Riluzole / ciprofloxacin heterozygote as well as derivative, preparation method and application of riluzole / ciprofloxacin heterozygote

Abstract

The invention relates to a riluzole / ciprofloxacin heterozygote, a derivative of the riluzole / ciprofloxacin heterozygote, a preparation method of the riluzole / ciprofloxacin heterozygote and anti-tumor application of the riluzole / ciprofloxacin heterozygote and the derivative of the riluzole / ciprofloxacin heterozygote and the derivative of the riluzole / ciprofloxacin heterozygote, and provides compounds LD-1, LD-2, LD-3, LD-4, LD-5, LD-6, LD-7 and LD-8, and the compounds have the activity of resisting proliferation of various tumor cells, have high anti-tumor cell proliferation activity and are superior to ciprofloxacin, riluzole and cis-chloroammine platinum. The compound as an MST3 inhibitor plays a potential important role in treatment of tumors and other diseases.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compound synthesis and pharmaceutical application, and specifically relates to a riluzole / ciprofloxacin hybrid and its derivatives, a preparation method thereof, and applications thereof as an MST3 inhibitor and an anti-tumor. Background Art

[0002] Protein kinase MST3 (mammalian ste20-like protein kinase 3, MST3), also known as protein kinase STK24 (serine / threonine-protein kinase 24, STK24), is a serine / threonine protein kinase belonging to the mammalian ste20-like protein kinase family. According to its function, MST3 is involved in regulating tumor cell proliferation, apoptosis, migration, invasion and other processes. Activated MST3 may promote the occurrence and development of tumors. At present, drug research based on MST3 inhibitors is in its infancy, and no related drugs have been found to enter clinical research. Therefore, it is of great significance to discover MST3 inhibitors with new structural types, high activity, high selectivity, and strong anti-cancer activity. Summary of the invention

[0003] Purpose of the invention: The present invention proposes riluzole / ciprofloxacin hybrids and their derivatives, as well as preparation methods and anti-tumor applications, to provide novel riluzole / ciprofloxacin hybrids and their derivatives with new structural types, high activity and high selectivity and MST3 inhibitory activity, and point out their applications in anti-tumor.

[0004] Technical solution:

[0005] The first aspect of the present invention provides a riluzole / ciprofloxacin hybrid and its derivatives, including the following compounds:

[0006]

[0008] The second aspect of the present invention provides a method for preparing the riluzole / ciprofloxacin hybrid and its derivatives, comprising the steps of:

[0009] (1) Dissolve ciprofloxacin (compound 1) in water / dioxane (1:1) containing 1 M NaOH, add Boc2O to the solution, and stir at room temperature (25°C) for 24 hours to obtain compound 2;

[0010] (2) Compound 2, HBTU and DMAP (catalytic amount) were dissolved in dry DCM, DIPEA was added, and the reaction mixture was stirred at room temperature for 30 min under nitrogen protection. Riluzole and its derivatives were added to the reaction mixture, respectively, and stirred at room temperature for 12 h to obtain the corresponding compounds 3a-h;

[0011] (3) Compounds 3a-h were dissolved in DCM solution, and trifluoroacetic acid was added dropwise under ice bath conditions to obtain the corresponding compounds LD-1(4a), LD-2(4a), LD-3(4a), LD-4(4a), LD-5(4a), LD-6(4a), LD-7(4a) and LD-8(4a).

[0012] Wherein, the structural formula of compound 1 is The structural formula of compound 2 is The structural formulas of compounds 3a-h are respectively

[0014] Furthermore, the derivative of riluzole in step (2) is one of 6-methoxybenzo[d]thiazol-2-amine, 5-methoxybenzo[d]thiazol-2-amine, benzo[d]thiazol-2-amine, 6-methylbenzo[d]thiazol-2-amine, 4-methylbenzo[d]thiazol-2-amine, 6-chlorobenzo[d]thiazol-2-amine and 4-chlorobenzo[d]thiazol-2-amine; the structural formulas of riluzole and its derivatives in step 2 are respectively

[0016] The third aspect of the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound or a pharmaceutically acceptable salt thereof.

