阅读说明：本技术 一类含氟噻唑酰胺衍生物在制备抗癌药物中的用途 (Application of fluorine-containing thiazole amide derivatives in preparation of anti-cancer drugs ) 是由 刘佳 栾庆先 郑铭 郭晓凤 于 2019-12-02 设计创作，主要内容包括：本发明提供了一类含氟噻唑酰胺衍生物在制备抗宫颈癌药物中的用途,本发明涉及一类含氟噻唑酰胺衍生物,其化学结构见式I：<Image he="364" wi="506" file="DSA0000196226720000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>本发明公开了上述化合物的化学结构式与用作抗宫颈癌药物的用途,其与医药上可接受的助剂或增效剂及与商品抗宫颈癌药物组合使用在防治宫颈癌中的用途及其药物制备方法。(The invention provides application of fluorine-containing thiazole amide derivatives in preparation of anti-cervical cancer drugs, and relates to fluorine-containing thiazole amide derivatives, wherein the chemical structure of the fluorine-containing thiazole amide derivatives is shown as a formula I: the invention discloses a chemical structural formula of the compound, application of the compound as an anti-cervical cancer medicament, application of the compound, a pharmaceutically acceptable auxiliary agent or synergist, application of the compound, a commercial anti-cervical cancer medicament in combination in preventing and treating cervical cancer and a preparation method of the medicament.)

1. A fluorine-containing thiazole amide derivative is characterized by having a chemical structural formula shown as a formula I:

2. the use of the fluorothiazoleamide derivative I of claim 1 in the preparation of a medicament for treating cervical cancer.

3. A pharmaceutical composition comprising the fluorothiazoleamide derivative I of claim 1 and an auxiliary, a surfactant or a synergist which can be used for the preparation of a medicament, the composition comprising the fluorothiazoleamide derivative I of claim 1 as an active ingredient, the content of the active ingredient being 0.1 to 99.9% by mass, the content of a solid or liquid auxiliary being 99.9 to 0.1% by mass, and optionally 0 to 25.0% by mass of a surfactant or a synergist; the sum of their contents being 100%.

4. A drug compound composition, the active ingredients of the compound composition are the fluorine-containing thiazole amide derivative I and any one or more commercial drugs for resisting cervical cancer according to claim 1, the ratio of the fluorine-containing thiazole amide derivative I and the commercial drugs for resisting cervical cancer according to claim 1 is 1 percent to 99 percent to 1 percent by mass percentage, the sum of the contents of the active ingredients is 1 to 99 percent by mass, the content of a solid or liquid auxiliary agent is 99.9 to 0.1 percent by mass, and the optional content of a surfactant or a synergist is 0 to 25.0 percent by mass; the sum of their contents being 100%.

Technical Field

The technical scheme of the invention relates to a preparation method and application of a fluorine-containing thiazole amide derivative in preparing an anti-cancer medicament, in particular to a preparation method and application of the compound in preparing an anti-cervical cancer medicament.

Background

The medicine is an important effective tool for guaranteeing the public health, the creation of the new medicine is complex system engineering, just like symptomatic treatment, the creation of the new medicine is often highly targeted, Bruton Tyrosine Kinase (BTK) is one of important targets of leukemia, BTK is expressed in hematopoietic cells such as bone marrow cells, mast cells and B cells, but is not expressed in T cells, plasma cells and NK cells (Smith, C.I.; et al., J Immunol 1994)152, 557-65), have become a hot target for B cell malignancies and autoimmune diseases. In recent years, a number of drug varieties have been created based solely on Bruton's Tyrosine Kinase (BTK), and ibrutinib is rather the star molecule in this class of agents. However, with BTK enzyme as an important target, lead optimization of ibrutinib has been reported in many ways, wherein patent literature reports a class of trisubstituted thiazole amide derivatives, and preparation methods and uses thereof (CN 201811414373.8): in the field of medicine, the inhibitory activity of the compound 7i on BTK enzyme is 99.78 + -1.04% per liter at 10. mu. mol, IC₅₀0.86 micromole per liter, an inhibitory activity of 99.76 + -1.0 for ibrutinib, IC₅₀0.002 micromole per liter in IC₅₀In comparison, the activity of compound 7i is about 1/430 for ibrutinib. However, IC of Compound 7i on Ramos cell proliferation inhibitory Activity under in vivo conditions₅₀IC of ibrutinib at 1.42 micromole per liter₅₀14.69 micromoles per liter in IC₅₀In comparison, compound 7i was 10.35 times more active on Ramos cells than ibrutinib; IC for inhibitory Activity on Raji cell proliferation₅₀IC of ibrutinib at 2.82 micromoles per liter₅₀15.99 micromoles per liter in IC₅₀In comparison, compound 7i was approximately 5.67 times more active on Ramos cells than ibrutinib. The compound 7i has good inhibitory activity on cell proliferation of Ramos and Raji cell lines of B cell lymphoma cell lines.

The solid cancer is different from lymph cancer, cervical cancer is one of the most common malignant solid cancers in female genital organ cancers around the world, the mortality caused in China accounts for the second place of female cancer patients, and the cause of the disease is not clear. Hela cells are cells with unlimited proliferation capacity under artificial culture conditions, and are strain cells separated from human cervical cancer tissues and common materials for researching cervical cancer.

Based on the great physiological and biochemical differences among different cancers, in order to search more candidate drug molecules for efficiently resisting cervical cancer, the invention creatively discovers that the fluorine-containing thiazole amide derivative which has good inhibitory activity on the proliferation of B cell lymphoma cells has excellent inhibitory activity on the proliferation of cervical cancer cell Hela cells.

Disclosure of Invention

The invention aims to provide a method and application of a fluorine-containing thiazole amide derivative in preparation of an anti-cervical cancer medicament, wherein the chemical structural formula of the fluorine-containing thiazole amide derivative is shown as I:

the test code of the target compound of the formula I is Gxf02-200-2, namely the compound 7I introduced in the background art, and the specific method for measuring the anti-cervical cancer activity comprises the following steps:

measurement of cancer cell proliferation inhibitory Activity:

hela cells are cultured, 3000 cells of 2000-. The compound treatment time of the invention is 48 hours and 72 hours respectively, 10 microliter of compound mother liquor of the invention and 10 microliter of CCK-8 reagent are added into each hole; the absorbance value (OD value) at 450 nm was then determined. The compounds of the invention were tested at a concentration of 10 or 5 micromoles per liter per compound. The cell proliferation inhibitory activity of the active compounds was calculated from the OD values, at least three replicates per concentration. The chemical structure of the compound of the present invention is closest to that of ibrutinib, and therefore, the present invention selects ibrutinib as a positive control agent.

The invention further specifically illustrates the synthesis of the fluorine-containing thiazole amide derivative I and the activity and application of resisting the proliferation of cervical cancer cells through specific preparation and biological activity determination examples, wherein the examples are only used for specifically illustrating the invention and not limiting the invention, and are only used for illustrating and not limiting the patent, and the specific embodiments are as follows:

example 1: the measurement results of the inhibitory activity of the fluorothiazoleamide derivative I of the present invention on Hela cell proliferation are as follows:

the fluorine-containing thiazole amide derivative I (Gxf02-200-2) is tested for the activity of inhibiting the proliferation of Hela cells according to the using method of the instruction, and the test results are shown in Table 1; the raw data are shown in table 2. As shown in the table, the fluorothiazole amide derivative I has better anti-cell proliferation activity on cervical cancer Hela cells, the cell proliferation inhibition rate in 48 hours is 44.69 percent, which is higher than the inhibition rate of a positive control medicament ibrutinib (15.70 percent), 28.99 percent, the cell proliferation inhibition rate in 72 hours is 47.13 percent, which is higher than the inhibition rate of the positive control medicament ibrutinib (26.16 percent), and the control medicament ibrutinib is a compound with the chemical structure closest to the structure of the fluorothiazole amide derivative I. Therefore, the irrutinib has almost no inhibitory activity on the proliferation of the cervical cancer cell Hela cells, and in order to further verify the influence of the irrutinib on the proliferation activity of the cervical cancer cell Hela cells, the average value of the inhibitory rate of the composition at 48h is 60.01%, compared with the inhibitory rate of the sole fluorine-containing thiazole amide derivative I, the activity is improved by about 15%, the ibrutinib has synergistic effect on the proliferation inhibition of the cervical cancer cell Hela cells in a short time, and along with the prolonging of time, the average value of the inhibitory rate of the composition at 72h is 51.96%, compared with the inhibitory rate of the sole fluorine-containing thiazole amide derivative I, the activity is improved by less than 5%; the test results again show that the activity of the irrutinib in combination with the fluorothiazole amide derivative I of the invention on the proliferation of the cervical cancer cell Hela cells only shows the activity of the fluorothiazole amide derivative I of the invention, and the irrutinib does not contribute to the inhibition of the proliferation of the cervical cancer cell Hela cells. The results of the present invention illustrate that: although the fluorine-containing thiazole amide derivative I has good inhibition activity on cell proliferation of Ramos and Raji cell lines in B cell lymphoma cell lines and also has good inhibition activity on cell proliferation of Hela cells which also cause other cancers such as cervical cancer, although the structure type of the ibrutinib is similar to that of the target compound, the ibrutinib has good inhibition activity on cell proliferation of Ramos and Raji cell lines in B cell lymphoma cell lines, but has no inhibition activity on cell proliferation of Hela cells which cause cervical cancer. Therefore, the results of the present invention also indicate that the results of the study of cancer cells in blood (B-cell lymphoma cells) cannot be generalized to other solid cancers (cervical cancer cells Hela cells).