CN111333578A - Preparation and application of cyanoacrylate containing 1-methyl-3- (4-fluorophenyl) -4-chloropyrazole unit - Google Patents
Preparation and application of cyanoacrylate containing 1-methyl-3- (4-fluorophenyl) -4-chloropyrazole unit Download PDFInfo
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- CN111333578A CN111333578A CN202010305906.XA CN202010305906A CN111333578A CN 111333578 A CN111333578 A CN 111333578A CN 202010305906 A CN202010305906 A CN 202010305906A CN 111333578 A CN111333578 A CN 111333578A
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- chloropyrazole
- fluorophenyl
- methyl
- cyanoacrylate
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- ZXALHDGQSTVONA-UHFFFAOYSA-N 4-chloro-3-(4-fluorophenyl)-1-methylpyrazole Chemical group CN1N=C(C(=C1)Cl)C1=CC=C(C=C1)F ZXALHDGQSTVONA-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 229920001651 Cyanoacrylate Polymers 0.000 title claims abstract description 17
- MWCLLHOVUTZFKS-UHFFFAOYSA-N Methyl cyanoacrylate Chemical compound COC(=O)C(=C)C#N MWCLLHOVUTZFKS-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 210000004881 tumor cell Anatomy 0.000 claims abstract description 10
- 230000000694 effects Effects 0.000 claims abstract description 5
- 230000005764 inhibitory process Effects 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 abstract description 13
- 210000004027 cell Anatomy 0.000 abstract description 12
- 229940079593 drug Drugs 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 8
- 230000000259 anti-tumor effect Effects 0.000 abstract description 6
- NLCKLZIHJQEMCU-UHFFFAOYSA-N cyano prop-2-enoate Chemical class C=CC(=O)OC#N NLCKLZIHJQEMCU-UHFFFAOYSA-N 0.000 abstract description 4
- FDCFZNLKFZPUBA-UHFFFAOYSA-N [4-chloro-5-(4-fluorophenyl)-2-methylpyrazol-3-yl]methanamine Chemical compound CN1N=C(C(=C1CN)Cl)C1=CC=C(C=C1)F FDCFZNLKFZPUBA-UHFFFAOYSA-N 0.000 abstract 1
- -1 acrylic ester Chemical class 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 5
- 229960002949 fluorouracil Drugs 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 229940126062 Compound A Drugs 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- BDXJANJAHYKTMI-UHFFFAOYSA-N 2,3,4,5-tetramethyl-1h-pyrrole Chemical compound CC=1NC(C)=C(C)C=1C BDXJANJAHYKTMI-UHFFFAOYSA-N 0.000 description 1
- NOIXNOMHHWGUTG-UHFFFAOYSA-N 2-[[4-[4-pyridin-4-yl-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]phenoxy]methyl]quinoline Chemical group C=1C=C(OCC=2N=C3C=CC=CC3=CC=2)C=CC=1C1=NN(CC(F)(F)F)C=C1C1=CC=NC=C1 NOIXNOMHHWGUTG-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 235000005811 Viola adunca Nutrition 0.000 description 1
- 240000009038 Viola odorata Species 0.000 description 1
- 235000013487 Viola odorata Nutrition 0.000 description 1
- 235000002254 Viola papilionacea Nutrition 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 229940125890 compound Ia Drugs 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/16—Halogen atoms or nitro radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the preparation and use of cyanoacrylates (I) containing 1-methyl-3- (4-fluorophenyl) -4-chloropyrazole units. Obtained by condensing 1-methyl-3- (4-fluorophenyl) -4-chloropyrazole-5-methylamine and substituted acrylic ester. The cyanoacrylate containing the 1-methyl-3- (4-fluorophenyl) -4-chloropyrazole unit has a good inhibition effect on tumor cells HepG2, and the compound can be used for preparing anti-tumor cell medicines.
Description
Technical Field
The invention relates to the field of medicines, in particular to preparation and application of cyanoacrylate containing 1-methyl-3- (4-fluorophenyl) -4-chloropyrazole units.
Background
Malignant tumor is one of three major diseases threatening human health, and the incidence of cancer has been gradually increased in recent years. Therefore, the search and discovery of effective anticancer drugs and therapeutic methods are one of the important research hotspots in the medical field.
Pyrazole compounds are an important class of nitrogen-containing heterocycles, many of which exhibit excellent inhibitory effects on tumor cells, and some of the pyrazole ring-containing drugs such as celecoxib and the like have been used for the treatment of many diseases.
Cyanoacrylate is also an important compound, and some cyanoacrylate compounds also show good inhibitory activity to tumor cells, for example, compound A prepared by Zhang et al shows better inhibitory action to human prostate cancer cell PC3, and the inhibitory activity of compound A to human prostate cancer cell PC3 reaches 80.1% under the concentration of 10 mug/mL (J.heterocyclic Chem.,2005,42, 1211-1214).
