CN110950856B - 8- (benzofuran-5-yl) benzoxazine diones and their use as anti-cancer agents - Google Patents
8- (benzofuran-5-yl) benzoxazine diones and their use as anti-cancer agents Download PDFInfo
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Abstract
The invention relates to 8- (benzofuran-5-yl) benzoxazine diones of formula (I):
wherein R is selected from: hydrogen, C 1 ～C 2 Alkyl radical, C 3 ～C 4 Straight or branched chain alkyl; r is 1 Selected from the group consisting of: hydrogen, C 1 ～C 2 An alkyl group.
Description
Technical Field
The invention relates to preparation and application of a new compound; in particular to 8- (benzofuran-5-yl) benzoxazine dione and application thereof as an anti-cancer medicament.
Background
The benzofuran compound has good application prospect in the field of chemical drug therapy of cancer. Many natural benzofuran compounds, such as ailanthoidal et al [ oncol. Rep.,2006, 16 (4): 921-927 has good antitumor effect. Simom et al [ j.med.chem.,2006, 49 (11): 3143-3152 describes the introduction of the benzofuran ring in the structural modification of combretastatin, an anticancer drug, to synthesize the compound ST2179, which can inhibit the proliferation of various cells and induce apoptosis. Benzofuran compounds PCI-24781 developed by Pharmacyclics is a novel HDAC inhibitor with high potency and broad spectrum of anticancer activity [ mol. 1309-1317].
The benzoxazine diketone has a structure rich in hydrogen bond donor and acceptor, can form strong interaction with biological macromolecules, and shows good biological activity in multiple fields: such as anti-allergic activity [ j.med.chem.,1985, 28 (1): 24-27], antitumor activity [ WO2002092083] and herbicidal activity [ pesticide.Sci., 1999, 55 (3): 281-287], and the like.
Loev et al (Journal of Medicinal Chemistry,1985,28 (1): 24) utilized o-aminophenol to react with oxalyl chloride in boiling toluene to obtain benzoxazine dione, and based on this, a series of benzoxazine-2, 3-dione compounds were designed and synthesized, and their inhibitory effect on rat passive skin allergy (PCA) reaction was studied. Test results show that the benzoxazine-2, 3-diketone compounds 1 and 2 have better PCA inhibitory activity.
Xiong et al [ WO 02/092083 A1] designed, synthesized benzoxazinedione 3 (scheme 2), and identified as potent activators of the cysteine protease cascade and inducers of apoptosis in tumor cells.
Disclosure of Invention
The invention aims to provide 8- (benzofuran-5-yl) benzoxazine dione, and 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 technical scheme of the invention is 8- (benzofuran-5-yl) benzoxazine dione shown in a chemical structural formula I:
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: hydrogen, C 1 ～C 2 An alkyl group.
Further, preferred compounds are selected from: 6-allyl-8- (2-methylbenzofuran-5-yl) -2H-benzo [ b ] [1,4] oxazine-2, 3 (4H) -dione.
The second aspect of the technical scheme of the invention provides a preparation method of the 8- (benzofuran-5-yl) benzoxazine dione, which is characterized in that the preparation reaction is as follows:
wherein R is selected from: hydrogen, C 1 ～C 2 Alkyl radical, C 3 ～C 4 Straight or branched chain alkyl; r is 1 Selected from: c 1 ～C 2 Alkyl, X is selected from bromine or iodine, or R 1 X is selected from methyl iodide, ethyl bromide, dimethyl sulfate or diethyl sulfate.
A third aspect of the present invention provides a pharmaceutical composition comprising a compound of the first aspect and a pharmaceutically acceptable salt thereof, the pharmaceutical composition comprising a therapeutically effective amount of the 8- (benzofuran-5-yl) benzoxazinedione 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 their pharmaceutically acceptable salts can be formulated into any dosage form suitable for human or animal use by combining them 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 into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
For the encapsulation of the administration units, the active ingredients of the compounds according to the invention and their pharmaceutically acceptable salts can be mixed with diluents, glidants and the mixture can be placed directly into hard or soft capsules. Or preparing the effective component of the compound and the pharmaceutically acceptable salt thereof into granules or pellets with a diluent, an adhesive and a disintegrating agent, and then placing the granules or pellets 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 the 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, in the preparation of lyophilized powder for injection, mannitol and glucose can also be added as proppant.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
For administration purposes, to enhance the therapeutic effect, the medicaments or pharmaceutical compositions of the invention may be administered by any known method of administration.
