptosis of colon cancer cells. The effect of treating colon cancer is better than that of the clinical drugs 5-Fu and dronedarone, and has good application prospects.

[0112] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features thereof may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A dronedarone derivative having broad-spectrum anticancer activity, characterized in that: The structural formula of the derivative is shown in the following formula (I): wherein M is selected from CR'; R' is selected from H, halogen, carbonyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 alkoxycarbonyl, substituted or unsubstituted C1-C6 acylamino, substituted or unsubstituted C1-C 10 alkyl; R is selected from substituted or unsubstituted C6-C 12 Aryl or heteroaryl, substituted or unsubstituted 3-12 membered cycloalkyl or heterocyclic group, substituted or unsubstituted C2-C6 alkenyl; The substitution refers to the substitution of one or more hydrogen atoms on the group by a substituent selected from the group consisting of a halogen atom, a carbonyl group, a carboxyl group, a hydroxyl group, an amino group, a nitro group, a cyano group, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a C1-C6 alkoxycarbonyl group, a C1-C6 acylamino group, a C1-C6 alkyl ... 10 Alkyl, C6-C 10 Aryl, five-membered heteroaryl, six-membered heteroaryl, or C1-C 10 Alkyl, C6-C 10 aryl or five-membered or six-membered heteroaryl.

2. The derivative according to claim 1, characterized in that The structural formula of the derivative is shown in the following formula (II):

3. The derivative according to claim 2, characterized in that The R is selected from substituted or unsubstituted phenyl, substituted or unsubstituted benzo 5-6 membered heterocyclic group, substituted or unsubstituted 3-12 membered cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted vinyl group.

4. The derivative according to claim 3, characterized in that The substitution is selected from alkyl substitution, alkoxy substitution, halogen substitution, haloalkyl substitution, and aryl substitution.

5. The derivative according to claim 4, characterized in that The substitution is C 1-4 Alkyl substitution, methoxy substitution, halogen substitution, trifluoromethyl substitution, trifluoromethoxy substitution, nitro substitution, phenyl substitution.

6. The derivative according to claim 5, characterized in that The R is selected from 4-chloro substituted phenyl, 4-trifluoromethyl substituted phenyl, 4-methoxy substituted phenyl, 4-nitro substituted phenyl, 4-trifluoromethoxy substituted phenyl, 3-fluoro substituted phenyl, 3-methyl substituted phenyl, vinyl phenyl, methylenedioxyphenyl, furan, morpholine, 2-chloropyridine, and cyclopropane.

7. The derivative according to claim 6, characterized in that The structural formula of the derivative is shown in any one of the following formulas (1) to (13):

8. Use of the derivative according to any one of claims 1 to 7 in the following applications: Application in the preparation of anti-tumor drugs; Application in the preparation of drugs for treating autoimmune diseases; Application in the preparation of drugs for treating inflammation; Application in the preparation of drugs for treating Alzheimer's disease.

9. The use according to claim 8, characterized in that The tumors include gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, cervical cancer and ampullary cancer.

10. The derivative according to any one of claims 1 to 7 is added with a pharmaceutically acceptable salt excipient to prepare any pharmaceutically acceptable dosage form.

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