CN108558763B - Indazole-containing chalcone derivative and application thereof - Google Patents
Indazole-containing chalcone derivative and application thereof Download PDFInfo
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Abstract
The invention discloses chalcone derivatives containing indazole and application thereof. The chalcone derivative containing indazole shown in the general formula I and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof have an anti-tumor effect. The pharmacological activity result of the indazole-containing chalcone derivative shows that the indazole-containing chalcone derivative has a remarkable inhibiting effect on human gastric cancer cells MKN45 and human lung adenocarcinoma cells A549, is particularly used for preparing medicines for treating and/or preventing gastric cancer and lung cancer, and has a good development and application prospect of antitumor medicines.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to novel chalcone derivatives containing indazole and having a structure shown in a general formula I, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, a preparation method of the derivatives, and application of a pharmaceutical composition containing the compounds in pharmacy, particularly in preparation of antitumor drugs.
Background
Cancer is a serious disease threatening the health of human life. 880 million people died from cancer worldwide in 2015, accounting for about one sixth of the worldwide deaths. It is expected that 2200 million cases per year will be reached in the next 20 years, with a surge in cancer deaths at the same time to 1300 million. The treatment of malignant tumor is a worldwide problem and greatly harms the life health of human beings. The research and development of new antitumor drugs are listed as the first research on drugs for ten diseases in the special guideline for the major new drug creation science and technology in China. Therefore, the treatment of cancer appears to be particularly urgent. Chalcone is a compound taking diaryl-substituted alpha, beta-unsaturated ketone as a basic skeleton, has a unique molecular structure, contains a plurality of reaction centers, has the characteristics of being used as a hydrogen bond receptor, electrophilicity and lipophilicity, showing appropriate flexibility in the whole molecule and the like, can be combined with a plurality of receptors, shows wide biological activity, and is a very important organic synthesis and drug synthesis intermediate. Chalcone compounds extracted and separated from natural products and synthesized by chemical, biological and other methods show various pharmacological properties such as tumor resistance, parasite resistance, virus resistance, bacteria resistance, inflammation resistance, platelet aggregation resistance and the like. Research has shown that chalcone compounds have significant effects on multiple stages of tumor development and development, including inhibition of tumor cell proliferation, induction of tumor cell differentiation and apoptosis, inhibition of tumor development and metastasis, and the like. Therefore, the research and development of chalcone compounds have become a hot research field of medicinal chemistry. On the other hand, indazole derivatives are important heterocyclic compounds, have wide biological activity, and especially have applications in antitumor drugs, and currently, various antitumor drugs containing indazole structural units are on the market or enter different stages of clinical research, such as: the indazole derivatives such as Axitinib, linibanib and Pictilisib (fig.1) have been the focus of research by researchers in the pharmaceutical field.
Disclosure of Invention
On the basis of the prior art, two structural units, namely chalcone and indazole with anti-tumor activity are spliced into one molecule, and a series of novel chalcone compounds containing indazole are designed and synthesized. In vitro activity screening shows that the compounds have obvious antitumor activity.
The invention relates to chalcone derivatives containing indazole shown in a general formula (I) and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
wherein:
R1and R2The same or different, are respectively and independently selected from hydrogen and C1-C10Alkyl radical, C3-C7Cycloalkyl radicalsOptionally substituted by 1 to 3 identical or different R3Substituted C1-C10Alkyl, or optionally substituted by 1-3R which may be the same or different3Substituted C3-C7A cycloalkyl group.
Or, R1And R2Together with the nitrogen atom to which they are attached form a 5-to 10-membered heterocyclic group, except for R1And R2Optionally containing 1 to 3 heteroatoms selected from N, O and S, and/or optionally comprising 1 or 2 carbon-carbon double or triple bonds, and/or optionally substituted by 1 to 3 identical or different R atoms, in addition to the nitrogen atom to which they are bonded3And (4) substitution.
R3Is C1-C6Alkyl radical, C1-C4Alkoxy, halogen, hydroxy, cyano, carboxy, or ester groups.
Ar is 6-10 membered aryl or 5-10 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Ar is optionally substituted with 1-5R, the same or different4And (4) substitution.