Therefore, in order to continue to search for and find drugs with good antitumor activity from cyanoacrylate compounds, it is reasonable to link together substituted pyrazole units with the cyanoacrylate backbone. The invention discloses cyanoacrylate containing 1-methyl-3- (4-fluorophenyl) -4-chloropyrazole units with medicinal value.
Disclosure of Invention
The invention aims to provide cyanoacrylate containing 1-methyl-3- (4-fluorophenyl) -4-chloropyrazole units, which has good inhibition effect on HepG2 tumor cells.
Another object of the present invention is to provide a process for the preparation of the above compounds.
The invention also aims to provide the application of the compound in preparing anti-tumor cell medicines.
In order to solve the technical problems, the invention provides cyanoacrylate containing 1-methyl-3- (4-fluorophenyl) -4-chloropyrazole units, which has a structure shown in a general formula I,
preferably, the cyanoacrylate containing 1-methyl-3- (4-fluorophenyl) -4-chloropyrazole units has the following structure:
the invention provides a preparation method of the cyanoacrylate containing 1-methyl-3- (4-fluorophenyl) -4-chloropyrazole unit, which is characterized by comprising the following steps:
dissolving the intermediate II in an organic solvent, adding the intermediate III, reacting for a period of time, stopping the reaction, removing the solvent, purifying the obtained crude product by silica gel column chromatography to obtain a target compound,
preferably, the preparation method of the cyanoacrylate containing 1-methyl-3- (4-fluorophenyl) -4-chloropyrazole unit comprises the following steps:
of these, intermediate II can be prepared by a method referred to in the literature (chi. j. org. chem.2015,35,2399), and intermediate III can be prepared by a method referred to in the literature (j.agric. food chem.2003,51,5030).
The compound of the general formula I shows good inhibition effect on tumor cells, and the tumor cells have HepG 2.
The cyanoacrylate containing the 1-methyl-3- (4-fluorophenyl) -4-chloropyrazole unit disclosed by the invention shows good inhibitory activity to tumor cells HepG2, so that the cyanoacrylate can be used for preparing anti-tumor cell medicines.
Detailed Description
To facilitate a further understanding of the invention, the following examples are provided to illustrate it in more detail. These examples are provided for illustrative purposes only and are not intended to limit the scope or the principles of the invention.
Example 1:
20mmol of intermediate II was dissolved in 50mL of dimethyl sulfoxide (DMSO), 20mmol of intermediate IIIa was added at room temperature, and after addition, the reaction was heated to 80 ℃ for 15 hours. After the solvent is removed, the obtained crude product is purified by silica gel column chromatography to obtain a target compound Ia;1H NMR(400MHz,CDCl3):δ10.23(s,1H,NH),7.83～7.86(m,2H,Ar-H),7.10～7.15(m,2H,Ar-H),4.86(d,J＝5.6Hz,2H,CH2),4.30(t,J＝4.8Hz,2H,CH2),3.92(s,3H,CH3),3.65(t,J＝4.8Hz,2H,CH2),3.39(s,3H,OCH3),2.73(s,3H,CH3).
example 2:
10mmol of intermediate II was dissolved in 30mL of 1, 4-dioxane, and 8mmol of intermediate IIIb was added thereto at room temperature, followed by heating and refluxing for 18 hours. After the solvent is removed, the obtained crude product is purified by silica gel column chromatography to obtain a target compound Ib;1H NMR(400MHz,CDCl3):δ10.24(s,1H,NH),7.83～7.86(m,2H,Ar-H),7.10～7.14(m,2H,Ar-H),4.86(d,J＝5.6Hz,2H,CH2),4.29(t,J＝5.0Hz,2H,CH2),3.92(s,3H,CH3),3.68(t,J＝5.0Hz,2H,CH2),3.56(q,J＝6.9Hz,2H,CH2),2.73(s,3H,CH3),1.19(t,J＝7.0Hz,3H,CH3).
example 3:
6mmol of intermediate II was dissolved in 35mL of N, N-Dimethylformamide (DMF), and 6mmol of intermediate IIIc was added thereto under stirring at room temperature, and after addition, stirring was continued at room temperature for 12 hours. After the solvent is removed, the obtained crude product is purified by silica gel column chromatography to obtain a target compound Ic;1H NMR(400MHz,CDCl3):δ10.22(s,1H,NH),7.83～7.87(m,2H,Ar-H),7.10～7.14(m,2H,Ar-H),6.95～7.01(m,1H,Ar-H),6.75～6.82(m,2H,Ar-H),4.87(d,J＝5.6Hz,2H,CH2),4.52(t,J＝4.8Hz,2H,CH2),4.31(t,J＝5.0Hz,2H,CH2),3.93(s,3H,CH3),2.74(s,3H,CH3).
