CN117185992A - Preparation method and application of benzamide derivative containing aryloxy bipyridine methyl thiourea unit - Google Patents
Preparation method and application of benzamide derivative containing aryloxy bipyridine methyl thiourea unit Download PDFInfo
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- CN117185992A CN117185992A CN202311087983.2A CN202311087983A CN117185992A CN 117185992 A CN117185992 A CN 117185992A CN 202311087983 A CN202311087983 A CN 202311087983A CN 117185992 A CN117185992 A CN 117185992A
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- aryloxy
- benzamide derivative
- methyl thiourea
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- bipyridyl
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- 150000003936 benzamides Chemical class 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 230000005764 inhibitory process Effects 0.000 claims abstract description 9
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 6
- 206010009944 Colon cancer Diseases 0.000 claims description 7
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 7
- 208000029742 colonic neoplasm Diseases 0.000 claims description 7
- 206010017758 gastric cancer Diseases 0.000 claims description 7
- 201000011549 stomach cancer Diseases 0.000 claims description 7
- 230000009982 effect on human Effects 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 210000004027 cell Anatomy 0.000 abstract description 18
- 150000001875 compounds Chemical class 0.000 abstract description 12
- 239000003814 drug Substances 0.000 abstract description 6
- 210000004881 tumor cell Anatomy 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 abstract 2
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 abstract 1
- 239000005711 Benzoic acid Substances 0.000 abstract 1
- 235000010233 benzoic acid Nutrition 0.000 abstract 1
- 125000001424 substituent group Chemical group 0.000 abstract 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- -1 benzotriazole-N, N, N ', N' -tetramethyluronium Hexafluorophosphate Chemical compound 0.000 description 4
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 229960002949 fluorouracil Drugs 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical group NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 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
- 239000008186 active pharmaceutical agent Substances 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
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- INVTYAOGFAGBOE-UHFFFAOYSA-N entinostat Chemical compound NC1=CC=CC=C1NC(=O)C(C=C1)=CC=C1CNC(=O)OCC1=CC=CN=C1 INVTYAOGFAGBOE-UHFFFAOYSA-N 0.000 description 1
- 229950005837 entinostat Drugs 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 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
- 239000013641 positive control Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 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
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method and application of benzamide derivatives containing aryloxy bipyridyl methyl thiourea units. Is obtained by condensing substituent o-phenylenediamine and benzoic acid containing aryloxy bipyridyl methyl thiourea unit. The benzamide derivative containing the aryloxy bipyridyl methyl thiourea unit has a good inhibition effect on tumor cells, and the compound can be used for preparing antitumor cell medicines.
Description
Technical Field
The invention relates to the field of medicines, in particular to a preparation method and application of a benzamide derivative containing an aryloxy bipyridyl methyl thiourea unit.
Background
Malignant tumors are one of the major diseases that seriously affect human health, and the incidence of cancer has been on the rise in recent years. Therefore, developing effective anticancer drugs and therapeutic methods is a hot research field in the current medical community.
Pyridines are important nitrogen-containing six-membered heterocycles, and many compounds containing pyridine heterocyclic units exhibit good inhibition on tumor cells. Meanwhile, the benzamide derivative also has excellent inhibition effect on tumor cells, such as medicines of entinostat and the like.
Therefore, in order to continue to develop a drug having good antitumor activity from benzamide derivatives, a substituted pyridine skeleton is organically linked to a benzamide unit. The invention discloses a benzamide derivative containing aryloxy bipyridine methyl thiourea unit with medicinal value.
Disclosure of Invention
The invention aims to provide benzamide derivatives containing aryloxy bipyridyl methyl thiourea units, which have good inhibition effect on human gastric cancer cells HGC-27 and human colon cancer cells HCT116.
It is another object of the present invention to provide a process for the preparation of the above compounds.
It is a further object of the present invention to provide the use of the above compounds for the preparation of a medicament for treating tumor cells.
In order to solve the technical problems, the invention provides a benzamide derivative containing aryloxy bipyridyl methyl thiourea unit, which has a structure shown in a general formula I,
preferably, the benzamide derivative containing an aryloxy bipyridylmethylthiourea unit has the following structure:
the invention provides a preparation method of the benzamide derivative containing the aryloxy bipyridyl methyl thiourea unit, which is characterized by comprising the following steps:
dissolving the intermediate III in an organic solvent, adding the intermediate II, stopping the reaction after reacting for a period of time, removing the solvent, purifying the crude product by silica gel column chromatography to obtain the target compound I,
preferably, the preparation method of the benzamide derivative containing the aryloxy bipyridyl methyl thiourea unit comprises the following reaction steps:
the compound I has a good inhibition effect on tumor cells, such as human gastric cancer cells HGC-27 and human colon cancer cells HCT116.
The benzamide derivative containing the aryloxy bipyridyl methyl thiourea unit disclosed by the invention has good inhibitory activity on human gastric cancer cells HGC-27 and human colon cancer cells HCT116, so that the benzamide derivative can be used for preparing antitumor cell medicaments.
Detailed Description
The examples provided below are presented in more detail to facilitate a further understanding of the present invention. These examples are provided only for illustration and are not intended to limit the scope or practice of the invention.
Example 1:
3mmol of intermediate IIIa, 4mmol of benzotriazole-N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU) are dissolved in 30mL of DMF, 6mmol of 4-Dimethylaminopyridine (DMAP) and 3mmol of intermediate IIa are added thereto at room temperature, after which stirring at room temperature is continued for 12 hours. Removing the solvent, and purifying the obtained crude product by silica gel column chromatography to obtain a target object Ia; 1 H NMR(400MHz，DMSO-d 6 )：δ9.92(s，1H，NH)，9.57(s，1H，NH)，8.43(s，1H，NH)，8.08(d，J＝2.0Hz，1H，Py-H)，7.90～7.94(m，3H，Ar-H and Py-H)，7.78(d，J＝2.4Hz，1H，Ar-H)，7.34～7.60(m，4H，Ar-H and Py-H)，7.14～7.16(m，2H，Ar-H)，6.80(d，J＝2.4Hz，1H，Ar-H)，6.58～6.60(m，1H，Ar-H)，5.24(s，2H，NH 2 )，4.71(d，J＝5.2Hz，2H，CH 2 ).
example 2:
4mmol of intermediate IIIb, 4mmol of benzotriazole-N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU) was dissolved in 35 mM DS SO, 10mmol of triethylamine and 5mmol of intermediate IIb were added thereto at room temperature, and after addition, the reaction was carried out at 40℃for 16 hours. Removing the solvent, and purifying the obtained crude product by silica gel column chromatography to obtain a target object Ib; 1 H NMR(400MHz，DMSO-d 6 )：δ9.90(s，1H，NH)，9.53(s，1H，NH)，8.41(s，1H，NH)，8.13(d，J＝1.6Hz，1H，Py-H)，7.86～7.95(m，3H，Ar-H and Py-H)，7.59(d，J＝7.6Hz，2H，Ar-H)，7.09～7.27(m，5H，Ar-H and Py-H)，7.04(d，J＝8.4Hz，1H，Ar-H)，6.53～6.56(m，1H，Ar-H)，6.33～6.38(m，1H，Ar-H)，5.22(s，2H，NH 2 )，4.71(d，J＝5.2Hz，2H，CH 2 ).
example 3:
5mmol of intermediate IIIc, 6mmol of benzotriazole-N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU) was dissolved in 40mL of LDMF, 20mmol of triethylamine and 6mmol of intermediate IIc were added thereto at room temperature, and after addition, stirring was continued at room temperature for 10 hours. After the solvent is removed, purifying the obtained crude product through silica gel column chromatography to obtain a target compound Ic; 1 H NMR(400MHz，DMSO-d 6 )：δ9.93(s，1H，NH)，9.61(s，1H，NH)，8.43(s，1H，NH)，8.15(d，J＝2.0Hz，1H，Py-H)，7.89～7.96(m，3H，Ar-H and Py-H)，7.59(d，J＝8.8Hz，2H，Ar-H)，7.34～7.52(m，2H，Ar-H and Py-H)，6.95～7.16(m，4H，Ar-H)，6.77～6.79(m，1H，Ar-H)，6.58～6.62(m，1H，Ar-H)，4.90(s，2H，NH 2 )，4.73(d，J＝5.2Hz，2H，CH 2 ).
example 4:
6mmol of intermediate IIId, 6mmol of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and 6mmol of 1-hydroxybenzotriazole (HOBt) were dissolved in 25mL of DMF, 7mmol of intermediate IIc was added at room temperature, and after addition stirring was continued at room temperature for 11 hours. After the solvent is removed, purifying the obtained crude product through silica gel column chromatography to obtain a target object Id; 1 H NMR(400MHz，DMSO-d 6 )：δ9.93(s，1H，NH)，9.60(s，1H，NH)，8.44(s，1H，NH)，8.16(s，1H，Py-H)，7.92～7.96(m，3H，Ar-H and Py-H)，7.45～7.68(m，6H，Ar-H and Py-H)，7.13～7.17(m，2H，Ar-H)，6.95～6.99(m，1H，Ar-H)，6.78(d，J＝8.0Hz，1H，Ar-H)，6.58～6.62(m，1H，Ar-H)，4.90(s，2H，NH 2 )，4.75(d，J＝4.8Hz，2H，CH 2 ).
example 5:
6mmol of intermediate IIIe, 5mmol of benzotriazole-N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU) were dissolved in 35mL of DMSO, 18mmol of 4-Dimethylaminopyridine (DMAP) and 5mmol of intermediate IIc were added thereto at room temperature, and after addition, the reaction was continued at room temperature for 20 hours. Removing the solvent, and purifying the obtained crude product by silica gel column chromatography to obtain a target object Ie; 1 H NMR(400MHz，DMSO-d 6 )：δ9.89(s，1H，NH)，9.60(s，1H，NH)，8.40(s，1H，NH)，8.05(s，1H，Py-H)，7.81～7.95(m，3H，Ar-H and Py-H)，7.59(d，J＝8.4Hz，2H，Ar-H)，7.10～7.24(m，4H，Ar-H and Py-H)，6.94～6.99(m，3H，Ar-H)，6.78(d，J＝7.6Hz，1H，Ar-H)，6.58～6.62(m，1H，Ar-H)，4.89(s，2H，NH 2 )，4.69(d，J＝4.4Hz，2H，CH 2 )，3.69(s，3H，OCH 3 ).
example 6:
activity screening of samples for tumor cells
The in vitro antitumor activity of the compounds was determined using the tetramethylazoblue colorimetric Method (MTT). The test subjects were human gastric cancer cell HGC-27 and human colon cancer cell HCT116. 5-fluorouracil (5-FU) was selected as a positive control. Preparing cancer cells in exponential growth phase into 4×10 3 Cell suspensions of individual cells/mL were seeded in 96-well plates at 37℃in 5% CO 2 Culturing in an incubator for 24 hours. Then, the test solution (10. Mu.L) of the sample to be tested was added to the test wells, 5 parallel wells were set for each concentration, and an equivalent amount of dimethyl sulfoxide was used as a blank control at 5% CO 2 After culturing in an incubator for 72 hours, the supernatant was discarded, 20. Mu.L of MTT (2 mg/mL in PBS) was added to each well, followed by culturing for 4 hours, and after the culture medium was aspirated, 150. Mu.L of dimethyl sulfoxide was added to each well, followed by shakingThe blue-violet precipitate formed was dissolved by shaking for 10 minutes, the OD value was measured at 490nm by using an ELISA reader, and the cell inhibition was calculated. Cell inhibition ratio = (OD value of negative control group-OD value of test substance group)/OD value of negative control group x 100%, IC of compound was calculated by probability unit weighted regression method 50 Values.
Data on antitumor Activity of Ia-Ie (IC 50 ，μM)
| Compounds of formula (I) | HGC-27 | HCT116 |
| Ia | 0.40 | 1.33 |
| Ib | 1.34 | 1.91 |
| Ic | 2.11 | 3.29 |
| Id | 1.42 | 2.12 |
| Ie | 0.33 | 2.21 |
| 5-FU | 34.10 | 19.60 |
As can be seen from Table 1, the compounds Ia-Ie have good inhibition effect on human gastric cancer cells HGC-27 and human colon cancer cells HCT116. The experimental results show that the synthesized compound has excellent anti-tumor effect on human gastric cancer cells HGC-27 and human colon cancer cells HCT116 by organically linking the substituted pyridine structure with the benzamide skeleton.
The foregoing has shown and described the basic principles, principal 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 by way of illustration of the principles of the present invention, and that various changes and modifications may be made therein without departing from the spirit and scope of the invention as defined in the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (3)
1. A benzamide derivative (I) containing aryloxy bipyridyl methyl thiourea unit is characterized by comprising the following structural components:
2. process for the preparation of benzamide derivatives (I) containing aryloxybipyridylmethylthiourea units according to claim 1, characterized in that it comprises the following steps:
3. use of a benzamide derivative (I) containing aryloxybipyridylmethylthiourea units according to claim 1 for antitumor cells, characterized in that: the benzamide derivative (I) containing the aryloxy bipyridyl methyl thiourea unit has good inhibition effect on human gastric cancer cells HGC-27 or human colon cancer cells HCT116.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202311087983.2A CN117185992A (en) | 2023-08-28 | 2023-08-28 | Preparation method and application of benzamide derivative containing aryloxy bipyridine methyl thiourea unit |
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| CN202311087983.2A CN117185992A (en) | 2023-08-28 | 2023-08-28 | Preparation method and application of benzamide derivative containing aryloxy bipyridine methyl thiourea unit |
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- 2023-08-28 CN CN202311087983.2A patent/CN117185992A/en active Pending
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