CN113004268B

CN113004268B - Thiazole compound for inhibiting tumor cell growth and application thereof

Info

Publication number: CN113004268B
Application number: CN202110331469.3A
Authority: CN
Inventors: 瞿军; 吴宏祥; 掌鹏程; 沈润溥
Original assignee: Yangzhou Prince Pharmaceutical Technology Co ltd
Current assignee: Jiangsu Sterric Chemical Industry Co ltd
Priority date: 2021-03-29
Filing date: 2021-03-29
Publication date: 2022-06-21
Anticipated expiration: 2041-03-29
Also published as: CN113004268A

Abstract

The invention relates to a thiazole compound for inhibiting the growth of tumor cells and application thereof in the field of pharmaceutical chemistry, wherein the preparation method of the thiazole compound comprises the following steps: taking 2- (p-fluorophenoxymethyl) -4- (N-isobutyl-aminomethyl) -thiazole and piperonyl chloride as raw materials and CH₂Cl₂As a solvent, triethylamine is used as an acid-binding agent to react the reaction solution at 40 ℃ while stirring for 8-10 hours, and after the reaction, an organic layer is separated and purified to finally obtain the 2- (p-fluorophenoxymethyl) -4- (N-isobutyl-N-piperonyl-aminomethyl) -thiazole. The thiazole compound is prepared into a novel compound containing a thiazole ring and an amide structure through one-step reaction. The novel compound can effectively inhibit the growth of various tumor cells, has obvious inhibition effect on pancreatic cancer cells, and lays a foundation for the development of novel antitumor drugs.

Description

Thiazole compound for inhibiting tumor cell growth and application thereof

Technical Field

The invention relates to the field of medicinal chemistry, in particular to a thiazole compound for inhibiting the growth of tumor cells and application thereof.

Background

Tumors are the first killers of human health and life at present, the incidence rate of the tumors is second to cardiovascular diseases, and the incidence rate of malignant tumors is in a rapid rising trend along with the influence of environmental pollution or peculiar factors. Malignant tumor has become a common disease and frequently encountered disease seriously threatening human health, along with the development of economy in China, the living standard of people is improved, the environment is worsened, the population is aged, and the malignant tumor has become a main reason for death of residents in China.

Cancer is a disease that is caused by a combination of factors and is characterized by the uncontrolled growth and spread of abnormal cells or tissues. Surgery, radiation therapy, chemotherapy and molecularly targeted drugs are today the few major means of treating cancer. Wherein the surgery and radiotherapy are local treatments, and the chemotherapy and molecular targeted drug treatment are systemic treatments. In addition, endocrine therapy, biotherapy, and the like are also available. Some minimally invasive treatment methods, such as interventional therapy, electrochemical therapy, laser therapy, microwave thermotherapy, ultrasonic thermotherapy, cryotherapy, radiofrequency therapy and the like, can also achieve treatment effects sometimes.

According to the difference of the sources of the medicines in the world, the medicines in the world can be divided into three types of chemically synthesized medicines, biological products and medicines of natural sources. Chemical drugs are still one of the main means of anticancer therapy at present, and the proportion of chemical synthetic drugs in anticancer drugs exceeds 50% in the past year. It is expected that chemically synthesized small molecule drugs will dominate the source of new drug development materials for a long period of time in the future. For example, in 2017, the number of chemically synthesized small-molecule drugs is 7855, the amplification is 4.2%, and the overall amplification is lower than 8.4% of the number of drugs in the world.

Therefore, the preparation of chemically synthesized drugs for alleviating cancer is urgent. Researchers prepare thiazole compounds based on the research thought, and the thiazole compounds have good effect of inhibiting lung cancer cells.

Disclosure of Invention

The invention provides a thiazole compound for preparing a medicament for inhibiting the growth and proliferation of cancer cells, aiming at the requirement of chemically synthesizing an anti-cancer medicament in the prior art.

The invention firstly provides a thiazole compound, which is 2- (p-fluorophenoxymethyl) -4- (N-isobutyl-N-piperonyl-aminomethyl) -thiazole and has a structural formula as follows:

。

further, the preparation method of the thiazole compound comprises the following steps: taking 2- (p-fluorophenoxymethyl) -4- (N-isobutyl-aminomethyl) -thiazole and piperonyl chloride as raw materials and CH₂Cl₂As a solvent, triethylamine is used as an acid-binding agent to enable reaction liquid to react at the temperature of 40 ℃ while stirring for 8-10 hours, after the reaction, an organic layer is separated and purified, and finally 2- (p-fluorophenoxymethyl) -4- (N-isobutyl-N-piperonyl-aminomethyl) -thiazole is obtained, wherein the specific process is as shown in the formula:

。

further, the molar ratio of the 2- (p-fluorophenoxymethyl) -4- (N-isobutyl-aminomethyl) -thiazole, the piperonyl chloride and the triethylamine is 1: (0.5-1).

Further, the separated and purified organic layer is purified by adopting a column layer separation column, and the volume ratio of a column passing solvent is 1: (10-15) A mixed solution of ethyl acetate and petroleum ether.

The novel thiazole compound prepared by the invention has the following beneficial effects:

1) the new compound containing thiazole ring and amide structure is prepared by one-step reaction, the method has mild condition, and the reaction and post-treatment operations are simple;

2) the preparation route of the thiazole compound is simple, and the raw materials and auxiliary materials participating in the reaction are simple and easy to obtain.

The second purpose of the invention is to provide a pharmaceutical application of the thiazole compound, which is mainly used for preparing a pharmaceutical preparation for inhibiting the growth of tumor cells. The medicinal preparation can be prepared into a preparation for inhibiting the growth of tumor cells by adopting a conventional preparation method of a medicinal preparation, taking the thiazole compound and/or the hydrate thereof as active ingredients and adding pharmaceutically acceptable medicinal auxiliary materials, and the specific preparation can be tablets, capsules, powder, syrup, liquid, suspending agents or injection.

Furthermore, the special medicament can be used for preparing a medicinal preparation for inhibiting the growth of tumor cells.

Furthermore, the medicinal preparation can effectively inhibit tumor cells of gastrointestinal stromal tumor, lung cancer, breast cancer and pancreatic cancer. Especially has obvious effect of inhibiting pancreatic cancer tumor cells.

Therefore, the thiazole compound has obvious inhibition effect on the growth of various tumor cells, particularly pancreatic cancer cells, and lays a solid foundation for the development of new antitumor drugs.

Drawings

FIG. 1 is a thiazole compound prepared in example 1Of an object¹H-NMR spectrum.

FIG. 2 shows 1 of the thiazole Compound prepared in example 1¹³C-NMR spectrum.

Detailed Description

EXAMPLE 1 preparation of Compound I

The compound 2- (p-fluorophenoxymethyl) -4- (N-isobutyl-aminomethyl) -thiazole (2.94 g, 10 mmol), methylene chloride (20 mL) and triethylamine (1 mL) were sequentially added to a 50mL three-necked flask, and the mixture was magnetically stirred at 40 ℃ to dissolve the compound. Then dropwise adding a mixed solution of piperonyl chloride (1.88 g, 10.2 mmol) and 5 mL of dichloromethane at room temperature while stirring, finishing dropwise adding for about 20 min, continuously stirring at 40 ℃ for reacting for 8h, after the reaction is completed, slowly pouring the reaction liquid into ice water, separating out an organic phase, washing the organic phase to be neutral by using a 5% sodium bicarbonate solution and water respectively, and spin-drying the organic phase to obtain a crude product, wherein the volume ratio of the crude product to the dichloromethane is 1: 12 as column solvent, and obtaining 3.29g of target product of thiazole compound shown in the following structural formula I as yellow solid after column purification with yield of 74.3%.

The product has the following structural formula:

。

the obtained product is detected and verified by an infrared spectrometer and is shown in figures 1 and 2; the nuclear magnetic verification result is as follows:

¹H NMR (400 MHz, DMSO-d ₆)δ 7.53 (br, 1H), 7.13 – 6.90 (m, 7H), 6.03 (s, 2H), 5.36 (s, 2H), 4.60 (br, 2H), 3.10 (br, 2H), 1.94 (br, 1H), 0.73 (br, 6H).

¹³C NMR (101 MHz, DMSO-d ₆)δ 170.90, 157.43 (d, J = 237.0 Hz), 154.29, 152.64 (d, J = 12.1 Hz), 147.91 (d, J = 85.2 Hz), 130.85, 121.48, 116.90, 116.82, 116.51, 116.28, 108.52, 108.00, 101.81, 67.60, 65.37, 51.57, 49.40, 20.33, 15.61.

EXAMPLE 2 in vitro antitumor Activity test of thiazole Compound

This example was carried out using the international MTT method and the thiazole compound of example 1 was tested for its tumor cell inhibitory activity in vitro: firstly, inoculating 5 multiplied by 104 tumor cells (gastrointestinal stromal tumor, lung cancer, breast cancer and pancreatic cancer) in logarithmic growth phase on a 96-well cell plate, paving the plate according to 5000 cells (namely 100 mu L per well) per well, adding samples to be detected of thiazole compounds with different concentrations after the cells are attached to the wall, and setting 6 drug concentration gradients (unit mu M) in total, wherein the concentrations are respectively: 1.0, 5.0, 25, 125, 250 and 500; adding DMEM or RPMI1640 culture solution containing 5% FBS into the blank group, and adding complete culture solution containing 1% DMSO into the DMSO group; after 72 hours, adding 20 mu L of 5mg/mL MTT solution into corresponding wells of a 96-well plate, continuing culturing for 3 hours, discarding supernatant in the well plate, adding 150 mu L DMSO for dissolving, detecting the light absorption value at 490nm by using an enzyme-labeling instrument, and calculating the half inhibition concentration IC of the sample to be detected of the thiazole compound on cell growth₅₀。

TABLE 1 IC of thiazole Compounds on respective tumor cells₅₀Value of

Experimental results show that the thiazole compound can inhibit the growth of tumor cells, and particularly has the best inhibition effect on pancreatic cancer cell strains. Has great significance for further developing novel effective cancer treatment drugs. Generally, the thiazole compound and/or the hydrate thereof can be used as an active ingredient by a conventional preparation method of a pharmaceutical preparation, and a pharmaceutically acceptable pharmaceutic adjuvant is added to prepare the preparation for inhibiting the growth of tumor cells, wherein the adopted pharmaceutic adjuvant can be one or more of spice, sweetener, liquid or solid filler and/or diluent, and can be finally prepared into tablets, capsules, powder, syrup, liquid, suspending agents, injection and the like.

The above description is provided for the purpose of describing the preferred embodiments of the present invention in more detail, and it should not be construed that the embodiments of the present invention are limited to the description above, and it will be apparent to those skilled in the art that the present invention can be implemented in many different forms without departing from the spirit and scope of the present invention.

Claims

1. A thiazole compound for inhibiting tumor cell growth, which is 2- (p-fluorophenoxymethyl) -4- (N-isobutyl-N-piperonyl-aminomethyl) -thiazole having the formula:

。

2. a thiazole compound for inhibiting tumor cell growth according to claim 1, wherein said thiazole compound is prepared by the following steps: taking 2- (p-fluorophenoxymethyl) -4- (N-isobutyl-aminomethyl) -thiazole and piperonyl chloride as raw materials and CH₂Cl₂As a solvent, triethylamine is used as an acid-binding agent to enable reaction liquid to react at the temperature of 40 ℃ while stirring for 8-10 hours, after the reaction, an organic layer is separated and purified, and finally 2- (p-fluorophenoxymethyl) -4- (N-isobutyl-N-piperonyl-aminomethyl) -thiazole is obtained, wherein the specific process is shown as the formula:

。

3. a thiazole compound for inhibiting tumor cell growth according to claim 2, wherein said 2- (p-fluorophenoxymethyl) -4- (N-isobutyl-aminomethyl) -thiazole, piperonyl chloride and triethylamine are used in a molar ratio of 1: (0.5-1).

4. A thiazole compound for inhibiting tumor cell growth according to claim 2 wherein the separated and purified organic layer is purified by column chromatography with a column solvent of 1: (10-15) A mixed solution of ethyl acetate and petroleum ether.

5. Use of a thiazole compound according to any of claims 1 to 4 for the preparation of a pharmaceutical formulation for inhibiting tumor cell growth.

6. Use of a thiazole compound according to claim 5, wherein said pharmaceutical formulation is effective in inhibiting tumor cells of gastrointestinal stromal tumors, lung cancer, breast cancer, pancreatic cancer.

7. Use of a thiazole compound according to claim 6, wherein said pharmaceutical preparation has a significant effect on the inhibition of pancreatic cancer tumor cells.