The fourth aspect of the technical scheme of the invention is to provide the 8- (benzofuran-5-yl) benzoxazine dione and pharmaceutically acceptable salts thereof in the first aspect of the invention and the application of the pharmaceutical composition in the third aspect of the invention in preparing anticancer drugs.
The beneficial technical effects are as follows:
the 8- (benzofuran-5-yl) benzoxazine dione disclosed by the invention is a novel 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) phenol
15mmol of honokiol and 0.225mmol of PdCl 2 1.5mmol of NaOAc with 56mL of DMA/H 2 O (6 2 And reacting for 16 hours in an oil bath at the temperature of 60 ℃. After the reaction, the reaction mixture was transferred to a separatory funnel and 100mL of H was added 2 Diluting with O, extracting with ethyl acetate for 3 times, mixing organic layers, and collecting anhydrous Na 2 SO 4 Drying and rotary evaporating to recover solvent. Purifying the crude product by column chromatography to obtain yellow oily liquid 4-allyl-2- (2-methylbenzofuran-5-yl) phenol with the yield of 86%; 1 H NMR(400MHz，CDCl 3 ) δ:7.53 (d, J =1.5Hz,1H, benzofuran ring 4-H), 7.50 (d, J =8.4Hz,1H, benzofuran ring 7-H), 7.26 (dd, J =8.4,1.5Hz,1H, benzofuran ring 6-H), 7.10-7.07 (m, 2H, C) 6 H 3 3,5-H)，6.94(d，1H，J＝8.8Hz，C 6 H 3 6-H), 6.41 (s, 1H, benzofuran ring 3-H), 6.04-5.93 (m, 1H, CH), 5.21 (s, 1H, OH), 5.12-5.04 (m, 2H, = CH) 2 )， 3.36(d，J＝6.7Hz，2H，CH 2 )，2.49(s，3H，CH 3 )； 13 C NMR(101MHz，CDCl 3 )δ：156.58， 154.44，151.10，138.08，132.29，131.79，130.83，130.21，129.00，128.75，124.43，120.87，115.98，115.75，111.34，102.93，39.61，14.19。
Example 2
Preparation of 4-allyl-2-nitroso-6- (2-methylbenzofuran-5-yl) phenol
10mmol of 4-allyl-2- (2-methylbenzofuran-5-yl) phenol and 15mmol of sodium nitrite, dissolving the mixture by using 25mL of acetonitrile and 5mL of water, dropwise adding 3mL of concentrated hydrochloric acid (36-38%) at room temperature, continuously reacting for 0.5h after about 1h of dropwise addition, and detecting by TLC to completely react; quenching by adding water, extracting by dichloromethane, drying an organic phase by using anhydrous sodium sulfate, and purifying by column chromatography to obtain a yellow solid 4-allyl-2-nitroso-6- (2-methylbenzofuran-5-yl) phenol with the yield of 76.9 percent; mp.58-60 ℃; 1 H NMR(400MHz，CDCl 3 )δ：11.04(s，1H，OH)，7.93(d，J＝2.2Hz，1H，C 6 H 2 5-H), 7.63 (d, J =1.7hz,1h, benzofuran ring 4-H), 7.50 (d, J =2.2hz,1h, c) 6 H 2 3-H), 7.47 (d, J =8.5hz,1h, benzofuran ring 7-H), 7.36 (dd, J =8.5,1.7hz,1h, benzofuran ring 6-H), 6.41 (s, 1H, benzofuran ring 3-H), 5.96 (ddt, J =17.2, 10.7,6.7hz,1h, CH), 5.18 to 5.11 (m, 2H, = CH) (= CH) 2 )，3.41(d，J＝6.7Hz，2H，CH 2 )，2.48(s，3H，CH 3 )； 13 C NMR(101MHz，CDCl 3 )δ： 156.34，154.51，151.41，139.42，136.07，133.88，133.53，131.78，130.31，129.38，124.61， 123.07，121.10，117.17，110.43，102.75，38.96，14.15。
Example 3
Preparation of 4-allyl-2-amino-6- (2-methylbenzofuran-5-yl) phenol
5.0mmol of 4-allyl-2-nitroso-6- (2-methylbenzofuran-5-yl) phenol and 1.0mmol of ammonium chloride were dissolved in 50 mL of ethanol and 10mL of water, and 25mmol of zinc powder and 2.5mL of acetic acid were added and reacted at room temperature for 0.5h. Filtering, diluting the filtrate with water, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, and purifying by column chromatography to obtain brown solid 4-allyl-2-amino-6- (2-methylbenzofuran-5-yl) phenol, yield 73.2%; mp.80-82 deg.C; 1 H NMR(400MHz， DMSO-d 6 ) δ:7.56 (s, 1H, benzofuran ring 4-H), 7.46 (d, J =8.5Hz,1H, benzofuran ring 7-H), 7.29 (d, J =8.5hz,1h, benzofuran ring 6-H), 6.58 (s, 1h, c) 6 H 2 )，6.46(s，1H，C 6 H 2 ) 6.31 (s, 1H, benzofuran ring 3-H), 5.98-5.87 (m, 1H, CH), 5.07 (d, J =17.0Hz,1H, = CH) 2 )， 5.00(d，J＝10.0Hz，1H，＝CH 2 )，4.72(br，1H)，3.20(d，J＝6.7Hz，2H，CH 2 )，2.45(s， 3H，CH 3 )； 13 C NMR(101MHz，DMSO-d 6 )δ：155.97，153.57，138.97，138.87，138.82， 134.47，131.91，130.42，129.11，125.16，121.06，118.96，115.56，114.34，110.29，103.34， 14.26。
Example 4
Preparation of 6-allyl-8- (2-methylbenzofuran-5-yl) -2H-benzo [ b ] [1,4] oxazine-2, 3 (4H) -dione
1.0mmol of 4-allyl-2-amino-6- (2-methylbenzofuran-5-yl) phenol was dissolved in 10mL of dichloromethane, 2.5mmol of triethylamine was added thereto, the mixture was stirred at room temperature, and 1mL of a dichloromethane solution containing 1.5mmol of oxalyl chloride was added dropwise over 10 min; adding water, separating, drying with anhydrous sodium sulfate, desolventizing, and purifying by column chromatography to obtain 6-allyl-8- (2-methylbenzofuran-5-yl) -2H-benzo [ b ]][1,4]Oxazine-2, 3 (4H) -dione, yield 42.4%; brown solid, mp.160-162 ℃; 1 H NMR(400MHz，CDCl 3 ) δ 8.57 (br, 1H, NH), 7.87 (s, 1H, benzofuran ring 4-H), 7.58 (d, J =8.5Hz,1H, benzofuran ring 7-H), 7.48 (d, J =8.5Hz,1H, benzofuran ring 6-H), 7.16 (s, 1H, C) 6 H 2 )，6.86(s，1H，C 6 H 2 ) 6.43 (s, 1H, benzofuran ring 3-H), 6.04-5.93 (m, 1H, CH), 5.17-5.10 (m, 2H, = CH) 2 )，3.45(d，J＝6.6Hz，2H，CH 2 )，2.49(s，3H，CH 3 )； 13 C NMR (101MHz，CDCl 3 )δ156.34，154.63，139.49，137.06，136.76，130.12，129.70，129.18， 124.66，123.56，122.68，120.16，116.35，110.81，108.82，102.90，40.16，14.15。
Example 5
Preparation of 4-methyl-6-allyl-8- (2-methylbenzofuran-5-yl) -2H-benzo [ b ] [1,4] oxazine-2, 3 (4H) -dione
6-allyl-8- (2-methylbenzofuran-5-yl) -2H-benzo [ b ] [1,4] oxazine-2, 3 (4H) -diketone reacts with dimethyl sulfate to prepare 4-methyl-6-allyl-8- (2-methylbenzofuran-5-yl) -2H-benzo [ b ] [1,4] oxazine-2, 3 (4H) -diketone.
