CN111171018A - Chalcone compound and application thereof - Google Patents
Chalcone compound and application thereof Download PDFInfo
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- CN111171018A CN111171018A CN201811345136.0A CN201811345136A CN111171018A CN 111171018 A CN111171018 A CN 111171018A CN 201811345136 A CN201811345136 A CN 201811345136A CN 111171018 A CN111171018 A CN 111171018A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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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
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to chalcone-containing compounds shown in a general formula (I), and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein a substituent R1、R2、R3、R4、R5、R6Q, n have the meaning given in the description. The invention also relates to application of the compound shown in the general formula (I) in preparation of antitumor drugs, and also relates to application of the compound and pharmaceutically acceptable salts, solvates and prodrugs thereof in preparation and/or prevention and alleviation of cancers caused by tumor cells of human tissues or organs. The cancer is preferably colon cancer, hepatocarcinoma, lymphoma, lung cancer, esophageal cancer, breast cancer, central nervous system tumor, melanoma, skin cancer, and ovarian cancerCervical cancer, renal cancer, leukemia, prostate cancer, pancreatic cancer, bladder cancer, rectal cancer, osteosarcoma, nasopharyngeal cancer, gastric cancer, etc.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a chalcone compound and application thereof in preventing and/or treating cancers.
Background
The literature Chinese Pharmacological Bulletin 2015 Jul; 967-72 relate to the study on the cell proliferation mechanism of licochalcone A for inhibiting melanoma B16F10, but do not study on the inhibition of other cancers such as lung cancer, bladder cancer, colon cancer and leukemia.
The patent CN105085220A relates to the research on the in vitro anti-tumor inhibitory activity of the compound A with the general formula, but the structure of the compound is obviously different from that of the compound of the invention.
Patent CN107235917A relates to licochalcone A dihydropyrimidine compounds which have certain biological activity but poor anticancer activity.
Despite the numerous patents mentioned in connection with the introduction, there is a continuing need to develop new anti-cancer compounds to control the harm of cancer to humans. All of the compounds disclosed in the above patents are structurally distinct from the compounds of the present invention.
Disclosure of Invention
The invention aims to provide a chalcone compound with a novel structure and application of the compound in preventing and/or treating cancer.
In order to achieve the purpose, the invention adopts the following technical scheme:
a chalcone compound, which is shown in a general formula (I),
in the formula (I), the compound is shown in the specification,
R1selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C unsubstituted or substituted by at least one1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C12Alkylthio radical, C1-C12Alkylsulfonyl radical, C1-C12Alkylcarbonyl or C1-C12Alkoxycarbonyl, such as halogen, hydroxy, amino, cyano or nitro;
R2selected from hydrogen, C1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl or heteroaryl;
R3selected from hydrogen, C1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl or heteroaryl;
R4selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the following are halogen, hydroxy, amino, cyano or nitro;
m is selected from 1 to 4;
R5selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the following are halogen, hydroxy, amino, cyano or nitro;
p is selected from 1-4;
R6selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C12Alkylthio radical, C1-C12Alkylsulfonyl radical, C1-C12Alkylcarbonyl or C1-C12Alkoxycarbonyl, such as halogen, hydroxyl, amino, cyano, nitro;
n is selected from 1-5;
or isomers of the compound shown in the general formula (I), and pharmaceutically acceptable salts, solvates or prodrugs thereof.
In the preferred general formula (i),
R1selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C1-C4Alkyl radical, C1-C4Alkoxy radical, C3-C6Cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C4Alkylthio radical, C1-C4Alkylsulfonyl radical, C1-C4Alkylcarbonyl group, C1-C4Alkoxycarbonyl, C substituted by one or more of the following groups1-C4Alkyl radical, C1-C4Alkoxy radical, C3-C6Cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C4Alkylthio radical, C1-C4Alkylsulfonyl radical, C1-C4Alkylcarbonyl or C1-C4Alkoxycarbonyl wherein the following are halogen, hydroxy, cyano, nitro or amino;
R2selected from hydrogen, C1-C4Alkyl or C3-C12A cycloalkyl group;
R3selected from hydrogen, C1-C4Alkyl radicalOr C3-C12A cycloalkyl group;
R4selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C1-C4Alkyl radical, C1-C4Alkoxy or C3-C6A cycloalkyl group;
m is selected from 1 to 4;
R5selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C1-C4Alkyl radical, C1-C4Alkoxy or C3-C6A cycloalkyl group;
p is selected from 1-4;
R6selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one halogen1-C4Alkyl radical, C1-C4Alkoxy radical, C3-C6Cycloalkyl, heterocyclyl, aryl or heteroaryl;
n is selected from 1-5;
or isomers of the compound shown in the general formula (I), and pharmaceutically acceptable salts, solvates or prodrugs thereof.