example 4:
screening of samples for Activity against tumor cells
The in vitro antitumor activity of the target is determined by adopting a tetramethylazole blue colorimetric Method (MTT). The test object is a human hepatoma cell strain HepG2. 5-fluorouracil (5-FU) is selected as a positive control drug, and the human hepatoma cell HepG2 in exponential growth phase is prepared into 1 × 104Cell suspension of individual cells/mL, seeded in 96-well plates at 37 ℃ with 5% CO2The culture was carried out in an incubator for 24 hours. Test solutions (10. mu.L) of test compounds were then added to the test wells in 5 parallel wells per concentration and an equivalent amount of DMSO was used as a blank in 5% CO2After 72 hours of incubation in an incubator, the supernatant was discarded, 20. mu.L of MTT (2mg/mL inPBS) was added to each well, the incubation was continued for 4 hours, the medium was aspirated and 150. mu.L of DMSO was added to each well, the blue-violet precipitate formed was dissolved by shaking with a shaker for 10 minutes, and then the OD value was measured at 490nm using a microplate reader to calculate the cell inhibitory rate (OD value of negative control group-OD value of test substance group)/OD value of negative control group × 100%50The value is obtained.
TABLE 1 cytotoxicity numbers of Ia-IcAccording to (IC)50,μM)
| Compound (I) | HepG2 |
| Ia | 27.99 |
| Ib | 21.05 |
| Ic | 34.66 |
| 5-FU | 37.80 |
As shown by the test results (Table 1), the synthesized compounds Ia-Ic have better inhibitory effect on human hepatoma cell line HepG2, and the antitumor activity of the compounds Ia-Ic on the human hepatoma cell line HepG2 is higher than that of a positive control drug 5-fluorouracil (5-FU). Experimental results show that the compound formed by introducing the 1-methyl-3- (4-fluorophenyl) -4-chloropyrazole group into the cyanoacrylate active unit has better anti-tumor effect on a human liver cancer cell strain HepG 2.
The foregoing shows and describes the general principles, essential features, and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited by the foregoing examples, which are provided to illustrate the principles of the invention, and that various changes and modifications may be made without departing from the spirit and scope of the invention, which is also intended to be covered by the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (3)
1. A cyanoacrylate I containing 1-methyl-3- (4-fluorophenyl) -4-chloropyrazole units is characterized by having the structure:
2. a process for the preparation of cyanoacrylic esters I containing 1-methyl-3- (4-fluorophenyl) -4-chloropyrazole units according to claim 1, characterized in that the process comprises:
3. use of cyanoacrylic esters I containing 1-methyl-3- (4-fluorophenyl) -4-chloropyrazole units according to claim 1 for combating tumour cells, characterized in that: cyanoacrylate I containing 1-methyl-3- (4-fluorophenyl) -4-chloropyrazole unit has a good inhibition effect on tumor cells HepG 2.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010305906.XA CN111333578B (en) | 2020-04-17 | 2020-04-17 | Preparation and application of cyanoacrylate containing 1-methyl-3- (4-fluorophenyl) -4-chloropyrazole unit |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202010305906.XA CN111333578B (en) | 2020-04-17 | 2020-04-17 | Preparation and application of cyanoacrylate containing 1-methyl-3- (4-fluorophenyl) -4-chloropyrazole unit |
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| Publication Number | Publication Date |
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| CN111333578A true CN111333578A (en) | 2020-06-26 |
| CN111333578B CN111333578B (en) | 2021-10-22 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1603307A (en) * | 2004-07-30 | 2005-04-06 | 贵州大学 | Cyanoacrylate derivatives and their preparation method and biological activity |
| CN101817799A (en) * | 2009-02-26 | 2010-09-01 | 南开大学 | Cyanoacrylate compound and application thereof in pesticide and medicine |
| CN107474015A (en) * | 2017-08-23 | 2017-12-15 | 南通大学 | Cyanoacrylate compound containing pyrrazole structure and its production and use |
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2020
- 2020-04-17 CN CN202010305906.XA patent/CN111333578B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1603307A (en) * | 2004-07-30 | 2005-04-06 | 贵州大学 | Cyanoacrylate derivatives and their preparation method and biological activity |
| CN101817799A (en) * | 2009-02-26 | 2010-09-01 | 南开大学 | Cyanoacrylate compound and application thereof in pesticide and medicine |
| CN107474015A (en) * | 2017-08-23 | 2017-12-15 | 南通大学 | Cyanoacrylate compound containing pyrrazole structure and its production and use |
Non-Patent Citations (3)
| Title |
|---|
| 石玉军，等: "新型含1,3,4-噁二唑环结构的氰基丙烯酸酯类化合物的合成及生物活性研究", 《有机化学》 * |
| 石玉军，等: "新型含5-芳基异噁唑结构的氰基丙烯酸酯类化合物的合成及生物活性", 《高等学校化学学报》 * |
| 石玉军，等: "新型含氟甲基吡唑结构的氰基丙烯酸酯类化合物的合成及其生物活性", 《有机化学》 * |
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| CN111333578B (en) | 2021-10-22 |
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Effective date of registration: 20231030 Address after: 226000 Gangzha West Nantong Gangzha industrial and Trade Park Patentee after: NANTONG NTEC MONOFILAMENT TECHNOLOGY Co.,Ltd. Address before: 226019 Jiangsu Province, Nantong City Chongchuan District sik Road No. 9 Patentee before: NANTONG University |