R4Is hydrogen, hydroxy, halogen, nitro, amino, cyano, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy radical, C1-C6Alkylthio, C substituted by hydroxy or amino or halogenated1-C6Alkyl, C substituted by hydroxy or amino or halogenated1-C6Alkoxy, mono-or di-C1-C6Alkyl-substituted amino, C1-C6Alkylamido, ester groups, free or salified or esterified or amidated carboxyl groups, C1-C6Alkylsulfinyl radical, C1-C6Alkylsulfonyl radical, C1-C6Alkanoyl, carbamoyl, or mono-or di-C1-C6Alkyl-substituted carbamoyl.
Furthermore, the indazole-containing chalcone derivatives and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
R1and R2Same or different, eachIndependently selected from hydrogen, C1-C4Alkyl radical, C3-C7Cycloalkyl optionally substituted by 1 to 3R which may be the same or different3Substituted C1-C4Alkyl, or optionally substituted by 1-3R which may be the same or different3Substituted C3-C7A cycloalkyl group.
Or, R1And R2Together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic group, except for R1And R2Optionally containing 1 to 3 heteroatoms selected from N, O and S, and/or optionally comprising 1 or 2 carbon-carbon double or triple bonds, and/or optionally substituted by 1 to 3 identical or different R atoms, in addition to the nitrogen atom to which they are bonded3And (4) substitution.
R3Is C1-C4Alkyl radical, C1-C4Alkoxy, halogen, hydroxy, or cyano.
Ar is phenyl, naphthyl, or 5-10 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Ar is optionally substituted with 1-3R, the same or different4And (4) substitution.
R4Is hydrogen, hydroxy, halogen, nitro, amino, cyano, C1-C6Alkyl radical, C1-C6Alkoxy, halogenated C1-C6Alkyl, halogenated C1-C6Alkoxy radical, C1-C6Alkylamido, ester group, C1-C6Alkylsulfonyl radical, C1-C6Alkanoyl, or mono-or di-C1-C6Alkyl-substituted carbamoyl.
Furthermore, the indazole-containing chalcone derivatives and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
R1and R2Together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic group, except for R1And R2Optionally containing, in addition to the nitrogen atom to which it is attached, 1 to 3 heteroatoms selected from N, O and S, and/or optionally substituted by 1 to 3R, which may be the same or different3And (4) substitution.
R3Is C1-C4Alkyl, or halogen.
Ar is phenyl, or 5-6 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Ar is optionally substituted with 1-3R, the same or different4And (4) substitution.
R4Is hydrogen, hydroxy, halogen, nitro, cyano, C1-C6Alkyl radical, C1-C6Alkoxy, ester, or methylsulfonyl.
Furthermore, the indazole-containing chalcone derivatives and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
R1and R2Together with the nitrogen atom to which they are attached form a 4-morpholinyl, or 4-methyl-1-piperazinyl group.
Ar is phenyl, pyridyl, or thiophene, and Ar is optionally substituted with 1-3R, which may be the same or different4And (4) substitution.
R4Is hydrogen, halogen, hydroxyl, nitro, methyl or methoxy.
Further, the indazole-containing chalcone derivatives and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof have the following structural formula:
compound 19
A pharmaceutical composition comprises the chalcone derivative containing indazole and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof as an active ingredient and pharmaceutically acceptable excipients.
The indazole-containing chalcone derivative, and pharmaceutically acceptable salt, hydrate, solvate or prodrug or pharmaceutical composition thereof are applied to preparation of medicines for treating and/or preventing proliferative diseases.
The indazole-containing chalcone derivative, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof or pharmaceutical composition can be applied to preparation of medicines for treating and/or preventing cancers.
The indazole-containing chalcone derivative, and pharmaceutically acceptable salt, hydrate, solvate or prodrug or pharmaceutical composition thereof are applied to preparation of medicines for treating and/or preventing gastric cancer and lung cancer.
The indazole-containing chalcone derivatives of formula (I) above of the present invention may be combined with an acid to form a pharmaceutically acceptable salt according to conventional methods known in the art. Pharmaceutically acceptable addition salts include inorganic and organic acid addition salts, with the following acids being particularly preferred: methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like.
In addition, the present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the invention are derivatives of formula (i) which may themselves be less active or even inactive, but which, upon administration, are converted under physiological conditions (e.g., by metabolism, solvolysis or otherwise) to the corresponding biologically active form.
