CN108440468A - 2- (benzofuran -5- bases) phenol and its application as anticancer drug - Google Patents

Abstract

The present invention relates to a class of 2-(benzofuran-5-yl)phenols as shown in chemical structural formula I and pharmaceutically acceptable salts thereof: Among them, R is selected from: hydrogen, C ₁ ~C ₂ alkyl, C ₃ ~C ₄ straight chain alkyl or branched chain alkyl; R ¹ is selected from: C ₁ ~C ₂ alkyl, C ₃ ~C ₆ straight Alkyl or branched chain alkyl. Application of 2-(benzofuran-5-yl)phenol and pharmaceutically acceptable salts thereof in the preparation of anti-human lung adenocarcinoma cell A549 medicine.

Description

2-(Benzofuran-5-yl)phenol and its application as an anticancer drug

technical field

The present invention relates to the preparation and application of a class of novel compounds; specifically, 2-(benzofuran-5-yl)phenol and its application as an anticancer drug.

Background technique

Chinese invention patent [CN201610052934.9] describes the preparation method of 1-(4-hydroxy-3-arylphenyl)-2-propanone; Chinese invention patent [CN201610100379.2 and CN2016101038556] describes the Acylhydrazone derivatives and their inhibitory effect on influenza virus.

Contents of the invention

The technical problem solved by the present invention is to provide a class of 2-(benzofuran-5-yl)phenol, its preparation method, pharmaceutical composition and application.

In order to solve the technical problems of the present invention, the present invention provides the following technical solutions:

The first aspect of the technical solution of the present invention is 2-(benzofuran-5-yl)phenol shown in chemical structural formula I and pharmaceutically acceptable salts thereof:

Among them, R is selected from: hydrogen, C ₁ ~C ₂ alkyl, C ₃ ~C ₄ straight chain alkyl or branched chain alkyl; R ¹ is selected from: C ₁ ~C ₂ alkyl, C ₃ ~C ₆ straight Alkyl or branched chain alkyl.

Further, preferred compounds are selected from: 4-allyl-2-(2-methylbenzofuran-5-yl)-6-((4-methylpiperazin-1-yl)methyl)phenol , 4-allyl-2-(2-methylbenzofuran-5-yl)-6-((4-ethylpiperazin-1-yl)methyl)phenol, 4-allyl-2 -(2-methylbenzofuran-5-yl)-6-((4-propylpiperazin-1-yl)methyl)phenol or 4-allyl-2-(2-ethylbenzo furan-5-yl)-6-((4-methylpiperazin-1-yl)methyl)phenol.

The second aspect of the technical solution of the present invention provides the preparation method of 2-(benzofuran-5-yl)phenol described in the first aspect, which is characterized in that its preparation reaction is as follows:

R is selected from: R is selected from: hydrogen, C ₁ ~C ₂ alkyl, C ₃ ~C ₄ straight chain alkyl or branched chain alkyl; R ¹ is selected from: C ₁ ~C ₂ alkyl, C ₃ ~C ₆ straight chain alkyl or branched chain alkyl.

The third aspect of the technical solution of the present invention is to provide a pharmaceutical composition containing the compound described in the first aspect and a pharmaceutically acceptable salt thereof. The pharmaceutical composition contains a therapeutically effective amount of 2-(benzofuran-5 -yl) phenol and pharmaceutically acceptable salts thereof, and optionally contain a pharmaceutically acceptable carrier. The pharmaceutical carrier mentioned therein refers to the commonly used pharmaceutical carrier in the field of pharmacy; the pharmaceutical composition can be prepared according to methods known in the art. Any dosage form suitable for human or animal use can be prepared by combining the compound of the present invention and a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The content of the compound of the present invention and its pharmaceutically acceptable salt in its pharmaceutical composition is usually 0.1%-95% by weight.

The compound of the present invention and its pharmaceutically acceptable salt or the pharmaceutical composition containing it can be administered in the form of unit dosage, and the route of administration can be enteral or parenteral, such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity , oral mucosa, eyes, lungs and respiratory tract, skin, vagina, rectum, etc.

The dosage form for administration may be a liquid dosage form, a solid dosage form or a semi-solid dosage form. Liquid dosage forms can be solutions (including true solutions and colloid solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including aqueous injections, powder injections and infusion solutions), eye drops Agents, nasal drops, lotions and liniments, etc.; solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, dripping pills, suppositories, films, patches, gas (powder) aerosols, sprays, etc.; semi-solid dosage forms can be ointments, Gels, pastes, etc.

