CN112745310B - Chromone 2-piperazine linked furazan derivative and preparation method and application thereof - Google Patents
Chromone 2-piperazine linked furazan derivative and preparation method and application thereof Download PDFInfo
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- CN112745310B CN112745310B CN201911042090.XA CN201911042090A CN112745310B CN 112745310 B CN112745310 B CN 112745310B CN 201911042090 A CN201911042090 A CN 201911042090A CN 112745310 B CN112745310 B CN 112745310B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Abstract
The invention relates to the field of natural medicines and pharmaceutical chemistry, and relates to a preparation method of a series of chromone 2-piperazine linked furazan derivatives with anti-tumor activity and a new application in preparation of anti-tumor medicines. The chromone 2-piperazine linked furazan derivative and pharmaceutically acceptable salt thereof are shown in a general formula I. Wherein R is as defined in the claims and the specification.
Description
Technical Field
The invention relates to the fields of natural medicines and pharmaceutical chemistry, and relates to a chromone 2-piperazine-linked furazan derivative, a preparation method and application thereof. In particular to a preparation method of a series of chromone 2-piperazine linked furazan derivatives with anti-tumor activity and application thereof in the aspect of anti-tumor.
Background
Since ancient times, various natural products have been used as traditional medicines and are a rich source of active compounds. Chromones are naturally occurring oxygen-containing heterocyclic compounds that have a particular structure that is considered a useful parent for the design of novel compounds with potential pharmacological activity. Piperazine is often used as an important pharmaceutical intermediate as a raw material for pharmaceutical synthesis.
The invention designs and synthesizes the chromone 2-piperazine linked furazan derivative, and tests the biological activity of the synthesized derivative in the aspect of anti-tumor.
Disclosure of Invention
The invention aims to solve the technical problem of finding a chromone 2-piperazine linked furazan derivative with good anti-tumor activity and pharmaceutically acceptable salts thereof, and further provides a pharmaceutical composition.
In order to solve the technical problems, the invention provides the following technical scheme:
the chromone 2-piperazine linked furazan derivative and pharmaceutically acceptable salt thereof have the structural general formula as shown in the specification I:
wherein R is an alkyl group having 1 to 8 carbon atoms or an alkoxy group having 1 to 8 carbon atoms.
Preferably, R is an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms.
More preferably, R is an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms.
Further, the present invention is preferably the following derivatives and pharmaceutically acceptable salts thereof:
the derivatives of the invention can be prepared by the following method:
from 2-hydroxy-acetophenone derivative 1 and Vilsmeier Haack reagent (POCl) 3 And DMF) to synthesize 4-oxo-4H-1-benzopyran-3-carboxaldehyde derivatives 2, and then oxidizing the derivatives into chromone-3-formic acid 3 by sulfamic acid and sodium chlorite;
conversion of raw material phenylthiol 4 to 2-phenylthioacetic acid 5 by treatment with chloroacetic acid, with H 2 O 2 Oxidizing the compound 5 with an aqueous solution to obtain 2-benzenesulfonylacetic acid 6, and reacting with fuming HNO 3 Reacting to generate diphenyl sulfonyl furazan 7, and then reacting with 1- (2-hydroxyethyl) -piperazine to obtain mono-benzene sulfonyl furazan 8;
dissolving chromone-3-formic acid 3 in dimethylformamide, adding 1-hydroxybenzotriazole (HOBt) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) for activation, then adding 8, reacting at room temperature for 3 hours, and performing silica gel column chromatography on a methylene dichloride-methanol (10:1-500:1) system to obtain the chromone 2-piperazine-linked furazan derivative 9.
Pharmacological tests prove that the chromone 2-piperazine linked furazan derivative and the pharmaceutically acceptable salt thereof have good anti-tumor cell proliferation effect, and can be used for further preparing anti-tumor drugs.
Further, the invention provides a pharmaceutical composition which comprises the chromone 2-piperazine linked furazan derivative, pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.
The pharmaceutical composition has a good anti-tumor cell proliferation effect, and can be used for preparing anti-tumor drugs.
