阅读说明：本技术 一种吲哚嗪类化合物的合成方法及用途 (Synthetic method and application of indolizine compound ) 是由 黄强 董凯凯 于 2020-07-10 设计创作，主要内容包括：一种吲哚嗪类化合物的合成方法,包括以下步骤：苯并吡喃酮衍生物、溴吡啶鎓盐衍生物、碱和溶剂混合在10ml圆底烧瓶中,并在25℃-100℃搅拌2-48小时；反应完成后,粗产物通过硅胶色谱纯化得到目标化合物,其结构式如式I所示,<Image he="490" wi="700" file="DDA0002578223460000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(A synthetic method of indolizine compounds comprises the following steps: mixing the benzopyrone derivative, the bromopyridinium salt derivative, the base and the solvent in a 10ml round-bottom flask, and stirring for 2-48 hours at 25-100 ℃; after the reaction is finished, the crude product is purified by silica gel chromatography to obtain a target compound, the structural formula of which is shown as formula I,)

1. A synthetic method of indolizine compounds is characterized by comprising the following steps: it comprises the following steps: mixing the benzopyrone derivative, the bromopyridinium salt derivative, the base and the solvent in a 10ml round-bottom flask, and stirring for 2-48 hours at 25-100 ℃; after the reaction is finished, the crude product is purified by silica gel chromatography to obtain a target compound, the structural formula of which is shown as formula I,

in the above structural formula:

R¹independently selected from one or more of H, halogen, alkyl, hydroxyl, amino, carboxyl, carbonyl, ester group, cyano, alkynyl, alkenyl, phenyl and aryl；

R²Is independently selected from one or more of H, hydroxyl, alkoxy, phenyl, pyridyl and aryl;

X₁selected from C and N;

X₂selected from OH and SH;

R³independently selected from one or more of H, halogen, alkyl, hydroxyl, amino, carboxyl, carbonyl, ester group, cyano, alkynyl, alkenyl, phenyl, pyridine, thiophene, heterocycle and aryl.

2. The synthetic method of indolizine compound according to claim 1, wherein: the aromatic group is selected from phenyl, naphthyl, anthryl, phenanthryl, pyridyl, thienyl, furyl, thiazolyl, imidazolyl, oxazolyl, indolizinyl, quinolyl, indolinyl, benzothiazolyl, benzisothiazolyl, triazolopyridyl, indolizinyl, benzoxazolyl, triazolopyridyl, pyridopyrazinyl, quinazolinyl, benzooxadiazolyl, benzothiadiazolyl, benzoindazinyl; the alkyl group is C_1-10A straight or branched chain saturated carbon chain; the halogen is selected from fluorine, chlorine, bromine and iodine.

3. The synthetic method of indolizine compound according to claim 1, wherein: benzopyrone derivative, bromopyridinium salt derivative, base and solvent were mixed in a 10ml round bottom flask and stirred at 80 ℃ for 12 hours; after completion of the reaction, the crude product was purified by silica gel chromatography to give the target compound.

4. The synthetic method of indolizine compound according to claim 3, characterized in that: the alkali is selected from one of DBU, DIPEA, potassium carbonate, sodium carbonate, potassium acetate, potassium hydroxide and sodium hydroxide; the solvent is selected from one of 1, 4-dioxane, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, toluene, NMP and THF.

5. The synthetic method of indolizine compound according to claim 3 or 4, characterized in that: the base is DBU; the solvent is 1, 4-dioxane.

6. The synthetic method of indolizine compound according to claim 1, wherein: benzopyrone, bromopyridinium salt and DBU were mixed in a 10ml round bottom flask and stirred at 80 ℃ for 6 hours; after completion of the reaction, the crude product was purified by silica gel chromatography to give the target compound.

7. The synthetic method of indolizine compound according to claim 1, wherein: benzopyrone, bromopyridinium salt, metal catalyst, base and 1, 4-dioxane were mixed in a 10ml round bottom flask and stirred at 60 ℃ for 6 hours; after completion of the reaction, the crude product was purified by silica gel chromatography to give the target compound.

8. The synthetic method of indolizine compound according to claim 7, wherein: the metal catalyst is selected from one of cuprous iodide, cuprous bromide, cuprous chloride, cupric chloride and cupric sulfate; the base is selected from DBU, DIPEA, potassium carbonate, sodium carbonate, potassium acetate, potassium hydroxide, and sodium hydroxide.