[0017] The fourth aspect of the present invention provides a preparation, wherein the pharmaceutical composition is prepared by adding one or more pharmaceutically acceptable excipients to the compound.

[0018] The fifth aspect of the present invention provides the use of the compound or a pharmaceutically acceptable salt thereof in the preparation of an anti-tumor drug.

[0019] The sixth aspect of the present invention provides the use of the compound or a pharmaceutically acceptable salt thereof in the preparation of an MST3 inhibitor.

[0020] Compared with the prior art, the present invention has the following significant features:

[0021] 1. The compounds proposed in the present invention have anti-proliferation activity against multiple tumor cells and have relatively high anti-proliferation activity against tumor cells. In particular, compound LD-1 has the best anti-proliferation activity against tumor cells, which is far superior to ciprofloxacin, riluzole and cisplatin. High selectivity

[0022] 2. The compounds proposed in the present invention have the activity and selectivity to inhibit MST3. Therefore, such compounds have a potentially important role as MST3 inhibitors in the treatment of tumors and other diseases.

[0023] 3. The preferred compound LD-1 of the present invention has the activity of inducing tumor cell apoptosis and inhibiting the growth of subcutaneous tumors in nude mice without obvious toxic side effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 Schematic diagram of the preparation method of compounds LD-1, LD-2, LD-3, LD-4, LD-5, LD-6, LD-7 and LD-8; (a) in the figure: (Boc)2O, 1M NaOH, THF, rt, 16h; (b) riluzole and its derivatives, HBTU, DMAP, DIPEA, dryDCM, rt, 6h; (c) 1:1TFA / DCM, 0℃ to rt, 6h;

[0025] Figure 2 The effect of compound LD-1 on apoptosis of HepG2 cells; A is a picture of LD-1 affecting apoptosis of HepG2 cells analyzed by flow cytometry, the lower left quadrant represents live cells, the lower right quadrant represents early apoptotic cells, the upper right quadrant represents late apoptotic cells, and the upper left quadrant represents necrotic cells; B is a bar graph of the proportion of apoptotic cells in each group, compared with the control group, ** represents p<0.01, *** represents p<0.001, **** represents p<0.0001;

[0026] Figure 3 The selectivity profile of compound LD-1 against 217 kinases;

[0027] Figure 4 This is a photo of the tumor sample 15 days after administration;

[0028] Figure 5 The curves of tumor volume changes in each drug-treated group;

[0029] Figure 6 is the tumor weight at 15 days after administration;

[0030] Figure 7 The figure shows the body weight change curves of each drug group. DETAILED DESCRIPTION

[0031] The present invention is described in more detail below in conjunction with the accompanying drawings. The solvents used in the present invention are all commercially available chemically pure or analytically pure.

[0032] The structure of the compound was determined by nuclear magnetic resonance (NMR). NMR was measured using a Bruker AVANCE-300 / 500 NMR instrument, the solvent used was CDCl3 or DMSO-d6, and the internal standard was TMS. Figure 1 shown.

[0033] Example 1

[0034] 7-[4-(tert-Butyloxycarbonyl)piperazin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (Compound 2)

[0035] Ciprofloxacin (Compound 1) (5 g, 15 mmol) was dissolved in 87.5 mL of water / dioxane (1:1) containing 22.5 mL of 1 m NaOH. Boc2O (4.91 g, 22.5 mmol) was added to the solution and stirred at room temperature (25°C) for 24 h. Three quarters of the solvent was removed under air and acetone (300 mL) was added to the crude reaction residue. The solid product was filtered, washed extensively with acetone, and dried under vacuum. The product was collected as a white solid (6 g, 92% yield). 1 H NMR (400MHz, CDCl3) δ8.77(s,1H),8.02(d,JH-F=12.9Hz,1H),7.35(d,J=6.8Hz,1H),3.71-3.60( m,4H),3.57-3.50(m,1H),3.35-3.25(m,4H),1.50(s,9H),1.43-1.35(m,2H),1.29-1.19(m,2H).

[0036] Example 2

[0037] 1-Cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1,4-dihydroquinoline-3-carboxamide (Compound LD-1)

[0038] Compound 2 (0.5mmol), HBTU (0.6mmol) and DMAP (catalytic amount) were dissolved in 100mL dry DCM, followed by the addition of DIPEA (1mmol), and the reaction mixture was stirred at room temperature for 30min under nitrogen protection. Riluzole (1mmol) was added and stirred at room temperature for 12h. After the reaction was completed, 50mL was added and washed with distilled water. The organic phase was dried over MgSO4, concentrated in vacuo, and purified by silica gel column chromatography to obtain compound 3a. Compound 3a was dissolved in DCM (5mL), and trifluoroacetic acid (2.5mL) was dripped into the reaction mixture under stirring under ice bath conditions, stirred at room temperature for 3 hours, and after compound 3a completely disappeared (monitored by TLC), the solvent was removed under vacuum. The product was added to ether and dissolved by ultrasound, and then precipitated. The obtained light yellow solid was washed with ether and dried in vacuo to obtain compound LD-1 with a yield of 66%. 1 H NMR(400MHz,)δ13.85(s,1H),9.42(s,1H),8.81(s,1H),8.15(d,J=2.5Hz,1H),7.98(d,J=13.1Hz,1H),7.86(d,J=8.8Hz,1H),7.60(d ,J=7.4Hz,1H),7.44(dd,J=8.8,2.5Hz,1H),3.87(dq,J=7.2,3.7Hz,1H),3.64–3.50(m,4H),1.40–1.31(m,2H),1.23(t,J=5.1Hz,2H). 13 C NMR (151MHz, DMSO-d6) δ174.8, 163.0, 162.9, 158.6, 152.9 (d, J = 248.7Hz), 148.3, 147.8, 143.7, 138.6, 133.2, 121. 1,121.7,120.4(q,J=256.2Hz),120.0,115.1,111.8(d,J=22.4Hz),107.4,46.4(2C),42.6(2C),36.4,7.7(2C).HRMS for C 25 H 22 F4N5O3S[M+H] + :calcd,548.1374; found,548.1372.

[0039] Example 3

[0040] 1-Cyclopropyl-6-fluoro-N-(6-methoxybenzo[d]thiazol-2-yl)-4-oxo-7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxamide (Compound LD-2)

[0041] Using 6-methoxybenzo[d]thiazol-2-amine instead of 6-(trifluoromethoxy)benzo[d]thiazol-2-amine (same as riluzole in Example 2), and other conditions remained unchanged, the operation of Example 2 was repeated to obtain a light yellow solid LD-2 with a yield of 66%. 1 H NMR (600MHz, DMSO-d6) δ13.68(s,1H),8.81(s,1H),8.40(br,1H),8.00(d,J=12.5Hz,1H),7.67(d,J=8.0Hz,1H),7.60(d,J=2.5Hz,1H),7.59(d,J =8.0Hz,1H),7.05(dd,J=8.0,2.5Hz,1H),3.88–3.83(m,1H),3.82(s,3H) ,3.47(t,J=4.8Hz,4H),3.28(t,J=4.8Hz,4H),1.34(m,2H),1.22(m,2H). 13 C NMR(151MHz,DMSO-d6)δ174.94,163.00,159.11,158.51,154.21,152.56,150.53,148.28,145.42,139.04 ,124.05,122.51,120.50,113.26,111.81,107.84,106.65,104.58,55.87,50.46,45.37,36.12,8.03.HRMS forC 25 H 24 FN5O3S[M+H] + :calcd,494.1657; found,494.1658.

[0042] Example 4

[0043] 1-Cyclopropyl-6-fluoro-N-(5-methoxybenzo[d]thiazol-2-yl)-4-oxo-7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxamide (Compound LD-3)

[0044] Using 5-methoxybenzo[d]thiazol-2-amine instead of 6-(trifluoromethoxy)benzo[d]thiazol-2-amine and keeping other conditions unchanged, the procedure of Example 2 was repeated to obtain a light yellow solid LD-3 with a yield of 51%. 1H NMR(600MHz,DMSO-d6)δ13.73(s,1H),9.52(br,1H),8.79(s,1H),7.98(d,J =13.1Hz,1H),7.85(d,J=8.7Hz,1H),7.58(d,J=7.4Hz,1H),7.32(d,J=2.5Hz ,1H),6.96(dd,J=8.7,2.5Hz,1H),3.87(pd,J=6.8,3.2Hz,1H),3.83(s,3H), 3.53-5.57(m,4H),3.36–3.26(m,4H),1.43–1.35(m,2H),1.26–1.20(m,2H). 13 C NMR (151MHz, CDCl3) δ174.9, 163.6, 162.7, 155.2 (d, J = 257.9Hz), 153.53, 149.12, 145.74, 145.68, 139.41, 136.33, 123.49, 120 .43,117.76,117.52,113.04,112.88(d,J=22.6Hz),106.72,99.21,56.21,46.53,44.33(2C),44.25(2C),37.25,8.42(2C).HRMS for C 25 H 24 FN5O3S[M+H] + :calcd,494.1657; found,494.1656.

[0045] Example 5

[0046] N-(Benzo[d]thiazol-2-yl)-1-cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxamide (Compound LD-4)

[0047] Using benzo[d]thiazol-2-amine instead of 6-(trifluoromethoxy)benzo[d]thiazol-2-amine and keeping other conditions unchanged, the procedure of Example 2 was repeated to obtain a light yellow solid LD-4 with a yield of 41%. 1 H NMR (600MHz, CDCl3) δ11.94(s,1H),9.17(s,1H),8.32(br,1H),7.96(m,2H),7.99–7.89(d,J=7.8Hz,1H),7.7 5–7.59(m,3H),3.94(p,J=6.0Hz,1H),3.76-3.82(m,4H),3.66–3.57(m,3H),1.54(m,2H),1.39–1.18(m,2H). 13C NMR (151MHz, CDCl3) δ174.7, 163.8, 162.6, 154.3 (d, J = 247.4Hz), 149.1, 147.2, 145.7, 139.4, 134.8, 129.8 ,127.6,126.0,122.9,120.1,116.1,112.8(d,J=21.5Hz),106.7,46.5(2C),44.3(2C),37.3,8.3(2C).HRMS for C2H 23 FN5O2S[M+H] + :calcd,464.1551; found,464.1587.

[0048] Example 6

[0049] 1-Cyclopropyl-6-fluoro-N-(6-methylbenzo[d]thiazol-2-yl)-4-oxo-7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxamide (Compound LD-5)

[0050] Using 6-methylbenzo[d]thiazol-2-amine instead of 6-(trifluoromethoxy)benzo[d]thiazol-2-amine and keeping other conditions unchanged, the procedure of Example 2 was repeated to obtain a light yellow solid LD-5 with a yield of 69%. 1 H NMR (600MHz, DMSO-d6) δ13.76(s,1H),9.57(dr,1H),8.80(d,J=1.8Hz,1H),7.98(d,J=12.2Hz,1H),7.77(d,J=7.7Hz,1H),7 .58(s,1H),7.46(d,J=2.5Hz,1H),7.33–7.27(m,1H),3.62–3.43(m,4H),3.31-3.22(m,4H),2.55(s,3H),1.39–1.16(m,4H). 13 C NMR (151MHz, CDCl3) δ175.0, 163.6, 161.8, 154.3 (d, J = 254.8Hz), 149.2, 145.7, 144.3, 139.5, 132.6, 131.4, 138.8, 12 6.2,122.6,120.3,115.7(d,J=22.6Hz),112.8,106.7,46.5(2C),44.3(2C),37.3,21.6,8.3(2C).HRMS:478.1710[M+H] + ,(calcd for C 25 H 25 FN5O2S,478.1708).HRMS for C25 H 25 FN5O2S[M+H] + :calcd,478.1708; found,478.1710.

[0051] Example 7

[0052] 1-Cyclopropyl-6-fluoro-N-(4-methylbenzo[d]thiazol-2-yl)-4-oxo-7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxamide (Compound LD-6)

[0053] Using 4-methylbenzo[d]thiazol-2-amine instead of 6-(trifluoromethoxy)benzo[d]thiazol-2-amine and keeping other conditions unchanged, the procedure of Example 2 was repeated to obtain a light yellow solid LD-6 with a yield of 72%. 1 H NMR (600MHz, DMSO-d6) δ13.80(s,1H),8.76(s,1H),7.90(d,J=13.4Hz,1H),7.79(d,J=7.8Hz,1H),7.49(d,J=7.4Hz,1H),7.25(d, J=7.3Hz,1H),7.21(t,J=7.6Hz,1H),3.82(p,J=6.0Hz,1H),3.44–2.89(m,8H),2.59(s,3H),1.37–1.28(m,2H),1.25–1.19(m,2H). 13 C NMR (151MHz, CDCl3) δ175.1, 163.4, 162.4, 154.2 (d, J = 253.4Hz), 149.3, 148.3, 145.5, 139.2, 134.1, 130.7, 127.6, 126.6, 126.0, 120.4, 120.1 112.8(d,J=22.6Hz),107.2,46.6(2C),43.9(2C),37.0,17.26,8.33(2C).HRMS for C 25 H 25 FN5O2S[M+H] + :calcd,478.1708; found,478.1703.

[0054] Example 8

[0055] N-(6-chlorobenzo[d]thiazol-2-yl)-1-cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxamide (Compound LD-7)

[0056] Using 6-chlorobenzo[d]thiazol-2-amine instead of 6-(trifluoromethoxy)benzo[d]thiazol-2-amine and keeping other conditions unchanged, the procedure of Example 2 was repeated to obtain a light yellow solid LD-7 with a yield of 27%. 1 H NMR (600MHz, DMSO-d6) δ13.87(s,1H),9.28(br,1H),8.83(s,1H),8.17(d,J=2.1Hz,1H),8.02(d,J=13.1Hz,1H),7.78(d,J= 8.4Hz,1H),7.62(d,J=7.4Hz,1H),7.52–7.46(m,1H),3.88(m,1H),3.38-3.31(m,4H),1.38-1.33(m,2H),1.25–1.19(m,2H). 13 C NMR (151MHz, CDCl3) δ175.2, 163.9, 162.8, 153.4 (d, J = 257.9Hz), 149.1, 147.9, 145.5, 139.4, 133.8, 133.5, 13 1.8,128.1,122.6,121.3,120.2,113.0(d,J=22.2Hz),106.76,47.9(2C),44.3(2C),37.33,8.41(2C).HRMSfor C 24 H 22 ClFN5O2S[M+H] + :calcd,498.1161; found,498.1150.

[0057] Example 9

[0058] N-(4-chlorobenzo[d]thiazol-2-yl)-1-cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxamide (Compound LD-8)

[0059] Using 4-chlorobenzo[d]thiazol-2-amine instead of 6-(trifluoromethoxy)benzo[d]thiazol-2-amine and keeping other conditions unchanged, the procedure of Example 2 was repeated to obtain a light yellow solid LD-8 with a yield of 51%. 1H NMR (600MHz, CDCl3) δ11.44(s,1H),9.02(s,1H),8.19(s,1H),7.88(d,J=12.3Hz 1H),7.79(d,J=8.3Hz,1H),7.64(d,J=7.7Hz,1H),7.58(s,1H),7.50(t,J=8.0Hz,1H), 3.84(p,J=6.0Hz,1H),3.68(m,4H),3.55(m,4H),1.47–1.38(m,2H),1.25–1.19(m,2H). 13 C NMR (151MHz, CDCl3) δ174.1, 162.9, 162.7, 153.5 (d, J = 257.9Hz), 148.6, 145.0, 138.6, 132.1, 128.8, 127.6 ,126.7,125.9,120.7,120.1,119.4,112.07(d,J=22.6Hz),106.1,45.7(2C),43.6(2C),36.4,7.6(2C).HRMS for C 24 H 22 ClFN5O2S[M+H] + :calcd,498.1161; found,498.1161.