The specific embodiment is as follows:
example 1
A solution of 0.90g (6 mmol) of 5-methyl-2-hydroxyacetophenone 1a in anhydrous N, N-dimethylformamide (12 mL) was allowed to stand for 30min. Phosphorus oxychloride (POCl) was added dropwise over 1h 3 ) 1.12mL (12 mmol). The mixture was stirred at room temperature for 15h, then poured into water (40 mL), the product filtered and washed with diethyl ether to give 3-formyl-6-methylchromone 2a 0.94g in 83% yield. Sodium chlorite (NaClO) was added at 0deg.C 2 An aqueous solution (25 mL) of 80%,32 mmol) was added dropwise to 0.94g (5 mmol) of dichloromethane (50 mL) and sulfamic acid (NH) of 3-formyl-6-methyl primary ketone 2a 2 SO 3 H) In 3.88g (40 mmol) of aqueous solution (50 mL) after 15h the reaction was extracted with dichloromethane. The combined organic phases were taken up in Na 2 SO 4 Drying, filtration and evaporation, and finally washing with diethyl ether gave the product 3a 0.92g in 90% yield.
24.2g (0.22 mol) of thiophenol, 8.8g (0.22 mol) of sodium hydroxide were dissolved in 110mL of 95% ethanol, and 200mL of an aqueous solution prepared from 22.7g (0.24 mol) of chloroacetic acid and 12.7g (0.12 mol) of sodium carbonate was added thereto, and the mixture was stirred at room temperature for 3 hours and refluxed for 1 hour. After cooling to room temperature, 6mol/L hydrochloric acid is added to adjust the pH to 2, ethanol is distilled off under reduced pressure, white precipitate is generated, and the white crystal is obtained by filtration, wherein the yield is 92 percent, and the yield is 34.0 g. 13.4g (0.08 mol) of compound 5 is dissolved in 65mL of glacial acetic acid, 16.2mL (0.16 mol) of hydrogen peroxide is added, the mixture is stirred for 2.5h at room temperature to obtain colorless clear solution, 32mL (0.72 mol) of 95% fuming nitric acid is added dropwise, the temperature is raised to 90 ℃ for reaction for 0.5h, the mixture is cooled to room temperature, white needle-shaped crystals are separated out, the mixture is filtered and dried to obtain 7.1 g of furazan nitrogen oxide donor compound, and the yield of the furazan nitrogen oxide donor compound in two steps is 76%. Furazan nitrogen oxide donor compound 7 (730 mg, 2 mmol) was dissolved in tetrahydrofuran at 0 ℃, 96mg (4 mmol) of sodium hydride was added, then 122mg (2 mmol) of 1- (2-hydroxyethyl) -piperazine was added, after 4 hours of reaction, the reaction was quenched by ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and chromatographed on silica gel column (dichloromethane: methanol=100:1) to give 8mg of white solid in 99% yield.
204mg of compound 3a (1.0 mmol) was dissolved in dimethylformamide, EDCI (292 mg,1.5 mmol), catalytic amounts of HOBt and 8 (284 mg,1.0 mmol) were added in succession and stirred at room temperature for 3h. The reaction was monitored by TLC, after completion of the reaction, about 15mL of water was added, extracted 3 times with dichloromethane 10mL each time, the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatographed on silica gel (dichloromethane: methanol=50:1) to give the title compound 9a as a yellow-white solid in 47.6% yield. 1 H NMR(400MHz,DMSO-d 6 )δ(ppm):14.1(s,1H,-COOH),8.03(m,2H,2',6'-ArH),7.92-7.89(m,1H,4'-ArH),7.86-7.83(d,1H,J＝9.0Hz,5-ArH),7.79-7.75(m,3H,3',5',8-ArH),7.19-7.17(dd,1H,J＝8.3Hz,6-ArH),4.56-4.54(t,1H,J＝5.1Hz,CH-O),3.54-3.52(t,3H,J＝4.6Hz,CH-O,Ar-N-CH 2 ),3.17(s,2H,N-CH 2 ),2.86-2.84(t,2H,J＝5.2Hz,N-CH 2 ),2.62-2.60(t,4H,J＝4.1Hz,-CH 2 -N-CH 2 -),2.25(s,3H,-CH 3 )； 13 C NMR(100MHz,DMSO-d 6 )δ(ppm):191.2,160.7,154.3,137.8,136.6,135.1,130.6,129.2,128.7,128.1,127.8,126.0,120.2,117.7,111.0,89.8,70.3,69.9,55.7,53.5,49.1,29.5,20.6；HRMS(ESI)m/z calcd for C 25 H 23 N 4 O 9 S[M-H] - 555.1186,found 555.1171。
Example 2
Compound 9b, a yellow solid, was prepared according to the synthetic method of example 1 in 37.8% yield. 1 H NMR(400MHz,DMSO-d 6 )δ(ppm):13.9(s,1H,-COOH),8.04(m,2H,2',6'-ArH),7.92-7.87(m,2H,4',5-ArH),7.79-7.75(m,3H,3',5',8-ArH),7.03-7.00(dd,1H,J＝8.9,3.0Hz,6-ArH),4.56-4.54(t,2H,J＝5.0Hz,CH 2 -O),3.75(s,3H,-OCH 3 ),3.55(s,4H,Ar-N-(CH 2 ) 2 ),2.86-2.84(t,2H,J＝5.0Hz,-N-CH 2 ),2.62-2.60(t,4H,J＝4.6Hz,-N-(CH 2 ) 2 )； 13 C NMR(100MHz,DMSO-d 6 )δ(ppm):190.8,157.2,156.9,154.6,151.5,137.8,136.6,130.6,128.7,126.0,121.6,120.6,120.4,118.6,113.0,105.2,89.8,69.9,60.4,56.4,56.2,55.7,29.5；HRMS(ESI)m/z calcd for C 25 H 23 N 4 O 10 S[M-H] - 571.1135,found 571.1122。
The following are the results of pharmacological experiments on some of the compounds of the invention:
experimental device and reagent
Instrument super clean bench (Sujing group Antai company)
Constant temperature incubator (Thermo electron Corporation)
Enzyme label instrument (BIO-RAD company)
Inverted biological microscope (Chongqing optical instrument factory)
Reagent cell culture medium RPMI-1640, DMEM (high sugar) (GIBCO Co.)
Fetal bovine serum (Hangzhou Jiqing Limited company)
CCK-8 (Biosharp company product)
Trypan blue (Solarbio company product)
DMSO (Sigma Co.)
Cell strain human chronic myelogenous leukemia cell K562, human liver cancer cell strain HepG2, human breast cancer cell MCF7, human colon cancer cell HCT116, human lung cancer cell strain A549, human normal liver cell L-02 and peripheral blood mononuclear cell PMBC
Experimental method
Cell inhibition activity experimental method
Cells were incubated at 37℃with 5% CO 2 Culturing in a saturated humidity incubator. The culture medium is RPMI1640 cell culture medium containing 10% heat-inactivated fetal bovine serum, penicillin 100U/mL and streptomycin 100U/mL. After 48h exchange of culture medium and cell attachment, passaging was performed by digestion with 0.25% trypsin. The experimental cells are all in logarithmic growth phase, and trypan blue dye exclusion method shows the cell activity>95％。
Taking one bottle of cells in good logarithmic phase, adding digestive juice (0.125% trypsin+0.01% EDTA) for digestion, counting 2-4×10 4 cell/mL, preparing cell suspension, inoculating to 96-well plate, 100 μl/well, placing at constant temperature CO 2 Culturing in an incubator for 24 hours. The solution was changed, and 100. Mu.L/well of the test drug was added thereto, followed by culturing for 72 hours. CCK-8 was added to 96-well plates, 50. Mu.L/well, and incubated in an incubator for 4h. The supernatant was aspirated, DMSO was added, 200. Mu.L/well, and the plate shaken for 10min. The test substance was examined at 6 concentrations of 0.001 to 100. Mu.M in ten-fold increments, absorbance per well was measured at a wavelength of 450nm using an ELISA monitor, and the cell inhibition rate at each concentration was calculated separately.