In a further preferred general formula (i),
R1selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C1-C4Alkyl radical, C1-C4Alkoxy, C substituted by one or more halogens1-C4Alkyl radical, C1-C4An alkoxy group;
R2selected from hydrogen, methyl, ethyl or cyclopropyl;
R3selected from hydrogen, methyl, ethyl or cyclopropyl;
R4selected from hydrogen, fluoro, chloro, methyl, ethyl or cyclopropyl;
m is selected from 1 to 4;
R5selected from hydrogen, fluoro, chloro, methyl, ethyl or cyclopropyl;
p is selected from 1-4;
R6selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, unsubstituted or substituted with one or more substituents selected from the group consisting ofC substituted by one less halogen1-C4Alkyl radical, C1-C4An alkoxy group;
n is selected from 1-5;
or isomers of the compound shown in the general formula (I), and pharmaceutically acceptable salts, solvates or prodrugs thereof.
Still further preferably, in the general formula (i),
R1selected from hydrogen, trifluoromethyl or methyl;
R2selected from hydrogen or methyl;
R3selected from hydrogen or methyl;
R4selected from hydrogen;
R5selected from hydrogen;
R6selected from hydrogen, halogen, hydroxy, methoxy, ethoxy, trifluoromethoxy, methyl, ethyl, isopropyl or trifluoromethyl;
n is selected from 1-5;
or isomers of the compound shown in the general formula (I), and pharmaceutically acceptable salts, solvates or prodrugs thereof.
More preferably, in the general formula (i),
R1is selected from trifluoromethyl;
R2selected from hydrogen;
R3selected from hydrogen;
R4selected from hydrogen;
R5selected from hydrogen;
R6selected from hydrogen, fluoro, chloro, hydroxy, methoxy or trifluoromethyl;
n is selected from 1-5;
or isomers of the compound shown in the general formula (I), and pharmaceutically acceptable salts, solvates or prodrugs thereof.
The salt corresponding to the compound of the general formula I or the isomer thereof is hydrochloride, sulfate, nitrate, bicarbonate, carbonate, phosphate, formate, acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, benzoate, citrate, malate, tartrate, maleate, succinate, ascorbate or oxalate.
According to the invention, prodrugs of compounds of formula (I) are derivatives of compounds of formula (I) which may themselves have a weaker activity or even no activity, but which, after administration, are converted under physiological conditions (e.g. by metabolism, solvolysis or otherwise) into the corresponding biologically active form.
The compound solvate of the general formula (I) is prepared by reacting the compound of the general formula (I) or an isomer thereof with methanol, ethanol, isopropanol, n-butanol, ethyl acetate, dichloromethane, petroleum ether and acetonitrile.
The application of the compound shown in the general formula (I), the isomer thereof, and the pharmaceutically acceptable salt, solvate or prodrug thereof in preparing a medicament for treating cell proliferation diseases.
The cell proliferation diseases are selected from cancer, infection, inflammation or autoimmune diseases.
The cancer is selected from colon cancer, liver cancer, lymphoma, lung cancer, esophageal cancer, breast cancer, central nervous system tumor, melanoma, skin cancer, ovarian cancer, cervical cancer, renal cancer, leukemia, prostate cancer, pancreatic cancer, bladder cancer, rectal cancer, osteosarcoma, nasopharyngeal cancer or gastric cancer.
A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-6, or an isomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and one or more pharmaceutically acceptable carriers or excipients.
The application of the pharmaceutical composition in preparing medicines for treating cell proliferation diseases.
In the definitions of the compounds of the general formula (I) given above, the terms used in the collection generally represent the following substituents:
halogen: refers to fluorine, chlorine, bromine or iodine. Alkyl groups: straight-chain or branched alkyl groups, such as methyl, ethyl, propyl, isopropyl or tert-butyl. Halogenated alkyl groups: straight-chain or branched alkyl radicals in which the hydrogen atoms may be partly or wholly replaced by halogen atomsExamples of the substituent include chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl and the like. Alkoxy groups: straight or branched chain alkyl groups attached to the structure via oxygen atom linkages. Cycloalkyl groups: substituted or unsubstituted heteroatom-containing cyclic alkyl groups, such as cyclopropyl, cyclopentyl, or cyclohexyl. Substituents such as methyl, halogen, and the like. Attached to the structure via an oxygen atom bond. Alkoxy groups: straight or branched chain alkyl groups attached to the structure via oxygen atom linkages. Alkylthio group: straight or branched chain alkyl groups attached to the structure via a sulfur atom. An alkylcarbonyl group: the linear or branched alkyl group is linked to the structure via a carbonyl group (-CO-), such as acetyl. Alkoxycarbonyl group: the alkoxy group is attached to the structure via a carbonyl group. Such as-COOCH3，-COOCH2CH3. An alkylsulfonyl group: straight-chain or branched alkyl group via sulfone group (-SO)2-) is attached to a structure, such as a methylsulfonyl group. Aryl includes phenyl or naphthyl and the like. Heteroaryl is a five or six membered ring containing 1 or more heteroatoms N, O, S. Such as furyl, pyrrolyl, pyrazolyl, thiazolyl, pyridyl, pyrimidinyl and the like.
In the compounds of the invention of the partial general formula I (R)6)nThe substituents are listed in Table 1, but do not limit the present invention.
