An alkoxy-coupled naphthamide derivative and its preparation and application

Abstract

The present invention relates to the field of medical technology, and in particular to an alkoxy-coupled naphthamide derivative and its preparation and application. The chemical structural formula of the alkoxy-coupled naphthamide derivative is shown in Formula I. The alkoxy-coupled naphthamide derivative described in Formula I of the present invention retains the basic skeleton of the binaphthyl structure of gossypol, introduces flexible and easily tortuous atomic chains between naphthalene rings to increase the molecular length, and modifies both ends of the molecule with amino acids, thereby reducing its toxicity, having the advantages of low acute toxicity and high drug safety, having broad-spectrum anti-tumor activity, and can be used as a broad-spectrum anti-tumor drug in clinical application.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to an alkoxy-coupled naphthamide derivative and a preparation method and application thereof. Background Art

[0002] Cottonpol, a yellow polyphenol compound, exists in the roots, stems and seeds of cotton, a plant of the Malvaceae family. It is a chiral optical isomer with multiple biological activities, including sperm inhibition, immunomodulation and anti-cancer, and is widely used in drug development and medical practice. In the 1980s, gossypol acetate tablets attracted widespread attention as an oral male contraceptive. At present, in clinical practice, this drug can be taken orally to treat female uterine bleeding, functional uterine bleeding, uterine fibroids with menorrhagia and endometriosis, including dysmenorrhea, excessive menstrual bleeding, long menstrual period, breast tenderness and abdominal pain during menstruation, etc., and its therapeutic effect is significant. In recent years, many studies have confirmed that by modifying cottonpol with different series of amino acid derivatives, small molecule dipeptides and tripeptides, D-glucosamine and certain amino alkanoic acids, it can not only effectively reduce the cytotoxicity of cottonpol, but also enhance the anti-HIV-1 and anti-influenza virus activity of cottonpol. Among them, the antiviral effect of cottonpol modified with amino acids is the best. From the antiviral structure-activity relationship of cottonpol and its derivatives, the formyl or phenolic hydroxyl group in its structure may not be an important active functional group, which is related to its toxicity. In the past decade, cottonpol and its derivatives have become a research hotspot for BCL-2 or BCL-xL inhibitors. Inspired by this, in order to find new skeleton anti-tumor drugs, we consider reducing the toxic side effects of cottonpol, simplifying the structure of cottonpol, designing a series of alkoxy-coupled naphthamide amino acid derivatives, and investigating their anti-tumor activity, so as to provide ideas for finding low-toxic, safe and effective anti-tumor drugs. Summary of the invention

[0003] In view of this, the present invention aims to provide an alkoxy-coupled naphthamide derivative, preparation and clinical application thereof in anti-tumor drugs, and provide a new strategy for preparing low-toxic, safe and effective anti-tumor drugs. The present invention starts from reducing the toxic and side effects of gossypol, simplifies the structure of gossypol, retains only the basic skeleton of the binaphthyl structure of gossypol, introduces flexible and easily tortuous atomic chains between naphthalene rings to increase the molecular length, and modifies the two ends of the molecule with amino acids, designs a series of alkoxy-coupled naphthamide amino acid derivatives, examines their anti-tumor activity, and provides ideas for finding low-toxic, safe and effective anti-tumor drugs.

[0004] The technical solution of the present invention is achieved in this way:

[0005] In a first aspect, the present invention discloses an alkoxy-coupled naphthamide derivative, wherein the chemical structure of the naphthamide derivative is as shown in Formula I:

[0006]

[0007] Among them, n is 1, 2 or 3, RNH includes Any one of .

[0008] In the present invention, the compound shown in the above general formula I can induce G0 / G1 arrest at low concentrations and S phase arrest at high concentrations, and may act on multiple links of the cell cycle through different targets, thereby achieving a broad-spectrum anti-tumor effect; at the same time, the alkoxy-coupled naphthamide derivative has the advantages of low acute toxicity and high drug safety. Specifically, the alkoxy-coupled naphthamide derivative of the present invention removes part of the structure that causes toxic side effects in cotton pol, and only retains the basic skeleton of the binaphthyl structure, which can reduce the structural features related to toxic side effects; introduces flexible and easily tortuous atomic chains between naphthalene rings to increase the molecular length, which helps to increase the flexibility and variability of the molecule, and may reduce the specific binding of the molecule to biological molecules, reducing toxic side effects; using amino acid modification at both ends of the molecule can improve the water solubility and biocompatibility of the molecule, help reduce the toxic effect on normal cells, and improve the targeting of the drug; introducing alkoxy groups by alkoxy coupling may change the biological activity and metabolic pathway of the molecule, and reduce the occurrence of toxic side effects.

