CN117186026A - Amide compound containing thiazole methoxy phenyl dithiourea group, and preparation method and application thereof - Google Patents
Amide compound containing thiazole methoxy phenyl dithiourea group, and preparation method and application thereof Download PDFInfo
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- CN117186026A CN117186026A CN202311096333.4A CN202311096333A CN117186026A CN 117186026 A CN117186026 A CN 117186026A CN 202311096333 A CN202311096333 A CN 202311096333A CN 117186026 A CN117186026 A CN 117186026A
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- dithiourea
- thiazole
- methoxy phenyl
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- -1 Amide compound Chemical class 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title abstract description 9
- 230000005764 inhibitory process Effects 0.000 claims abstract description 9
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 6
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 7
- 206010017758 gastric cancer Diseases 0.000 claims description 7
- 201000007270 liver cancer Diseases 0.000 claims description 7
- 208000014018 liver neoplasm Diseases 0.000 claims description 7
- 201000011549 stomach cancer Diseases 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 3
- 230000009982 effect on human Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 210000004027 cell Anatomy 0.000 abstract description 18
- 239000003814 drug Substances 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 6
- 210000004881 tumor cell Anatomy 0.000 abstract description 6
- 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
- 150000001875 compounds Chemical class 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 239000002904 solvent Substances 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
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 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
- 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
- 206010028980 Neoplasm Diseases 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms 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
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 1
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- YJQPYGGHQPGBLI-UHFFFAOYSA-N Novobiocin Natural products O1C(C)(C)C(OC)C(OC(N)=O)C(O)C1OC1=CC=C(C(O)=C(NC(=O)C=2C=C(CC=C(C)C)C(O)=CC=2)C(=O)O2)C2=C1C YJQPYGGHQPGBLI-UHFFFAOYSA-N 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
- 229960005370 atorvastatin Drugs 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 description 1
- 229960001596 famotidine Drugs 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
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- YJQPYGGHQPGBLI-KGSXXDOSSA-N novobiocin Chemical compound O1C(C)(C)[C@H](OC)[C@@H](OC(N)=O)[C@@H](O)[C@@H]1OC1=CC=C(C(O)=C(NC(=O)C=2C=C(CC=C(C)C)C(O)=CC=2)C(=O)O2)C2=C1C YJQPYGGHQPGBLI-KGSXXDOSSA-N 0.000 description 1
- 229960002950 novobiocin Drugs 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
- 239000000047 product Substances 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
- 150000003557 thiazoles Chemical class 0.000 description 1
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea group Chemical group NC(=S)N UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to an amide compound containing thiazole methoxy phenyl dithiourea groups, a preparation method and application thereof. The preparation method is characterized by comprising the step of reacting benzoic acid containing thiazole methoxy phenyl dithiourea groups with substituent o-phenylenediamine. The amide compound containing the thiazole methoxy phenyl dithiourea group has excellent inhibition effect on tumor cells, and can be used for preparing antitumor cell medicines.
Description
Technical Field
The invention relates to the field of medicines, in particular to an amide compound containing thiazole methoxy phenyl dithiourea groups, a preparation method and application thereof.
Background
Malignant tumor is one of three diseases threatening human health, and the incidence of cancer has been gradually increasing in recent years. Therefore, finding and finding effective anticancer drugs and therapeutic methods is one of the important research hotspots in the current medical community.
Thiazole compounds are an important nitrogen-containing heterocycle, a plurality of thiazole heterocyclic compounds show excellent inhibition effect on tumor cells, and some thiazole ring-containing medicaments such as famotidine and the like have been used for treating various diseases.
Amide bonds are widely present in natural and synthetic products, and many drugs contain amide bond pharmacophores, such as atorvastatin for the treatment of hypercholesterolemia, and the natural product novobiocin, etc., belong to the class of amide drugs.
Therefore, in order to find out and discover the medicine with better anti-tumor activity from the amide compounds, the substituted thiazole ring unit is reasonably connected with the amide skeleton. The invention discloses an amide compound containing thiazole methoxy phenyl dithiourea group with medicinal value.
Disclosure of Invention
The invention aims to provide an amide compound containing thiazole methoxy phenyl dithiourea groups, which has good inhibition effect on human gastric cancer cells HGC-27 and human liver cancer cells HepG 2.
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 an amide compound containing thiazole methoxy phenyl dithiourea group, which has a structure of a general formula I,
preferably, the amide compound containing a thiazole methoxy phenyl dithiourea group has the following structure:
the invention provides a preparation method of the amide compound containing the thiazole methoxy phenyl dithiourea group, which is characterized by comprising the following steps:
dissolving the intermediate II in an organic solvent, adding the intermediate III, 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 amide compound containing the thiazole methoxy phenyl dithiourea group comprises the following steps:
the compound I has good inhibition effect on tumor cells, wherein the tumor cells comprise human gastric cancer cells HGC-27, human liver cancer cells HepG2 and the like.
The amide compound containing the thiazole methoxy phenyl dithiourea group disclosed by the invention has good inhibition activity on human gastric cancer cells HGC-27 and human liver cancer cells HepG2, so that the amide compound can be used for preparing antitumor cell medicines.
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:
6mmol of intermediate II a, 7mmol of benzotriazole-N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU) were dissolved in 30mL of N, N-Dimethylacetamide (DMA), and 15mmol of N, N-Diisopropylethylamine (DIPEA) and 5mmol of intermediate IIIa were added thereto under ice-bath conditions, after which the reaction was carried out at room temperature for 19 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 )：δ9.87(s，1H，NH)，9.57(s，1H，NH)，8.37(s，1H，NH)，7.93～7.95(m，2H，Ar-H)，7.80(s，1H，Thiazole-H)，7.61～7.63(m，2H，Ar-H)，7.45(m，1H，Ar-H)，7.27～7.33(m，2H，Ar-H)，7.16～7.18(m，1H，Ar-H)，6.95～6.99(m，1H，Ar-H)，6.77～6.79(m，1H，Ar-H)，6.58～6.62(m，1H，Ar-H)，5.43(s，2H，CH 2 )，4.91(s，2H，NH 2 )，4.70(d，J＝5.6Hz，2H，CH 2 ).
example 2:
5mmol of intermediate II b, 6mmol of benzotriazol-N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU) were dissolved in 30mL of N, N-Dimethylformamide (DMF), and 20mmol of triethylamine was added thereto under ice-bath conditionsAnd 5mmol of intermediate IIIa, and after addition, was reacted at 35℃for 10 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 )：δ9.81(s，1H，NH)，9.57(s，1H，NH)，8.27(s，1H，NH)，7.92～7.95(m，2H，Ar-H)，7.77(s，1 H，Thiazole-H)，7.63～7.65(m，2H，Ar-H)，7.14～7.17(m，2H，Ar-H)，6.95～6.98(m，3H，Ar-H)，6.77～6.79(m，1H，Ar-H)，6.58～6.62(m，1H，Ar-H)，5.29(s，2H，CH 2 )，4.87(s，2H，NH 2 )，4.66(d，J＝5.2Hz，2H，CH 2 )，3.76(s，3H，OCH 3 ).
example 3:
8mmol of intermediate II c and 8mmol of benzotriazole-N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU) were dissolved in 25mL of N, N-Dimethylacetamide (DMA), 21 mmol of triethylamine and 9mmol of intermediate IIIa were added under ice-bath conditions, and after the addition, the reaction was carried out for 15 hours under ice-bath conditions. 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 )：δ10.98(s，1H，NH)，9.67(s，1H，NH)，9.17(s，1H，NH)，7.95～7.97(m，2H，Ar-H)，7.81～7.83(m，3H，Ar-H and Thiazole-H)，7.26～7.30(m，1H，Ar-H)，7.16～7.18(m，1H，Ar-H)，7.06(s，1H，Ar-H)，6.92～6.99(m，3H，Ar-H)，6.77～6.79(m，1H，Ar-H)，6.58～6.61(m，1H，Ar-H)，5.35(s，2H，CH 2 )，4.93(s，2H，NH 2 )，4.76(d，J＝5.2Hz，2H，CH 2 ).
