RELATED APPLICATIONS

The instant application is related to Chinese Patent Application, 201811622426.5, filed on Dec. 28, 2018, which is incorporated herein by reference.

FIELD OF THE INVENTION

The present disclosure relates to the field of drug preparation and in particular relates to melatonin derivatives, a method thereof, and a use thereof.

BACKGROUND OF THE INVENTION

Melatonin (also known as N-acetyl-5-methichylamine) is an amine hormone produced by pineal glands of animals and humans and has a wide range of effects on the body. It can maintain the circadian rhythm, assist with sleep, enhance human immunity, assist with anti-aging, inhibit tumor growth, inhibit psychiatric diseases, provide vascular protection, and perform other functions. Melatonin is also an ancient pyridine plant hormone that plays an important role in plant growth regulation and resistance to harsh environments. Melatonin also has a powerful antioxidant function and can be used as a cosmetic skin care product. Studies have shown that melatonin is one of the least toxic substances, and human experiments have shown that taking up to a few grams a day for up to a month has almost no toxic side effects. Therefore, melatonin has attracted more and more attention from researchers. However, due to its molecular characteristics, its water solubility in water is extremely low, which greatly limits its medicinal efficacy. Due to its low water solubility, melatonin cannot be dissolved well in water during the preparation of drugs and plant growth regulators, and it can only be dissolved in organic solvents. Organic solvents increase the toxicity and side effects of melatonin. Moreover, due to the low water solubility of melatonin and its high fat solubility, it quickly penetrates the blood-brain barrier and stays in the blood in the brain for only a short period of time, affecting its efficacy. In studying the effects of melatonin on animals and humans, researchers also need to dissolve melatonin in water, which has limited its progress due to its low water solubility.

SUMMARY OF THE INVENTION

The present disclosure provides melatonin derivatives, a method thereof, and a use thereof to solve deficiencies of the existing techniques, greatly improving water solubility of melatonin.

The present disclosure provides melatonin derivatives having chemical structures as follows:



R1is —(CH2)n— or —CHO—(CH2)n-1—, n=0-4.

R2is one selected from —SO3Na, —CO2Na, —OH, —SO3H, or —CO2H.

The present disclosure further provides a method for preparing melatonin derivatives having chemical structures as follows:



R1is —(CH2)n— or —CHO—(CH2)n-1—, n=0-4.

R2is selected from —SO3Na, —CO2Na, —OH, —SO3H, or —CO2H.

The method comprises: dissolving melatonin in a solvent, adding a catalyst while maintaining the solvent at 0° C. to obtain a first reaction solution, stirring the first reaction solution, adding reactants in the first reaction solution, continually stirring at room temperature (e.g., 20-25° C.) or at refluxing reaction temperature (e.g., 50-80° C.) until, when analyzing by thin layer chromatography, the first reaction solution is fully reacted, quenching the reaction with ice water, concentrating the first reaction solution to obtain a residue of the first reaction solution, and purifying the residue of the first reaction solution by column chromatography to obtain the melatonin derivatives. The reactants are at least one selected from 1-4 butyrolactone, 1-3 propane sultone, sodium bromoethylsulfonate, sodium bromomethylsulfonate.

In a preferred embodiment, the solvent is at least one selected from tetrahydrofuran or acetonitrile.

In a preferred embodiment, the catalyst is at least one selected from sodium hydride or sodium carbonate.

The present disclosure further provides a method for preparing melatonin derivatives having chemical structures as follows:



R1is —(CH2)n— or —CHO—(CH2)n-1—, n=0-4.

R2is selected from —SO3Na, —CO2Na, —OH, —SO3H, or —CO2H.

The method comprises: dissolving melatonin in a solvent, adding a catalyst while maintaining the solvent at 0° C. to obtain a first reaction solution, stirring the first reaction solution, adding reactants in the first reaction solution, continually stirring at room temperature (e.g., 20-25° C.) or at refluxing reaction temperature (e.g., 50-80° C.) until, when analyzing by thin layer chromatography, the first reaction solution is fully reacted, quenching the reaction with ice water, concentrating the first reaction solution to obtain a residue of the first reaction solution, purifying the residue of the first reaction solution by column chromatography, adding alcohol and an alkali to the residue of the first reaction solution to obtain a second reaction solution, stirring the second reaction solution and reacting at room temperature (e.g., 20-25° C.), rotary evaporating the second reaction solution, and purifying a residue of the second reaction solution by the column chromatography to obtain the melatonin derivatives. The reactants is at least one selected from chlorosulfonic acid, ethyl bromoacetate, ethyl 3-bromopropionate, ethyl 4-bromobutyrate, ethyl 5-bromovalerate, glutaric anhydride, succinic anhydride, or ethyl malonyl chloride.

In a preferred embodiment, the solvent is at least one selected from dichloromethane or N,N-dimethylformamide.

In a preferred embodiment, the catalyst is at least one selected from 4-Dimethylaminopyridine or triethylamine.

The present disclosure further provides a use of the melatonin derivatives in a preparation of a sleep aid drug, an enhancing human immunity drug, an anti-aging drug, an anti-tumor drug, an anti-psychiatric disease drug, a vascular protection drug, or a plant growth promoter.

The present disclosure further provides a method, the method comprises: using the melatonin derivatives for treating a sleep deficiency, enhancing human immunity, treating aging, mitigating tumor growth, treating an anti-psychiatric disease, improving vascular protection, or improving plant growth.

Compared with existing techniques, the technical solution provided by the present disclosure has the following advantages.

The present disclosure provides for a melatonin derivative, prepared according to a method provided by the present disclosure, having water solubility that is nearly 700 times higher than that of melatonin, thereby avoiding toxicity and side effects caused by the use of organic solvents to dissolve melatonin during preparation of a drug.

Because the melatonin derivative is highly water-soluble, its fat solubility is low, thereby prolonging its residence time in the brain blood and increasing its efficacy. Researchers can easily dissolve the melatonin derivative in water for further research, which facilitates research work.

The melatonin derivative prepared by the present disclosure has almost the same physiological functions as melatonin (for example, treating a sleep deficiency, etc.) and can be applied to industries such as agriculture, cosmetics and medicine, and therefore has broad application prospects.