TABLE 1
Further, some of the compounds of formula (I) may be represented by Table 2,
TABLE 2
The compounds of the general formula (I) according to the invention can be prepared as follows. The reaction is as follows, wherein the groups are as defined above unless otherwise indicated:
synthetic routes of general formula (I):
the preparation process comprises the following steps:
the method comprises the following steps: dissolving ethyl acetoacetate in a solvent, and dropwise adding a mixed solution of a chlorinating agent and the solvent at the temperature of-5 ℃. Stirring for 12 hours at normal temperature after dripping. And pouring the reaction liquid into an ice-water bath to quench the reaction, extracting, drying and desolventizing to obtain the cpd.2 product.
Step two: and dissolving cpd.2 and cpd.3 in a solvent, heating and refluxing for 6h to react, removing the raw materials, cooling and desolventizing, and carrying out column chromatography to obtain the product cpd.4.
Step three: dissolving cpd.4 in a solvent, adding alkali, reacting at room temperature for 8h, dissolving the raw material, adjusting Ph to 5, extracting with ethyl acetate, drying, and desolventizing to obtain a white solid cpd.5.
Step four: dissolving cpd.5 in a solvent, adding a chlorinating agent, heating and refluxing for 3 hours, and removing the solvent to obtain cpd.6 after the raw materials disappear.
Step five: cpd.7 and cpd.8 are dissolved in a solvent, added with an aqueous solution of alkali, stirred for 8 hours at normal temperature, extracted by ethyl acetate and subjected to column chromatography to obtain cpd.9.
Step six: and dissolving cpd.9 and cpd.6 in a solvent, adding alkali, stirring for 8 hours at 55 ℃, and carrying out column chromatography to obtain a product cpd.10, namely the compound shown in the general formula (I).
The chlorinating agent may be selected from thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, Vilesmeier-Haack reagent, sulfuryl chloride, and the like.
The base is selected from sodium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, and potassium bicarbonate.
The solvent used in each step can be selected from ethanol, acetonitrile, tetrahydrofuran, toluene, xylene, benzene, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetone or butanone, etc.
The reaction temperature in the above steps may be between room temperature and the boiling temperature of the solvent, preferably in the range of 20-100 ℃.
Cpd.1, cpd.3, cpd.7 and cpd.8 in the above reactions are commercially available.
The salts of the compounds of the formula (I) can be prepared from the compounds of the formula (I) and the corresponding acids in a conventional manner. Suitable acids are selected from hydrochloric, sulfuric, nitric, carbonic, phosphoric, formic, acetic, trifluoroacetic, benzenesulfonic, p-toluenesulfonic, methanesulfonic, benzoic, citric, malic, tartaric, maleic, succinic, ascorbic or oxalic acids and the like; further preferred are hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
The invention comprises a preparation prepared by taking the compound contained in the general formula (I) as an active ingredient and a preparation consisting of the preparation. The preparation method comprises the following steps: dissolving the compound covered by the present invention in a water-soluble organic solvent, a nonionic surfactant, a water-soluble lipid, various cyclodextrins, fatty acids, fatty acid esters, phospholipids or a combination thereof to prepare a preparation solution; adding physiological saline to obtain 1-20% carbohydrate. The organic solvent includes polyethylene glycol (PEG), ethanol, propylene glycol or a combination of these solvents.
The compounds covered in the general formula (I) and the salts and prodrugs thereof are used for preparing anti-tumor medicaments or medicinal preparations for treating, preventing or relieving tumor, and the active ingredients of the medicaments are one or more chalcone compounds shown in the general formula (I). Is especially suitable for treating or relieving cancer caused by tumor cells of human tissues or organs. The cancer is preferably colon cancer, hepatocarcinoma, lymphoma, lung cancer, esophageal cancer, breast cancer, central nervous system tumor, melanoma, ovarian cancer, cervical cancer, renal cancer, leukemia, prostatic cancer, pancreatic cancer, bladder cancer, rectal cancer, osteosarcoma, nasopharyngeal carcinoma or gastric cancer.
The compound synthesized by the invention can be used as an active component of an anti-tumor medicament, can be used independently, and can also be used together with other anti-tumor and anti-virus medicaments. The combination therapy of the present invention includes the use of at least one compound of the present invention and its active derivatives in combination with one or more other anti-tumor and anti-viral agents to increase the overall therapeutic effect. The dosage and administration time of the combination should be determined according to the most reasonable therapeutic effect obtained under different conditions.
The pharmaceutical formulation contemplated includes an effective dose of the compound of formula (I). An "effective amount" as used herein refers to the amount of the compound required to produce a therapeutic effect in the subject being treated. The effective dose or dosages may be varied by the experiential person according to the recommendations of the individual case. For example, the types of tumors to be treated are different, and the use of drugs is different; whether the composition is used together with other treatment methods such as other antitumor drugs or antiviral drugs, etc., the dosage can be changed. Can be made into any available dosage form. If certain compounds have basic or acidic properties and can form non-toxic acids or salts, the salt forms of the compounds can be used. Pharmaceutically acceptable organic acid salts include physiologically acceptable negative ion salts such as p-toluenesulfonate, methanesulfonate, acetate, benzoate, citrate, malate, tartrate, maleate, succinate, ascorbate or glycerophosphate, and the like; inorganic salts that may be used include chlorides, bromides, fluorides, iodides, sulfates, nitrates, bicarbonates, carbonates, or phosphates, and the like; basic compounds such as amines with suitable acids can be prepared in the form of the salts; the carboxylic acid compounds may form usable salts with alkali metals or alkaline earth metals.
The compounds encompassed in the general formula (I) in the present invention are generally easily soluble in organic solvents, water-soluble solvents, and mixed solvents of organic solvents and water-soluble solvents with water. The water-soluble solvent is preferably alcohol, polyethylene glycol, N-methyl-2-pyrrolinone, N-dimethylacetamide, N-dimethylformamide, dimethylsulfoxide, acetonitrile, or a combination thereof. The alcohol is preferably methanol, ethanol, isopropanol, glycerol or ethylene glycol. The compounds of the present invention can be formulated by mixing with conventional formulation carriers. Dissolving the compound in water-soluble organic solvent, aprotic solvent, water-soluble lipid, cyclodextrin, fatty acid, phospholipid or their mixture to obtain medicinal solution; adding physiological saline to obtain 1-20% carbohydrate, such as glucose water solution. The thus-prepared preparation is stable and useful for animals and clinics.
The product medicine prepared by using the compound in the general formula (I) as an active ingredient can be administrated by oral or parenteral routes, and also can be administrated by a medicine pump transplanted in vivo and other methods, wherein the parenteral route administration refers to perfusion, subcutaneous intracutaneous, intramuscular, intravenous, intra-arterial, intra-atrial, intra-synovial, intrasternal, intrathecal, intra-traumatic, intracranial injection or instillation technology and the like. The technical personnel mix the components by a conventional method to finally obtain the required medicament form. Can be made into tablet, pill, capsule, granule, syrup, injection, lyophilized powder for injection, emulsion, powder, lyophilized powder, dripping pill, emulsion suspension, aqueous suspension, water solution, colloid solution, sustained release preparation, nanometer preparation, or other dosage forms for animal or clinical use.
The compound in the general formula (I) is used for preparing a medicine for treating or relieving cancer of a certain tissue or organ. The cancer includes but is not limited to colon cancer, liver cancer, lymphoma, lung cancer, esophageal cancer, breast cancer, central nervous system tumor, melanoma, ovarian cancer, cervical cancer, renal cancer, leukemia, prostate cancer, pancreatic cancer, bladder cancer, rectal cancer, osteosarcoma, nasopharyngeal cancer or gastric cancer.
Detailed Description
The following specific examples are provided to further illustrate the present invention, but the present invention is not limited to these examples. (all materials are commercially available unless otherwise noted)
Synthetic examples
Example 1: preparation of Compound 1
The method comprises the following steps: ethyl trifluoroacetoacetate (9.2g,50mmol) was dissolved in dichloromethane (10mL) and a mixed solution of thionyl chloride (7.43g,55mmol) and dichloromethane (30mL) was added dropwise at-5 ℃. Stirring for 12 hours at normal temperature after dripping. The reaction was quenched by pouring the reaction solution into an ice-water bath, extracted with dichloromethane (50mL x 3), dried, and desolventized to give 10.5g of product.
Step two: dissolving the intermediate a (7.33mmol,1.6g) and 2-aminopyridine (5.31mmol,0.5g) in 15mL ethanol, refluxing for 6h, stopping the reaction, cooling, precipitating, and performing column chromatography to obtain 0.4g of a product.
Step three: the intermediate b (1.55mmol,0.4g) was dissolved in 50mL of absolute ethanol, lithium hydroxide (5mmol,0.12g) was added to the solution and reacted at room temperature for 8 hours, the reaction was stopped, Ph was adjusted to 5, and extraction with ethyl acetate was followed by drying and desolventizing to obtain 0.288g of a white solid.
Step four: dissolving the intermediate c (1.25mmol,0.288g) in 5mL of toluene, adding 3mL of thionyl chloride and 1 drops of DMF, heating and refluxing for 3h, and desolventizing the reaction solution to obtain 0.310g of a product.
Step five: intermediate e (2.2mmol,0.3g) and intermediate f (2.2mmol,0.31g) were dissolved in methanol (5mL), an aqueous solution of sodium carbonate (15%, 1.5mL) was added, stirred at room temperature for 8h, extracted with ethyl acetate and subjected to column chromatography to give 0.3g of product.
Step six: intermediate g (1.167mmol,0.3g) and intermediate d (1.167mmol,0.29g) were dissolved in DCM (15mL), TEA (3.501mmol,0.353g) was added, stirred at 55 deg.C for 8h, and column chromatography gave 0.3g of product.
1H NMR(600MHz,Chloroform-d)δ11.97(s,1H),8.97(dd,J＝7.1,1.3Hz,1H),8.61(d,J＝8.3Hz,1H),8.02(dd,J＝8.0,1.5Hz,1H),7.82–7.78(m,1H),7.76(d,J＝15.5Hz,1H),7.67(td,J＝7.9,7.2,1.4Hz,1H),7.56(d,J＝8.2Hz,2H),7.52(d,J＝15.5Hz,1H),7.48(ddt,J＝9.3,6.8,1.3Hz,1H),7.39(d,J＝8.2Hz,2H),7.30(t,J＝7.6Hz,1H),7.07(td,J＝7.0,1.4Hz,1H).MS:469.08.
