CN108440468B - 2- (benzofuran-5-yl) phenol and application thereof as anticancer drug - Google Patents
2- (benzofuran-5-yl) phenol and application thereof as anticancer drug Download PDFInfo
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- CN108440468B CN108440468B CN201810340899.XA CN201810340899A CN108440468B CN 108440468 B CN108440468 B CN 108440468B CN 201810340899 A CN201810340899 A CN 201810340899A CN 108440468 B CN108440468 B CN 108440468B
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- Prior art keywords
- phenol
- benzofuran
- pharmaceutically acceptable
- application
- acceptable salts
- Prior art date
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- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to 2- (benzofuran) shown as a chemical structural formula I-5-yl) phenol and pharmaceutically acceptable salts thereof:
wherein R is selected from: hydrogen, C 1 ～C 2 Alkyl radical, C 3 ～C 4 Straight or branched chain alkyl; r 1 Selected from: c 1 ～C 2 Alkyl radical, C 3 ～C 6 Straight chain alkyl or branched alkyl. 2- (benzofuran-5-yl) phenol and application of pharmaceutically acceptable salts thereof in preparation of medicaments for resisting human lung adenocarcinoma cells A549.
Description
Technical Field
The invention relates to preparation and application of a new compound; in particular to 2- (benzofuran-5-yl) phenol and application thereof as an anti-cancer medicament.
Background
The Chinese patent of invention [ CN201610052934.9] describes the preparation method of 1- (4-hydroxy-3-aryl phenyl) -2-acetone; chinese invention patents [ CN201610100379.2 and CN2016101038556] describe acylhydrazone derivatives containing a benzofuran ring and their inhibitory effects on influenza virus.
Disclosure of Invention
The invention aims to provide 2- (benzofuran-5-yl) phenol, a preparation method, a pharmaceutical composition and application thereof.
In order to solve the technical problem, the invention provides the following technical scheme:
the first aspect of the present invention is a 2- (benzofuran-5-yl) phenol of formula i and pharmaceutically acceptable salts thereof:
wherein R is selected from: hydrogen, C 1 ～C 2 Alkyl radical, C 3 ～C 4 Straight or branched chain alkyl; r 1 Selected from: c 1 ～C 2 Alkyl radical, C 3 ～C 6 Straight chain alkyl or branched 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-ethylbenzofuran-5-yl) -6- ((4-methylpiperazin-1-yl) methyl) phenol.
The second aspect of the present invention provides the process for producing 2- (benzofuran-5-yl) phenol according to the first aspect, characterized in that the reaction is as follows:
r is selected from: r is selected from: hydrogen, C 1 ～C 2 Alkyl radical, C 3 ～C 4 Straight or branched chain alkyl; r 1 Selected from the group consisting of: c 1 ～C 2 Alkyl radical, C 3 ～C 6 Straight chain alkyl or branched alkyl.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the first aspect and a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition comprises a therapeutically effective amount of the 2- (benzofuran-5-yl) phenol and a pharmaceutically acceptable salt thereof of the present invention, and optionally a pharmaceutically acceptable carrier. Wherein the medicinal carrier refers to a medicinal carrier commonly used in the field of pharmacy; the pharmaceutical composition may be prepared according to methods well known in the art. The compounds of the present invention and pharmaceutically acceptable salts thereof may be formulated into any dosage form suitable for human or animal use by combining with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The compounds of the present invention and their pharmaceutically acceptable salts are generally present in the pharmaceutical compositions in an amount of 0.1% to 95% by weight.
The compounds of the present invention and their pharmaceutically acceptable salts or pharmaceutical compositions containing them may be administered in unit dosage form by enteral or parenteral routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ocular, pulmonary and respiratory, dermal, vaginal, rectal, and the like.
The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.
The compound and the pharmaceutically acceptable salt thereof can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle delivery systems.
For tableting the compounds of the present invention and pharmaceutically acceptable salts thereof, a wide variety of excipients known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
The tablets may be further formulated as coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layered and multi-layered tablets.
In order to encapsulate the administration unit, the active ingredient of the compound of the present invention and a pharmaceutically acceptable salt thereof may be mixed with a diluent and a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule. Or the effective component of the compound and the pharmaceutically acceptable salt thereof can be prepared into granules or pellets with a diluent, an adhesive and a disintegrating agent, and then the granules or pellets are placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, glidants used to prepare the compounds of the present invention and their pharmaceutically acceptable salt tablets may also be used to prepare capsules of the compounds of the present invention and their pharmaceutically acceptable salts.
In order to prepare the compound and the pharmaceutically acceptable salt thereof into injection, water, ethanol, isopropanol, propylene glycol or a mixture of the water, the ethanol, the isopropanol and the propylene glycol can be used as a solvent, and a proper amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator which are commonly used in the field can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-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 example, mannitol and glucose can be added as proppant for preparing lyophilized powder for injection.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
For the purpose of administration, enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
The fourth aspect of the technical scheme of the invention is to provide the 2- (benzofuran-5-yl) phenol and the pharmaceutically acceptable salts thereof in the first aspect of the invention and the application of the pharmaceutical composition in preparing a medicament for resisting human lung adenocarcinoma cells A549 in the third aspect of the invention.
The beneficial technical effects are as follows:
the 2- (benzofuran-5-yl) phenol of the invention is a new structural type compound with anticancer activity.
Detailed Description
The following examples are intended to illustrate the invention without further limiting it.