[0009] On the basis of the above technical solution, preferably, the naphthamide derivative is any one of compounds 1 to 8, wherein the chemical structures of compounds 1 to 8 are as follows:

[0010]

[0011] In a second aspect, the present invention provides a method for preparing an alkoxy-coupled naphthamide derivative, comprising the following steps:

[0012] S1, subjecting compound A and dibromoalkane to a nucleophilic substitution reaction to obtain compound B;

[0013] S2, subjecting compound B to oxidation reaction to obtain compound C;

[0014] S3, subjecting compound C and compound D to a condensation reaction to obtain the naphthamide derivative;

[0015] Among them, the chemical structural formulas of compounds A, B, C, and D are as follows:

[0016] Among them, the chemical structure of compound A is The chemical structure of compound B is The chemical structure of compound C is The chemical structure of compound D is RNH2, wherein the molecular structure of RNH2 includes Any one of .

[0017] Based on the above technical solution, preferably, step S1 specifically includes: dissolving compound A in an organic solvent, adding dibromoalkane and potassium carbonate, reacting under alkaline conditions for 3.5 to 4.5 hours to obtain compound B, wherein the molar ratio of compound A, dibromoalkane and potassium carbonate is 1: (0.4 to 0.6): (1.4 to 1.6). The alkaline conditions are pH 8 to 10, the reaction temperature is 35 to 45°C, and the organic solvent is a solvent that can dissolve compound A and does not affect the reaction, such as DMF. The molecular formula of the dibromoalkane is C x H 2x Br2, where x is 1-4.

[0018] On the basis of the above technical scheme, preferably, step S2 specifically comprises: dissolving compound B in an organic solvent, adding sodium chlorite and formic acid, and reacting for 20 to 40 minutes to obtain compound C, wherein the molar ratio of compound B to sodium chlorite is 1:(2.3 to 2.5), and the organic solvent is a solvent that can dissolve compound B and does not affect the reaction, such as DMF.

[0019] On the basis of the above technical solution, preferably, step S3 specifically includes:

[0020] S31, dissolving compound C in an organic solvent, adding DIPEA and HATU, and reacting for 20 to 40 minutes;

[0021] S32, then add compound D, and react at 25-27° C. for 16-20 h to obtain the naphthamide derivative.

[0022] Further, step S32 specifically includes: dissolving compound D and DIPEA in an organic solvent to obtain a mixed solution, adding the mixed solution to the reaction solution of step S31, reacting at 25-27°C for 16-20 hours, and purifying the crude product obtained by the reaction by column chromatography to obtain the naphthamide derivative. In step S31, the reaction progress is monitored by TLC. When TLC shows that compound C is completely reacted and an intermediate is generated, step S32 is performed. The organic solvent is a solvent that can dissolve compounds C and D and does not affect the reaction, such as DMF.

[0023] Based on the above technical solution, preferably, in step S31, the molar ratio of compound C, DIPEA and HATU is 1:(2.3-2.5):(2.3-2.5). In step S32, the molar ratio of compound C to compound D is 1:(2.2-2.4); the molar ratio of compound D to DIPEA is 1:(2.2-2.4).

[0024] In a third aspect, the present invention discloses a pharmaceutical composition, which comprises at least one alkoxy-coupled naphthamide derivative as described above, or a pharmaceutically acceptable salt, solvate, hydrate thereof and one or more pharmaceutically acceptable carriers or excipients.

[0025] The pharmaceutical composition contains a therapeutically effective dose of the alkoxy-coupled naphthamide derivative of the present invention, and optionally contains a pharmaceutical carrier; wherein the pharmaceutically acceptable carrier refers to a pharmaceutical carrier commonly used in the pharmaceutical field; the pharmaceutical composition can be prepared according to a method known in the art.

[0026] According to the present invention, the term "pharmaceutically acceptable salt" of the compounds of the present invention includes the salts of the compounds of the present invention formed with pharmaceutically acceptable inorganic or organic acids or the alkali salts formed with pharmaceutically acceptable bases. The acid salts include, but are not limited to, hydrochlorides, hydrobromides, hydroiodides, nitrates, sulfates, bisulfates, phosphates, hydrogen phosphates, acetates, propionates, butyrates, oxalates, trimethylacetates, adipates, alginate, lactates, citrates, tartrates, succinates, maleates, fumarates, picrates, aspartates, gluconates, benzoates, methanesulfonates, ethanesulfonic acid, salts, benzenesulfonates, p-toluenesulfonates and pamoates; the alkali salts include, but are not limited to, ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, organic alkali salts such as dicyclohexylamine and N-methyl-D-glucosamine salts, and amino acid salts such as arginine and lysine salts.

[0027] The pharmaceutically acceptable carrier includes, but is not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human albumin, buffer substances such as phosphates, glycerol, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, beeswax, and lanolin.

[0028] On the basis of the above technical solutions, preferably, the pharmaceutical composition can be prepared into any one of tablets, pills, capsules, injections, suspensions, emulsions and implants, including but not limited to.

[0029] In a fourth aspect, the present invention discloses the use of the alkoxy-coupled naphthamide derivative or the pharmaceutical composition as described above in an anti-tumor drug. The anti-tumor drug acts on cancer diseases, including but not limited to one or more of liver cancer, glioma, lung cancer, pancreatic cancer and melanoma.

[0030] It should also be pointed out that the specific dosage and method of use of the compounds of the present invention for different patients are determined by many factors, including the patient's age, weight, gender, natural health status, nutritional status, activity strength of the compound, time of administration, metabolic rate, severity of the disease and the subjective judgment of the treating physician.

[0031] The alkoxy-coupled naphthamide derivative of the present invention and its preparation and application have the following beneficial effects compared with the prior art:

[0032] (1) The alkoxy-coupled naphthamide derivatives of the general formula I of the present invention retain the basic skeleton of the binaphthyl structure of gossypol, introduce flexible and easily bendable atomic chains between the naphthalene rings to increase the molecular length, and are modified with amino acids at both ends of the molecule, thereby reducing the toxic and side effects of gossypol and having the advantages of low acute toxicity and high drug safety.

[0033] (2) The present invention conducted a cell biological activity test on the prepared alkoxy-coupled naphthamide derivatives, and preliminarily proved through pharmacological experiments that some of the derivatives (such as compounds 1 to 8) have a certain inhibitory effect on various cell lines such as liver cancer, glioma, lung cancer, pancreatic cancer and melanoma; especially compound 3, which can induce G0 / G1 arrest at low concentrations and S phase arrest at high concentrations, and may act on multiple links of the cell cycle through different targets; at the same time, it can also induce cell apoptosis, has a broad-spectrum anti-tumor activity, and can be used as a broad-spectrum anti-tumor drug in clinical application;

[0034] (3) The present invention provides a method for preparing an alkoxy-coupled naphthamide derivative of general formula I. The preparation process takes into account the advantages of yield, purity, stability and operability, and the preparation process is simple, providing a reliable method and reference for the effective synthesis of alkoxy-coupled naphthamide derivatives. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0036] Figure 1 is the compound 1 in Example 1 of the present invention 1 HNMR spectra;

[0037] Figure 2 is the compound 2 in Example 2 of the present invention 1 HNMR spectra;

[0038] Figure 3 is the compound 3 in Example 3 of the present invention 1 HNMR spectra;

[0039] Figure 4 is the compound 4 in Example 4 of the present invention 1 HNMR spectra;

[0040] Figure 5 is the compound 5 in Example 5 of the present invention 1 HNMR spectra;

[0041] Figure 6 is the compound 6 in Example 6 of the present invention 1 HNMR spectra;

[0042] Figure 7 is the compound 7 in Example 7 of the present invention 1 HNMR spectra;

[0043] Figure 8 is the compound 8 in Example 8 of the present invention 1 HNMR spectrum. DETAILED DESCRIPTION

[0044] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0045] For all the following examples, standard operations and purification methods known to those skilled in the art can be used. Unless otherwise stated, all temperatures are expressed in ° C (Celsius). The structure of the compound is confirmed by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The melting point of the compound is determined by a RY-1 melting point instrument, and the thermometer is uncalibrated and is given in ° C. 1HNMR is measured by a JEOL JNM-ECA-400 nuclear magnetic resonance instrument. The mass spectrum is measured by an API3000 (ESI) mass spectrometer. All reaction solvents are pre-treated by standardization unless otherwise specified.

[0046] In the following examples, unless otherwise specified, % refers to mass percentage.

[0047] Example 1

[0048] This embodiment provides an alkoxy-coupled naphthamide derivative and a preparation method thereof, wherein the alkoxy-coupled naphthamide derivative is specifically compound 1, and the specific preparation steps are as follows:

[0049]

[0050] S1. Take 10.00 g (58.1 mmol) of compound 1-A and place it in a 100 mL eggplant-shaped bottle, add 50 mL of DMF, heat to 40°C in a water bath, stir for 15 min, and wait until it is completely dissolved, add 5.05 g (29.1 mmol) of dibromomethane, add 12.04 g (87.1 mmol) of potassium carbonate, and maintain the pH value between 8 and 10. The reaction was continued for 4 h. The reactants were cooled to room temperature and filtered. 16 mL of distilled water (i.e., one-third of the volume of the filtrate) was added to the filtrate and slowly added dropwise while stirring. After stirring for 5 min, a large amount of light yellow precipitate was obviously seen. The precipitate was filtered and rinsed with 30 mL of ethanol until the color became lighter. The precipitate was drained and the liquid was discarded. An appropriate amount of saturated sodium carbonate solution was added to the obtained solid. The mixture was stirred, filtered, and washed with water three times until the pH value was neutral to obtain an off-white solid. The solid was recrystallized with DMF, filtered, washed with ethanol, and dried to obtain an off-white solid, i.e., compound 1-B, with a yield of 75% and a melting point of 180.5 to 181.4 °C.

[0051] 1 H NMR (600MHz, DMSO-d6) δ10.09(s,2H),8.51(s,2H),8.13(d,J=9.0Hz,2H),8.00(d,J =8.5Hz,2H),7.87(d,J=8.7Hz,2H),7.75(s,2H),7.45(d,J=9.1Hz,2H),6.23(s,2H); 13 C NMR (150MHz, DMSO-d6) δ193.03,156.93,137.76,134.73,132.99,132.11,128.50,123.58,120.11,110.63,90.10.

[0052] S2. Take compound 1-B 2.00g (5.6mmol) and place it in a 100mL eggplant-shaped bottle, add 15mL DMF, heat to 40℃ in a water bath, stir to completely dissolve, take 1.22g (13.5mmol) of sodium chlorite solid, add it to the reaction solution in small amounts and multiple times, add 0.2mL of formic acid at the same time, react for 0.5h under stirring, and monitor the reaction progress by TLC (developing solvent is petroleum ether / ethyl acetate / glacial acetic acid: 20 / 10 / 3). Cool to room temperature, filter, wash the solid layer with 10mL ethanol, drain, and treat the filtrate and filter cake separately: ① Place the filter cake in a beaker, add 15mL distilled water, stir, and heat to 50℃ in a water bath and stir for 10min, cool to room temperature and filter, wash with water until the pH value is neutral, and obtain a white solid. ② Slowly add 5mL of distilled water to the filtrate, and precipitate appears during the addition. Stir for 5min, let stand, filter, and obtain a white solid. The white solids were combined, namely compound 1-C, with a total yield of 48% and a melting point of 269.7-271.5°C.

[0053] 1 H NMR(600MHz,DMSO-d6)δ12.93(s,2H),8.51(s,2H),8.06(d,J=9.0Hz,2H),7.99 –7.85(m,4H),7.68(d,J=2.5Hz,2H),7.36(dd,J=9.0,2.5Hz,2H),6.16(s,2H); 13 CNMR(150MHz,DMSO-d6)δ167.81,156.25,136.66,131.73,130.80,128.70,127.70,126.92,126.31,119.82,110.25,90.23.

[0054] S3, take compound 1-C 0.50 g (1.3 mmol) and place it in a 100 mL eggplant-shaped bottle, add 30 mL DMF, stir for 15 min, add DIPEA 0.40 g (3.1 mmol), stir for 30 min, add HATU 1.18 g (3.1 mmol), react for 0.5 h under stirring, take a sample, dilute with a small amount of DMF, use TLC (developing solvent is petroleum ether / ethyl acetate: 1 / 1) to monitor the reaction process, and an intermediate has been generated. Take compound 1-D 0.52 g (3 mmol) and DIPEA 0.89 g (6.9 mmol) and dissolve them in 5 mL DMF, and add them to the reaction solution. React at room temperature for 18 h. After the reaction is completed, slowly add 30 mL of distilled water to generate a large amount of precipitate. Let it stand, centrifuge, wash the precipitate 3 times with 5-fold diluted ammonia water, and then wash with distilled water until the pH value is neutral. A white solid was obtained, which was purified by column chromatography using PE / EA (1 / 1) as the mobile phase to obtain a light yellow solid, namely compound 1, with a yield of 61.6% and a melting point of 211.7-212.4°C.

[0055] like Figure 1 As shown: 1 H NMR (600MHz, DMSO-d6) δ8.70(d,J=7.8Hz,2H),8.49(s,2H),8.02(d,J=9.0Hz,2H),7.99–7.92(m,4H),7.70(d,J=2.6Hz,2H),7.40(dd ,J=9.0,2.6Hz,2H),6.18(s,2H),4.36(t,J=7.6Hz,2H),3.67(s,6H),2.26–2.18(m,2H),1.02(d,J=6.7Hz,6H),0.96(d,J=6.8Hz,6H); 13 CNMR(150MHz,DMSO-d6)δ172.95,156.06,136.11,131.50,130.22,128.82,128.48,128.43,127.57,125.84,125.7 9,119.99,119.94,110.42,90.59,59.38,59.30,52.29,52.22,30.24,30.21,30.16,19.82,19.78,19.74; HRMS(ESI + ): m / zcalcd for C 35 H 38 N2O8[M+H] + 615.27009, found 615.27002.

[0056] Example 2

[0057] This embodiment provides an alkoxy-coupled naphthamide derivative and a preparation method thereof, wherein the alkoxy-coupled naphthamide derivative is specifically compound 2, and the specific preparation steps are as follows:

[0058]

[0059] The preparation method is the same as that of Example 1, except that in step S3, compound 2-D is used instead of compound 1-D, and the synthetic route of step S3 is as above, and a light yellow solid, namely compound 2, is obtained with a yield of 63%. Melting point: 235.8-236.1°C.