[0060] Example 10: Evaluation of the anti-tumor cell proliferation activity of the target compound

[0061] The MTT assay was used. The cells in exponential growth phase were seeded in 96-well plates (3×10 3 ) and cultured overnight. Then different concentrations of compounds were added and incubated for 72 hours. Thereafter, 20 μL of 10% MTT (5 mg / mL, PBS) reagent was added to each well and incubated in the incubator for another 4 hours. Subsequently, the supernatant was discarded, 100 μL of DMSO was added, and oscillation was performed for 8 minutes. The absorbance of the cells was measured at 490 nm on a microplate reader. Growth inhibition percentage = 100–100×(OD 样品 -OD 空白 ) / (OD 对照 -OD 空白 GI was calculated using nonlinear regression analysis (percent growth versus concentration). 50 The results are shown in Table 1. The results show that most of the riluzole / ciprofloxacin hybrids and their derivatives have moderate anti-tumor cell proliferation activity. In particular, compound LD-1 has the best anti-tumor cell proliferation activity.

[0062] Table 1 Activity of target compounds in inhibiting tumor cell proliferation

[0063]

[0064]

[0065] a GI 50 The values ​​are 50% inhibition concentrations after drug treatment for 72 hours. All values ​​are expressed as m±SEM. The experiment was repeated three times, and three replicate wells were used for each concentration in each experiment. b Liver cancer, c Colon cancer, d Lung cancer.

[0066] Example 11: Effect of LD-1 on apoptosis of HepG2 cell line

[0067] Annexin V-FITC and PI methods were used to evaluate the apoptotic effect of compound LD-1 on HepG2 cell lines. Figure 2 ). After 24h treatment with 0.5μM, 1.0μM and 2.0μM LD-1, the proportion of apoptotic cells was 24.2%, 28.1% and 64%, respectively. The above results show that LD-1 can induce apoptosis of HepG2 cells in a concentration-dependent manner. Other compounds have similar effects and will not be repeated here.

[0068] Example 12: Evaluation of the inhibitory effect of target compounds on MST3 enzyme activity

[0069] Mobility shift assay was used for detection, and Sunitinib was used as the reference standard. IC values ​​of LD-1 to LD-8 for inhibition of MST3 activity 50 The values ​​are shown in Table 2. From the results, it can be seen that most compounds have good MST3 inhibitory activity, among which compounds LD-1 and LD-3 have better inhibitory activity against MST3.

[0070] Table 2 Evaluation of the target compounds in inhibiting MST3 enzyme activity a

[0071]

[0072] a For one experiment, each concentration was tested in duplicate.

[0073] Example 13: Inhibitory activity of LD-1 against 217 kinases

[0074] To explore the selectivity of the compound for MST3, we selected LD-1 for kinase profile experiments. At a concentration of 1 μM, the inhibition of LD-1 on 217 kinases is shown in the following table. Figure 3As shown in Table 3. The results showed that the inhibition rate of LD-1 on MST3 was 95.49% at a concentration of 1 μM, while the inhibition rate on AKT2, which ranked second, was only 66.52%, while the inhibition rates on YSK1, MST1, and MST2, which had higher homology, were 8.64%, 27.06%, and <1.00%, respectively. It can be seen that LD-1 has a high selectivity for MST3.

[0075] Table 3 Inhibition of 217 kinases by LD-1 a

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082] a: One experiment, two replicate wells.