Example 2: preparation of Compound 2
Intermediate d was prepared as in example 1. The preparation method of the compound 7 comprises the following steps:
the method comprises the following steps: intermediate e (2.2mmol,0.3g) and intermediate f (2.2mmol,0.38g) were dissolved in methanol (5mL), an aqueous solution of sodium carbonate (15%, 1.5mL) was added, stirred at room temperature for 8h, extracted with ethyl acetate and subjected to column chromatography to give 0.4g of product.
Step two: intermediate g (1.375mmol,0.4g) and intermediate d (1.4mmol,0.347g) were dissolved in DCM (15mL), TEA (4.2mmol,0.424g) was added, stirred at 55 deg.C for 8h, and column chromatographed to give 0.5g of product.
1H NMR(600MHz,Chloroform-d)δ11.96(s,1H),8.98(dd,J＝7.1,1.2Hz,1H),8.64(dd,J＝8.4,1.1Hz,1H),8.05(dd,J＝8.0,1.5Hz,1H),7.88(s,1H),7.85–7.77(m,3H),7.69(ddd,J＝8.7,7.4,1.6Hz,2H),7.61(d,J＝15.6Hz,1H),7.56(t,J＝7.8Hz,1H),7.48(ddd,J＝9.1,6.8,1.2Hz,1H),7.32(td,J＝7.6,1.1Hz,1H),7.07(td,J＝6.9,1.2Hz,1H).MS:503.11.
Example 3: preparation of Compound 3
Intermediate d was prepared as in example 1. The preparation method of the compound 7 comprises the following steps:
the method comprises the following steps: intermediate e (2.2mmol,0.3g) and intermediate f (2.2mmol,0.27g) were dissolved in methanol (5mL), an aqueous solution of sodium carbonate (15%, 1.5mL) was added, stirred at room temperature for 8h, extracted with ethyl acetate and subjected to column chromatography to give 0.3g of a product.
Step two: intermediate g (1.167mmol,0.28g) and intermediate d (1.167mmol,0.29g) were dissolved in DCM (15mL), TEA (3.501mmol,0.353g) was added, stirred at 55 deg.C for 8h, and column chromatography gave 0.3g of product.
1H NMR(600MHz,DMSO-d6)δ9.35(dt,J＝7.0,1.2Hz,1H),8.10(dd,J＝8.3,1.5Hz,1H),8.07–8.00(m,2H),7.92(t,J＝2.0Hz,1H),7.83(dt,J＝7.6,1.3Hz,2H),7.68(d,J＝15.4Hz,1H),7.59(t,J＝7.9Hz,1H),7.49(td,J＝7.0,1.2Hz,1H),7.44(s,2H),7.39(ddd,J＝8.0,2.4,1.0Hz,1H),7.29(ddd,J＝8.4,6.9,1.5Hz,1H),6.82(dd,J＝8.4,1.2Hz,1H),6.58(ddd,J＝8.2,6.9,1.2Hz,1H).MS:451.11.
Example 4: preparation of Compound 4
Intermediate d was prepared as in example 1. The preparation method of the compound 4 comprises the following steps:
the method comprises the following steps: intermediate e (2.2mmol,0.3g) and intermediate f (2.2mmol,0.352g) were dissolved in methanol (5mL), an aqueous solution of sodium carbonate (15%, 1.5mL) was added, stirred at room temperature for 8h, extracted with ethyl acetate and subjected to column chromatography to give 0.33g of a product.
Step two: intermediate g (1.167mmol,0.32g) and intermediate d (1.167mmol,0.29g) were dissolved in DCM (15mL), TEA (3.501mmol,0.353g) was added, stirred at 55 deg.C for 8h, and column chromatography gave 0.28g of product.
1H NMR(600MHz,DMSO-d6)δ11.66(s,1H),8.76(dt,J＝6.9,1.2Hz,1H),8.14–8.08(m,2H),7.95(q,J＝7.7Hz,1H),7.86(dt,J＝9.2,1.2Hz,1H),7.80(d,J＝15.9Hz,1H),7.73(td,J＝7.8,7.3,1.5Hz,1H),7.67–7.59(m,2H),7.48–7.39(m,2H),7.24(td,J＝6.9,1.3Hz,1H).MS:489.09.
Example 5: preparation of Compound 5
Intermediate d was prepared as in example 1. The preparation method of the compound 5 comprises the following steps:
the method comprises the following steps: intermediate e (2.2mmol,0.3g) and intermediate f (2.2mmol,0.365g) were dissolved in methanol (5mL), an aqueous solution of sodium carbonate (15%, 1.5mL) was added, stirred at room temperature for 8h, extracted with ethyl acetate and subjected to column chromatography to give 0.33g of a product.
Step two: intermediate g (1.167mmol,0.33g) and intermediate d (1.167mmol,0.29g) were dissolved in DCM (15mL), TEA (3.501mmol,0.353g) was added, stirred at 55 deg.C for 8h, and column chromatography gave 0.4g of product.