The inhibition rate calculation method comprises the following steps:
drug sensitive well relative OD value = drug sensitive well absolute OD value-blank control well absolute OD value
Experimental results
Table 1 example IC of antiproliferative activity on 5 human cancer cell lines and 2 human normal cells 50 Value (mu M)
Pharmacological tests prove that the target derivative has better anti-tumor cell proliferation activity, has certain selectivity on tumor cells and normal cells, and can be used for further preparing anti-tumor drugs.
Claims (9)
1. Chromone 2-piperazine linked furazan derivatives represented by general formula I and pharmaceutically acceptable salts thereof:
wherein R is an alkoxy group having 1 to 8 carbon atoms.
2. The chromone 2-piperazinyl linked furazan derivative of claim 1 and pharmaceutically acceptable salts thereof:
wherein R is an alkoxy group having 1 to 6 carbon atoms.
3. The chromone 2-piperazinyl linked furazan derivative of claim 1 and pharmaceutically acceptable salts thereof:
wherein R is an alkoxy group having 1 to 4 carbon atoms.
4. The following chromone 2-piperazine linked furazan derivatives and pharmaceutically acceptable salts thereof are selected from the group consisting of:
。
5. a pharmaceutical composition comprising a therapeutically effective amount of the derivative of any one of claims 1-4, and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
6. The preparation method of the chromone 2-piperazine linked furazan derivative and the pharmaceutically acceptable salt thereof is characterized by comprising the following steps:
synthesis of 4-oxo-4 from 2-hydroxy-acetophenone derivative 1 by reaction with Vilsmeier Haack reagentH-1-benzopyran-3-carboxaldehyde derivatives 2, then being oxidized by sulfamic acid and sodium chlorite to chromone-3-formic acid 3, the Vilsmeier Haack reagent is POCl 3 And DMF;
conversion of raw material phenylthiol 4 to 2-phenylthioacetic acid 5 by treatment with chloroacetic acid, with H 2 O 2 Oxidizing the compound 5 with an aqueous solution to obtain 2-benzenesulfonylacetic acid 6, and reacting with fuming HNO 3 Reacting to generate diphenyl sulfonyl furazan 7, and then reacting with 1- (2-hydroxyethyl) -piperazine to obtain mono-benzene sulfonyl furazan 8;
dissolving chromone-3-formic acid 3 in dimethylformamide, adding 1-hydroxybenzotriazole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride for activation, then adding 8, reacting at room temperature for 3h, and performing silica gel column chromatography by a methylene dichloride-methanol (10:1 to 500:1) system to obtain a chromone 2-piperazine-linked furazan derivative 9;
wherein R is as claimed in claim 1.
7. Use of a chromone 2-piperazine linked furazan derivative of general formula I as defined in any one of claims 1-4 and pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment of a neoplastic disease.
8. Use of the pharmaceutical composition of claim 5 for the preparation of a medicament for the treatment of neoplastic diseases.
9. The use according to claim 7 or 8, wherein the tumour is a leukemia, liver cancer, breast cancer, colon cancer or lung cancer.
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| CN106946868A (en) * | 2016-12-18 | 2017-07-14 | 何黎琴 | Nitric oxide donator type coumarin derivative, its preparation method and medical usage |
| CN108658962A (en) * | 2017-03-30 | 2018-10-16 | 复旦大学 | 3- substituted cumarins Furazan Derivatives and its purposes in preparing anti-multidrug resistance of tumor drug |
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Patent Citations (6)
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| CN102000072A (en) * | 2009-09-01 | 2011-04-06 | 奇复康药物研发(苏州)有限公司 | Anti-tumor natural medicine coupled with nitric oxide donor and medical use thereof |
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| CN105153142A (en) * | 2014-06-03 | 2015-12-16 | 复旦大学 | Furazan derivative of coumarin parent nucleus and antineoplastic activity |
| CN106946868A (en) * | 2016-12-18 | 2017-07-14 | 何黎琴 | Nitric oxide donator type coumarin derivative, its preparation method and medical usage |
| CN108658962A (en) * | 2017-03-30 | 2018-10-16 | 复旦大学 | 3- substituted cumarins Furazan Derivatives and its purposes in preparing anti-multidrug resistance of tumor drug |
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