[0083] Example 14: Effects of LD-1 on subcutaneous tumor-bearing nude mice.

[0084] Based on the above experimental results, we selected LD-1 for in vivo tumor bearing experiments (other compounds also have the potential to inhibit tumor growth in vivo). Other compounds have similar effects and will not be repeated here. Each mouse was injected with 200 μL (1×10 7 7 days after injection of a cell suspension of 100 HepG2 cells suspended in 50% PBS, the tumor volume of the mice reached about 100 mm 3 The tumor-bearing mice were randomly divided into 3 groups (n=5) according to the tumor volume, and 0.9% NaCl, Sorafenib (40 mg / kg) and LD-1 (40 mg / kg) were given by gavage, respectively. The mice were weighed at a fixed time every day, and the tumor volume was measured with a vernier caliper. The measurement formula of tumor volume was: tumor volume (mm 3 )=(length×width 2 ) / 2, relative tumor volume (RTV) = tumor volume on the 15th day / tumor volume on the 0th day, relative tumor volume inhibition rate (TGI) = (RTV tumor volume of the drug group / RTV tumor volume of the control group) × 100%. Figure 4 The following are photos of tumor samples taken 15 days after administration. Figure 5Figure 2 is the tumor volume change curve of each group. The TGI of Sorafenib (40 mg / kg) group and LD-1 (40 mg / kg) group were 32.52% and 47.64%, respectively. Figure 6 The tumor weight of each group after 15 days of administration was statistically significant compared with the control group (p<0.05). Figure 7 The body weight change curves of each group. Figures 4 to 6 It shows that LD-1 has a good effect in inhibiting the growth of subcutaneous tumors. Figure 7 This indicates that LD-1 has no significant effect on the body weight of nude mice and has a certain degree of safety.

[0085] In summary, the riluzole / ciprofloxacin hybrid and its derivatives proposed in the present invention can be used to prepare anti-tumor drugs, and the dosage forms of the drugs include but are not limited to tablets, powders, pills, granules, capsules, solutions, suspensions or injections.

[0086] The embodiments described above are only descriptions of the preferred modes of the present invention, and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should all fall within the protection scope determined by the claims of the present invention.

Claims

1. A riluzole / ciprofloxacin hybrid and its derivatives, characterized in that: Includes the following compounds:

2. A method for preparing the riluzole / ciprofloxacin hybrid and its derivatives as claimed in claim 1, characterized in that: The steps are: (1) dissolving ciprofloxacin in water / dioxane containing 1 M NaOH, adding Boc2O to the solution, and stirring at room temperature to obtain compound 2; (2) Compound 2, HBTU and DMAP were dissolved in dry DCM, DIPEA was added, and the reaction mixture was stirred at room temperature under nitrogen protection. Riluzole or its derivatives were added to the reaction mixture, respectively, and stirred at room temperature to obtain the corresponding compounds 3a-h; (3) Compounds 3a-h were dissolved in DCM solution, and trifluoroacetic acid was added dropwise under ice bath conditions to obtain the corresponding compounds LD-1, LD-2, LD-3, LD-4, LD-5, LD-6, LD-7 and LD-8.

3. The preparation method according to claim 2, characterized in that: The derivative of riluzole in step (2) is one of 6-methoxybenzo[d]thiazol-2-amine, 5-methoxybenzo[d]thiazol-2-amine, benzo[d]thiazol-2-amine, 6-methylbenzo[d]thiazol-2-amine, 4-methylbenzo[d]thiazol-2-amine, 6-chlorobenzo[d]thiazol-2-amine and 4-chlorobenzo[d]thiazol-2-amine.

4. A pharmaceutical composition, characterized in that Contains pharmaceutically acceptable excipients and the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

5. A preparation, characterized in that A preparation prepared by adding one or more pharmaceutically acceptable excipients to the compound as claimed in claim 1.

6. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of anti-tumor drugs.

7. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of an MST3 inhibitor.

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