In the present invention, "halogen" means fluorine, chlorine, bromine or iodo; "alkyl" refers to straight or branched chain alkyl; "cycloalkyl" refers to a substituted or unsubstituted cycloalkyl; "aryl" means a monocyclic or polycyclic aromatic ring system of carbon atoms, such as phenyl, naphthyl, and the like; "heteroaryl" means a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, the ring system being aromatic, such as imidazolyl, pyridyl, pyrazolyl, (1,2,3) -and (1,2,4) -triazolyl, furyl, thienyl, pyrrolyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, naphthyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, and the like; "Heterocyclyl" means a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, such as pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, pyrazolidinyl, imidazolidinyl, thiazolinyl, and the like.
Through in vitro inhibition activity tests of human gastric cancer cells MKN45 and human lung adenocarcinoma cells A549, the compound has a significant inhibition effect on human gastric cancer cells and lung cancer cells, and is particularly used for preparing medicaments for treating and/or preventing gastric cancer and lung cancer.
Detailed Description
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and their methods of preparation. It should be understood that the scope of the following examples and preparations are not intended to limit the scope of the invention in any way.
The following synthetic schemes describe the preparation of the derivatives of formula I of the present invention, all starting materials are prepared by the procedures described in the following synthetic schemes, by methods well known to those of ordinary skill in the art of organic chemistry, or are commercially available. All final derivatives of the invention are prepared by the methods described in the synthetic schemes below or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. Substituents R of all compounds in the scheme1、R2Ar is as defined in the claims. The synthetic route is as follows:
the following examples are intended to illustrate, but not limit, the scope of the invention. The nuclear magnetic resonance hydrogen spectrum of the compound is measured by Bruker ARX-600, and the mass spectrum is measured by Agilent 6460 QQQ; all reagents used were analytically or chemically pure.
General method for preparation
Step A2-fluoro-6-morpholinylbenzonitrile (a)
Adding 20.0g of 2, 6-difluorobenzonitrile, 40.0g of anhydrous potassium carbonate and 200mL of dimethyl sulfoxide into a 500mL eggplant-shaped bottle, heating to 90 ℃, slowly dropping 13.20g of morpholine while stirring, detecting the reaction process by TLC, and naturally cooling the reaction solution to room temperature after the reaction is finishedAnd (3) pouring the mixture into a stirred ice-water solution to separate out 18.0g of white solid powder, namely the 2-fluoro-6-morpholinyl benzonitrile (a). IR (KBr, cm)-1):3096,2950,2879,2869，2226,1605,1567,1474,1460,1230,1114.
Step B3-amino-4-morpholino-1H-indazole (B)
Adding 30.0g of 2-fluoro-6-morpholinobenzonitrile (a) and 40mL of N-methylpyrrolidone into a 500mL eggplant-shaped bottle, heating to 70 ℃ after dissolving, dropwise adding 100mL of 80% hydrazine hydrate under stirring, stirring for reacting for 2 days, detecting that raw materials are completely consumed by TLC, cooling to room temperature, pouring reaction liquid into ice water solution under stirring, separating out a large amount of solids, filtering, washing filter cakes with water until the filtrate is neutral, and drying the filter cakes to obtain 28.8g of white solids, namely 3-amino-4-morpholino-1H-indazole (b). IR (KBr, cm)-1):3475,337,3272,2950,2854,2836,1603,1526,1509,1452,1236,1108；1H NMR(CDCl3):δ7.25(m,1H,J＝5.7Hz,Ph-H),6.7(d,1H,J＝4.2Hz),6.6(d,1H,J＝3.6Hz),5.5(s,2H),3.9(m,4H),3.1(m,4H).
Step C chalcone-4-carboxylic acid (C)
Adding 3.0g of p-aldehyde benzoic acid, 2.5g of acetophenone and 150mL of methanol into a 250mL eggplant-shaped bottle, stirring to dissolve the mixture, adding 40mL of 1.0mol/L sodium hydroxide solution under stirring, stirring at room temperature to react for 12H, adding 100mL of water into reaction liquid, adjusting the pH to be acidic by using 1.0mol/L hydrochloric acid, separating out a large amount of solid, filtering, washing filter cakes with water until the filtrate is neutral, and obtaining dry white solid powder, namely chalcone-4-formic acid (c), ESI-MS (Electron fluorescence Spectroscopy-Mass Spectrometry) (M-H)]-(m/z):351.3。
Step D general method for synthesizing indazole-containing chalcone compounds
1.00mmol of 3-amino-4-morpholino-1H-indazole (b), 1.20mmol of chalcone-4-carboxylic acid (c), 1.20mmol of HATU, 1.20mmol of triethylamine and 15ml of DMF are added into a reaction flask, and the mixture is stirred at room temperature overnight, and the reaction is completed. The reaction solution was poured into 100mL of 20% aqueous potassium carbonate solution, extracted three times with 50mL of dichloromethane, the organic phases were combined, the organic phase was washed three times with 20% aqueous potassium carbonate solution, the organic layer was washed twice with saturated brine, and the separated organic layer was dried over anhydrous sodium sulfate. Filtering, decompressing and steaming to remove dichloromethane, and pulping by ethanol to obtain the product.
The compounds of examples 1-19 were prepared according to the general procedure (see Table 1), respectively.
Table 1:
in vitro antitumor cell Activity
The chalcone derivatives partially containing indazole and having the general formula I are screened for inhibiting the activity of human gastric cancer cells MKN45 and human lung adenocarcinoma cells A549 in vitro.
(1) After cells were thawed and passaged for 2-3 stabilities, they were digested from the bottom of the flask with trypsin solution (0.25%). After pouring the cell digest into the centrifuge tube, the culture medium is added to stop the digestion. Centrifuging the centrifuge tube at 800r/min for 10min, discarding supernatant, adding 5mL culture solution, blowing and beating the mixed cells, sucking 10 μ L cell suspension, adding into cell counting plate, counting, and adjusting cell concentration to 104Per well. 100. mu.L of the cell suspension was added to the 96-well plate except that the A1 well was a blank well and no cells were added. The 96-well plate was placed in an incubator for 24 h.
(2) The test sample was dissolved in 50. mu.L of dimethyl sulfoxide, and then an appropriate amount of culture solution was added to dissolve the sample to 2mg/mL of the liquid, and then the sample was diluted to 20,4,0.8,0.16, 0.032. mu.g/mL in a 24-well plate.
3 wells were added for each concentration, two columns of cells surrounding each, which were greatly affected by the environment, and only used as blank wells. The 96-well plate was placed in an incubator for 72 h.
(3) Discarding the culture solution with drug from 96-well plate, and adding phosphoric acidThe cells were washed twice with buffer solution (PBS), 100. mu.L of MTT (tetrazolium) (0.5mg/mL) was added to each well and placed in an incubator for 4 hours, the MTT solution was discarded, and 100. mu.L of dimethyl sulfoxide was added. And oscillating on a magnetic oscillator to fully dissolve the viable cells and the MTT reaction product formazan, and putting the formazan into an enzyme labeling instrument to measure the result. Determination of drug IC by Bliss method50The value is obtained.
The results of human gastric cancer cells MKN45 and human lung adenocarcinoma cells A549 with sorafenib as a positive control are shown in Table II.
TABLE 2
As is clear from the test results in Table 2, the compound of formula I to be protected by the present invention has good in vitro anti-tumor activity, which is equal to or superior to that of the control drug Sorafenib. The compounds have good development and application prospects of antitumor drugs. Although the preferred embodiments of the present invention have been described in detail, the present invention is not limited to the details of the above embodiments, and various equivalent changes may be made to the technical solution of the present invention within the technical concept of the present invention, and various possible combinations of the present invention will not be described in detail in order to avoid unnecessary repetition. Any modification, equivalent replacement or improvement made within the technical spirit of the present invention is included in the scope of protection of the present invention.
Claims (5)
1. An indazole-containing chalcone derivative shown in a general formula (I) or a pharmaceutically acceptable salt thereof,
wherein:
R1and R2Together with the nitrogen atom to which they are attached form a 4-morpholinyl group;
ar is phenyl and Ar is optionally substituted with 1 to 3R, which may be the same or different4Substitution;
R4is halogen, methyl, or methoxy.
2. The indazole-containing chalcone derivative according to claim 1, or a pharmaceutically acceptable salt thereof, having the following structural formula:
3. a pharmaceutical composition comprising the indazole-containing chalcone derivative according to claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient.
4. Use of the indazole-containing chalcone derivative according to claim 1 or 2 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 3 for the preparation of a medicament for the treatment and/or prevention of cancer.
5. Use of the indazole-containing chalcone derivative according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 3 for the preparation of a medicament for the treatment and/or prevention of gastric and lung cancer.
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