CN112724142A - Antidepressant theophylline derivative and preparation method thereof - Google Patents
Antidepressant theophylline derivative and preparation method thereof Download PDFInfo
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- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
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Abstract
The invention discloses an antidepressant theophylline derivative and a preparation method thereof, belonging to the technical field of drug synthesis and organic compound preparation, wherein the preparation method comprises the following steps: using theophylline as a raw material, adding 4- (alpha-chlorobenzyl) biphenyl into an organic solvent, using alkali as a catalyst, carrying out reflux reaction at the temperature of 80-120 ℃ for 6-10 h, purifying by using a silica gel column, and recrystallizing by using absolute ethyl alcohol to obtain a theophylline derivative; pharmacodynamic studies show that the theophylline derivative can obviously shorten the immobility time of tail suspension of a mouse and the immobility time of forced swimming of the mouse, has good anti-depression activity, and can be used for preparing anti-depression drugs or foods; the preparation method provided by the invention is simple, mild in reaction condition, environment-friendly and easy to realize industrial production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis and organic compound preparation, and relates to an antidepressant theophylline derivative and a preparation method thereof.
Background
Theophylline is white amorphous crystalline alkaloid contained in tea, is theobromine isomer, has the action and the structure similar to those of caffeine, and has the effects of enhancing memory, easing mind and exciting central nervous system according to the research of alkali compounds contained in tea leaves. However, the treatment concentration of theophylline is only 6-15 mug/mL, once the concentration exceeds 15 mug/mL, a poisoning phenomenon occurs, the poisoning phenomenon can affect a vascular system, a digestive system and the like, and theophylline poisoning does not have a special detoxification therapy. Therefore, in order to utilize the biological activity of theophylline more efficiently and safely, it is necessary to modify the structure thereof.
Disclosure of Invention
In order to solve the technical problems, the invention provides an antidepressant theophylline derivative, which has a molecular structure shown in formula (I):
another object of the present invention is to provide a method for preparing an antidepressant theophylline derivative, comprising the steps of:
(1) removing water in a reaction vessel, setting the atmosphere of the reaction vessel as an inert gas environment, dissolving theophylline serving as a raw material in an organic solvent, adding 4- (alpha-chlorobenzyl) biphenyl, taking alkali as a catalyst, performing reflux reaction at the temperature of 80-120 ℃ for 6-10 h, cooling a reaction solution to room temperature after the reaction is finished, distilling the organic solvent, performing multiple extraction, sequentially washing with hydrochloric acid, saturated salt water and water, drying with anhydrous sodium sulfate, distilling the extraction solvent, and concentrating to obtain a crude product of the theophylline derivative;
(2) taking a mixed solution composed of petroleum ether and ethyl acetate as an eluent, separating and purifying the crude product obtained in the step (1) by silica gel column chromatography, collecting eluent, concentrating the eluent under reduced pressure, and recrystallizing with absolute ethyl alcohol to obtain a theophylline derivative;
the molar ratio of the theophylline to the 4- (alpha-chlorobenzyl) biphenyl is 1: 1.0-1: 4.5;
the organic solvent is benzene, toluene, dichloromethane, n-butyl ether, diethyl ether, petroleum ether, methyl tert-butyl ether, diethyl ether, 1, 4-dioxane, acetone, acetonitrile, n-hexane or cyclohexane;
the alkali is sodium hydride, potassium carbonate, sodium carbonate, potassium phosphate, monopotassium phosphate, sodium hydroxide, calcium hydroxide, ammonia water, triethylamine or pyridine;
the volume ratio of the petroleum ether to the ethyl acetate is 10-50: 1.
According to a preferred embodiment of the above preparation method, the method comprises the following steps:
(1) removing water in a reaction vessel, setting the atmosphere of the reaction vessel as an inert gas environment, dissolving 20g of theophylline serving as a raw material in a toluene solution, adding 30.9g of 4- (alpha-chlorobenzyl) biphenyl, taking sodium hydride as a catalyst, carrying out reflux reaction at the temperature of 120 ℃ for 10 hours, cooling a reaction solution to room temperature after the reaction is finished, distilling an organic solvent, extracting for multiple times, sequentially washing with hydrochloric acid, saturated salt water and water, drying with anhydrous sodium sulfate, distilling an extraction solvent, and concentrating to obtain a crude product of the theophylline derivative;
(2) and (2) taking a mixed solution composed of petroleum ether and ethyl acetate as an eluent, wherein the volume ratio of the petroleum ether to the ethyl acetate is 50:1, separating and purifying the crude product obtained in the step (1) by silica gel column chromatography, collecting the eluent, concentrating the eluent under reduced pressure, and recrystallizing with absolute ethyl alcohol to obtain the theophylline derivative.
Compared with the prior art, the invention has the beneficial effects that:
the invention eliminates the biotoxicity of theophylline by structural modification, and obtains a theophylline derivative with a novel structure; the compound has a brand new molecular structure different from the existing antidepressant compound, and experiments prove that the compound has good antidepressant activity, has no obvious toxic or side effect, is beneficial to large-scale popularization and utilization in marketization, and has wide application prospect.
Drawings
FIG. 1: nuclear magnetic resonance hydrogen spectrum of antidepressant theophylline derivative of example 1.
Detailed Description
The present invention will be described in further detail with reference to specific embodiments for the purpose of making the objects, technical solutions and advantages of the present invention more apparent, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following examples.
Example 1
(1) Removing water in a reaction vessel, setting the atmosphere of the reaction vessel as an inert gas environment, taking 20g of theophylline as a raw material, dissolving the theophylline in 100mL of toluene solution, adding 30.9g of 4- (alpha-chlorobenzyl) biphenyl, taking 11.5g of sodium hydride as a catalyst, carrying out reflux reaction at the temperature of 120 ℃ for 10 hours, cooling a reaction solution to room temperature after the reaction is finished, distilling an organic solvent, extracting for multiple times, sequentially washing with hydrochloric acid, saturated salt water and water, drying anhydrous sodium sulfate, distilling an extraction solvent, and concentrating to obtain a crude product of the theophylline derivative;
(2) and (2) taking a mixed solution composed of petroleum ether and ethyl acetate as an eluent, wherein the volume ratio of the petroleum ether to the ethyl acetate is 50:1, separating and purifying the crude product obtained in the step (1) by silica gel column chromatography, collecting the eluent, concentrating the eluent under reduced pressure, and recrystallizing with absolute ethyl alcohol to obtain the theophylline derivative. The yield was 79.48%.
And (3) nuclear magnetic resonance hydrogen spectrum detection:
the sample was placed in a sample tube, and 0.5ml of DCL3 (deuterated chloroform) was injected into the sample tube with a syringe to dissolve the sample sufficiently. The sample and the reagent are required to be fully mixed, the solution is clear and transparent, and has no suspended matters or other impurities, and a nuclear magnetic resonance hydrogen spectrogram is obtained through nuclear magnetic resonance identification, and the result is shown in figure 1.
EXAMPLE 2 pathological Studies of Compounds of the invention
1. Protective effect of compound of the invention on corticosterone-induced PC12 cell damage
PC12 cells were prepared in a cell count of 2X 10/ml using DMEM medium containing 10% fetal bovine serum5The suspension of (4) was inoculated into a 96-well plate at 100. mu.L per well, and then charged with 5% CO at 37 ℃2Culturing in an incubator, after incubation for 24h, sucking cell liquid after cells grow to the bottom of a hole, and adding a serum-free culture medium into a blank group (a control group 1); model group (control group 2) was added with a solution containing 4X 10-4M corticosterone serum-free medium; the experimental groups were 7 groups, each containing 4X 10-4Adding 0.01, 0.1, 1.0, 1.1, 13, 1.5 and 1.7g/L theophylline derivative serum-free culture medium into the M corticosterone; the positive drug group (control group 3) contained 4X 10-4M corticosterone with 1X 10 amitriptyline added-5mol/L serum-free medium. After 48h of incubation, adding 10 mu L of MTT solution into each well, continuously culturing for 4h, absorbing the supernatant by using a pipette, then adding 100 mu L of DMSO into each well, placing on an oscillator, oscillating until crystals are completely dissolved, measuring the light absorption value of each well by using a microplate reader at the wavelength of 570nm, and calculating the cell survival rate, wherein the calculation result is shown in table 1.
TABLE 1 Theline derivatives protective action against corticosterone injury PC12 cells
The data in table 1 show that compared with the normal group, the absorbance value of the model group PC12 cell is significantly lower than that of the normal control group, indicating that the modeling is successful; after the positive medicament and the theophylline derivative are administered, the absorbance values are increased to different degrees, wherein when the concentration of the theophylline derivative is 1.1g/L, the absorbance value is relatively highest, the cell survival rate is highest and reaches 85.26%, and the cell survival rate is higher than that of the positive medicament (83.05%), which indicates that the theophylline derivative has better biological activity.
2. Antidepressant in vivo pharmaceutical experiments
(1) Tail suspension experiment of mice
Healthy mice are selected, freely ingest and drink water, and are randomly divided into a blank control group (a control group 1), a positive drug amitriptyline group (a control group 2) and a theophylline derivative group (an experimental group) at room temperature (22 +/-2 ℃). After the mice are fed with the feed for 60min, the tail part of the mouse, which is 2cm away from the tail end, is fixedly suspended in a box of 20cm multiplied by 25cm, the head part of the mouse, which is about 10cm away from the bottom of the box, is suspended for 6min, and the immobility time within 4min is accumulated. Judging the immobilization standard: the mouse stops struggling in the air, and the body is in a vertical overhang shape and is still.
(2) Forced swimming test for mice
Healthy mice are selected, freely ingest and drink water, and are randomly divided into a blank control group (a control group 1), a positive drug amitriptyline group (a control group 2) and a theophylline derivative group (an experimental group) at room temperature (22 +/-2 ℃). Feeding mice for 60min, placing into a cylindrical glass jar with height of 20cm and diameter of 10cm, one jar at water depth of 10cm and water temperature of 25 deg.C, observing for 6min, and accumulating the standing time within 4 min. And (3) judging the immobility standard: the mouse stopped struggling in the water, or was floating, with only minor limb movements to keep the head floating on the water.
TABLE 2 Effect of theophylline derivatives on immobility time in forced swimming and tail suspension in mice
The experimental results in Table 2 show that the immobility time in forced swimming and the immobility time in tail suspension of the mice are reduced after the positive drug and the theophylline derivative are administered compared with the blank control group, and when the dosage of the theophylline derivative is 110mg/kg, the immobility time in forced swimming and the immobility time in tail suspension of the mice are relatively shortest, namely 70.20 +/-27.26 s and 56.10 +/-28.30 s respectively, which are equivalent to the positive drug. It is demonstrated that the theophylline derivatives of the present invention have relatively good biological activity.
(3) Rat forced swimming experiment
Healthy rats are selected to freely eat and drink water, and are randomly divided into a blank control group (a control group 1), a positive drug amitriptyline group (a control group 2) and a theophylline derivative group (an experimental group) at room temperature (22 +/-2). On the 1 st day of the experiment, each rat was taken out after pre-swimming for 15min, wiped dry and placed in a cage, and the experiment was performed 24h later. Feeding rat for 60min, placing into glass jar with inner diameter of 20cm and height of 40cm, water depth of 24cm, water temperature of 28-29 deg.C, and accumulating the immobile time of rat in water for 5min, wherein the immobile time is determined by floating the rat on water surface and only performing micro action of maintaining body balance and exposing head.
TABLE 3 Effect of theophylline derivatives on the immobility time of forced swimming in rats
As shown in the data in Table 3, the immobility time of the rats decreased after the administration of the positive drug and the theophylline derivative compared to the blank control group, and was relatively shortest when the dose of the theophylline derivative was 120mg/kg, which was 75.67. + -. 33.48s, respectively, and was equivalent to the positive drug. It is demonstrated that the theophylline derivatives of the present invention have relatively good biological activity.
3. Preliminary acute toxicity test of the Compound of the present invention
20 SPF mice were selected, randomly divided into two groups, and fasted for 12h before the experiment. The oral administration group is prepared by ultrapure water, the maximum dissolving amount is 1.5mg/mL, and the oral administration group is administrated by feeding for 4 times in 24h, each time is 0.3mL/10g of body weight, and the total amount is 110 mg/kg. The intraperitoneal injection group is prepared by normal saline, the maximum dissolving amount is 1.0mg/mL, and the drug is administrated by feeding 4 times in 24h, 0.3mL/10g body weight each time, and the total amount is 110 mg/kg. After the administration, the mice were observed for a toxic reaction for 7 consecutive days.
The experimental result shows that when the theophylline derivative is administrated by feeding and intraperitoneal injection at 110mg/kg, the state of the mouse is good, the weight is stably increased, and no obvious toxic or side effect is seen.
Claims (3)
1. An antidepressant theophylline derivative having the molecular structure of formula (I):
2. a preparation method of an antidepressant theophylline derivative is characterized by comprising the following steps:
(1) removing water in a reaction vessel, setting the atmosphere of the reaction vessel as an inert gas environment, dissolving theophylline serving as a raw material in an organic solvent, adding 4- (alpha-chlorobenzyl) biphenyl, taking alkali as a catalyst, performing reflux reaction at the temperature of 80-120 ℃ for 6-10 h, cooling a reaction solution to room temperature after the reaction is finished, distilling the organic solvent, performing multiple extraction, sequentially washing with hydrochloric acid, saturated salt water and water, drying with anhydrous sodium sulfate, distilling the extraction solvent, and concentrating to obtain a crude product of the theophylline derivative;
(2) taking a mixed solution composed of petroleum ether and ethyl acetate as an eluent, separating and purifying the crude product obtained in the step (1) by silica gel column chromatography, collecting the eluent, concentrating the eluent under reduced pressure, and recrystallizing with absolute ethyl alcohol to obtain the theophylline derivative;
the molar ratio of the theophylline to the 4- (alpha-chlorobenzyl) biphenyl is 1: 1.0-1: 4.5;
the organic solvent is benzene, toluene, dichloromethane, n-butyl ether, diethyl ether, petroleum ether, methyl tert-butyl ether, diethyl ether, 1, 4-dioxane, acetone, acetonitrile, n-hexane or cyclohexane;
the alkali is sodium hydride, potassium carbonate, sodium carbonate, potassium phosphate, monopotassium phosphate, sodium hydroxide, calcium hydroxide, ammonia water, triethylamine or pyridine;
the volume ratio of the petroleum ether to the ethyl acetate is 10-50: 1.
3. The process for preparing the antidepressant theophylline derivative according to claim 2, characterized in that it comprises the following steps:
(1) removing water in a reaction vessel, setting the atmosphere of the reaction vessel as an inert gas environment, dissolving 20g of theophylline serving as a raw material in a toluene solution, adding 30.9g of 4- (alpha-chlorobenzyl) biphenyl, taking sodium hydride as a catalyst, carrying out reflux reaction at the temperature of 120 ℃ for 10 hours, cooling a reaction solution to room temperature after the reaction is finished, distilling an organic solvent, extracting for multiple times, sequentially washing with hydrochloric acid, saturated salt water and water, drying with anhydrous sodium sulfate, distilling an extraction solvent, and concentrating to obtain a crude product of the theophylline derivative;
(2) and (2) taking a mixed solution composed of petroleum ether and ethyl acetate as an eluent, wherein the volume ratio of the petroleum ether to the ethyl acetate is 50:1, separating and purifying the crude product obtained in the step (1) by silica gel column chromatography, collecting the eluent, concentrating the eluent under reduced pressure, and recrystallizing absolute ethyl alcohol to obtain the theophylline derivative.
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Cited By (2)
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| CN112876469A (en) * | 2021-01-19 | 2021-06-01 | 籍建亚 | Lupine derivative with effects of relieving cough and reducing phlegm and preparation method thereof |
| CN113173895A (en) * | 2021-05-12 | 2021-07-27 | 籍建亚 | Andrographolide derivative for resisting influenza virus infection and preparation method thereof |
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Application publication date: 20210430 |