CN108191756B

CN108191756B - Quinoline derivative and preparation method and application thereof

Info

Publication number: CN108191756B
Application number: CN201711316481.7A
Authority: CN
Inventors: 肖慧泉
Original assignee: University of Shaoxing
Current assignee: University of Shaoxing
Priority date: 2017-12-12
Filing date: 2017-12-12
Publication date: 2020-08-25
Anticipated expiration: 2037-12-12
Also published as: CN108191756A

Abstract

The invention belongs to the technical field of quinoline heterocyclic compounds, and particularly relates to a quinoline derivative, a preparation method and an application thereof, wherein the quinoline derivative is 6-decyloxy-7-ethoxy-quinoline-3-carboxylic acid ethyl ester or a hydrate, a prodrug and a pharmaceutically acceptable salt thereof, and the quinoline derivative has a structural formula as follows:

and the preparation method and the application thereof and the pharmaceutical composition prepared by the quinoline derivative are improved. The quinoline derivative provided by the invention has higher medicinal value, and is used for treating, treating or relieving metastatic breast cancer and postmenopausal female advanced breast cancer.

Description

Quinoline derivative and preparation method and application thereof

Technical Field

The invention belongs to the technical field of quinoline heterocyclic compounds, and particularly relates to a quinoline derivative and a preparation method and application thereof.

Background

Breast cancer is a common malignancy in women, with about 120 million women suffering from breast cancer each year worldwide, and about 50 million people die of the disease. In the united states, women have a high one-eighth probability of developing breast cancer for their lifetime, the second most malignant tumor of mortality. The incidence of breast cancer in China is rising year by year, the incidence of diseases in big cities such as Beijing, Shanghai and the like reaches 56/10 ten thousand, and the breast cancer becomes the first malignant tumor of the incidence of diseases of women.

At present, the search for a drug with high efficiency, stability and low side effect is still the key problem for treating breast cancer. Therefore, it is of great significance to further develop new effective therapeutic drugs.

Quinolines are an important class of compounds in the azacycle and are the parent nucleus of many natural products and bioactive drug structures, such as quinoline, chloroquinoline, camelinine a, camptothecin. Wang et al reported in Bioorg Med Chem Lett,2011,21:2313 that a novel quinoline derivative I separated from streptomyces sp. Neau50 has an IC50 of 29.3ug/mL against A549 tumor cells, and is a good tumor lead compound. Through the continuous research of pharmacologists, a large number of quinoline derivatives are synthesized and have official biological activities, such as: anti-tumor, antibacterial, antimalarial, antiasthmatic, anti-platelet aggregation, etc. Therefore, quinoline derivatives are receiving increasing attention from researchers.

Disclosure of Invention

In order to solve the problems in the prior art, the invention provides a quinoline derivative which has higher medicinal value and is used for treating, treating or relieving metastatic breast cancer and postmenopausal female advanced breast cancer.

In order to achieve the technical purpose, the technical scheme of the invention is as follows: a quinoline derivative characterized by: the quinoline derivative is 6-decyloxy-7-ethoxy-quinoline-3-carboxylic acid ethyl ester or hydrate, prodrug and pharmaceutically acceptable salt thereof, and the structural formula is as follows:

is denoted as compound III.

The preparation method of the quinoline derivative comprises the steps of taking a compound II as a raw material, adding a catalyst and an organic solvent, and performing a closed-loop reaction by adopting a one-pot method to obtain a product 6-decyloxy-7-ethoxy-quinoline-3-carboxylic acid ethyl ester, namely a compound III, wherein the reaction process is as follows:

the catalyst adopts organic acid, and the proportion of the addition amount of the organic acid to the molar amount of the diethyl 2- ((4-decyloxy-3-ethoxyphenylamino) methine) maleate is 1-20: 1.

preferably, the ratio of the molar amount of the catalyst to diethyl 2- ((4-decyloxy-3-ethoxyphenylamino) methine) maleate is 1 to 3: 1.

an organic solvent is added in the one-pot reaction process, and the organic solvent is one of organic carboxylic acid, trichloromethane, dichloromethane or toluene.

The ratio of the added volume amount of the organic solvent to the molar amount of the raw material is 800-1200mL/mol, and preferably, the ratio of the added volume amount of the organic solvent to the molar amount of the raw material is 1184-1480 mL/mol.

The reaction temperature of the one-pot method is 70-80 ℃, and the reaction time is 3-8 h.

The course of the reaction was followed by thin layer chromatography.

After the one-pot reaction is finished, evaporating the reaction solution to dryness to remove the organic solvent, neutralizing the catalyst, and then carrying out silica gel column chromatography purification.

The quinoline derivatives are used in medicaments for treating, treating or relieving metastatic breast cancer and postmenopausal advanced breast cancer in women.

A pharmaceutical composition comprises compound III and its hydrate as active ingredient, and prodrug, pharmaceutically acceptable salt or pharmaceutically acceptable carrier.

The dosage form of the pharmaceutical composition is a common dosage form in pharmaceutics, such as tablets, capsules, pills and the like.

Pharmaceutically acceptable carriers are those conventional in the pharmaceutical art and refer to one or more inert, non-toxic solid or liquid fillers, diluents, adjuvants and the like that do not interact with the active compound or the patient.

From the above description, it can be seen that the present invention has the following advantages:

1. the quinoline derivative provided by the invention has higher medicinal value, and is used for treating, treating or relieving metastatic breast cancer and postmenopausal female advanced breast cancer.

2. The invention adopts a one-pot method as a preparation method, which not only has good reaction efficiency and reaction stability, but also has less side reaction and high purity.

3. The method adopts a drying-by-distillation mode to recover the organic solvent, can solve the pollution problem of the organic solvent, meets the current environmental protection requirement, simultaneously adopts the thin-layer chromatography to track the reaction progress, can effectively control the reaction to be carried out, and effectively ensures the high efficiency of the reaction.

Drawings

FIG. 1 is a nuclear magnetic diagram of the hydrogen spectrum of ethyl 6-decyloxy-7-ethoxy-quinoline-3-carboxylate III in example 1 of the present invention.

FIG. 2 is a carbon spectrum nuclear magnetic diagram of ethyl 6-decyloxy-7-ethoxy-quinoline-3-carboxylate III in example 1 of the present invention.

FIG. 3 is a DEPT spectrum of ethyl 6-decyloxy-7-ethoxy-quinoline-3-carboxylate III in example 1 of the present invention

Detailed Description

A specific embodiment of the present invention will be described in detail with reference to fig. 1 and 2, but the present invention is not limited thereto.

Example 1

As shown in fig. 1 and 2, 9.26 g of compound II (0.02mol) and 30ml of trifluoroacetic acid were sequentially added to a 100 ml three-necked reaction flask, heated at 75 ℃ and reacted, followed by detection of the reaction by thin layer chromatography (developing solvent: ethyl acetate: petroleum ether: 1: 3), and the reaction was terminated in about 5 hours. Recovering trifluoroacetic acid under reduced pressure, adding 50 ml of dichloromethane, dropwise adding 20% sodium hydroxide aqueous solution to adjust to neutrality, washing with water, drying, filtering, removing solvent, and purifying the residue by column chromatography (eluent ethyl acetate: petroleum ether: 1:6) to obtain 5.85 g of 6-decyloxy-7-ethoxy-quinoline-3-carboxylic acid ethyl ester, the melting point is 52-53 ℃, and the yield is 72.9%.

According to the detection, the hydrogen spectrum nuclear magnetism diagram, the carbon spectrum nuclear magnetism diagram and the DEPT spectrum nuclear magnetism diagram of the 6-decyloxy-7-ethoxy-quinoline-3-carboxylic acid ethyl ester prepared in the embodiment are shown in the figure 1 and the figure 2 respectively:

¹HNMR(,ppm,400MHz,CDCl₃)：9.207(s,1H,-C＝CH-)；8.591(s,1H,-C＝CH-)；7.388(s,1H,-C＝CH-)；7.067(s,1H,-C＝CH-)；4.440-4.423(q,2H,-CH₂-)；4.258-4.209(q,2H,-CH₂-)；4.106-4.075(t,2H,-CH₂-)；1.909-1.874(m,2H,-CH₂-)；1.543-1.245(m,20H,-CH₂-,-CH₃),0.852-0.836(t,3H,CH₃)

¹³CNMR(,ppm,100MHz,CDCl₃)：165.77；154.05；150.03；147.83；136.25；122.34；121.29；108.43；106.89；69.10；64.53；61.10；31.87；29.53；29.50；29.34；29.29；28.84；25.95；22.64；14.42；14.33；14.07。

DEPT135 CNMR(,ppm,100MHz,CDCl₃)：147.8；136.25；108.38；106.85；69.08(D)；64.53(D)；61.09(D)；31.87(D)；29.53(D)；29.50(D)；29.34(D)；29.29(D)；28.84(D)；25.95(D)；22.64(D)；14.42；14.33；14.07。

example 2 to example 4

9.26 g (0.02mol) of compound II and 30mL of an organic carboxylic acid were sequentially added to a 100 mL four-necked reaction flask, and the mixture was stirred at a certain temperature to react, followed by detection by thin layer chromatography until the reaction was completed, neutralized with dropwise an alkali, separated, washed with water, dried, and then the solvent was recovered under reduced pressure, subjected to silica gel column chromatography (eluent: ethyl acetate: petroleum ether: 1:6), weighed, and the yield was calculated, the results being shown in table 1.

