CN109734682B

CN109734682B - Cyclic alkenylimine medical intermediate, preparation method and application thereof as medicament for inhibiting growth of cancer cells

Info

Publication number: CN109734682B
Application number: CN201910120144.3A
Authority: CN
Inventors: 王龙; 徐文恒; 胡为民; 黄年玉
Original assignee: China Three Gorges University CTGU
Current assignee: China Three Gorges University CTGU
Priority date: 2019-02-18
Filing date: 2019-02-18
Publication date: 2022-10-21
Anticipated expiration: 2039-02-18
Also published as: CN109734682A

Abstract

The invention provides a cyclic alkenylimine medical intermediate, a preparation method and an inhibitory activity of the cyclic alkenylimine medical intermediate on the growth of cancer cells. The general formula is as follows

In the formula R ¹ Is n-butyl, tert-butyl, phenyl, cyclohexyl or benzyl, R ² Is alkyl such as methyl, ethyl, isopropyl, n-hexyl and the like, aryl such as phenyl, substituted phenyl and the like or heteroaryl. R is ³ Is alkyl such as methyl, ethyl, isopropyl, n-hexyl, etc., aryl such as phenyl, substituted phenyl, etc., or heteroaryl. The position and the number of the substituent groups are not fixed. The preparation method comprises the steps of substituting an alpha-phosphinimine for an acrolein derivative, an acid and an isonitrile, reacting in a solvent of anhydrous 1, 2-dichloroethane, removing the solvent under reduced pressure after the reaction is finished, and carrying out column chromatography on residues to obtain the target compound shown in the general formula (I). The invention provides a novel efficient synthesis method to synthesize a class of cyclic alkenylene imine derivatives, and the derivatives show certain inhibitory activity to human liver cancer cells HepG-2 and lung cancer cells A549-1, thereby being beneficial to being applied as medicines.

Description

Cyclic alkenylimine medical intermediate, preparation method and application thereof as medicament for inhibiting growth of cancer cells

Technical Field

The invention relates to a cyclic alkenylimine medical intermediate, a preparation method and an inhibitory activity of the cyclic alkenylimine medical intermediate on the growth of cancer cells.

Background

In recent years, cancer has gradually become the first enemy of human health, and cancer treatment has been receiving attention. In the treatment of cancer, drug therapy is an important link, and the use of effective anti-cancer drugs can help patients to obtain longer survival time and hold the hope of survival. Currently, only about 150 anticancer drugs are approved to be on the market in various countries around the world. Because of the variety of cancers and the shortage of the types of drugs, the research and development of more novel anticancer drug molecules with better curative effect is urgent. In the patent, a class of cyclic alkenylimine medical intermediates with novel structures is prepared. The medical intermediate has certain inhibition effect on the growth of two cancer cells, namely human liver cancer cell HepG-2 and lung cancer cell A549-1.

Disclosure of Invention

The invention mainly aims to provide a cyclic alkenylimine medical intermediate, a preparation method and anticancer activity thereof.

The invention provides a cyclic alkenylimine medical intermediate (I):

wherein R in the formula ¹ Is n-butyl, tert-butyl, phenyl, cyclohexyl or benzyl, R ² Is alkyl such as methyl, ethyl, isopropyl, n-hexyl and the like, aryl such as phenyl, substituted phenyl and the like or heteroaryl. R ³ Is alkyl such as methyl, ethyl, isopropyl, n-hexyl, etc., aryl such as phenyl, substituted phenyl, etc., or heteroaryl. The position and the number of the substituent groups are not fixed.

The preparation method for synthesizing the cyclic alkenylimine medical intermediate comprises the following synthetic route:

the method specifically comprises the following steps:

mixing alpha-phosphinimine substituted acrolein derivative with acid and isonitrile according to a molar ratio of 1:0.1-3:0.1 to 3 are added into a flask filled with anhydrous 1, 2-dichloroethane in sequence, and reacted at 30 ℃ for 6 to 48 hours, after the reaction is finished, the solvent is removed under reduced pressure, and the residue is subjected to column chromatography to obtain the cyclic alkenyl imine compound 4 with the general formula (I).