1H NMR(500MHz,DMSO-d6)δ11.88(s,1H),8.79(dt,J＝7.0,1.2Hz,1H),8.21(ddd,J＝16.6,8.1,1.3Hz,2H),7.86(dt,J＝9.2,1.1Hz,1H),7.74–7.69(m,1H),7.67(d,J＝4.6Hz,2H),7.65–7.60(m,1H),7.50(d,J＝2.1Hz,1H),7.41(td,J＝7.6,1.2Hz,1H),7.37(dd,J＝8.4,2.0Hz,1H),7.23(td,J＝6.9,1.2Hz,1H),7.01(d,J＝8.4Hz,1H),3.84(s,3H),3.82(s,3H).MS:495.14.
Example 6: preparation of Compound 6
Intermediate d was prepared as in example 1. The preparation method of the compound 6 comprises the following steps:
the method comprises the following steps: intermediate e (2.2mmol,0.3g) and intermediate f (2.2mmol,0.233g) were dissolved in methanol (5mL), an aqueous solution of sodium carbonate (15%, 1.5mL) was added, stirred at room temperature for 8h, extracted with ethyl acetate and subjected to column chromatography to give 0.35g of product.
Step two: intermediate g (1.167mmol,0.26g) and intermediate d (1.167mmol,0.29g) were dissolved in DCM (15mL), TEA (3.501mmol,0.353g) was added, stirred at 55 deg.C for 8h, and column chromatography gave 0.34g of product.
1H NMR(600MHz,Chloroform-d)δ11.99(s,1H),8.97(dd,J＝7.1,1.1Hz,1H),8.60(dd,J＝8.4,1.1Hz,1H),8.04(dd,J＝8.0,1.5Hz,1H),7.85–7.77(m,2H),7.69–7.65(m,1H),7.64(dd,J＝6.6,3.0Hz,2H),7.55(d,J＝15.6Hz,1H),7.47(ddd,J＝9.0,6.8,1.2Hz,1H),7.43(dd,J＝5.0,1.9Hz,3H),7.30(td,J＝7.7,1.1Hz,1H),7.06(td,J＝7.0,1.2Hz,1H).MS:435.12.
And (3) obtaining the compound shown in the general formula (I) according to the preparation method, and reacting the obtained compound with a corresponding salt to obtain a pharmaceutically acceptable salt of the compound shown in the general formula (I).
Determination of antitumor Activity
Example 1: the in vitro assay for tumor cell inhibition (MTT assay) was as follows:
the human cancer tumor cell line: human lung cancer A-549, human colon cancer HT-29, etc.
The inhibition rate of 2 concentrations (2ug/ml or 20ug/ml) of test samples on the growth of each human cancer cell was determined by conventional MTT assay using in vitro cell culture techniques.
The cells were removed from the incubator, washed twice with PBS solution, digested with 0.25% trypsin solution, digested by addition of RPMI1640 complete medium (containing 10% FBS), centrifuged, and the supernatant was spun off, and the cell suspension was formed by addition of complete medium, and counted under an inverted microscope. Cells were formulated at a concentration of 5x104Adding 100 mu L of cells into each hole of a 96-hole plate, placing the 96-hole plate into 5 percent carbon dioxide, culturing the 96-hole plate in humid air at 37 ℃ overnight, throwing off supernatant, adding complete culture medium to dilute the mixture into two compounds obtained in the above embodiment to be tested with different concentration gradients of 20 mu g/mL and 2 mu g/mL, throwing off the supernatant after the compounds act for 48 hours, adding 100 mu L of 0.5mg/mL MTT, reacting for 4 hours, and reducing the MTTtrazolium (tetrazole) component by living cells to generate forThe supernatant was decanted off with mazan (formazan), after which 100 μ L DMSO was added to dissolve formazan, and finally absorbance was measured at 490nm,630nm on a 96-well plate reader.
Cell inhibition ═ 1-experimental absorbance/blank absorbance) × 100%
Some of the test results are as follows:
TABLE 3 inhibition of growth of human lung carcinoma cells A-549 and human colon carcinoma cells HT-29 by compounds
Example 2: the in vitro assay for tumor cell inhibition (MTT and CCK-8) was as follows:
the human cancer tumor cell line: human lung cancer A-549, human colon cancer HT-29, human epidermoid carcinoma cell A-431, human cervical carcinoma cell Hela, human prostate cancer cell PC-3, human ovarian cancer cell SK-OV-3, human liver cancer cell HepG2, human bladder transitional cell carcinoma cell T24, human malignant melanoma cell A375, human anaplastic large cell lymphoma cell KAPPAS299, etc.
By adopting an in vitro Cell culture technology, adherent cells, namely human lung cancer A-549, human colon cancer HT-29, human epidermal cancer cells A-431, human cervical cancer cells Hela, human prostate cancer cells PC-3, human ovarian cancer cells SK-OV-3, human liver cancer cells HepG2, human bladder transitional Cell cancer cells T24 and human malignant melanoma cells A375 are subjected to a conventional MTT method, and suspension Cell human degeneration large Cell lymphoma cells KAPPAS299 are subjected to Cell Counting Kit (CCK-8 method) to determine the inhibition rate of 5 concentrations of test samples on the growth of each human cancer Cell.
MTT method: the cells were removed from the incubator, washed twice with PBS solution, digested with 0.25% trypsin solution, digested by addition of RPMI1640 complete medium (containing 10% FBS), centrifuged, and the supernatant was spun off, and the cell suspension was formed by addition of complete medium, and counted under an inverted microscope. Cells were formulated at a concentration of 5x104Adding 100 mu L of cells into each hole of a 96-well plate, placing the cell suspension in 5% carbon dioxide, culturing in humidified air at 37 ℃ overnight, removing supernatant,the compound obtained in the above example was allowed to react for 48h by adding the compound obtained in the assay in complete medium diluted to five different concentration gradients of 40. mu.g/mL, 8. mu.g/mL, 1.6. mu.g/mL, 0.32. mu.g/mL and 0.064. mu.g/mL, discarding the supernatant, adding 100. mu.L of MTT 5mg/mL, reacting for 4 hours, viable cells reducing the MTT tetrazolium component to yield formazan (formazan) and discarding the supernatant, adding 100. mu.L of DMSO to dissolve formazan, and measuring absorbance at 490nm and 630nm on a 96-well plate reader.
CCK-8 method: the KAPPAS299 cells were removed from the incubator, centrifuged to discard the supernatant, pipetted into RPMI1640 complete medium (containing 10% FBS) to form a cell suspension, and counted under an inverted microscope. Cells were formulated at a concentration of 1x104Adding 50 mu L of cells into each well of a 96-well plate, placing the plate in 5% carbon dioxide, culturing the plate in humidified air at 37 ℃ overnight, adding 50 mu L of complete culture medium to dilute the solution into 80 mu g/mL, 16 mu g/mL, 3.2 mu g/mL, 0.64 mu g/mL and 0.128 mu g/mL of the compound obtained in the above example to be tested with five different concentration gradients, allowing the solution to act for 48 hours, adding 10 mu LCCK-8, reacting the solution for 4 hours, WST-8 (chemical name: 2- (2-methoxy-4-nitrobenzene) -3- (4-nitrophenyl) -5- (2, 4-disulfobenzene) -2H-tetrazole monosodium salt) is reduced to water-soluble orange yellow formazan by mitochondrial dehydrogenase, and finally absorbance at 450nm is measured on a 96-well plate reader.
The cell inhibition rate (1-absorbance of experiment/absorbance of control) x 100%
According to the inhibition rate of 5 concentration test samples, IC is calculated by GraphPad Prism6 software by a nonlinear regression method50The value is obtained. Part of the test results (see table 4) are as follows:
TABLE 4 cytotoxic Activity of Compounds on human tumor cells
"-" indicates no activity measured
The data in the table show that the chalcone compound has better anti-tumor activity and can effectively inhibit the growth of various tumor cells. The above-described embodiments of the present invention should not be construed as limiting the scope of the present invention. Any other corresponding changes and modifications made according to the technical idea of the present invention should be included in the protection scope of the claims of the present invention.
Claims (10)
1. A chalcone compound, comprising: the compound is shown in a general formula (I),
in the formula (I), the compound is shown in the specification,
R1selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C unsubstituted or substituted by at least one1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C12Alkylthio radical, C1-C12Alkylsulfonyl radical, C1-C12Alkylcarbonyl or C1-C12Alkoxycarbonyl, such as halogen, hydroxy, amino, cyano or nitro;
R2selected from hydrogen, C1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl or heteroaryl;
R3selected from hydrogen, C1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl or heteroaryl;
R4selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the following are halogen, hydroxy, amino, cyano or nitro;
m is selected from 1 to 4;
R5selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the following are halogen, hydroxy, amino, cyano or nitro;
p is selected from 1-4;
R6selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one1-C12Alkyl radical, C1-C12Alkoxy radical, C3-C12Cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C12Alkylthio radical, C1-C12Alkylsulfonyl radical, C1-C12Alkylcarbonyl or C1-C12Alkoxycarbonyl, such as halogen, hydroxyl, amino, cyano, nitro;
n is selected from 1-5;
or isomers of the compound shown in the general formula (I), and pharmaceutically acceptable salts, solvates or prodrugs thereof.
2. Chalcone according to claim 1, characterized in that: in the general formula (I), the first step is,
R1selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C1-C4Alkyl radical, C1-C4Alkoxy radical, C3-C6Cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C4Alkylthio radical, C1-C4Alkylsulfonyl radical, C1-C4Alkylcarbonyl group, C1-C4Alkoxycarbonyl, C substituted by one or more of the following groups1-C4Alkyl radical, C1-C4Alkoxy radical, C3-C6Cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C4Alkylthio radical, C1-C4Alkylsulfonyl radical, C1-C4Alkylcarbonyl or C1-C4Alkoxycarbonyl wherein the following are halogen, hydroxy, cyano, nitro or amino;
R2selected from hydrogen, C1-C4Alkyl or C3-C12A cycloalkyl group;
R3selected from hydrogen, C1-C4Alkyl or C3-C12A cycloalkyl group;
R4selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C1-C4Alkyl radical, C1-C4Alkoxy or C3-C6A cycloalkyl group;
m is selected from 1 to 4;
R5selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C1-C4Alkyl radical, C1-C4Alkoxy or C3-C6A cycloalkyl group;
p is selected from 1-4;
R6selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one halogen1-C4Alkyl radical, C1-C4Alkoxy radical, C3-C6Cycloalkyl, heterocyclyl, aryl or heteroaryl;
n is selected from 1-5;
or isomers of the compound shown in the general formula (I), and pharmaceutically acceptable salts, solvates or prodrugs thereof.
3. Chalcone according to claim 2, characterized in that: in the general formula (I), the first step is,
R1selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C1-C4Alkyl radical, C1-C4Alkoxy, C substituted by one or more halogens1-C4Alkyl radical, C1-C4An alkoxy group;
R2selected from hydrogen, methyl, ethyl or cyclopropyl;
R3selected from hydrogen, methyl, ethyl or cyclopropyl;
R4selected from hydrogen, fluoro, chloro, methyl, ethyl or cyclopropyl;
m is selected from 1 to 4;
R5selected from hydrogen, fluoro, chloro, methyl, ethyl or cyclopropyl;
p is selected from 1-4;
R6selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, C unsubstituted or substituted by at least one halogen1-C4Alkyl radical, C1-C4An alkoxy group;
n is selected from 1-5;
or isomers of the compound shown in the general formula (I), and pharmaceutically acceptable salts, solvates or prodrugs thereof.
4. Chalcone according to claim 3, characterized in that: in the general formula (I), the first step is,
R1selected from hydrogen, trifluoromethyl or methyl;
R2selected from hydrogen or methyl;
R3selected from hydrogen or methyl;
R4selected from hydrogen;
R5selected from hydrogen;
R6selected from hydrogen, halogen, hydroxy, methoxy, ethoxy, trifluoromethoxy, methyl, ethyl, isopropyl or trifluoromethyl;
n is selected from 1-5;
or isomers of the compound shown in the general formula (I), and pharmaceutically acceptable salts, solvates or prodrugs thereof.
5. The compound of any one of claims 1-4, wherein: the salt corresponding to the compound of the general formula I or the isomer thereof is hydrochloride, sulfate, nitrate, bicarbonate, carbonate, phosphate, formate, acetate, trifluoroacetate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, benzoate, citrate, malate, tartrate, maleate, succinate, ascorbate or oxalate.
6. Use of a compound according to claim 1, wherein: the compound shown in the general formula (I), isomers thereof, pharmaceutically acceptable salts thereof, solvates thereof or prodrugs thereof are applied to preparation of medicines for treating cell proliferation diseases.
7. Use of a compound according to claim 6, characterized in that: the cell proliferation diseases are selected from cancer, infection, inflammation or autoimmune diseases.
8. Use of a compound according to claim 7, characterized in that: the cancer is selected from colon cancer, liver cancer, lymphoma, lung cancer, esophageal cancer, breast cancer, central nervous system tumor, melanoma, skin cancer, ovarian cancer, cervical cancer, renal cancer, leukemia, prostate cancer, pancreatic cancer, bladder cancer, rectal cancer, osteosarcoma, nasopharyngeal cancer or gastric cancer.
9. A pharmaceutical composition characterized by: containing a therapeutically effective amount of a compound of any one of claims 1 to 6, or an isomer thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in combination with one or more pharmaceutically acceptable carriers or excipients.
10. Use of the pharmaceutical composition according to claim 9 for the preparation of a medicament for the treatment of a cell proliferative disorder.
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| WO2000012496A1 (en) * | 1998-09-01 | 2000-03-09 | Lg Chemical Ltd. | Novel cdk inhibitors having flavone structure |
| CN1964946A (en) * | 2004-04-12 | 2007-05-16 | 托伦脱药品有限公司 | 2-propylene-1-ones as hsp70 inducer |
| CN105085220A (en) * | 2014-05-15 | 2015-11-25 | 吴久鸿 | Chalcone derivative, preparation method and application in medicine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000012496A1 (en) * | 1998-09-01 | 2000-03-09 | Lg Chemical Ltd. | Novel cdk inhibitors having flavone structure |
| CN1964946A (en) * | 2004-04-12 | 2007-05-16 | 托伦脱药品有限公司 | 2-propylene-1-ones as hsp70 inducer |
| CN105085220A (en) * | 2014-05-15 | 2015-11-25 | 吴久鸿 | Chalcone derivative, preparation method and application in medicine |
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| CN113979851A (en) * | 2020-07-27 | 2022-01-28 | 中国医学科学院药物研究所 | 2' -halogenated chalcone derivative, preparation method, pharmaceutical composition and application thereof |
| CN113979851B (en) * | 2020-07-27 | 2024-01-12 | 中国医学科学院药物研究所 | 2' -halogenated chalcone derivative, preparation method, pharmaceutical composition and application thereof |
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