Example 6
Anticancer activity of 8- (benzofuran-5-yl) benzoxazinedione
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 ]. 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 on antitumor Activity
Sample preparation: EXAMPLES Compounds
Cell line: chronic granulocytic leukemia cell line K562.
Reagent: thiazole blue (MTT), RPMI 1640 culture solution (Hyclone, USA), newborn bovine serum (Hangzhou Biotechnology, inc., zhejiang sky), and antibiotics (Invitrogen Life technologies, USA); 96-well culture plates (corning, usa); dimethyl sulfoxide (Sigma, USA).
The instrument comprises: HFsafe-1500 model superclean bench, forma 3111CO 2 Incubator (Thermo corporation, usa); IX70 fluorescent inverted microscope (OLYMPUS, japan Co., ltd.); synergy HTX multifunctional microplate detector (Berton instruments, inc., USA); pure water instrument Pure Maxima LS (ELGA, uk).
And (3) experimental operation: test samples were tested for inhibitory activity against K562 cells in vitro. In the experiment process, each sample is provided with 5 concentration gradients (the concentration gradient setting range is 128 mu mol/L-8 mu mol/L), each concentration is 6 parallel samples, each group of experiments are paralleled for 3 times, and the conclusion is obtained through blank group comparison. And detecting the OD value of each hole by using a microplate reader, wherein the detection wavelength is 490nm.
3. Evaluation of antitumor Activity
1) Calculating the cell inhibition rate:
2)IC 50 value calculation
The logarithmic value of the sample concentration and the cell inhibition rate are linearly regressed, and the half inhibition concentration IC of the sample on the cells is calculated by using software SPSS13.0 50 The value is obtained. 6-allyl-8- (2-methylbenzofuran-5-yl) -2H-benzo [ b][1,4]IC of oxazine-2, 3 (4H) -dione for chronic myelogenous leukemia cell strain K562 cells 50 Was 18.07. Mu.M.
The activity test result shows that the 8- (benzofuran-5-yl) benzoxazine dione has good inhibitory activity on cells of a chronic myelogenous leukemia cell strain K562, and can be used for preparing anticancer drugs.
Claims (6)
1. A class of 8- (benzofuran-5-yl) benzoxazinediones of the formula I:
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: hydrogen, C 1 ～C 2 An alkyl group.
2. The 8- (benzofuran-5-yl) benzoxazinedione of claim 1, the selected compound being 6-allyl-8- (2-methylbenzofuran-5-yl) -2H-benzo [ b ] [1,4] oxazine-2, 3 (4H) -dione.
3. A preparation method of 8- (benzofuran-5-yl) benzoxazine diketone is characterized by comprising the following preparation reactions of:
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, X is selected from bromine or iodine, or R 1 X is selected from methyl iodide, ethyl bromide, dimethyl sulfate or diethyl sulfate.
4. Use of the 8- (benzofuran-5-yl) benzoxazinedione of claim 1 for the preparation of an anti-leukemic drug.
5. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
6. A pharmaceutical composition comprising a compound of claim 2 and a pharmaceutically acceptable carrier.
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| CN104876924A (en) * | 2015-05-12 | 2015-09-02 | 湖南大学 | 3-[5-(1,2,4-triazolyl-1-yl)thiazolyl-2-yl]benzoxazinone, and preparation method and application thereof |
| CN108440468A (en) * | 2018-04-17 | 2018-08-24 | 南华大学 | 2- (benzofuran -5- bases) phenol and its application as anticancer drug |
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| CN104876924A (en) * | 2015-05-12 | 2015-09-02 | 湖南大学 | 3-[5-(1,2,4-triazolyl-1-yl)thiazolyl-2-yl]benzoxazinone, and preparation method and application thereof |
| CN108440468A (en) * | 2018-04-17 | 2018-08-24 | 南华大学 | 2- (benzofuran -5- bases) phenol and its application as anticancer drug |
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