Example 1
Preparation of 4-allyl-2- (2-methylbenzofuran-5-yl) -6- ((4-methylpiperazin-1-yl) methyl) phenol
2.0mmol of 4-allyl-2- (2-methylbenzofuran-5-yl) phenol, 10mL of methanol, 6.0mmol of 4-methylpiperazine and 6.0mmol of 37% aqueous formaldehyde solution, and reacted at 60 ℃ for 6 hours. The reaction solution is desolventized and purified by column chromatography to obtain 4-allyl-2- (2-methylbenzofuran-5-yl) -6- ((4-methylpiperazin-1-yl) methyl) phenol with the yield of 68.0 percent; a light yellow oily liquid; 1 H NMR(400MHz，CDCl 3 ) Delta 7.65(s, 1H, benzofuran ring 4-H), 7.45-7.39 (m, 2H, benzofuran 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 to 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 )δ155.59，153.97，152.98，137.91，133.02，130.50，130.41，129.31，129.16，127.78，124.77，121.32，120.86，115.52，110.06，102.82，61.61，54.51，52.10，45.52，39.48，14.14。
Example 2
Anticancer activity of 2- (benzofuran-5-yl) phenol
1. Principle of antitumor activity
The MTT method, also known as MTT colorimetry, is a classical method for determining mitochondrial dehydrogenase activity in living cells. MTT analysis method uses living cells to metabolize reducing agent thiazole blue [3- (4, 5-dimethyl-2-thiazole) -2,5 diphenyl bromide tetrazole; 3- (4, 5-dimethylthiozol-2-yl) -2,5-diphenyltetrazolium bromide, MTT ] as a base. MTT is a dye that can accept hydrogen atoms. NADP-related dehydrogenases in mitochondria of living cells can convert yellow MTT into insoluble blue-violet formazan (formazn), while dead cells do not. After formazan is dissolved in DMSO, the optical density value is measured by an enzyme-labeling instrument under a certain wavelength, and the survival rate of cells can be quantitatively measured. And observing the inhibition effect of the sample on the tumor cell strain according to the change of the optical density value.
2. Experiment of antitumor Activity
Sample preparation: EXAMPLES Compounds
Cell line: human lung adenocarcinoma cell strain A549.
Reagent: thiazole blue (MTT), RPMI 1640 medium, neonatal fetal bovine serum, neonatal bovine serum, double antibody (Gibco); pancreatin (Gibco); a 96-well plate; dimethyl sulfoxide (national drug group).
The instrument comprises: HFsafe-1500 model superclean, HF151UV model CO2 incubator (Shanghai Shen scientific instruments Co., Ltd.); XSP-15C type inverted microscope (Shanghai rectangular optics, Inc.); multiskan MK3 microplate reader (Thermo, usa); ultrapure water preparation apparatus (Milli-Q, USA).
And (3) experimental operation: test of a549 cells in test samples. The experimental procedure for the sample on the four cells was the same. A blank control group is arranged in each group of experiments, a sample is divided into 5 concentration gradients, each concentration is provided with 4 multiple holes, and each group of experiments are measured in parallel for three times. OD values of the wells were measured at a wavelength of 570nm, and the cytotoxic activity of the samples against the respective cell lines was calculated from the change in OD.
3. Evaluation of antitumor Activity
1) Calculating the cell proliferation inhibition rate:
2)IC 50 value calculation
Analyzing by SPSS software, linearly regressing the logarithm value of the sample concentration and the cell inhibition rate,calculating the half inhibitory concentration IC of the compound on each cell line 50 The value is obtained. IC of 4-allyl-2- (2-methylbenzofuran-5-yl) -6- ((4-methylpiperazin-1-yl) methyl) phenol on A549 cells 50 Is 25.15. mu.M.
The activity test result shows that the 2- (benzofuran-5-yl) phenol and the pharmaceutically acceptable salt thereof have good inhibitory activity on human lung adenocarcinoma cells A549 and can be used for preparing anti-cancer drugs.
Claims (3)
1. A2- (benzofuran-5-yl) phenol of the formula I:
wherein R is selected from: a methyl group; r 1 Selected from the group consisting of: a methyl group.
2. A process for the preparation of 2- (benzofuran-5-yl) phenol according to claim 1, characterized in that it is prepared by the following reaction:
wherein R and R 1 Is as defined in claim 1.
3. The use of 2- (benzofuran-5-yl) phenol and pharmaceutically acceptable salts thereof according to claim 1 in the preparation of a medicament against human lung adenocarcinoma cells a 549.
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| CN101675931A (en) * | 2008-09-19 | 2010-03-24 | 天津药物研究院 | New uses of acyl chloride and sulfonyl chloride derivatives in preparing anti-tumor drug |
| CN101678013A (en) * | 2007-06-08 | 2010-03-24 | 詹森药业有限公司 | piperidine/piperazine derivatives |
| CN110950825A (en) * | 2018-09-27 | 2020-04-03 | 湖南大学 | 6- (piperazinemethyl) -2- (benzofuran-5-yl) phenol and application thereof |
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| CN101678013A (en) * | 2007-06-08 | 2010-03-24 | 詹森药业有限公司 | piperidine/piperazine derivatives |
| CN101675931A (en) * | 2008-09-19 | 2010-03-24 | 天津药物研究院 | New uses of acyl chloride and sulfonyl chloride derivatives in preparing anti-tumor drug |
| CN110950825A (en) * | 2018-09-27 | 2020-04-03 | 湖南大学 | 6- (piperazinemethyl) -2- (benzofuran-5-yl) phenol and application thereof |
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