Benzo[1,6]naphthyridine derivatives and their medical uses

Abstract

The present invention chemically modifies the structure of the benzo[1,6]naphthyridine mother nucleus of the marine natural product Aaptamine, and obtains a class of benzo[1,6]naphthyridine derivatives through a simple and easy method. The benzo[1,6]naphthyridine derivatives have both anti-tumor and antifungal activities and have potential development and application value.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to benzo[1,6]naphthyridine derivatives and their medical uses. Background Art

[0002] The ocean is the cradle of life and a treasure trove of natural medicine resources. Its special living environment has created a diversity of secondary metabolites of marine organisms, which is the source of innovative marine drug development. In view of the rich and diverse chemical structures and outstanding pharmacological activities of marine natural products, discovering new drugs from marine natural products or their derivatives has become the goal of many drug developers at home and abroad.

[0003] Aaptamine is a type of marine alkaloid unique to sponges. It was first isolated by Japanese scientist Nakamura et al. from the sponge Aaptos collected from the coast of the Okinawa Islands. Aaptamine and its derivatives have a unique benzo[1,6]naphthyridine skeleton. This type of compound usually has good biological activity, including anti-tumor, anti-fungal, antioxidant, anti-HIV, etc.

[0004]

[0005] Aaptos sponge crude extract can show antimicrobial activity against some bacteria, and the Aaptamine derivatives isolated from South China Sea sponges by Hao-Bing Yu et al. show antifungal activity against 6 fungi (Mar Drugs, 12, 12, 6003-13). US2005187240A1 also discloses the antimicrobial activity of Aaptamine derivatives. At the same time, Aaptamine derivatives also show antitumor activity. For example, Gul, W. et al. reported that aaptamine derivatives with ester groups connected at C-9 are cytotoxic to cancer cells.

[0006] The present invention chemically modifies the structure of the benzo[1,6]naphthyridine mother nucleus of Aaptamine in order to discover new antimicrobial and antitumor compounds. Summary of the invention

[0007] The purpose of the present invention is to provide a class of benzo[1,6]naphthyridine derivatives, and a preparation method and medical use thereof.

[0008] The technical solution of the present invention is as follows:

[0009] A benzo[1,6]naphthyridine derivative or a pharmaceutically acceptable salt thereof has the following general formula:

[0010]

[0011] Where n = 1 to 2, R 1 and R 2 Optional from H, CH 3 , CH 2 CH 3 , the condition is that when n = 1, R 1 and R 2 Not all are H.

[0012] The pharmaceutically acceptable salts refer to organic acid salts and inorganic acid salts of the compounds of the present invention. Inorganic acid salts include hydrochlorides, hydrobromides, sulfates, phosphates, etc., and organic acid salts include oxalates, acetates, tartrates, maleates, citrates, succinates, malonates, etc.

[0013] A method for preparing a benzo[1,6]naphthyridine derivative comprises the following steps:

[0014] Bisdemethylaaptamine is used as a raw material, and a cyclization reaction is carried out with acetone formate, 1,2-dibromoethane, 2,3-butanediol di-p-toluenesulfonate, etc. to obtain a benzo[1,6]naphthyridine derivative with a structure shown in formula (I).

[0015] Preferably, bisdemethylaaptamine is used as a raw material and reacted with acetone formate (2,2-dimethoxypropane) in an organic solvent, the organic solvent is selected from acetone, dichloromethane, toluene, tetrahydrofuran, ether, DMF, dioxane, and the reaction temperature is 20-90°C.

[0016] Preferably, bisdemethylaaptamine is used as a raw material and reacted with 1,2-dibromoethane or 1,2-diiodoethane in an organic solvent, the organic solvent is selected from acetonitrile, acetone, toluene, tetrahydrofuran, DMF, and the reaction temperature is 50-80°C.

[0017] Preferably, bisdemethylaaptamine is used as a raw material to react with 2,3-butanediol di-p-toluenesulfonate in an organic solvent, the organic solvent is selected from DMF, ethanol, acetonitrile, acetone, toluene, tetrahydrofuran, and the reaction temperature is 60-80°C.

[0018] A pharmaceutical composition comprises a benzo[1,6]naphthyridine derivative represented by formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0019] An antifungal drug, which uses a benzo[1,6]naphthyridine derivative represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0020] An anti-tumor drug, which uses a benzo[1,6]naphthyridine derivative represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0021] A use of a benzo[1,6]naphthyridine derivative represented by formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in the preparation of an antifungal drug.

[0022] A use of a benzo[1,6]naphthyridine derivative represented by formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in the preparation of an anti-tumor drug.

[0023] Preferably, the drug has activity against Candida albicans.

[0024] Preferably, the drug has activity against liver cancer, breast cancer, non-small cell lung cancer, and cervical cancer.

[0025] The present invention provides a class of benzo[1,6]naphthyridine derivatives, which can be prepared by a simple and easy method. The benzo[1,6]naphthyridine derivatives have both anti-tumor and anti-fungal activities and have potential development and application value. DETAILED DESCRIPTION

[0026] The preferred embodiments of the present invention are described in detail below.

[0027] Example 1 Preparation of Compound 1

[0028]

[0029] Weigh bisdemethylaaptamine (15.0 mg) and dissolve it in acetone. Add a trace amount of p-toluenesulfonic acid and drop 8 mL of 2,2-dimethoxypropane. React at room temperature. After the reaction is complete, filter, concentrate under reduced pressure, and purify by column chromatography to obtain the target product.

[0030] 1 H NMR (400 MHz, CDCl 3 )δ7.80(d,1H),7.35(d,1H),7.05(s,1H),6.85(d,1H),6.50(d,1H),1.79(s,3H),1.78(s,3H);

[0031] LC-MS m / z(ESI)=241.2[M+1].

[0032] Example 2 Preparation of Compound 2

[0033]

[0034] Weigh bisdemethylaaptamine (15.0 mg) and dissolve it in acetonitrile. Add anhydrous potassium carbonate (100 mg) and stir for 1 h. Add 1,2-dibromoethane (0.15 mL) dropwise and stir at 60-70 °C. After the reaction is completed, add water and extract with DCM three times. Combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by column chromatography to obtain the target product.

[0035] 1 H NMR (400 MHz, CDCl 3 )δ7.82(d,1H),7.36(d,1H),7.06(s,1H),6.85(d,1H),6.52(d,1H),4.45-4.37(m,4H);

[0036] LC-MS m / z(ESI)=227.1[M+1].

[0037] Example 3 Preparation of Compound 3

[0038]

[0039] Weigh bisdemethylaaptamine (15.0 mg) and dissolve it in DMF. Add anhydrous potassium carbonate (100 mg) and stir for 1 h. Then slowly drop 2,3-butanediol di-p-toluenesulfonate (35 mg). Stir and react at 70-80 °C. After the reaction is completed, add water, extract with DCM three times, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by column chromatography to obtain the target product.

[0040] 1 H NMR (400 MHz, CDCl 3 )δ7.82(d,1H),7.36(d,1H),7.06(s,1H),6.86(d,1H),6.52(d,1H),4.50-4.40(m,2H),1,36(s,3H),1.37(s,3H);

[0041] LC-MS m / z(ESI)=255.2[M+1].

[0042] Effect Example 1

[0043] The minimum inhibitory concentration (MIC) of compounds 1-3 against Candida albicans was determined by micro-dilution method. 80 (Drug mass concentration when fungal growth is 80% inhibited), with fluconazole as the positive control drug.

[0044] After the strain was activated twice, the concentration of the bacterial solution was adjusted to 1×10 3 ~5×10 3 / ml. The test sample was dissolved in DMSO to prepare a bacterial solution with a concentration of 256μg / mL, and the concentration gradient between 128μg / mL and 1μg / mL was finally obtained by the two-fold dilution method. Three parallel experiments were performed for each test sample, and a blank control (200μL RPMI1640 culture medium per well) and a positive control (200μL bacterial solution per well) were set up. After the operation was completed, the results were determined in a constant temperature incubator for 24 hours. The OD value of each well was measured at 630nm using an enzyme-labeled analyzer. Compared with the positive control well, the drug concentration in the lowest concentration well where the OD value dropped by more than 80% was the MIC. 80 .

[0045] Table 1. MIC of the tested samples against Candida albicans and Candida parapsilosis 80 (μg / mL)

[0046] Compound No. <![CDATA[Candida albicans (MIC 80 μg / mL)]]> Compound 1 32 Compound 2 32 Compound 3 16 Fluconazole 2

[0047] The data in Table 1 show that the benzo[1,6]naphthyridine derivatives of the present application have good anti-Candida albicans activity.

[0048] Effect Example 2

[0049] The MTT method was used to test the in vitro anti-tumor cell proliferation activity of compounds 1-3. The test cell lines were Hep G-2 cells, MCF-7 cells, A549 cells, and Hela cells. The above cells in the logarithmic growth phase were collected and the cell concentration was adjusted to 5×10 5 / mL, inoculated into a 96-well plate at 100 μL / well, and incubated at 37°C and 5% CO 2 Culture in the incubator for 24 hours. Dilute the compound to be tested into 6 dose groups with concentration gradients, with concentrations of 40, 20, 10, 5, 2.5, and 1.25 μmol / L, respectively. Add 20 μL of each concentration solution to a 96-well plate, with 3 replicate wells for each dose. After adding the drug, incubate in the incubator for 48 hours. After 48 hours, discard the culture medium, add 20 μL (1 mg / mL) MTT solution to each well, continue to culture at 37°C for 4 hours, centrifuge and discard the supernatant, add 60 μL DMSO to each well and shake to dissolve, measure the optical density (OD) of each well at a wavelength of 570 nm using an enzyme-linked immunosorbent assay, and calculate the inhibition rate and IC of the target compound on the cells. 50 value.

[0050] Table 2. IC values ​​of the tested samples for Hep G-2 cells, MCF-7 cells, A549 cells, and Hela cells 50 value.

[0051]

[0052] The data in Table 2 show that the benzo[1,6]naphthyridine derivatives of the present application have good anti-tumor activity.

Claims

1. A benzo[1,6]naphthyridine derivative or a pharmaceutically acceptable salt thereof, characterized in that: The benzo[1,6]naphthyridine derivative has the following structure:

2. The benzo[1,6]naphthyridine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt, wherein the inorganic acid salt is hydrochloride, hydrobromide, sulfate or phosphate, and the organic acid salt is oxalate, acetate, tartrate, maleate, citrate, succinate or malonate.

3. A pharmaceutical composition comprising the benzo[1,6]naphthyridine derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2, and a pharmaceutically acceptable carrier.

4. An antifungal drug, comprising the benzo[1,6]naphthyridine derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2 as an active ingredient, wherein the fungus is Candida albicans.

5. An antitumor drug, comprising the benzo[1,6]naphthyridine derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2 as an active ingredient, wherein the tumor is liver cancer, breast cancer or cervical cancer.

6. Use of the benzo[1,6]naphthyridine derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2 or the pharmaceutical composition according to claim 3 in the preparation of an antifungal drug, wherein the fungus is Candida albicans.

7. Use of the benzo[1,6]naphthyridine derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2 or the pharmaceutical composition according to claim 3 in the preparation of an anti-tumor drug, wherein the tumor is liver cancer, breast cancer or cervical cancer.

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