The invention has the following beneficial effects:

1. the invention reports a novel cyclic alkenylimine medical intermediate;

2. the invention provides a preparation method of a novel cyclic alkenylimine medical intermediate.

3. The invention synthesizes a novel cyclic alkenylimine medical intermediate, and the alkenylimine structure has certain P-pi conjugation effect and pi-pi accumulation effect on metal ions at the centers of targets of human liver cancer cells HepG-2 and lung cancer cells A549-1, so that the compound has certain inhibition effect on the conventional growth of two cancer cells, and is worthy of further research and development.

Detailed Description

The following examples are included to further illustrate the preparation and utility of the compounds of formula (I) of this invention.

Instruments and reagents:

the melting point was measured by an X4 type melting point apparatus (manufactured by Beijing, third Optic Instrument Co., ltd.), and the thermometer was not corrected; ¹ h NMR and ¹³ c NMR was measured using a Varian Mercury 400 model 400MHz NMR spectrometer or a Varian Mercury 600 model 600MHz NMR spectrometer using deuterated chloroform (CDCl) ₃ ) Or deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Is solvent, TMS is internal standard; MS was determined using a FinniganTrace mass spectrometer; elemental analysis was determined using a Vario EL III elemental analyzer; the reagent is chemically pure or analytically pure. The solvent toluene was dried by redistillation and triethylamine was treated by redistillation.

Example 1

Preparation of (2)

A50 mL flask was charged with t-butylisonitrile 1a (1.2 mmol), benzoic acid 2a (1.1 mmol) and α -phosphinimine-substituted cinnamaldehyde 3a (1.0 mmol) to react at 30 ℃ in a reaction solvent of 1, 2-dichloroethane (5 mL), and after 24 hours of reaction, the solvent of 1, 2-dichloroethane was removed under reduced pressure, and column chromatography of the residue gave 0.200g of the objective compound 4a in 60% yield.

¹ H NMR(CDCl ₃ ,600MHz)δ(ppm)8.12(d,J＝7.8Hz,2H),7.68(d,J＝7.2 Hz,2H),7.64(t,J＝7.2Hz,1H),7.51(t,J＝7.8Hz,2H),7.42-7.29(m,4H),6.15(s, 1H),6.06(s,1H),1.42(s,9H)；

¹³ C{ ¹ H}NMR(CDCl ₃ ,150MHz)δ(ppm)165.1,164.3,135.5,134.2,133.8, 129.8,129.3,129.0,128.8,128.7,128.1,118.3,78.8,51.9,28.6；

HRMS(ESI-TOF)m/z[M+H] ⁺ calcd for C ₂₁ H ₂₃ N ₂ O ₂ 335.1754；found 335.1757.

Example 2

A5 mL flask was charged with t-butylisonitrile 1a (0.12 mmol), benzoic acid 2a (0.11 mmol) and α -phosphinimine-substituted cinnamaldehyde 3a (0.10 mmol) to react at 30 ℃ in a reaction solvent of 1, 2-dichloroethane (0.5 mL), and after 24 hours of reaction, the solvent 1, 2-dichloroethane was removed under reduced pressure and column chromatography of the residue gave 0.022g of the objective compound 4a in 67% yield.

Example 3

To a 500mL flask were added tert-butylisonitrile 1a (12 mmol), benzoic acid 2a (11 mmol) and α -phosphinimine-substituted cinnamaldehyde 3a (10 mmol) and reacted at 30 ℃ in a reaction solvent of 1, 2-dichloroethane (50 mL), after 24 hours of reaction, the solvent of 1, 2-dichloroethane was removed under reduced pressure, and column chromatography of the residue gave 1.87g of the objective compound 4a in 56% yield.

Example 4

A50 mL flask was charged with t-butylisonitrile 1a (1.2 mmol), benzoic acid 2a (1.1 mmol), and α -phosphinimine-substituted cinnamaldehyde 3a (1.0 mmol) to react at 30 ℃ in a reaction solvent of 1, 2-dichloroethane (10 mL), and after 12 hours of the reaction, the solvent of 1, 2-dichloroethane was removed under reduced pressure, and the residue was subjected to column chromatography to give 0.117g of the objective compound 4a in 35% yield.

Example 5

Preparation of

A50 mL flask was charged with cyclohexyl isonitrile 1b (1.2 mmol), benzoic acid 2a (1.1 mmol) and α -phosphinimine substituted cinnamaldehyde 3a (1.0 mmol) and reacted at 30 ℃ with 1, 2-dichloroethane (5 mL) as the reaction solvent, after 24 hours of reaction, the solvent 1, 2-dichloroethane was removed under reduced pressure and column chromatography of the residue gave 0.198g of the title compound 4b in 55% yield.

Example 6

Preparation of

A50 mL flask was charged with t-butylisonitrile 1a (1.2 mmol), acetic acid 2c (1.1 mmol), and α -phosphinimine-substituted crotonaldehyde 3c (1.0 mmol) and reacted at 30 ℃ in the presence of 1, 2-dichloroethane (5 mL) as a reaction solvent, after 24 hours of reaction, the solvent 1, 2-dichloroethane was removed under reduced pressure, and column chromatography of the residue gave 0.101g of the title compound 4c in 48% yield.

Example 7

Preparation of

To a 50mL flask were added benzylisonitrile 1d (1.2 mmol), p-methylbenzoic acid 2d (1.1 mmol) and α -phosphinimine-substituted p-chlorocinnamaldehyde 3d (1.0 mmol) and reacted at 30 ℃ in the presence of 1, 2-dichloroethane (5 mL) as a reaction solvent, after 24 hours of reaction, the solvent 1, 2-dichloroethane was removed under reduced pressure and column chromatography of the residue gave 0.213g of the objective compound 4d in 51% yield.

Example 8

Experiment on anticancer Activity

TABLE 1 inhibitory Activity of Compounds 4a-4d against two cancer cells

As can be seen from the above Table 1, the compound represented by the formula (I) of the present invention has certain inhibitory effect on the growth of cancer cells, including hepatoma carcinoma cells HepG-2 and lung carcinoma cells A549-1. Among them, compound 4d is most effective. The reason is probably that the alkenylimine structure has certain P-pi conjugation effect and pi-pi conjugation accumulation effect on metal ions at the centers of target spots of two types of cancer cells, so that the normal growth and metabolism of the two types of cells are influenced, and a certain inhibition effect on the growth of the two types of cancer cells is shown.

The above-described embodiments are merely preferred technical solutions of the present invention, and should not be construed as limiting the present invention, and the embodiments and features in the embodiments in the present application may be arbitrarily combined with each other without conflict. The protection scope of the present invention is defined by the claims, and includes equivalents of technical features of the claims. I.e., equivalent alterations and modifications within the scope hereof, are also intended to be within the scope of the invention.

Claims

1. A cyclic alkenyl imine compound is characterized by having a structure expressed by a general formula (I):

2. the method for producing a cyclic alkenylimine compound according to claim 1, wherein the synthetic route is as follows:

the alpha-phosphinimine substituted acrolein derivative, acid and isonitrile are sequentially added into a container filled with anhydrous 1, 2-dichloroethane for reaction at 28-30 ℃ for 6-48 hours, after the reaction is finished, the solvent is removed under reduced pressure, and the residue is subjected to column chromatography to obtain the cyclic alkenyl imine compound 4 with the general formula (I), wherein the alpha-phosphinimine substituted acrolein derivative is any one of alpha-phosphinimine cinnamaldehyde, alpha-phosphinimine crotonaldehyde and alpha-phosphinimine substituted p-chlorocinnamaldehyde.

3. The method for preparing cyclic alkenyl imines compound of claim 2, wherein said isonitrile is any one of t-butyl isonitrile, n-butyl isonitrile, cyclohexyl isonitrile, phenyl isonitrile, or benzyl isonitrile.

4. The method of claim 2, wherein the acid is any one of benzoic acid, p-methyl-substituted benzoic acid, formic acid, and acetic acid.

5. The method for producing a cyclic alkenylimine compound according to claim 2, wherein the molar ratio of the α -phosphinimine-substituted acrolein derivative to the acid to the isonitrile fed is 1:0.1-3:0.1-3.

6. The application of the cyclic alkenyl imine compound in preparing the medicine for inhibiting the growth of human liver cancer cells HepG-2 and lung cancer cells A549-1 is characterized in that the structural formula of the compound is as follows: