CN106188099B

CN106188099B - 1, 4-thiazepine derivative and synthetic method thereof

Info

Publication number: CN106188099B
Application number: CN201610575778.4A
Authority: CN
Inventors: 张崇; 彭秋菊; 孙广飞; 倪冬喧; 朱十伟
Original assignee: Xinxiang Medical University
Current assignee: Xinxiang Medical University
Priority date: 2016-07-21
Filing date: 2016-07-21
Publication date: 2021-05-07
Anticipated expiration: 2036-07-21
Also published as: CN106188099A

Abstract

The invention provides a 1, 4-thiazepine derivative and a synthetic method thereof. The method comprises the steps of uniformly mixing sesamin, 3-bromo-4-methoxybenzaldehyde, thioglycolic acid and p-toluenesulfonic acid in the amount of a catalyst, heating and stirring, controlling the temperature at 120-. The 1, 4-thiazepine derivative of the invention introduces 3-bromo-4-methoxyphenyl and methylenedioxy structures, so that the derivative has stronger activity and is more beneficial to absorption. The method has the characteristics of environmental protection, easily obtained raw materials, simple operation and high yield.

Description

1, 4-thiazepine derivative and synthetic method thereof

Technical Field

The invention relates to a 1, 4-thiazepine derivative, in particular to a 9- (3-bromo-4-methoxy-phenyl) -5, 9-dihydro-1, 3-dioxa-8-thia-5-aza cyclohepta [ alpha ], [ alphaf]Indan-6-one.

Background

In recent years, the incidence and mortality of cancer have increased year by year, which seriously threatens human health and life, and the development and research of novel effective antitumor drugs are important subjects and long-term tasks in the field of biomedical research.

The 1, 4-sulfur nitrogen compound is an important seven-membered heterocyclic compound, which is widely existed in natural products and drug molecules and has various biological activities of cancer resistance, anti-inflammation, antibiosis, antioxidation and the like.

Methylenedioxy is widely distributed in natural active substances, such as piperine, cepharanthine, sanguinarine, narasin, etc. The existence of a methylene dioxy structural unit is the key of a plurality of natural and synthetic drugs with certain pharmacological activity, and the combination of the methylene dioxy and 1, 4-thiazepine can obviously increase the activity of the compound.

Due to its unique physical, chemical and biological properties, bromine-containing organic compounds, such as bromhexine hydrochloride, ambroxol hydrochloride, benzbromarone, scopolamine butylbromide, are used in many drugs.

The innovation point of the invention is that a 4-thiazepine derivative containing bromine atoms and methylene dioxy structures is synthesized, the compound is not reported at present, and the compound has stronger anticancer activity through preliminary pharmacological activity determination.

Disclosure of Invention

The invention aims to provide a novel 4-thiazepine derivative.

The invention also aims to provide a synthetic method of the compound.

To achieve the object of the present invention, the 4-thiazepine derivative of the present invention is a compound having a structure represented by formula I:

I。

specifically, the 9- (3-bromo-4-methoxy-phenyl) -5, 9-dihydro-1, 3-dioxa-8-thia-5-azacyclohepta [ 2 ], [ of the present inventionf]Indan-6-one of the formula: c₁₇H₁₄BrNO₄S, molecular weight: 406.98, appearance: light yellow solid, melting point: 219-221.

The synthesis method of the 1, 4-thiazepine derivative comprises the steps of firstly uniformly mixing sesamin, 3-bromo-4-methoxybenzaldehyde, thioglycolic acid and p-toluenesulfonic acid with the amount of a catalyst, heating and stirring, controlling the temperature at 120 ℃ and 130 ℃, reacting for 2-3 hours, dissolving a reaction mixture with dichloromethane after reaction, washing twice with water, drying with anhydrous sodium sulfate, evaporating the solvent, and recrystallizing a crude product with a mixed solvent of ethanol and acetone to obtain the compound as claimed in claim 1.

The reaction formula is as follows:

the in vitro cytotoxicity test of the 1, 4-thiazepine derivative shows that the compound has stronger inhibiting effect on tested cancer cells and can be further developed as an anti-cancer medicament or a lead compound.

The synthesis method adopts a solvent-free one-step synthesis method, and has the characteristics of environmental protection, easily obtained raw materials, simple operation and high yield.

Detailed Description

The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.

Example 1

1.37 g of sesamin, 2.14 g of 3-bromo-4-methoxybenzaldehyde, 0.91 g of thioglycolic acid and 0.17 g of p-toluenesulfonic acid were put together in a 25 ml reaction flask and mixed uniformly, heated and stirred, the temperature was controlled at 120 ℃, and after 2 hours of reaction, the reaction was carried out. The reaction mixture was dissolved in 25 ml of dichloromethane, washed twice with 25 ml of water, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and recrystallized from a mixed solvent of ethanol and acetone to give the corresponding pale yellow product 9- (3-bromo-4-methoxy-phenyl) -5, 9-dihydro-1, 3-dioxa-8-thia-5-azacyclohepta [ 2 ]f]Indan-6-one 1.47 g, yield 36.2%.

Through detection, the molecular formula is as follows: c₁₇H₁₄BrNO₄S, molecular weight: 406.98, appearance: light yellow solid, melting point: 219- > 221;¹H NMR (400 MHz, Dmso-d₆) δ: 9.36 (s, 1H), 7.65 (d, 1H，J = 2.0 Hz), 7.48-7.46 (m, 1H), 7.15 (d, 2H，J = 8.4 Hz), 6.62 (s, 1H), 6.46 (s, 1H), 6.02 (d, 2H, J= 8.4 Hz), 5.53 (s, 1H)，3.87(s, 3H)，2.93 (d, 1H, J = 12.0 Hz); ¹³C NMR (100 MHz, Dmso-d₆) δ: 169.2, 161.0, 147.3，146.0,140.6,131.7,127.4, 107.6，107.5,105.5,102.1,100.1, 55.7，47.4, 31.2；IR(KBr):2928, 1671, 1155, 728 cm^-1; HRMS-ESI (m/z): calcd for C₁₇H₁₄BrNO₄S [M+Na]⁺406.9827, found: 431.9695.

example 2

6.85 g of sesamin, 11.77 g of 3-bromo-4-methoxybenzaldehyde, 4.55 g of thioglycolic acid and 0.85 g of p-toluenesulfonic acid are put together in a 50 ml reaction bottle and uniformly mixed, heated and stirred, the temperature is controlled at 120 ℃, and the reaction is carried out for 2 hours. The reaction mixture was dissolved in 150 ml of dichloromethane, washed twice with 150 ml of water, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and recrystallized from a mixed solvent of ethanol and acetone to give the corresponding pale yellow product 9- (3-bromo-4-methoxy-phenyl) -5, 9-dihydro-1, 3-dioxa-8-thia-5-azacyclohepta [ 2 ]f]Indan-6-one 6.71 g, yield 32.9%.

Example 3

13.7 g of sesamin, 25.68 g of 3-bromo-4-methoxybenzaldehyde, 9.1 g of thioglycolic acid and 1.7 g of p-toluenesulfonic acid are put together in a 100 ml reaction bottle and mixed uniformly, heated and stirred, the temperature is controlled at 130 ℃, and after reaction for 3 hours. The reaction mixture was dissolved in 250 ml of dichloromethane, washed twice with 250 ml of water, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and recrystallized from a mixed solvent of ethanol and acetone to give the corresponding pale yellow product, 9- (3-bromo-4-methoxy-phenyl) -5, 9-dihydro-1, 3-dioxa-8-thia-5-azacycloheptane [, [ 2 ]f]Indan-6-one 13.63 g, yield 33.5%.

Antitumor Activity test

The MTT method is adopted to test the antitumor activity of the target compound. Using human esophagus cancer cell Ec9706 as test cell strain, selecting adherent tumor cell in logarithmic growth phase, and trypsinizingAfter the transformation, a 5000/mL cell suspension was prepared in 10% calf serum-containing RPMI L640 medium and inoculated into 96-well plates at 37 ℃ in a volume of 200. mu.L per well and 5% CO₂And culturing for 24 h. Setting up a negative control group, a positive control group and an administration group. The experimental group is replaced by new culture medium containing samples to be tested with different concentrations, the control group is replaced by culture medium containing equal volume of solvent, and the positive control group is given positive control drug of ultraviolet triol (diluted to 10 mu mol. L with complete culture medium)^{- 1}) Each group is provided with 3-5 parallel holes at 37 ℃ and 5% CO₂Culturing for 4-5 days. The supernatant was discarded and 200. mu.L of freshly prepared serum-free medium containing 0.2 mg/mL MTT was added to each well. The culture was continued at 37 ℃ for 4 h. The supernatant was carefully discarded, 200. mu.L of DMSO was added, and after mixing well with a micro ultrasonic oscillator, the optical density was measured on a microplate reader at a test wavelength of 570 nm and a reference wavelength of 450 nm. The inhibition rate of the drug on the growth of tumor cells was calculated according to the following formula: tumor cell growth inhibition ═ 1-OD assay/OD control) × 100%. Is prepared from 9- (3-bromo-4-methoxy-phenyl) -5, 9-dihydro-1, 3-dioxa-8-thia-5-aza-cyclohepta [ 2 ], [ 2 ]f]Plotting different concentrations of indan-6-one on the tumor cell growth inhibition rate can obtain a dose response curve, and calculating the half killing concentration IC of the sample₅₀. IC thereof₅₀The value was 8.23. mu.M.

Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.

Claims

1. A1, 4-thiazepine derivative has the following structural formula:

。

2. a synthetic method for preparing the compound of claim 1, which comprises the steps of uniformly mixing sesamin, 3-bromo-4-methoxybenzaldehyde, thioglycolic acid and p-toluenesulfonic acid in the amount of a catalyst, heating and stirring, controlling the temperature at 120 ℃ and 130 ℃, reacting for 2-3 hours, dissolving the reaction mixture with dichloromethane after the reaction, washing twice with water, drying with anhydrous sodium sulfate, evaporating the solvent, and recrystallizing the crude product with a mixed solvent of ethanol and acetone to obtain the compound of claim 1, wherein the molar ratio of the sesamin to the 3-bromo-4-methoxybenzaldehyde to the thioglycolic acid is 1: 1-1.2: 1.