[0060] like Figure 2 As shown: 1 H NMR(600MHz,DMSO-d6)δ8.71(d,J=7.7Hz,2H),8.48(s,2H),8.02(d,J=9.0Hz,2H ),7.98–7.90(m,4H),7.70(d,J=2.5Hz,2H),7.40(dd,J=9.0,2.5Hz,2H),6.18(s ,2H),4.42(dt,J=8.0,3.8Hz,2H),3.67(s,6H),2.04–1.95(m,2H),1.59–1.50(m ,2H),1.31(dp,J=20.5,6.9Hz,2H),0.93(d,J=6.9Hz,6H),0.88(t,J=7.4Hz,6H); 13 C NMR (150MHz, DMSO-d6) δ172.96,167.41,156.04,131.49,130.13,128.79,128.46,127.55,125.81,119.97 ,110.40,110.36,90.57,58.05,57.95,52.23,36.30,25.91,25.88,16.17,16.14,11.52,11.49; HRMS(ESI + ): m / z calcd for C 37 H 42 N2O8[M+H] + 643.30139,found 643.30096.

[0061] Example 3

[0062] This embodiment provides an alkoxy-coupled naphthamide derivative and a preparation method thereof, wherein the alkoxy-coupled naphthamide derivative is specifically compound 3, and the specific preparation steps are as follows:

[0063]

[0064] S1. The preparation method is the same as that of Example 1, except that dibromoethane is used instead of dibromomethane to obtain a white solid, namely compound 3-B, with a yield of 71% and a melting point of 185.6-187.1°C.

[0065] 1 H NMR (600MHz, DMSO-d6) δ10.08(s,2H),8.51(s,2H),8.10(d,J=8.9Hz,2H),7.96(d,J=8.5Hz, 2H),7.87(d,J=8.5Hz,2H),7.57(d,J=2.4Hz,2H),7.37(dd,J=9.0,2.4Hz,2H),4.60(s,4H); 13 C NMR (150MHz, DMSO-d6) δ192.98,159.26,138.20,134.74,132.55,131.84,128.23,123.55,120.30,107.82,66.97.

[0066] S2. The preparation method is the same as that of Example 1, except that compound 3-B is used to replace compound 1-B to obtain a white solid, namely compound 3-C, with a yield of 65% and a melting point of 286.9-288.1°C.

[0067] 1 H NMR (600MHz, DMSO-d6) δ12.87(s,2H),8.51(d,J=1.6Hz,2H),8.01(d,J=9.0Hz,2H),7.91 (d,J=1.6Hz,2H),7.87(s,2H),7.48(d,J=2.5Hz,2H),7.28(d,J=9.0Hz,2H),4.54(s,4H); 13 C NMR (150MHz, DMSO-d6) δ167.94,158.51,137.07,131.47,130.81,128.04,127.42,126.30,126.25,119.98,107.30,66.91.

[0068] S3. The preparation method is the same as that of Example 1, except that compound 3-C is used to replace compound 1-C, and a white solid, namely compound 3, is obtained with a yield of 67.3%. Melting point: 287.9-288.1°C.

[0069] like Figure 3 As shown: 1H NMR (600MHz, DMSO-d6) δ8.65(d,J=7.8Hz,2H),8.45(d,J=1.7Hz,2H),8.00–7.85(m,6H),7.50(d,J=2.5Hz,2H),7.30(dd,J=8.9,2.5 Hz,2H),4.56(s,4H),4.35(t,J=7.6Hz,2H),3.67(s,6H),2.22(dq,J=13.9,6.9Hz,2H),1.02(d,J=6.7Hz,6H),0.96(d,J=6.8Hz,6H); 13 C NMR(150MHz,DMSO-d6)δ172.76,167.46,158.01,131.03,128.23,127.91,127.0 7,125.51,119.91,107.24,66.87,59.13,52.07,30.01,19.62,19.56; HRMS(ESI + ): m / z calcd for C 36 H 40 N2O8[M+H] + 629.28574, found 629.28522.

[0070] Example 4

[0071] This embodiment provides an alkoxy-coupled naphthamide derivative and a preparation method thereof, wherein the alkoxy-coupled naphthamide derivative is specifically compound 4, and the specific preparation steps are as follows:

[0072]

[0073] The preparation method is the same as that of Example 3, except that compound 4-D is used instead of compound 3-D in step S3. The synthetic route of step S3 is as above to obtain a white solid, namely compound 4, with a yield of 69% and a melting point of 238.9-239.3°C.

[0074] like Figure 4 As shown: 1H NMR(600MHz,DMSO-d6)δ8.80(d,J=7.6Hz,2H),8.45(d,J=1.6Hz,2H),8.00–7 .92(m,4H),7.89(d,J=8.6Hz,2H),7.50(d,J=2.5Hz,2H),7.31(dd,J=9.0,2.5 Hz,2H),4.59–4.55(m,6H),3.66(s,6H),1.86–1.81(m,2H),1.74(ddd,J=8.6 ,4.6,2.1Hz,2H),1.62(td,J=9.0,4.6Hz,2H),0.93(dd,J=25.1,6.5Hz,12H); 13 C NMR (150MHz, DMSO-d6) δ167.09,158.04,136.27,131.02,129.35,128.11,127.95,127. 14,125.33,119.95,107.27,66.88,52.30,51.45,51.36,24.91,23.31,21.65; HRMS(ESI + ): m / z calcdfor C 38 H 44 N2O8[M+H] + 657.31704, found 657.31671.

[0075] Example 5

[0076] This embodiment provides an alkoxy-coupled naphthamide derivative and a preparation method thereof, wherein the alkoxy-coupled naphthamide derivative is specifically compound 5, and the specific preparation steps are as follows:

[0077]

[0078] The preparation method is the same as that of Example 3, except that compound 5-D is used instead of compound 3-D in step S3. The synthetic route of step S3 is as above to obtain a white solid, namely compound 5, with a yield of 64% and a melting point of 244.6-246.1°C.

[0079] like Figure 5 As shown: 1H NMR (600MHz, DMSO-d6) δ8.67(d,J=7.7Hz,2H),8.46(d,J=1.7Hz,2H),7.97(d,J=9.0 Hz,2H),7.94(dd,J=8.5,1.8Hz,2H),7.89(d,J=8.7Hz,2H),7.50(d,J=2.5Hz,2H),7 .30(dd,J=8.9,2.5Hz,2H),4.56(s,4H),4.44–4.41(m,2H),3.67(s,6H),2.03–1.99 (m,2H),1.56(ddd,J=13.7,7.4,4.2Hz,2H),1.34–1.30(m,2H),0.94–0.88(m,12H); 13 C NMR (150MHz, DMSO-d6) δ167.36,158.02,136.26,131.03,129.42,128.23,127.92,127. 06,125.51,119.90,107.25,66.87,57.83,52.02,36.14,25.71,15.98,11.33; HRMS(ESI + ): m / z calcd for C 38 H 44 N2O8[M+H] + 657.31704, found 657.31659.

[0080] Example 6

[0081] This embodiment provides an alkoxy-coupled naphthamide derivative and a preparation method thereof, wherein the alkoxy-coupled naphthamide derivative is specifically compound 6, and the specific preparation steps are as follows:

[0082]

[0083] The preparation method is the same as that of Example 3, except that compound 6-D is used in place of compound 3-D in step S3. The synthetic route of step S3 is as above to obtain a white solid, namely compound 6, with a yield of 67% and a melting point of 279.4-281.9°C.

[0084] like Figure 6 As shown: 1H NMR (600MHz, DMSO-d6) δ8.93(d,J=7.7Hz,2H),8.37(d,J=1.5Hz,2H),7.95(d,J=9.0Hz,2H),7.92–7.79(m,4H),7.49( d,J=2.6Hz,2H),7.39–7.16(m,12H),4.73(ddd,J=10.0,7.7,5.4Hz,2H),4.56(s,4H),3.65(s,6H),3.25–3.11(m,4H); 13 C NMR(150MHz,DMSO-d6)δ172.69,166.92,158.05,138.15,136.26,131.02,129.50,129.25,128 .68,128.08,127.91,127.16,126.92,125.17,119.98,107.26,66.88,54.80,52.37; HRMS(ESI + ): m / z calcd for C 44 H 40 N2O8[M+H] + 725.28574, found 725.28461.

[0085] Example 7

[0086] This embodiment provides an alkoxy-coupled naphthamide derivative and a preparation method thereof, wherein the alkoxy-coupled naphthamide derivative is specifically compound 7, and the specific preparation steps are as follows:

[0087]

[0088] S1. The preparation method is the same as that of Example 1, except that dibromopropane is used instead of dibromomethane to obtain a white solid, namely compound 7-B, with a yield of 76% and a melting point of 203.9-205.1°C.

[0089] 1 H NMR (600MHz, DMSO-d6) δ10.07(s,2H),8.48(s,2H),8.07(d,J=9.0Hz,2H),7.93(d,J=8.6Hz,2H),7.8 4(d,J=8.5Hz,2H),7.51(s,2H),7.33(d,J=8.9Hz,2H),4.37(t,J=6.3Hz,4H),2.36(t,J=6.3Hz,2H); 13C NMR (150MHz, DMSO-d6) δ192.94,159.47,138.26,134.71,132.44,131.74,128.15,123.48,120.35,107.65,65.11,28.87.

[0090] S2. The preparation method is the same as that of Example 1, except that compound 7-B is used to replace 1-B. The white solid, namely compound 7-C, has a yield of 39% and a melting point of 295.8-297.4°C.

[0091] 1 H NMR(600MHz,DMSO-d6)δ12.93(s,2H),8.74–8.34(m,2H),8.14(s,2H),8.0 1(s,2H),7.87(s,2H),7.45(s,2H),7.27(s,2H),4.35(s,4H),2.35(s,2H); 13 C NMR (150MHz, DMSO-d6) δ167.95,158.71,137.13,131.37,130.79,127.93,127.35,126.19,123.43,120.02,107.15,65.01,28.93.

[0092] S3. The preparation method is the same as that of Example 1, except that compound 7-C is used to replace 1-C to obtain a white solid, namely compound 7, with a yield of 69% and a melting point of 291.5-293.2°C.