Product yields of example 2-example 4

	Catalyst and process for preparing same	Yield (%)	Reaction temperature
				Example 2	Trifluoroacetic acid	73	78
Example 3	Acetic acid	20	78
				Example 4	Formic acid	35	78

Example 5-example 8

Adding 9.26 g (0.02mol) of the compound II and 5 ml of trifluoroacetic acid into a four-mouth reaction bottle with a proper solvent of 30ml to 100 ml, stirring the mixture at a certain temperature for reaction, detecting the reaction by thin-layer chromatography, dropping alkali for neutralization, separating liquid, washing with water, drying, recovering the solvent under reduced pressure, carrying out silica gel column chromatography (eluent: ethyl acetate: petroleum ether: 1:6), weighing, calculating the yield,

product yields of examples 5-8

Example 9 in vitro antitumor activity assay experiment:

the experiment is carried out by adopting an international general MTT method, and the compound III is subjected to an in vitro tumor cell inhibitory activity experiment: firstly, inoculating 2 × 104 breast cancer cells BS524(T47D) in logarithmic growth phase on a 96-well cell plate, repeating 3 wells, adding samples to be detected with different concentrations after the cells are attached to the wall, and setting 7 drug concentration gradients (unit ug/mL) in total, wherein the concentrations are respectively as follows: 1.0, 5.0, 10, 20, 30, 40 and 50 of the compound i sample set; and after 72 hours, adding 20uL 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 100uL DMSO for dissolving, detecting an absorbance value at a wavelength of 570nm by using an enzyme-labeling instrument, and calculating half inhibition concentration IC50 of the sample to be detected on cell growth, wherein IC50 of the sample to be detected is 18.05 ug/mL. The experimental result shows that the compound has obvious inhibition effect on breast cancer cell strains, provides a lead compound for developing new antitumor drugs, and has important significance.

It should be understood that the detailed description of the invention is merely illustrative of the invention and is not intended to limit the invention to the specific embodiments described. It will be appreciated by those skilled in the art that the present invention may be modified or substituted equally as well to achieve the same technical result; as long as the use requirements are met, the method is within the protection scope of the invention.

Claims

1. A quinoline derivative characterized by: the quinoline derivative is 6-decyloxy-7-ethoxy-quinoline-3-carboxylic acid ethyl ester and pharmaceutically acceptable salt, and the structural formula is as follows:

is represented as a compound III, wherein C in the structural formula₁₀H₂₁O-is n-C₁₀H₂₁O-。

2. A process for the preparation of a quinoline derivative as claimed in claim 1, characterized in that: the preparation method of the quinoline derivative comprises the steps of taking the compound II as a raw material, adding a catalyst, and preparing a product 6-decyloxy-7-ethoxy-quinoline-3-carboxylic acid ethyl ester, namely a compound III, C in a structural formula through a closed-loop reaction by adopting a one-pot method₁₀H₂₁O-is n-C₁₀H₂₁O-, the reaction process is as follows:

3. the method for producing a quinoline derivative according to claim 2, wherein: the catalyst adopts organic acid, and the ratio of the addition amount of the organic acid to the molar amount of the compound II is 1-20: 1.

4. A method for preparing a quinoline derivative according to claim 3, wherein: the ratio of the molar weight of the catalyst to the compound II is 1-3: 1.

5. The method for producing a quinoline derivative according to claim 2, wherein: an organic solvent is added in the one-pot reaction process, and the ratio of the added volume amount of the organic solvent to the molar weight of the raw material is 800-1200 mL/mol; the organic solvent is one of organic carboxylic acid, chloroform, dichloromethane or toluene.

6. The method for producing a quinoline derivative according to claim 5, wherein: the reaction temperature of the one-pot method is 70-80 ℃, and the reaction time is 3-8 h.

7. The method for producing a quinoline derivative according to claim 2, wherein: the reaction process is tracked by adopting thin-layer chromatography; after the one-pot reaction is finished, evaporating the reaction solution to dryness to remove the organic solvent, neutralizing the catalyst, and then carrying out silica gel column chromatography purification.

8. Use of a quinoline derivative according to claim 1, characterized in that: the quinoline derivative is applied to the preparation of medicaments for metastatic breast cancer and postmenopausal female advanced breast cancer.

9. A pharmaceutical composition comprising the compound III according to claim 1 as an active ingredient in combination with compound III or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier; the dosage form of the pharmaceutical composition adopts a common dosage form in pharmaceutics, and is selected from tablets, capsules and pills.