The compounds of the present invention and their pharmaceutically acceptable salts can be made into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

In order to make the compound of the present invention and its pharmaceutically acceptable salt into tablets, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, auxiliary agents, etc. Fluid. Diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; wetting agents can be water, ethanol, iso Propanol, etc.; binders can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, arabic mucilage, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hypromellose Base cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked poly Vinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium dodecylsulfonate, etc.; lubricant and flow aid The agent can be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol and the like.

Tablets can also be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

In order to make the administration unit into a capsule, the active ingredient compound of the present invention and its pharmaceutically acceptable salt can be mixed with a diluent and a glidant, and the mixture can be directly placed in a hard capsule or a soft capsule. The active ingredient compound of the present invention and its pharmaceutically acceptable salts can also be prepared into granules or pellets with diluents, binders, and disintegrating agents, and then placed in hard capsules or soft capsules. Various diluents, binders, wetting agents, disintegrants, and glidants used to prepare the compound of the present invention and pharmaceutically acceptable salt tablets thereof can also be used to prepare the compound of the present invention and pharmaceutically acceptable salt thereof. Salt capsules.

In order to prepare the compound of the present invention and its pharmaceutically acceptable salts into injections, water, ethanol, isopropanol, propylene glycol or their mixtures can be used as a solvent and an appropriate amount of commonly used solubilizers, co-solvents, pH regulators, Osmotic regulator. The solubilizer or co-solvent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be Sodium chloride, mannitol, glucose, phosphate, acetate, etc. For preparation of freeze-dried powder injection, mannitol, glucose, etc. can also be added as proppants.

In addition, coloring agents, preservatives, fragrances, flavoring agents or other additives can also be added to the pharmaceutical preparations, if necessary.

In order to achieve the purpose of medication and enhance the therapeutic effect, the medicine or pharmaceutical composition of the present invention can be administered by any known administration method.

The fourth aspect of the technical solution of the present invention is to provide 2-(benzofuran-5-yl)phenol and its pharmaceutically acceptable salt in the first aspect of the present invention and the pharmaceutical composition described in the third aspect in the preparation of anti-human Drug application in lung adenocarcinoma cell A549.

Beneficial technical effects:

The 2-(benzofuran-5-yl)phenol of the present invention is a new type of compound with anticancer activity.

Detailed ways

The following examples are intended to illustrate the present invention without further limiting the invention.

Example 1

Preparation of 4-allyl-2-(2-methylbenzofuran-5-yl)-6-((4-methylpiperazin-1-yl)methyl)phenol

2.0mmol 4-allyl-2-(2-methylbenzofuran-5-yl)phenol, 10mL methanol, 6.0mmol 4-methylpiperazine and 6.0mmol 37% formaldehyde aqueous solution were reacted at 60°C for 6h. The reaction solution was desolvated and purified by column chromatography to obtain 4-allyl-2-(2-methylbenzofuran-5-yl)-6-((4-methylpiperazin-1-yl)methanol base) phenol, yield 68.0%; light yellow oily liquid; ¹ H NMR (400MHz, CDCl ₃ ) δ7.65 (s, 1H, benzofuran ring 4-H), 7.45～7.39 (m, 2H, benzofuran ring Furan ring 6,7-H), 7.10(s, 1H, C ₆ H ₂ 3-H), 6.80(s, 1H, C ₆ H ₂ 5-H), 6.38(s, 1H, benzofuran ring 3 -H), 5.97(dt, J=16.6, 7.0Hz, 1H, CH), 5.29(br, 1H, OH), 5.12～5.02(m, 2H, =CH ₂ ), 3.75(s, 2H, CH ₂ ), 3.33 (d, J=7.0Hz, 2H, CH ₂ ), 2.62 (br, 8H, piperazinyl 2,3,5,6-H), 2.46 (s, 3H, NCH ₃ ), 2.29 (s , 3H, CH ₃ ); ¹³ C NMR (101MHz, CDCl ₃ ) δ155.59, 153.97, 152.98, 137.91, 133.02, 130.50, 130.41, 129.31, 129.16, 127.78, 124.77, 121.32, 120.86, 110.52 61.61, 54.51, 52.10, 45.52, 39.48, 14.14.

Example 2

Anticancer Activity of 2-(Benzofuran-5-yl)phenol

1. Principle of antitumor activity

The MTT method, also known as the MTT colorimetric method, is a classic method for determining the activity of mitochondrial dehydrogenase in living cells. The MTT assay uses living cells to metabolize the reducing agent thiazolium blue [3-(4,5-dimethyl-2-thiazole)-2,5 diphenyltetrazolium bromide; 3-(4,5-dimethylthiazol-2 -yl)-2,5-diphenyltetrazoliumbromide, MTT] as the basis. MTT is a dye that can accept hydrogen atoms. The dehydrogenase associated with NADP in the mitochondria of living cells can convert yellow MTT into insoluble blue-purple formazan (formazn), while dead cells have no such function. After dissolving formazan with DMSO, measure the optical density value with a microplate reader at a certain wavelength, and the survival rate of the cells can be quantitatively measured. The inhibitory effect of the sample on the tumor cell line was observed according to the change of the optical density value.

2. Antitumor activity experiment

Sample: Example compound

Cell line: human lung adenocarcinoma cell line A549.

Reagents: thiazolium blue (MTT), RPMI 1640 medium, neonatal calf serum, neonatal bovine serum, double antibody (Gibco); trypsin (Gibco); 96-well plate; dimethyl sulfoxide (Sinopharm Group).

Instruments: HFsafe-1500 ultra-clean bench, HF151UV CO2 incubator (Shanghai Lishen Scientific Instrument Co., Ltd.); XSP-15C inverted microscope (Shanghai Changfang Optical Instrument Co., Ltd.); Multiskan MK3 microplate reader (Thermo company); ultrapure water preparation instrument (Milli-Q Company, USA).

Experimental operation: the test of the sample on A549 cells. The experimental process of the sample acting on the four kinds of cells is the same. A blank control group was set up for each group of experiments, the samples were divided into 5 concentration gradients, and 4 replicate holes were set for each concentration, and each group of experiments was measured three times in parallel. Set the wavelength to 570nm to detect the OD value of each well, and calculate the cytotoxic activity of the sample on each cell line through the change of OD.

3. Evaluation of antitumor activity

1) Calculation of cell proliferation inhibition rate:

2) Calculation of IC ₅₀ value

SPSS software was used for analysis, and the logarithmic value of the sample concentration was linearly regressed with the cell inhibition rate to calculate the IC ₅₀ value of the half inhibitory concentration of the compound on each cell line. The IC ₅₀ of 4-allyl-2-(2-methylbenzofuran-5-yl)-6-((4-methylpiperazin-1-yl)methyl)phenol on A549 cells was 25.15 μM .

The activity test results show that 2-(benzofuran-5-yl)phenol and its pharmaceutically acceptable salt have good inhibitory activity on human lung adenocarcinoma cell A549, and can be used to prepare anticancer drugs.

Claims (4)

1. A class of 2-(benzofuran-5-yl)phenols as shown in chemical structural formula I and pharmaceutically acceptable salts thereof: Among them, R is selected from: hydrogen, C ₁ ~C ₂ alkyl, C ₃ ~C ₄ straight chain alkyl or branched chain alkyl; R ¹ is selected from: C ₁ ~C ₂ alkyl, C ₃ ~C ₆ straight Alkyl or branched chain alkyl. 2. 2-(benzofuran-5-yl) phenol described in claim 1 is selected from: 4-allyl-2-(2-methylbenzofuran-5-yl)-6-((4 -Methylpiperazin-1-yl)methyl)phenol, 4-allyl-2-(2-methylbenzofuran-5-yl)-6-((4-ethylpiperazine-1- base)methyl)phenol, 4-allyl-2-(2-methylbenzofuran-5-yl)-6-((4-propylpiperazin-1-yl)methyl)phenol or 4 - Allyl-2-(2-ethylbenzofuran-5-yl)-6-((4-methylpiperazin-1-yl)methyl)phenol. 3. the preparation method of 2-(benzofuran-5-yl)phenol as claimed in claim 1 is characterized in that, its preparation reaction is as follows: Among them, R is selected from: hydrogen, C ₁ ~C ₂ alkyl, C ₃ ~C ₄ straight chain alkyl or branched chain alkyl; R ¹ is selected from: C ₁ ~C ₂ alkyl, C ₃ ~C ₆ straight Alkyl or branched chain alkyl. 4. The application of 2-(benzofuran-5-yl)phenol and its pharmaceutically acceptable salts in the preparation of anti-human lung adenocarcinoma A549 medicament according to claim 1.