[0093] like Figure 7 As shown: 1 H NMR (600MHz, DMSO-d6) δ8.65(d,J=7.7Hz,2H),8.45(d,J=1.7Hz,2H),7.95(d,J=9.0Hz,2H),7.91(d,J=1.8Hz,2H),7.87(s,2H),7.44(d,J=2.5Hz,2H), 7.27(dd,J=9.0,2.5Hz,2H),4.35(d,J=6.7Hz,6H),3.67(s,6H),2.35(t,J= 6.2Hz,2H),2.24–2.20(m,2H),1.02(d,J=6.7Hz,6H),0.96(d,J=6.8Hz,6H); 13C NMR(150MHz,DMSO-d6)δ172.76,167.46,158.22,136.32,130.93,129.33,128.22,127.8 2,127.00,125.45,119.95,107.09,64.95,59.13,52.05,30.02,30.00,28.97; HRMS(ESI + ): m / z calcd for C 37 H 42 N2O8[M+H] + 643.30139, found 643.30115.

[0094] Example 8

[0095] This embodiment provides an alkoxy-coupled naphthamide derivative and a preparation method thereof, wherein the alkoxy-coupled naphthamide derivative is specifically compound 8, and the specific preparation steps are as follows:

[0096]

[0097] The preparation method is the same as that of Example 7, except that compound 8-D is used instead of compound 7-D in step S3. The synthetic route of step S3 is as above to obtain a white solid, namely compound 8, with a yield of 61% and a melting point of 275.5-275.7°C.

[0098] like Figure 8 As shown: 1 H NMR (600MHz, DMSO-d6) δ8.87–8.84(m,2H),8.43(d,J=1.6Hz,2H),7.96–7.86(m,6H),7.45(d,J=2.5Hz,2H),7.28(dd,J= 9.0, 2.5Hz, 2H), 4.53 (q, J = 7.1Hz, 2H), 4.35 (t, J = 6.3Hz, 4H), 3.66 (s, 6H), 2.35 (t, J = 6.2Hz, 2H), 1.44 (d, J = 7.3Hz, 6H); 13 CNMR(150MHz,DMSO-d6)δ166.77,158.24,136.32,130.92,129.17,128.08,127.8 5,127.08,125.20,120.00,107.12,64.96,52.31,48.77,28.96,17.25; HRMS(ESI + ): m / z calcd for C 33 H 34 N2O8[M+H]+ 587.23879, found 587.23834.

[0099] Application Example 1

[0100] This application example provides an anti-tumor activity experiment of compounds 1-8, as follows:

[0101] (1) Cell culture and subculture

[0102] Human hepatoma cell line (HepG2), human malignant melanoma cell line (A375), human non-small cell lung cancer cell line (A549), human pancreatic cancer cell line (panc1) and human glioma cell line (U251) were cultured in DMEM high-glucose medium containing 10% FBS, passaged when grown to 80-90% abundance, and cultured at 37°C, 5% CO2 environment.

[0103] (2) Preparation of new compounds

[0104] The test compounds 1-8 were dissolved in DMSO to prepare a 25 μM stock solution for the initial screening of anti-tumor activity. In addition, compounds 3, 4, 5, 10 and 5-Fu were dissolved in DMSO to prepare a 50 mg / mL stock solution, and then diluted with 5% FBS high-glucose DMEM medium to 50 μg / mL, 15 μg / mL, 5 μg / mL, 1.5 μg / mL, 0.5 μg / mL, 0.15 μg / mL, 0.05 μg / mL, 0.015 μg / mL series concentrations for anti-tumor activity IC 50 5-Fu (pentafluorouracil) was used as a positive control drug.

[0105] (3) Preliminary screening of antitumor activity of new compounds

[0106] When the tumor cells grow to 80-90% abundance, they are inoculated in a 96-well plate, with about 2000 cells in each well. The next day, after the cells adhered, the culture medium was replaced with 5% FBS high-glucose DMEM culture medium containing 25μM compound, and cultured at 37°C, 5% CO2 for 72 hours. MTT powder was dissolved in 0.1mol / L PBS to prepare a 5mg / mL MTT solution, and 10μL MTT solution was added to each well, and incubated in a cell culture incubator for 4 hours in the dark. After 4 hours of MTT staining, the supernatant was aspirated with a pipette, and 100μLDMSO was added to each well to dissolve the purple crystals at the bottom of the plate. The absorbance of each well at 570nm was detected by an enzyme reader, and the inhibition rate of the compound on tumor cell growth was calculated by the following formula. Inhibition rate = (OD control group-OD drug group) / OD control group*100%. The experimental results are shown in Table 1.

[0107] Table 1 Preliminary screening of antitumor activity of new compounds

[0108]

[0109] (4) Antitumor activity IC of new compounds 50 Determination

[0110] Further testing of the anti-tumor activity IC of compounds 3, 4, 5, and 10 50 , the method is as follows: when the tumor cells grow to 80-90% abundance, they are inoculated in a 96-well plate, with about 2,000 cells in each well. The next day, after the cells adhere to the wall, the culture medium is replaced with 5% FBS high-glucose DMEM medium containing compounds at concentrations of 50μg / mL, 15μg / mL, 5μg / mL, 1.5μg / mL, 0.5μg / mL, 0.15μg / mL, 0.05μg / mL, and 0.015μg / mL, respectively, and cultured at 37°C and 5% CO2 for 72 hours. MTT powder is dissolved in 0.1mol / L PBS to prepare a 5mg / mL MTT solution, 10μL MTT solution is added to each well, and incubated in a cell culture incubator for 4 hours in the dark. After 4 hours of MTT staining, the supernatant was aspirated with a pipette, 100 μL of DMSO was added to each well to dissolve the purple crystals at the bottom of the plate, and the absorbance of each well at 570 nm was detected by an ELISA reader. The inhibition rate of each concentration of the compound on tumor cell growth was calculated by the following formula. Inhibition rate = (OD control group - OD drug group) / OD control group * 100%. The IC of each compound was calculated by graphpadprism9 software 50 , the experimental results are shown in Table 2.

[0111] Table 2 Antitumor activity of new compounds

[0112]

[0113] From the results in Table 1 and Table 2, the nine compounds all showed different inhibitory activities against tumor cells. Compound 3 had a strong inhibitory effect on the proliferation of five standard strains, including A375, PANC-1, MCF-7, HepG2 and A549, and its inhibitory activity on four standard strains, including A375, PNC-1, MCF-7 and A549, was better than 5-fluorouracil, showing good application prospects; while compounds 4, 5 and 8 only had a strong inhibitory effect on the proliferation of MCF-7, which was better than that of 5-fluorouracil, but had no obvious inhibitory activity on other tumors. Application Example 2 Acute Toxicity Test of New Compounds

[0114] The new compound 3 with the best activity was selected for acute toxicity experiment. 18-22g mice were randomly divided into normal saline group, low-dose group 200mg / kg and high-dose group 500mg / kg, with 10 mice in each group. After the mice were given the drug for 7 consecutive days, there was no obvious change in body weight and hair, and no death occurred, indicating that the new compound 3 has low toxicity and can be used for anti-tumor drug research.

[0115] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. An alkoxy-coupled naphthamide derivative, characterized in that: The naphthamide derivative is any one of compounds 1 to 8, wherein the chemical structures of compounds 1 to 8 are as follows: ； 。 2. The method for preparing an alkoxy-coupled naphthamide derivative according to claim 1, characterized in that: The following steps are involved: S1. dissolving compound A in an organic solvent, adding dibromoalkane and potassium carbonate, and subjecting the mixture to a nucleophilic substitution reaction to obtain compound B; S2, dissolving compound B in an organic solvent, adding sodium chlorite and formic acid, and performing an oxidation reaction to obtain compound C; S3, subjecting compound C and compound D to a condensation reaction to obtain the alkoxy-coupled naphthamide derivative; Step S3 specifically includes: S31, dissolving compound C in an organic solvent, adding DIPEA and HATU, and reacting for 20-40 min; S32, then adding compound D, reacting at 25-27° C. for 16-20 h to obtain the alkoxy-coupled naphthamide derivative; Among them, the chemical structure of compound A is , the chemical structure of compound B is , the chemical structure of compound C is , where n is 1, 2 or 3; the chemical structure of compound D is , , , and Any one of .

3. The method for preparing an alkoxy-coupled naphthamide derivative according to claim 2, characterized in that: Step S1 specifically comprises: dissolving compound A in an organic solvent, adding dibromoalkane and potassium carbonate, and reacting under alkaline conditions for 3.5 to 4.5 hours to obtain compound B, wherein the molar ratio of compound A, dibromoalkane and potassium carbonate is 1: (0.4 to 0.6): (1.4 to 1.6).

4. The method for preparing an alkoxy-coupled naphthamide derivative according to claim 2, characterized in that: Step S2 specifically comprises: dissolving compound B in an organic solvent, adding sodium chlorite and formic acid, and reacting for 20 to 40 minutes to obtain compound C, wherein the molar ratio of compound B to sodium chlorite is 1:(2.3 to 2.5).

5. The method for preparing an alkoxy-coupled naphthamide derivative according to claim 2, characterized in that: In step S31, the molar ratio of compound C, DIPEA and HATU is 1:(2.3-2.5):(2.3-2.5); in step S32, the molar ratio of compound C to compound D is 1:(2.2-2.4).

6. A pharmaceutical composition, characterized in that: The pharmaceutical composition comprises at least one alkoxy-coupled naphthamide derivative as claimed in claim 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

7. A pharmaceutical composition according to claim 6, characterized in that: The pharmaceutical composition can be prepared into any one of tablets, pills, capsules, injections, suspensions, emulsions or implants.

8. Use of the alkoxy-coupled naphthamide derivative according to claim 1 or the pharmaceutical composition according to claim 6 in the preparation of anti-tumor drugs.

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