example 4:
5mmol of intermediate IIb, 5mmol of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), 5mmol of 1-hydroxybenzotriazole(HOBt) was dissolved in 30mL of N, N-Dimethylacetamide (DMA), and 4mmol of intermediate IIIb was added at room temperature, and after addition, the reaction was carried out at 50℃for 13 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 )：δ9.86(s，1H，NH)，9.53(s，1H，NH)，8.32(s，1H，NH)，7.93～7.95(m，2H，Ar-H)，7.76(s，1H，Thiazole-H)，7.63～7.65(m，2H，Ar-H)，7.05～7.13(m，3H，Ar-H)，6.88～6.90(m，1H，Ar-H)，6.53～6.56(m，1H，Ar-H)，6.34～6.39(m，1H，Ar-H)，5.29(s，2H，CH 2 )，5.23(s，2H，NH 2 )，4.68(d，J＝4.4Hz，2H，CH 2 )，3.78(s，3H，OCH 3 ).
example 5:
activity screening of samples for tumor cells
The in vitro antitumor activity of the target was determined using the tetramethylazoblue colorimetric Method (MTT). The test subjects are human gastric cancer cells HGC-27 and human liver cancer cells HepG2, and 5-fluorouracil (5-FU) is used as a positive control drug. 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, a test solution (10. Mu.L) of the test compound was added to the test wells, 5 parallel wells were set for each concentration, and an equivalent amount of DMSO was used as a blank control in 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, and after further culturing for 4 hours, 150. Mu.L of DMSO was added to each well, and the resulting blue-violet precipitate was dissolved by shaking with a shaker for 10 minutes, and then the OD value was measured at 490nm using an ELISA reader, and the cell inhibition ratio 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 ao Values.
TABLE 1 anti-tumor Activity data for Ia-Id (IC 50 ，μM)
| Compounds of formula (I) | HGC-27 | HepG2 |
| Ia | 0.97 | 0.95 |
| Ib | 0.89 | 0.93 |
| Ic | 8.66 | 10.70 |
| Id | 1.49 | 4.33 |
| 5-FU | 34.10 | 35.20 |
From the test data in Table 1, it can be seen that the prepared compound Ia-Id has a good inhibition effect on both human gastric cancer cells HGC-27 and human liver cancer cells HepG 2. Experimental results show that the thiazole methoxy phenyl unit is organically linked with the amide unit through the thiourea group, and the formed compound has good anti-tumor effect on human gastric cancer cells HGC-27 and human liver cancer cells HepG 2.
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. An amide compound I containing thiazole methoxy phenyl dithiourea groups is characterized by comprising the following structural components:
2. the process for preparing an amide compound I containing a thiazole methoxy phenyl dithiourea group as set forth in claim 1, which is characterized in that the process comprises the following steps:
3. use of an amide compound I containing a thiazole methoxy phenyl dithiourea group according to claim 1 for anti-tumor cells, characterized in that: the amide compound containing thiazole methoxy phenyl dithiourea group has excellent inhibition effect on human gastric cancer cells HGC-27 and human liver cancer cells HepG 2.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311096333.4A CN117186026A (en) | 2023-08-28 | 2023-08-28 | Amide compound containing thiazole methoxy phenyl dithiourea group, and preparation method and application thereof |
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| CN202311096333.4A CN117186026A (en) | 2023-08-28 | 2023-08-28 | Amide compound containing thiazole methoxy phenyl dithiourea group, and preparation method and application thereof |
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| CN117186026A true CN117186026A (en) | 2023-12-08 |
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