9. The synthesis method of indolizine compounds according to claim 7 or 8, characterized in that: the metal catalyst is cuprous iodide; the base is DBU.

10. The use of indolizine compounds according to claim 1, characterized in that: the indolizine compound used for tumor or cancer is gastric cancer, cervical adenocarcinoma, colon cancer, lung cancer, liver cancer, glioma, esophageal cancer, intestinal cancer, nasopharyngeal cancer, breast cancer, lymph cancer, kidney cancer, pancreatic cancer, bladder cancer, ovarian cancer, uterine cancer, bone cancer, gallbladder cancer, lip cancer, melanoma, tongue cancer, laryngeal cancer, leukemia, prostate cancer, brain tumor, squamous carcinoma, skin cancer, hemangioma, lipoma, cervical cancer and thyroid cancer.

Technical Field

The invention belongs to the technical field of chemistry and medicine, and particularly relates to a preparation method of a novel indolizine compound and application of the compound in treating tumors.

Background

Cancer (malignant tumor) is one of the diseases that seriously threaten the global human health, and is also a great problem facing the medical field all over the world. According to epidemiological investigation, the global cancer incidence rate is up to 2 per thousand in 2018. In China, about 380 million new cancer cases and about 229 million deaths are caused each year, the average annual incidence rate of the cancer is increased by about 3.9 percent, the incidence rate and the mortality rate are on the annual increasing trend, and the treatment and the prevention of the cancer are widely regarded. At present, the treatment methods of tumors mainly comprise surgical excision, radiotherapy and chemotherapy, but mainly comprise chemical drug treatment. The current clinical chemical drugs for treating cancer are in a wide variety, such as platinum, nitrogen mustard, triazole and the like, but most drugs are limited in application due to high toxicity, multiple adverse reactions and low bioavailability. Therefore, the development of highly effective and low toxic anticancer drugs has become a key research topic in the field of current medicinal chemistry.

In view of the potential application of indolizine anticancer drugs in tumor treatment, research surrounding small molecule drugs with indolizine skeleton as core pharmacophore is the current hotspot. Among the indolizines found, the known biological activities are antibacterial, antitubercular, anticancer, anti-inflammatory, antioxidant, antihistaminic and uterotrophic activities, and may also be useful as aromatase inhibitors, phosphodiesterase inhibitors, phosphatase inhibitors and Angiotensin Converting Enzyme (ACE) inhibitors. In combination with the research work, the novel indolizine compound is further found to have potential value in the treatment of malignant tumors.

Disclosure of Invention

The invention aims to solve the technical problem that a novel substituted indolizine compound can effectively inhibit various cancers or tumors.

In order to solve the technical problems, the invention adopts the following technical scheme:

a synthetic method of indolizine compounds comprises the following steps: the benzopyrone derivative, bromopyridinium salt derivative, base and solvent were mixed in a 10ml round bottom flask and stirred at 25 ℃ to 100 ℃ for 2 to 48 hours. After the reaction is finished, the crude product is purified by silica gel chromatography to obtain a target compound, the structural formula of which is shown as formula I,

in the above structural formula:

R¹independently selected from one or more of H, halogen, alkyl, hydroxyl, amino, carboxyl, carbonyl, ester group, cyano, alkynyl, alkenyl, phenyl and aryl;

R²is independently selected from one or more of H, hydroxyl, alkoxy, phenyl, pyridyl and aryl;

X₁selected from C and N;

X₂selected from OH and SH;

R³independently selected from H, halogenAnd one or more of an element, an alkyl group, a hydroxyl group, an amino group, a carboxyl group, a carbonyl group, an ester group, a cyano group, an alkynyl group, an alkenyl group, a phenyl group, a pyridine, a thiophene, a heterocycle and an aryl group.

The aromatic group is selected from phenyl, naphthyl, anthryl, phenanthryl, pyridyl, thienyl, furyl, thiazolyl, imidazolyl, oxazolyl, indolizinyl, quinolyl, indolinyl, benzothiazolyl, benzisothiazolyl, triazolopyridyl, indolizinyl, benzoxazolyl, triazolopyridyl, pyridopyrazinyl, quinazolinyl, benzooxadiazolyl, benzothiadiazolyl, benzoindazinyl; the alkyl group is C_1-10A straight or branched chain saturated carbon chain; the halogen is selected from fluorine, chlorine, bromine and iodine.

The synthetic method of indolizine compound comprises the steps of mixing benzopyrone, bromopyridinium salt, alkali and solvent in a 10ml round-bottom flask, and stirring for 12 hours at 80 ℃; after completion of the reaction, the crude product was purified by silica gel chromatography to give the target compound.

The alkali is selected from one of DBU, DIPEA, potassium carbonate, sodium carbonate, potassium acetate, potassium hydroxide and sodium hydroxide; the solvent is selected from one of 1, 4-dioxane, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, toluene, NMP and THF.

The base is preferably DBU; the solvent is preferably 1, 4-dioxane.

The synthetic method of indolizine compound comprises the steps of mixing benzopyrone, bromopyridinium salt and DBU in a 10ml round-bottom flask, and stirring for 6 hours at 80 ℃; after completion of the reaction, the crude product was purified by silica gel chromatography to give the target compound.

The synthetic method of indolizine compound comprises the steps of mixing benzopyrone, bromopyridinium salt, metal catalyst, alkali and 1, 4-dioxane in a 10ml round-bottom flask, and stirring for 6 hours at 60 ℃; after completion of the reaction, the crude product was purified by silica gel chromatography to give the target compound. The metal catalyst is selected from one of cuprous iodide, cuprous bromide, cuprous chloride, cupric chloride and cupric sulfate; the base is selected from DBU, DIPEA, potassium carbonate, sodium carbonate, potassium acetate, potassium hydroxide, and sodium hydroxide.

The metal catalyst is preferably cuprous iodide; the base is preferably DBU.

The indolizine compound used for tumor or cancer is gastric cancer, cervical adenocarcinoma, colon cancer, lung cancer, liver cancer, glioma, esophageal cancer, intestinal cancer, nasopharyngeal cancer, breast cancer, lymph cancer, kidney cancer, pancreatic cancer, bladder cancer, ovarian cancer, uterine cancer, bone cancer, gallbladder cancer, lip cancer, melanoma, tongue cancer, laryngeal cancer, leukemia, prostate cancer, brain tumor, squamous carcinoma, skin cancer, hemangioma, lipoma, cervical cancer and thyroid cancer.

The invention also provides methods for treating tumors or cancers, limited to in vitro cell testing.

The invention relates to the inhibitory activity of the compound on human liver cancer cells and ovarian cancer cells.

Tumor cell inhibition rate ═ 100% for [1- (experimental-blank)/(control-blank). Interpretation of terms: "alkyl" is intended to include both branched and straight chain saturated hydrocarbon radicals having the specified number of carbon atoms. "halogen" refers to fluorine, chlorine, bromine and iodine atoms. "indolizine" may also be referred to as indolizine or indolizine.

English abbreviation: DBU refers to 1, 8-diazabicycloundecen-7-ene; DIPEA refers to N, N-diisopropylethylamine; NMP refers to N-methylpyrrolidone; THF means tetrahydrofuran.

The beneficial effect of adopting above-mentioned technical scheme is:

the invention provides three different preparation methods for synthesizing novel indolizine antitumor compounds, and activity tests show that the compounds have tumor cell inhibitory activity, so that the types of candidate drugs for treating tumors are further widened.

Detailed Description

It must be noted that the examples of the present invention are for illustrating the present invention and not for limiting the present invention. Simple modifications of the invention in accordance with its spirit fall within the scope of the claimed invention.

While the foregoing specification illustrates the invention, examples are provided to illustrate the practice and significance of the invention.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The specific conditions in the examples are not limited to a certain one, and the solvent used in the preparation of the compounds 1 to 10 may be 1, 4-dioxane, N-dimethylformamide, thionyl chloride, methanol, ethanol, etc., the temperature may be in the range of 25 to 100 ℃, and the base may be DBU, triethylamine, potassium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, among which DBU is most preferable. Unless otherwise indicated, percentages and parts are percentages and parts by weight.

The test materials and reagents used in the following examples are commercially available without specific reference.

In each example, NMR spectra were determined by Bruker Ascend III 400M NMR (TMS as internal standard); high resolution mass spectrometry was determined using Bruker micrtof Q II; the melting point is measured by using an X-6 precise microscopic melting point tester; the silica gel is 200-300 meshes.

Wherein, the Chinese name table of the reagent represented by the chemical formula or English letter abbreviation is as follows: