KR20240123157A - Ascorbic acid derivatives combined with polyamine and method of preparation for the same - Google Patents

Abstract

The present invention relates to an ascorbic acid derivative having a polyamine of the following chemical formula (1), a stereoisomer thereof, a salt thereof, or a solvate thereof, and further relates to a cosmetic composition, a quasi-drug, a medical device, and a method for producing the same, including the derivative, etc.:
[Chemical Formula 1]
.

Description

{ASCORBIC ACID DERIVATIVES COMBINED WITH POLYAMINE AND METHOD OF PREPARATION FOR THE SAME}

The present invention relates to an ascorbic acid derivative having a polyamine of the following chemical formula (1), a stereoisomer thereof, a salt thereof, or a solvate thereof, and further relates to a cosmetic composition, a quasi-drug, a medical device, and a method for producing the same, including the derivative, etc.:

[Chemical Formula 1]

.

In particular, the present invention relates to a method for producing (3-O-carboxymethyl-polyamine)-(5,6-O-isopropyl)-L-ascorbic acid by protecting two hydroxyl groups at the 5,6-positions of ascorbic acid, introducing a carboxyl group at the 3-position, reacting the same with a polyamine derivative to obtain an intermediate (3-O-carboxymethyl-polyamine)-(5,6-O-isopropyl)-L-ascorbic acid, and then removing the isopropyl group and the Boc protecting group.

L-ascorbic acid (vitamin C) is known as one of the substances that is attracting attention in the cosmetics and pharmaceutical fields due to its useful functions for the skin, such as whitening effect, effect of restoring skin elasticity by promoting collagen synthesis in the dermis layer of the skin, and effect of eliminating harmful oxygen generated by ultraviolet rays, etc. Vitamin C, which is responsible for various roles mentioned above, has hydrophilicity due to the hydroxyl (-OH) groups located at carbons 2, 3, 5, and 6 of the molecule. In a neutral pH such as water, these hydroxyl groups, especially carbons 2 and 3, have negative charges, which allows them to dissolve quickly and completely in aqueous solutions, but in organic environments such as skin, which are not aqueous solutions, their solubility is limited. In addition, vitamin C does not dissolve well in organic solvents officially used in external preparations, such as glycerin, propylene glycol, and various fats, which limits the transport of vitamin C to the skin. That is, when vitamin C is not ionized, it easily passes through the skin barrier and is absorbed, but there is a limitation that the pH must be below 4.2 to maintain the non-ionic state.

As mentioned above, although vitamin C exhibits various effects, many studies have been conducted to improve its safety, stability, and skin absorption due to its low safety. Various derivatives such as palmitic acid ester, sulfuric acid ester, and phosphate ester have been synthesized and examined for the stabilization of L-ascorbic acid, but palmitic acid ester causes odor and discoloration over time, which greatly reduces its water solubility and antioxidant effect. Phosphate ester has been frequently used recently, but its antioxidant effect is low and its stability cannot be said to be safe. A compound that achieves both stability and antioxidant effect has not yet been developed. Accordingly, since the autooxidation of L-ascorbic acid is promoted by the dissociation of the hydroxyl group at the 3rd position, compounds in which the hydroxyl group at the 3rd position is selectively substituted with lower alkyl, lower carbonyl, or lower alkenyl have been studied.

Polyamines are organic compounds with two or more primary amino groups (-NH ₂ ). Polyamines that are found in large quantities in both eukaryotic and prokaryotic cells and that affect physiological functions are putrescine (H ₂ N(CH ₂ ) ₄ NH ₂ ), spermidine (NH ₂ (CH ₂ ) ₃ NH(CH ₂ ) ₄ NH ₂ ), and spermine (NH ₂ (CH ₂ ) ₃ NH(CH ₂ ) ₄ NH(CH ₂ ) ₃ NH ₂ ):

.

These polyamines are essential for cell growth from bacteria to mammals. The functions of polyamines are very diverse and play a role in regulating various intracellular pathways. That is, polyamines bind to RNA and regulate protein synthesis, and also interact with DNA and ATP and convert B-DNA to Z-DNA. Polyamine deficiency delays the cell cycle and affects apoptosis. In addition, intracellular spermine blocks ion channels and inhibits the rectification of inward K ⁺ channels. Since polyamines affect intracellular pathways in this way, malfunctions in their metabolism and function are linked to diseases. Polyamines are synthesized through highly regulated pathways, but their actual functions are very unclear. However, the clinical use of acrolein is very promising. Acrolein is produced when spermine is metabolized by spermine oxidase. Since acrolein is effectively produced when cells are damaged, it is a good marker for diseases related to cell damage. In patients with renal failure, putrescine and acrolein are increased. In addition, PC-Acro (protein conjugated acrolein) is significantly increased in patients with brain stroke. Therefore, acrolein can be used for diagnosis. Polyamines promote cell division and differentiation, accumulate in cancer tissues, and increase in concentration in the serum of cancer patients. Therefore, they are used to determine the success of cancer screening and treatment. Recently, the development of cancer treatment agents has been active, and a-difluoromethylornithine, an enzyme inhibitor, has been developed as an anticancer agent, but its therapeutic effect was not sufficient. Recently, Ant4, which is an anticancer agent anthracene conjugated to putrescine, was created, and it was shown to selectively remove cancer cells. In addition, research on anticancer agents using polyamines, such as spermidine and spermine analogs, and polyamine/metal complexes, is also active.

Recent reports have shown that microorganisms regulate various skin metabolisms and affect aging, and that spermidine, which is produced during the metabolism process, directly affects skin anti-aging. In addition, it has been confirmed that spermidine activates collagen synthesis and lipid secretion in the skin, thereby providing skin hydration, elasticity, and anti-aging effects.

Korean Patent No. 1863344 (registered on May 25, 2018) relates to an invention for a cosmetic composition for skin anti-aging containing a serum-free culture medium of stem cells as an effective ingredient, and a technology for including vitamin C and putrescine dihydrochloride in the culture medium is disclosed. In addition, Korean Patent No. 2164218 (registered on October 5, 2020) relates to an invention for a multilayer cationic liposome for promoting skin absorption and a method for preparing the same, and a technology for including N4-cholesteryl-spermine in the phospholipid layer constituting the liposome and including ascorbic acid inside the liposome is disclosed.

However, these prior technologies are not competitive enough for commercialization because they require complicated steps such as stem cell culture and liposome formation. Therefore, there is still a market demand for a simple technology that can complement the aforementioned shortcomings of vitamin C.

Korean Patent No. 1863344 (registered on May 25, 2018) Korean Patent No. 2164218 (registered on October 5, 2020)

The present invention has been made to solve the above problems, and its purpose is to provide an ascorbic acid derivative bound to a polyamine of the following chemical formula (1), a stereoisomer thereof, a salt thereof, or a solvate thereof:

[Chemical Formula 1]

.

In addition, another object of the present invention is to provide a cosmetic composition including the above derivatives.

In addition, another purpose of the present invention is to provide a pharmaceutical product including the above derivatives.

In addition, another purpose of the present invention is to provide a medical device including the above derivatives.

In addition, another purpose of the present invention is to provide a method for producing the above derivatives.

The present invention may also aim to achieve other purposes, other than the above-mentioned clear purpose, which can be easily derived by a person skilled in the art from this purpose and the overall description of the present specification.

In order to achieve the above-described purpose, the present invention is characterized by providing an ascorbic acid derivative bound to a polyamine of the following chemical formula (1), a stereoisomer thereof, a salt thereof, or a solvate thereof:

[Chemical Formula 1]

.

Meanwhile, the cosmetic composition of the present invention comprises an ascorbic acid derivative bound to a polyamine of the following chemical formula (1), a stereoisomer thereof, a salt thereof, or a solvate thereof, and

Physiologically acceptable cosmetic base

characterized by including:

[Chemical Formula 1]

.

And, the cosmetic composition may be a formulation selected from the group consisting of a toner, an emulsion, a cream, a pack, and a cosmetic solution.

In addition, the cosmetic composition may additionally contain a sunscreen or a light scattering agent.

Meanwhile, the quasi-drug of the present invention is characterized by including an ascorbic acid derivative bound to a polyamine of the following chemical formula (1), a stereoisomer thereof, a salt thereof, or a solvate thereof:

[Chemical Formula 1]

.

Meanwhile, the medical device of the present invention is characterized by including an ascorbic acid derivative bound to a polyamine of the following chemical formula (1), a stereoisomer thereof, a salt thereof, or a solvate thereof:

[Chemical Formula 1]

.

Meanwhile, the method for producing an ascorbic acid derivative bound to a polyamine of the chemical formula (1) of the present invention is characterized by reacting a compound of the chemical formula 9 with 1Boc-putrescine, 2Boc-spermidine or 3Boc-spermine to produce a compound of the chemical formula 10, 11 or 12, and then removing the protecting group to produce a compound of the chemical formula 1, as shown in the following reaction scheme 6:

[Reaction Formula 6]

.

Additionally, the molar number of 1Boc-putrescine, 2Boc-spermidine or 3Boc-spermine reacting with 1 mol of the compound of the above chemical formula 9 may be 0.8 to 2.0 mol, or 1 to 1.5 mol.

And, in the reaction of the compound of the above chemical formula 9 with 1Boc-putrescine, 2Boc-spermidine or 3Boc-spermine, the reaction temperature may be -5 to 10°C, or 0 to 5°C.

And, in the reaction of the compound of the above chemical formula 9 with 1Boc-putrescine, 2Boc-spermidine or 3Boc-spermine, the reaction time may be 45 minutes to 8 hours, or 1 to 5 hours.

And, in the reaction of the compound of the above chemical formula 9 with 1Boc-putrescine, 2Boc-spermidine or 3Boc-spermine, the reaction solvent may be dichloromethane, tetrahydrofuran, dimethylformamide or a mixture thereof.

And, before the reaction of the compound of the above chemical formula 9 with 1Boc-putrescine, 2Boc-spermidine or 3Boc-spermine, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride can be added to the reaction solvent.

And, the amount of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride added may be 1.2 to 2.5 mol, or 1.5 to 2 mol per 1 mol of the compound of chemical formula 9.

And, the removal of the above protective group can be accomplished in a hydrochloric acid solution in a mixed solvent of dioxane and water, dioxane and methanol, or dioxane and ethanol.

And, the weight ratio of dioxane: water, methanol, or ethanol in the mixed solvent may be 1:0.15 to 0.4, or 1:0.2 to 0.35.

And, the concentration of the hydrochloric acid solution can be 0.05 to 2 M, or 0.1 to 1 M.

And, the removal of the protective device can be performed over a period of 1.5 to 8 hours, or over a period of 2 to 5 hours.

And, the compound of the chemical formula 9 can be prepared by reacting the compound of the chemical formula 8 with lithium hydroxide or sodium hydroxide, as shown in the following reaction scheme 5:

[Reaction Formula 5]

.

And, the molar number of lithium hydroxide or sodium hydroxide reacting with 1 mol of the compound of the chemical formula 8 may be 2 to 8 mol, or 3 to 5 mol.

And, in the reaction of the compound of the above chemical formula 8 with lithium hydroxide or sodium hydroxide, the reaction solvent may be a mixed solvent of tetrahydrofuran and water.

And, the weight ratio of tetrahydrofuran:water in the mixed solvent may be 2.5 to 8:1, or 3 to 5:1.

And, in the reaction of the compound of the above chemical formula 8 with lithium hydroxide or sodium hydroxide, the reaction temperature may be -5 to 10°C, or 0 to 5°C.

And, in the reaction of the compound of the above chemical formula 8 with lithium hydroxide or sodium hydroxide, the reaction time can be 20 to 90 minutes, or 30 to 60 minutes.

And, the compound of the above chemical formula 8 can be prepared by reacting ascorbic acid acetonide with bromo ethylacetate as shown in the following reaction scheme 4:

[Reaction Formula 4]

.

And, the molar number of bromo ethylacetate reacting with 1 mol of ascorbic acid acetonide may be 0.8 to 1.5 mol, or 1 to 1.2 mol.

And, in the reaction of ascorbic acid acetonide and bromo ethylacetate, the reaction solvent may be dimethyl sulfoxide or dimethylformamide.

And, before the reaction of ascorbic acid acetonide with bromo ethylacetate, N,N-diisopropylethylamine can be added to the reaction solvent.

And, the amount of added N,N-diisopropylethylamine may be 0.8 to 2.0 mol, or 1 to 1.5 mol per 1 mol of ascorbic acid acetonide.

And, in the reaction of ascorbic acid acetonide and bromo ethylacetate, the reaction temperature may be 15 to 30°C, or 20 to 25°C.

And, in the reaction of ascorbic acid acetonide and bromo ethylacetate, the reaction time can be 4 to 15 hours, or 6 to 12 hours.

And, the above 1Boc-putrescine can be prepared by reacting 1,4-diamino butane with di-tert-butyl dicarbonate as shown in the following reaction scheme 1:

[Reaction Formula 1]

.

And, the molar number of di-tert-butyl dicarbonate reacting with 1 mol of 1Boc-putrescine may be 0.07 to 1.0 mol, or 0.1 to 0.5 mol.

And, in the reaction of the above 1Boc-putrescine and di-tert-butyl dicarbonate, the reaction solvent may be dichloromethane or chloroform.

And, in the reaction of the above 1Boc-putrescine and di-tert-butyl dicarbonate, the reaction temperature may be 15 to 30° C., or 20 to 25° C.

And, in the reaction of the above 1Boc-putrescine and di-tert-butyl dicarbonate, the reaction time can be 3 to 9 hours, or 4 to 6 hours.

And, the above 2Boc-spermidine can be produced by sequentially reacting 1Boc-putrescine with acrylonitrile and di-tert-butyl dicarbonate, and then hydrogenating the same in the presence of a catalyst, as in the following reaction scheme 2:

[Reaction Formula 2]

.

And, the molar number of acrylonitrile reacting with 1 mol of the above 1Boc-putrescine may be 0.8 to 1.5 mol, or 1 to 1.2 mol.

And, in the reaction of the above 1Boc-putrescine and acrylonitrile, the reaction solvent may be methanol.

And, in the reaction of the above 1Boc-putrescine and acrylonitrile, the reaction temperature may be 15 to 30° C., or 20 to 25° C.

And, in the reaction of the above 1Boc-putrescine and acrylonitrile, the reaction time can be 9 to 30 hours, or 12 to 24 hours.

And, the molar number of di-tert-butyl dicarbonate reacting with 1 mol of the compound of the above chemical formula 3 may be 0.8 to 1.5 mol, or 1 to 1.2 mol.

And, in the reaction of the compound of the above chemical formula 3 and di-tert-butyl dicarbonate, the reaction solvent may be methanol.

And, in the reaction of the compound of the above chemical formula 3 with di-tert-butyl dicarbonate, the reaction temperature may be 15 to 30°C, or 20 to 25°C.

And, in the reaction of the compound of the above chemical formula 3 with di-tert-butyl dicarbonate, the reaction time can be 64 to 15 hours, or 6 to 12 hours.

And, the catalyst for the hydrogenation reaction may be Raney nickel and a basic aqueous solution.

And, the basic aqueous solution may be a sodium hydroxide aqueous solution.

And, the hydrogenation reaction can be carried out under hydrogen conditions in a solvent such as ethanol, tetrahydrofuran, or dioxane.

And, the above 3Boc-spermine can be manufactured by sequentially reacting 1,4-diamino butane with acrylonitrile and di-tert-butyl dicarbonate, followed by hydrogenation in the presence of a catalyst, and then reacting again with di-tert-butyl dicarbonate, as in the following reaction scheme 3:

[Reaction Formula 3]

.

And, the molar number of acrylonitrile reacting with 1 mol of the 1,4-diamino butane may be 1.5 to 3.5 mol, or 2 to 2.5 mol.

And, in the reaction of the above 1,4-diamino butane and acrylonitrile, the reaction solvent may be methanol.

And, in the reaction of the above 1,4-diamino butane and acrylonitrile, the reaction temperature may be -5 to 10°C, or 0 to 5°C.

And, in the reaction of the above 1,4-diamino butane and acrylonitrile, the reaction time can be 1.5 to 8 hours, or 2 to 5 hours.

And, before the hydrogenation reaction, the molar number of di-tert-butyl dicarbonate reacting with 1 mol of the compound of chemical formula 5 may be 1.5 to 3.5 mol, or 2 to 2.5 mol.

And, in the reaction of the compound of chemical formula 5 with di-tert-butyl dicarbonate before the hydrogenation reaction, the reaction solvent may be methanol.

And, in the reaction of the compound of chemical formula 5 with di-tert-butyl dicarbonate before the hydrogenation reaction, the reaction temperature may be 15 to 30° C., or 20 to 25° C.

And, in the reaction of the compound of chemical formula 5 with di-tert-butyl dicarbonate before the hydrogenation reaction, the reaction time can be 9 to 30 hours, or 12 to 24 hours.

And, the catalyst for the hydrogenation reaction may be Raney nickel and a basic aqueous solution.

And, the basic aqueous solution may be a sodium hydroxide aqueous solution.

And, the hydrogenation reaction can be carried out under hydrogen conditions in a solvent such as ethanol, tetrahydrofuran, or dioxane.

And, the reaction time of the hydrogenation reaction can be 9 to 30 hours, or 12 to 24 hours.

And, after the hydrogenation reaction, the molar number of di-tert-butyl dicarbonate reacting with 1 mol of the compound of chemical formula 7 may be 0.3 to 1.5 mol, or 0.5 to 1 mol.

And, in the reaction of the compound of chemical formula 7 with di-tert-butyl dicarbonate after the hydrogenation reaction, the reaction solvent may be dichloromethane.

And, in the reaction of the compound of chemical formula 7 with di-tert-butyl dicarbonate after the hydrogenation reaction, the reaction temperature may be 15 to 30° C., or 20 to 25° C.

And, in the reaction of the compound of chemical formula 7 with di-tert-butyl dicarbonate after the hydrogenation reaction, the reaction time can be 3 to 9 hours, or 4 to 6 hours.

According to the problem-solving means of the present invention as examined above, various effects including the following can be expected. However, the present invention is not established only when all of the following effects are exhibited.

The ascorbic acid derivative combined with the polyamine of the chemical formula (1) according to the present invention has high antioxidant efficacy and thermal stability, as well as safety with low cytotoxicity, and thus can be applied in the fields of cosmetics, pharmaceuticals, food, feed, etc. In particular, it is expected to be actively used in cosmetics as a whitening agent.

This is because the skin penetration ability has been improved by combining biocompatible polyamine with L-ascorbic acid (vitamin C), which has useful functions for the skin, specifically a whitening effect, an effect of restoring skin elasticity by promoting collagen synthesis in the dermal layer of the skin, and an effect of eliminating harmful oxygen generated by ultraviolet rays, etc.

Furthermore, the polyamine is not only being studied as a reactant for the synthesis of new anticancer agents, but it is also reported to have a synergistic effect with L-ascorbic acid by activating collagen synthesis and lipid secretion, thereby moisturizing the skin and improving elasticity and anti-aging effects.

Figure 1 is a ¹ H-NMR spectrum of 3-O-ethyloxycarbonylmethyl-5,6-isopropylidene-L-ascorbic (8) in the present invention.
Figure 2 is a ¹ H-NMR spectrum of 3-O-carboxymethyl-5,6-isopropylidene-L-ascorbic (9) in the present invention.
Figure 3 is a ¹ H-NMR spectrum of ascorbyl-putrescine (13) of the present invention.
Figure 4 is a ¹ H-NMR spectrum of ascorbyl-spermidine (14) of the present invention.
Figure 5 is a ¹ H-NMR spectrum of ascorbyl-spermine (15) of the present invention.
Figure 6 is a graph showing the results of antioxidant efficacy evaluation for spermidine, spermine, ascorbyl-spermidine (AA-spermidine), ascorbyl-putrescine (AA-putrescine), and vitamin C (AA).
Figure 7 is a graph showing the results of total antioxidant capacity evaluation for spermidine, spermine, ascorbyl-spermidine (AA-spermidine), ascorbyl-putrescine (AA-putrescine), and vitamin C (AA).
Figure 8 is a graph showing the results of thermal stability evaluation of ascorbyl-putrescine (AA-P), ascorbyl-spermidine (AA-SPM), and ascorbyl-spermine (AA-SM).
Figure 9 is a graph showing the results of cytotoxicity evaluation of ascorbic acid (AA), spermidine (SP), ascorbyl-spermidine (AA-SP), and a mixture of ascorbic acid and spermidine (AA+SP mixture).

Hereinafter, preferred embodiments of the present invention will be described in detail.

However, the following are only specific examples to be described in detail, and since the present invention can be variously modified and can have various forms, the present invention is not limited to the specific examples illustrated. It should be understood that the present invention includes all modifications, equivalents, or substitutes included in the spirit and technical scope of the present invention.

In addition, many specific details, such as specific components, are described in the following description, but these are provided only to help a more general understanding of the present invention, and it will be obvious to those skilled in the art that the present invention can be practiced without these specific details. In addition, when describing the present invention, if it is determined that a specific description of a related known function or configuration may unnecessarily obscure the gist of the present invention, the detailed description is omitted.

In addition, the terminology used in this application is only used to describe specific embodiments and is not intended to limit the present invention. Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by those of ordinary skill in the art to which this invention belongs. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with the meaning they have in the context of the relevant art, and shall not be interpreted in an idealized or overly formal sense unless explicitly defined in this application.

In this application, singular expressions include plural expressions unless the context clearly indicates otherwise.

In this application, the terms first, second, etc. may be used to describe various components, but the components should not be limited by the terms. The terms are used only for the purpose of distinguishing one component from another. For example, without departing from the scope of the present invention, the first component may be referred to as the second component, and similarly, the second component may also be referred to as the first component.

In this application, terms such as “include,” “contain,” or “have” are intended to indicate the presence of features, components (or constituents) described in the specification, but do not imply that one or more other features or components are not present or cannot be added.

Regarding the ‘non-medicinal products’ used in this specification, the ‘Pharmaceutical Affairs Act’

"A. Fibers, rubber products or similar products used for the purpose of treating, alleviating, managing or preventing diseases of humans or animals.

B. Things that have a weak effect on the human body or do not directly affect the human body, and are not instruments or machines or similar things

D. Preparations used for sterilization, insecticides, and similar purposes to prevent infectious diseases"

It is defined as such, and as a specific example of a double-headed tree, in the delegated administrative regulation (designation of the scope of non-medical products) No. 2,

"Bar. External disinfectants containing hydrogen peroxide, isopropyl alcohol, benzalkonium chloride, cresol or ethanol as main ingredients for direct use on the human body.

Ointment, cataplasma and spray patch as specified in the standard manufacturing standards for over-the-counter drugs notified by the Commissioner of the Ministry of Food and Drug Safety

Ah. Oral preparations

1) Low-content vitamin and mineral preparations as specified in the standard manufacturing standards for over-the-counter drugs established and announced by the Commissioner of the Ministry of Food and Drug Safety

2) A preparation corresponding to the liquid form as a nutritional tonic prescribed in the standard manufacturing standards for over-the-counter drugs established and announced by the Commissioner of the Ministry of Food and Drug Safety.

3) Preparations corresponding to liquid preparations for internal use as digestive aids and solid preparations for internal use as intestinal preparations as specified in the standard manufacturing standards for over-the-counter drugs notified by the Commissioner of the Ministry of Food and Drug Safety"

Therefore, the quasi-drug of the present invention is defined as corresponding thereto.

As used in this specification, the 'Medical Device Act' refers to the 'Medical Device Act'

'Apparatus, machine, device, material, software or similar products used alone or in combination for humans or animals'

As,

"1. Products used for the purpose of diagnosing, treating, alleviating, curing or preventing diseases.

2. Products used for the purpose of diagnosing, treating, alleviating, or correcting injuries or disabilities.

3. Products used for the purpose of inspecting, replacing, or modifying structure or function.

4. Products used for the purpose of regulating pregnancy"

Therefore, the medical device of the present invention is defined as corresponding thereto.

The present invention has been completed by specifically confirming that the whitening effect is maintained without side effects on the skin and stability is maintained even after long-term storage by introducing biocompatible polyamines (putrescine, spermidine or spermine) with various physiological activities into ascorbic acid, which is used as a conventional whitening agent.

Specifically, the present invention is characterized by providing an ascorbic acid derivative bound to a polyamine of the following chemical formula (1), a stereoisomer thereof, a salt thereof, or a solvate thereof:

[Chemical Formula 1]

.

Meanwhile, the cosmetic composition of the present invention comprises an ascorbic acid derivative bound to a polyamine of the following chemical formula (1), a stereoisomer thereof, a salt thereof, or a solvate thereof, and

Physiologically acceptable cosmetic base

characterized by including:

[Chemical Formula 1]

.

And, the cosmetic composition may be a formulation selected from the group consisting of a toner, an emulsion, a cream, a pack, and a cosmetic solution.

In addition, the cosmetic composition may additionally contain a sunscreen or a light scattering agent.

Meanwhile, the quasi-drug of the present invention is characterized by including an ascorbic acid derivative bound to a polyamine of the following chemical formula (1), a stereoisomer thereof, a salt thereof, or a solvate thereof:

[Chemical Formula 1]

.

Meanwhile, the medical device of the present invention is characterized by including an ascorbic acid derivative bound to a polyamine of the following chemical formula (1), a stereoisomer thereof, a salt thereof, or a solvate thereof:

[Chemical Formula 1]

.

Meanwhile, the method for producing an ascorbic acid derivative bound to a polyamine of the chemical formula (1) of the present invention is characterized by reacting a compound of the chemical formula 9 with 1Boc-putrescine, 2Boc-spermidine or 3Boc-spermine to produce a compound of the chemical formula 10, 11 or 12, and then removing the protecting group to produce a compound of the chemical formula 1, as shown in the following reaction scheme 6:

[Reaction Formula 6]

.

In addition, the molar number of 1Boc-putrescine, 2Boc-spermidine or 3Boc-spermine reacting with 1 mol of the compound of the chemical formula 9 may be 0.8 to 2.0 mol, or 1 to 1.5 mol. If the molar number of 1Boc-putrescine, 2Boc-spermidine or 3Boc-spermine is less than the above range, some of the compound of the chemical formula 9 may remain in an unreacted state, and conversely, if it exceeds the above range, it is disadvantageous in terms of the purchase cost of the reactant or the purification cost of the product.

And, in the reaction of the compound of the above chemical formula 9 with 1Boc-putrescine, 2Boc-spermidine or 3Boc-spermine, the reaction temperature may be -5 to 10°C, or 0 to 5°C. If the reaction temperature is below the above range, there is a problem that the reaction speed becomes slow, and conversely, if it exceeds the above range, an undesirable side reaction may occur.

And, in the reaction of the compound of the above chemical formula 9 with 1Boc-putrescine, 2Boc-spermidine or 3Boc-spermine, the reaction time may be 45 minutes to 8 hours, or 1 to 5 hours. If the reaction time is less than the above range, there is a problem that the reaction does not proceed sufficiently and the yield is low, and conversely, even if it exceeds the above range, the increase in yield is minimal, which is disadvantageous in terms of production cost.

And, in the reaction of the compound of the above chemical formula 9 with 1Boc-putrescine, 2Boc-spermidine or 3Boc-spermine, the reaction solvent may be dichloromethane, tetrahydrofuran, dimethylformamide or a mixture thereof.

And, before the reaction of the compound of the above chemical formula 9 with 1Boc-putrescine, 2Boc-spermidine or 3Boc-spermine, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride can be added to the reaction solvent.

And, the amount of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride added may be 1.2 to 2.5 mol, or 1.5 to 2 mol, per 1 mol of the compound of formula 9. If the amount added is less than the above range, a portion of the compound of formula 9 may remain in an unreacted state, and conversely, if it exceeds the above range, it is disadvantageous in terms of the purchase cost of the reactant or the purification cost of the product.

And, the removal of the above protective group can be accomplished in a hydrochloric acid solution in a mixed solvent of dioxane and water, methanol and water, or ethanol and water.

And, the weight ratio of dioxane, methanol, or ethanol:water in the mixed solvent may be 1:0.15 to 0.4, or 1:0.2 to 0.35.

And, the concentration of the hydrochloric acid solution can be 0.05 to 2 M, or 0.1 to 1 M.

And, the removal of the protective group can be carried out for 1.5 to 8 hours, or 2 to 5 hours. If the reaction time is less than the above range, there is a problem that the reaction does not proceed sufficiently and the yield is low, and conversely, even if the above range is exceeded, the increase in yield is minimal, which is disadvantageous in terms of production cost.

And, the compound of the chemical formula 9 can be prepared by reacting the compound of the chemical formula 8 with lithium hydroxide or sodium hydroxide, as shown in the following reaction scheme 5:

[Reaction Formula 5]

.

And, the molar number of lithium hydroxide or sodium hydroxide reacting with 1 mol of the compound of the above chemical formula 8 may be 2 to 8 mol, or 3 to 5 mol. If the molar number is less than the above range, some of the compound of the above chemical formula 8 may remain unreacted, and conversely, if it exceeds the above range, it is disadvantageous in terms of the purchase cost of the reactant or the purification cost of the product.

And, in the reaction of the compound of the above chemical formula 8 with lithium hydroxide or sodium hydroxide, the reaction solvent may be a mixed solvent of tetrahydrofuran and water.

And, the weight ratio of tetrahydrofuran:water in the mixed solvent may be 2.5 to 8:1, or 3 to 5:1.

And, in the reaction of the compound of the above chemical formula 8 with lithium hydroxide or sodium hydroxide, the reaction temperature may be -5 to 10°C, or 0 to 5°C. If the reaction temperature is below the above range, there is a problem that the reaction speed becomes slow, and conversely, if it exceeds the above range, an undesirable side reaction may occur.

And, in the reaction of the compound of the above chemical formula 8 with lithium hydroxide or sodium hydroxide, the reaction time can be 20 to 90 minutes, or 30 to 60 minutes. If the reaction time is less than the above range, there is a problem that the reaction does not proceed sufficiently and the yield is low, and conversely, even if the reaction time exceeds the above range, the increase in the yield is minimal, which is disadvantageous in terms of production cost.

And, the compound of the above chemical formula 8 can be prepared by reacting ascorbic acid acetonide with bromo ethylacetate as shown in the following reaction scheme 4:

[Reaction Formula 4]

.

And, the molar number of bromo ethylacetate reacting with 1 mol of the ascorbic acid acetonide may be 0.8 to 1.5 mol, or 1 to 1.2 mol. If the molar number is less than the above range, some of the ascorbic acid acetonide may remain unreacted, and on the contrary, if it exceeds the above range, it is disadvantageous in terms of the purchase cost of the reactant or the purification cost of the product.

And, in the reaction of ascorbic acid acetonide and bromo ethylacetate, the reaction solvent may be dimethyl sulfoxide or dimethylformamide.

And, before the reaction of ascorbic acid acetonide with bromo ethylacetate, N,N-diisopropylethylamine can be added to the reaction solvent.

And, the amount of added N,N-diisopropylethylamine may be 0.8 to 2.0 mol, or 1 to 1.5 mol, per 1 mol of ascorbic acid acetonide. If the mol number is less than that range, some may remain unreacted, and conversely, if it exceeds the range, a lot of by-products may be generated, which may result in a low yield.

And, in the reaction of ascorbic acid acetonide and bromo ethylacetate, the reaction temperature may be 15 to 30° C., or 20 to 25° C. If the reaction temperature is below the above range, there is a problem that the reaction speed becomes slow, and conversely, if it exceeds the above range, an undesirable side reaction may occur.

And, in the reaction of the ascorbic acid acetonide and bromo ethylacetate, the reaction time can be 4 to 15 hours, or 6 to 12 hours. If the reaction time is less than the above range, there is a problem that the reaction does not proceed sufficiently and the yield is low, and conversely, even if the reaction time exceeds the above range, the increase in the yield is minimal, which is disadvantageous in terms of production cost.

And, the above 1Boc-putrescine can be prepared by reacting 1,4-diamino butane with di-tert-butyl dicarbonate as shown in the following reaction scheme 1:

[Reaction Formula 1]

.

And, the molar number of di-tert-butyl dicarbonate reacting with 1 mol of 1Boc-putrescine may be 0.07 to 1.0 mol, or 0.1 to 0.5 mol. If the molar number is less than the above range, a portion of 1Boc-putrescine may remain unreacted, and conversely, if it exceeds the above range, it is disadvantageous in terms of the purchase cost of the reactant or the purification cost of the product.

And, in the reaction of the above 1Boc-putrescine and di-tert-butyl dicarbonate, the reaction solvent may be dichloromethane or chloroform.

And, in the reaction of the above 1Boc-putrescine and di-tert-butyl dicarbonate, the reaction temperature may be 15 to 30° C., or 20 to 25° C. If the reaction temperature is below the above range, there is a problem that the reaction speed becomes slow, and conversely, if it exceeds the above range, an undesirable side reaction may occur.

And, in the reaction of the above 1Boc-putrescine and di-tert-butyl dicarbonate, the reaction time can be 3 to 9 hours, or 4 to 6 hours. If the reaction time is less than the above range, there is a problem that the reaction does not proceed sufficiently and the yield is low, and conversely, even if the reaction time exceeds the above range, the increase in the yield is minimal, which is disadvantageous in terms of production cost.

And, the above 2Boc-spermidine can be produced by sequentially reacting 1Boc-putrescine with acrylonitrile and di-tert-butyl dicarbonate, and then hydrogenating the same in the presence of a catalyst, as in the following reaction scheme 2:

[Reaction Formula 2]

.

And, the molar number of acrylonitrile reacting with 1 mol of the above 1Boc-putrescine may be 0.8 to 1.5 mol, or 1 to 1.2 mol. If the molar number is less than the above range, some of the compound of chemical formula 9 may remain unreacted, and on the contrary, if it exceeds the above range, it is disadvantageous in terms of the purchase cost of the reactant or the purification cost of the product.

And, in the reaction of the above 1Boc-putrescine and acrylonitrile, the reaction solvent may be methanol.

And, in the reaction of the above 1Boc-putrescine and acrylonitrile, the reaction temperature may be 15 to 30° C., or 20 to 25° C. If the reaction temperature is below the above range, there is a problem that the reaction speed becomes slow, and conversely, if it exceeds the above range, an undesirable side reaction may occur.

And, in the reaction of the above 1Boc-putrescine and acrylonitrile, the reaction time can be 9 to 30 hours, or 12 to 24 hours. If the reaction time is less than the above range, there is a problem that the reaction does not proceed sufficiently and the yield is low, and conversely, even if the reaction time exceeds the above range, the increase in the yield is minimal, which is disadvantageous in terms of production cost.

And, the molar number of di-tert-butyl dicarbonate reacting with 1 mol of the compound of the above chemical formula 3 may be 0.8 to 1.5 mol, or 1 to 1.2 mol. If the molar number is less than the above range, some of the compound of the above chemical formula 3 may remain unreacted, and on the contrary, if it exceeds the above range, it is disadvantageous in terms of the purchase cost of the reactant or the purification cost of the product.

And, in the reaction of the compound of the above chemical formula 3 and di-tert-butyl dicarbonate, the reaction solvent may be methanol.

And, in the reaction of the compound of the above chemical formula 3 with di-tert-butyl dicarbonate, the reaction temperature may be 15 to 30° C., or 20 to 25° C. If the reaction temperature is below the above range, there is a problem that the reaction speed becomes slow, and conversely, if it exceeds the above range, an undesirable side reaction may occur.

And, in the reaction of the compound of the above chemical formula 3 with di-tert-butyl dicarbonate, the reaction time can be 6 4 to 15 hours, or 6 to 12 hours. If the reaction time is less than the above range, there is a problem that the reaction does not proceed sufficiently and the yield is low, and conversely, even if the reaction time exceeds the above range, the increase in the yield is minimal, which is disadvantageous in terms of production cost.

And, the catalyst for the hydrogenation reaction may be Raney nickel and a basic aqueous solution.

And, the basic aqueous solution may be a sodium hydroxide aqueous solution.

And, the hydrogenation reaction can be carried out under hydrogen conditions in a solvent such as ethanol, tetrahydrofuran, or dioxane.

And, the above 3Boc-spermine can be manufactured by sequentially reacting 1,4-diamino butane with acrylonitrile and di-tert-butyl dicarbonate, followed by hydrogenation in the presence of a catalyst, and then reacting again with di-tert-butyl dicarbonate, as in the following reaction scheme 3:

[Reaction Formula 3]

.

And, the molar number of acrylonitrile reacting with 1 mol of the 1,4-diamino butane may be 1.5 to 3.5 mol, or 2 to 2.5 mol. If the molar number is less than the above range, some of the 1,4-diamino butane may remain unreacted, and conversely, if it exceeds the above range, it is disadvantageous in terms of the purchase cost of the reactant or the purification cost of the product.

And, in the reaction of the above 1,4-diamino butane and acrylonitrile, the reaction solvent may be methanol.

And, in the reaction of the above 1,4-diamino butane and acrylonitrile, the reaction temperature may be -5 to 10° C., or 0 to 5° C. If the reaction temperature is below the above range, there is a problem that the reaction speed becomes slow, and conversely, if it exceeds the above range, an undesirable side reaction may occur.

And, in the reaction of the above 1,4-diamino butane and acrylonitrile, the reaction time can be 1.5 to 8 hours, or 2 to 5 hours. If the reaction time is less than the above range, there is a problem that the reaction does not proceed sufficiently and the yield is low, and conversely, even if the reaction time exceeds the above range, the increase in yield is minimal, which is disadvantageous in terms of production cost.

And, before the hydrogenation reaction, the molar number of di-tert-butyl dicarbonate reacting with 1 mol of the compound of chemical formula 5 may be 1.5 to 3.5 mol, or 2 to 2.5 mol. If the molar number is less than the above range, a portion of the compound of chemical formula 9 may remain unreacted, and conversely, if it exceeds the above range, it is disadvantageous in terms of the purchase cost of the reactant or the purification cost of the product.

And, in the reaction of the compound of chemical formula 5 with di-tert-butyl dicarbonate before the hydrogenation reaction, the reaction solvent may be methanol.

And, in the reaction of the compound of chemical formula 5 before the hydrogenation reaction and di-tert-butyl dicarbonate, the reaction temperature may be 15 to 30° C., or 20 to 25° C. If the reaction temperature is below the above range, there is a problem that the reaction speed becomes slow, and conversely, if it exceeds the above range, an undesirable side reaction may occur.

And, in the reaction of the compound of chemical formula 5 before the hydrogenation reaction and di-tert-butyl dicarbonate, the reaction time can be 9 to 30 hours, or 12 to 24 hours. If the reaction time is less than the above range, there is a problem that the reaction does not proceed sufficiently and the yield is low, and conversely, even if the reaction time exceeds the above range, the increase in the yield is minimal, which is disadvantageous in terms of production cost.

And, the catalyst for the hydrogenation reaction may be Raney nickel and a basic aqueous solution.

And, the basic aqueous solution may be a sodium hydroxide aqueous solution.

And, the hydrogenation reaction can be carried out under hydrogen conditions in a solvent such as ethanol, tetrahydrofuran, or dioxane.

And, the reaction time of the hydrogenation reaction can be 9 to 30 hours, or 12 to 24 hours. If the reaction time is less than the above range, there is a problem that the reaction does not proceed sufficiently and the yield is low, and conversely, even if the reaction time exceeds the above range, the increase in the yield is minimal, which is disadvantageous in terms of production cost.

And, after the hydrogenation reaction, the molar number of di-tert-butyl dicarbonate reacting with 1 mol of the compound of chemical formula 7 may be 0.3 to 1.5 mol, or 0.5 to 1 mol. If the molar number is less than the above range, some of the compound of chemical formula 7 may remain unreacted, and conversely, if it exceeds the above range, it is disadvantageous in terms of the purchase cost of the reactant or the purification cost of the product.

And, in the reaction of the compound of chemical formula 7 with di-tert-butyl dicarbonate after the hydrogenation reaction, the reaction solvent may be dichloromethane.

And, in the reaction of the compound of chemical formula 7 with di-tert-butyl dicarbonate after the hydrogenation reaction, the reaction temperature may be 15 to 30° C., or 20 to 25° C. If the reaction temperature is below the above range, there is a problem that the reaction speed becomes slow, and conversely, if it exceeds the above range, an undesirable side reaction may occur.

And, in the reaction of the compound of chemical formula 7 with di-tert-butyl dicarbonate after the hydrogenation reaction, the reaction time can be 3 to 9 hours, or 4 to 6 hours. If the reaction time is less than the above range, there is a problem that the reaction does not proceed sufficiently and the yield is low, and conversely, even if the reaction time exceeds the above range, the increase in yield is minimal, which is disadvantageous in terms of production cost.

Hereinafter, embodiments of the present invention will be described.

Example

Manufacturing example 1: Synthesis of 1Boc-putrescine

[Reaction Formula 1]

In a 200-mL round bottom flask, 3.8 mL (37.94 mmol) of 1,4-diaminobutane was dissolved in 35 mL of dichloromethane. Then, 1.67 mL (7.3 mmol) of di-tert-butyl dicarbonate (Boc ₂ O) dissolved in 35 mL of dichloromethane was slowly added dropwise using a dropping funnel over 2 hours, and the mixture was stirred for 2 more hours at room temperature. After the reaction, 50 mL of a saturated sodium bicarbonate (NaHCO ₃ ) aqueous solution was added to the product mixture, the organic layer was separated, and it was recovered. The recovered organic layer was concentrated under reduced pressure and colorless liquid 1Boc-putrescine was obtained using column chromatography (methanol: ammonia water = 9:1). Yield = 95%

¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.11 (brs, 1H), 3.63 (t, 2H), 2.84 (t, 2H), 2.21 (brs, 2H), 2.02 (brs, 2H), 1.55 (t , 2H), 1.25 (s, 9H).

Manufacturing Example 2: Synthesis of tert-butyl (4-((tert-butoxycarbonyl)amino)butyl)(2-cyanoethyl)carbamate (4)

[Reaction Formula 2]

2.08 g (11.05 mmol) of 1Boc-putrescine was dissolved in 20 mL of methanol, 0.80 mL (12.15 mmol) of acrylonitrile was added, and the mixture was stirred at room temperature for 12 hours. After confirming that the starting material had completely disappeared, 2.54 mL (11.05 mmol) of Boc ₂ O was added to the reaction solution, and the mixture was stirred at room temperature for about 6 hours. 50 mL of a saturated sodium bicarbonate aqueous solution was added to the reaction mixture, the organic layer was separated, and it was recovered. The recovered organic layer was concentrated under reduced pressure and purified by column chromatography (hexane: ethyl acetate = 1:1) to obtain colorless liquid tert-butyl (4-((tert-butoxycarbonyl)amino)butyl)(2-cyanoethyl)carbamate (4). Yield = 93%

¹ H NMR (400 MHz, CDCl ₃ ) δ: 4.79 (brs, 1H), 3.35 (t, 2H), 3.16 (t, 2H), 3.05-2.97 (m, 2H), 2.55-2.43 (m, 2H) , 1.50-1.40 (m, 4H), 1.35 (s, 9H), 1.32 (s, 9H).

Manufacturing Example 3: Synthesis of 2Boc-spermidine

2.5 g (7.3 mmol) of tert-butyl (4-((tert-butoxycarbonyl)amino)butyl)(2-cyanoethyl)carbamate (4) was dissolved in 50 mL of ethanol, and 1.5 g of Raney nickel and 10 mL of 10% sodium hydroxide aqueous solution were added. The mixture was stirred under hydrogen (H ₂ ) conditions for 24 h. The catalyst was removed using Celite, and the ethanol filtrate was concentrated under reduced pressure. Colorless liquid 2Boc-spermidine was obtained using column chromatography (methanol: ammonia water = 9:1). Yield = 88%

¹ H NMR (400 MHz, CDCl ₃ ) δ: 4.58 (brs, 1H) 3.23-3.09 (m, 6H), 2.68-2.62 (m, 2H), 2.08-1.95 (m, 2H), 1.70-1.61 (m) , 2H), 1.60-1.48 (m, 2H), 1.41 (s, 18H).

Manufacturing Example 4: Synthesis of di-tert-butyl butane-1,4-diylbis((cyanomethyl)carbamate) (6)

[Reaction Formula 3]

In a 200-mL round bottom flask, 2.3 mL (22.69 mmol) of 1,4-diamino butane was dissolved in 10 mL of methanol. After dissolving in 100 mL of methanol, 2.97 mL (45.4 mmol) of acrylonitrile solution was slowly added dropwise using a dropping funnel at 0 °C and stirred for 2 more hours at room temperature. After confirming that the starting material had completely disappeared, 12.0 mL (52.2 mmol) of Boc ₂ O was added to the reaction solution and stirred at room temperature for about 12 hours. After the reaction was completed, 50 mL of a saturated sodium bisulfate (NaHSO ₄ ) aqueous solution was added to the product mixture, the organic layer was separated, and it was recovered. The recovered organic layer was concentrated under reduced pressure and purified by column chromatography (hexane: ethyl acetate = 1:1) to obtain di-tert-butyl butane-1,4-diylbis((cyanomethyl)carbamate) (6) as a white solid. Yield = 95%

¹ H NMR (400 MHz, CDCl ₃ ): δ 3.45 (t, 4 H), 3.29 (m, 4 H), 1.56-1.63 (m, 4 H), 1.52-1.56 (m, 4 H), 1.47 ( s, 18 H).

Manufacturing Example 5: Synthesis of di-tert-butyl butane-1,4-diylbis((3-aminopropyl)carbamate) (7)

1 g (2.53 mmol) of di-tert-butyl butane-1,4-diylbis((cyanomethyl)carbamate) (6) was dissolved in 50 mL of ethanol, and 1.0 g of Raney Ni and 10 mL of 10% sodium hydroxide aqueous solution were added. The mixture was stirred under hydrogen (H ₂ ) conditions for 24 hours. The catalyst was removed using Celite, and the ethanol filtrate was concentrated under reduced pressure. Colorless liquid di-tert-butyl butane-1,4-diylbis((3-aminopropyl)carbamate) (7) was obtained using column chromatography (methanol: ammonia water = 9:1). Yield = 88%

¹ H NMR (400 MHz, CDCl ₃ ): δ 3.28-3.16 (m, 8 H), 2.69 (s, 4 H), 1.67-1.63 (m, 4 H), 1.50 (s, 4 H), 1.32 ( s, 4 H).

Manufacturing Example 6: Synthesis of 3Boc-spermine

di-tert-butyl butane-1,4-diylbis((3-aminopropyl)carbamate) (7) 0.91 g (2.26 mmol) was dissolved in 100 mL of dichloromethane, and a solution of 0.52 mL (2.26 mmol) of Boc ₂ O dissolved in 60 mL of dichloromethane was slowly added dropwise over 2 hours using a dropping funnel, and the mixture was stirred for another 2 hours at room temperature. 50 mL of a saturated sodium bicarbonate (NaHCO ₃ ) aqueous solution was added to the reaction mixture, the organic layer was separated, and it was recovered. The recovered organic layer was concentrated under reduced pressure, and colorless liquid 3Boc-spermine was obtained using column chromatography (methanol: ammonia water = 9:1). Yield = 45%

¹ H NMR (400 MHz, CDCl3): δ 3.21-3.07 (m, 10 H), 2.66 (s, 2 H), 2.15-2.12 (m, 4 H), 1.63 (s, 4 H), 1.43 (s) , 27 H).

Manufacturing Example 7: Synthesis of 3-O-ethyloxycarbonylmethyl-5,6-isopropylidene-L-ascorbic (8)

[Reaction Formula 4]

Ascorbic acid acetonide (5 g, 23.13 mmol) was dissolved in dimethyl sulfoxide (DMSO) (20 mL), N,N-diisopropylethylamine (DIPEA) (4.8 mL, 27.8 mmol) and bromo ethylacetate (23.13 mmol) were added, and the mixture was stirred at room temperature for about 6 hours. After the reaction, 50 mL of water and 100 mL of ethyl acetate were added to the resulting mixture, and the organic layer was separated. The organic solvent was washed with a saturated sodium bisulfate (NaHSO ₄ ) aqueous solution, and the organic layer was recovered. The recovered organic layer was concentrated under reduced pressure and recrystallized using hexane to obtain a white solid 3-O-ethyloxycarbonylmethyl-5,6-isopropylidene-L-ascorbic (8), and its ¹ H-NMR spectrum is shown in Figure 1. Yield = 82%

¹ H NMR (400 MHz, CDCl3): δ 5.91 (brs, 1 H), 5.04-4.91 (ABq, 2 H), 4.71 (d, 1 H), 4.34-4.27 (m, 3 H), 4.21 (t , 1 H), 4.09-4.06(m, 1H), 1.42(s, 3H), 1.39(s, 3H), 1.32(t, 3H).

Manufacturing Example 8: Synthesis of 3-O-carboxymethyl-5,6-isopropylidene-L-ascorbic (9)

[Reaction Formula 5]

3-O-ethyloxycarbonylmethyl-5,6-isopropylidene-L-ascorbic (8) 3.53 g (11.68 mmol) was dissolved in 30 mL of a mixed solvent of tetrahydrofuran (THF)/water (3:1), cooled to 0 °C, and 0.84 g (35.04 mmol) of lithium hydroxide (LiOH) was added. The reaction mixture was stirred at this temperature for about 30 minutes, adjusted to pH = 3 to 4 using concentrated hydrochloric acid (HCl), and extracted using ethyl acetate. The recovered organic layer was concentrated under reduced pressure to obtain 3-O-carboxymethyl-5,6-isopropylidene-L-ascorbic (9) in a gummy form, and its ¹ H-NMR spectrum is shown in Fig. 2. Yield = 95%.

¹ H NMR (400 MHz, MeOD-d ₄ ): δ 5.09-4.82 (ABq, 2 H), 4.92 (d, 1 H), 4.76 (d, 1 H), 4.34-4.30 (m, 1 H), 4.21 (t, 1 H), 4.05-4.02 (m, 1 H), 1.37(s, 3H), 1.35(s, 3H).

Example 1: Synthesis of ascorbyl-putrescine (13)

[Reaction Formula 5]

2.3 g (8.39 mmol) of 3-O-carboxymethyl-5,6-isopropylidene-L-ascorbic (9) was dissolved in 50 mL of dichloromethane, cooled to 0 °C, and 2.4 g (12.6 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC HCl) was added and stirred for about 5 minutes. 1.9 g (10 mmol) of 1Boc-putrescine was added to the reaction mixture and stirred at this temperature for about 1 hour. After the reaction was completed, 50 ml of a saturated sodium bisulfate (NaHSO ₄ ) aqueous solution was added to the product mixture, and the organic layer was separated. The separated organic layer was washed with a saturated sodium bicarbonate (NaHCO ₃ ) aqueous solution, and then the organic layer was recovered. The recovered organic layer was concentrated under reduced pressure to obtain a white solid compound 10, which was used in the next reaction without purification. Compound 10 was dissolved in a mixed solvent of 4 M HCl in dioxane/water (9:1) (30 ml), and stirred at room temperature for about 2 hours. The solvent was concentrated under reduced pressure to obtain a white ascorbyl-putrescine (13), and its ¹ H-NMR spectrum is as shown in Figure 3. Yield = 95%

¹ H NMR (400 MHz, MeOD-d ₄ ): δ 5.09-4.82 (ABq, 2 H), 4.92 (d, 1H), 3.99-3.95 (m, 1 H), 3.70(d, 2 H), 3.33 (t, 2H), 2.94(t, 2H), 1.68-1.59 (m, 4H).

Example 2: Synthesis of ascorbyl-spermidine (14)

1.2 g (4.37 mmol) of 3-O-carboxymethyl-5,6-isopropylidene-L-ascorbic (9) was dissolved in 50 mL of dichloromethane, cooled to 0 °C, and 1.25 g (6.56 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC HCl) was added and stirred for about 5 minutes. 1.8 g (5.25 mmol) of 2Boc-spermidine was added to the reaction mixture and stirred at this temperature for about 1 hour. After the reaction, 50 ml of a saturated sodium bisulfate (NaHSO ₄ ) aqueous solution was added to the product mixture, and the organic layer was separated. The separated organic layer was washed with a saturated sodium bicarbonate (NaHCO ₃ ) aqueous solution, and then the organic layer was recovered. The recovered organic layer was concentrated under reduced pressure to obtain a white solid compound 11, which was used in the next reaction without purification. Compound 11 was dissolved in a mixed solvent of 4 M HCl in dioxane/water (9:1) (30 ml), and stirred at room temperature for about 2 hours. The solvent was concentrated under reduced pressure to obtain a white ascorbyl-spermidine (14), and its ¹ H-NMR spectrum is as shown in Figure 4. Yield = 93%

¹ H NMR (400 MHz, MeOD-d ₄ ): δ 5.15-4.87 (ABq, 2 H), 4.95 (d, 1H), 4.01 (t, 1 H), 3.70(d, 2 H), 3.42 (t , 2H), 3.05-2.97 (m, 6H), 1.95-1.77(6H).

Example 3: Synthesis of ascorbyl-spermine (15)

3-O-carboxymethyl-5,6-isopropylidene-L-ascorbic (9) 1.5 g (5.47 mmol) was dissolved in 50 mL of dichloromethane, cooled to 0 °C, and 1.57 g (8.21 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC HCl) was added and stirred for about 5 minutes. 3.3 g (6.56 mmol) of 3Boc-spermine was added to the reaction mixture and stirred at this temperature for about 1 hour. After the reaction, 50 ml of a saturated sodium bisulfate (NaHSO ₄ ) aqueous solution was added to the product mixture, and the organic layer was separated. The separated organic layer was washed with a saturated sodium bicarbonate (NaHCO ₃ ) aqueous solution, and then the organic layer was recovered. The recovered organic layer was concentrated under reduced pressure to obtain a white solid compound 12, which was used in the next reaction without purification. Compound 12 was dissolved in a mixed solvent of 4 M HCl in dioxane/water (9:1) (30 ml), and stirred at room temperature for about 2 hours. The solvent was concentrated under reduced pressure to obtain a white ascorbyl-spermine (15), and its ¹ H-NMR spectrum is as shown in Figure 5. Yield = 94%

¹ H NMR (400 MHz, MeOD-d ₄ ): δ 5.15-4.87 (ABq, 2 H), 4.95 (d, 1H), 4.03 (t, 1 H), 3.71 (d, 2 H), 3.42 (t , 2H), 3.16-3.01 (m, 10H), 2.22-2.16 (m, 2H), 1.93-1.88 (m, 2H), 1.79-1.78 (m, 4H).

Test Example 1: Evaluation of Antioxidant Efficacy (DPPH Antioxidant Assay)

The antioxidant activity of five samples, including test substances spermidine, spermine, ascorbyl-spermidine (AA-spermidine), ascorbyl-putrescine (AA-putrescine), and vitamin C (AA), was evaluated. All five samples were reacted with 2,2-diphenyl-1-picrylhydrazyl (DPPH) at concentrations of 12.5, 25, 50, 100, and 200 μM for 20 minutes, and the absorbance at 525 nm was measured, which is shown in Fig. 6 and Table 1. The DPPH radical content was expressed as a % value converted from the absorbance ratio of the sample-added group and the control group.

Sample

IC ₅₀ / μM

Spermidine

-

Spermin

-

Ascorbyl-spermidine

36

Ascorbyl-Putrisine

36.6

Vitamin C

19.4

As a result, as can be confirmed in Table 1 above, spermine and spermidine showed no activity, while ascorbyl-spermidine (AA-spermidine) and ascorbyl-putrescine (AA-putrescine) samples showed concentration-dependent antioxidant activity in the concentration range used in the test, and the IC ₅₀ values were evaluated as 36 μM and 36.6 μM, respectively, and the IC ₅₀ value of vitamin C (ascorbic acid) used as an antioxidant control was measured as 19.4 μM.

Test Example 2: Total Antioxidant Capacity (TAC) Assay

The total antioxidant capacity of five samples, including test substances spermidine, spermine, ascorbyl-spermidine (AA-spermidine), ascorbyl-putrescine (AA-putrescine), and vitamin C (AA), was evaluated. All five samples were reacted with ^Cu2+ at concentrations of 0.67, 0.34, 0.167, 0.083, and 0.042 mM for 30 minutes, and then measured at 450 nm.

The total antioxidant capacity was calculated by subtracting the background O.D. and the absorbance ratio between the control group and the comparison group was converted into antioxidant capacity (%), as shown in Figure 7 and Table 2.

Sample

IC ₅₀ / μM

Spermidine

-

Spermin

-

Ascorbyl-spermidine

371

Ascorbyl-Putrisine

394

Vitamin C

298

As a result, as can be confirmed in Table 2 above, spermine and spermidine showed no activity, while ascorbyl-spermidine (AA-spermidine) and ascorbyl-putrescine (AA-putrescine) samples showed concentration-dependent total antioxidant activity increasing over the concentration range used in the test, and the IC ₅₀ values were evaluated as 371 μM and 394 μM, respectively, and the IC ₅₀ value of vitamin C (ascorbic acid) used as an antioxidant control was measured as 298 μM.

Test Example 3: Thermal Stability Test

The temperature stability of the test substances, ascorbyl-putrescine (AA-P), ascorbyl-spermidine (AA-SPM), and ascorbyl-spermine (AA-SM), was evaluated. The test substance samples were dissolved in distilled water to a concentration of 100 μM, and ascorbic acid (AA) as a control was dissolved in distilled water to a concentration of 100 μM, left under harsh conditions at 50°C for one week, analyzed using HPLC, and the results are shown in Fig. 8. As a result, as shown in Fig. 8, while ascorbic acid (AA) was completely oxidized and disappeared from the first day at 50°C, it was confirmed that the ascorbic acid derivatives bound to polyamines were more than 89% stable after one week.

Test Example 4: Cell Cytotoxicity Assay

This study was conducted to evaluate the cytotoxicity of test substances, ascorbic acid (AA), spermidine (SP), ascorbyl-spermidine (AA-SP), and a mixture of ascorbic acid and spermidine (AA+SP mixture), using human skin keratinocytes (HaCaT cells). HaCaT cells were seeded in a 48-well culture plate at 6.5× ¹⁰⁴ cells/well. The next day, AA, SP, AA-SP, and AA+SP mixture samples were diluted stepwise in the medium used for cell culture (DMEM 10% FBS) and treated to the cells. After culturing for 24 hours, the presence or absence of cytotoxicity was evaluated using the WST-8 cell viability assay, which is shown in Fig. 9.

The cytotoxicity of AA, SP, and AA-SP samples was expressed as % of control, and the test results showed that no cytotoxicity was observed in the concentration range of 100 μg/㎖ for all four types of samples, but at a concentration of 1 mM, the AA sample showed 60% cytotoxicity, and the AA+SP mixture sample also showed approximately 33% cytotoxicity. However, the SP sample and AA+SP sample did not show any toxicity at all.

As a result of evaluating the cytotoxicity of the test substance on human skin keratinocytes, it was confirmed that the SP alone treatment group and the ascorbyl-spermidine (AA-SP) sample treatment group showed no cytotoxicity at all in the concentration range used, compared to the group treated with the ascorbic acid (AA) sample alone and the group treated with a simple mixture of AA and SP. This confirmed that the toxicity of ascorbic acid (AA) on human skin keratinocytes was eliminated by chemically combining AA and SP.

Although the preferred embodiments of the present invention have been described above, the present invention is not limited to the specific embodiments described above, and it goes without saying that those skilled in the art can make various modifications without departing from the gist of the present invention. Therefore, the scope of the present invention should not be interpreted as being limited to the above embodiments, but should be determined not only by the claims described below but also by equivalents of the claims.

Claims (6)

An ascorbic acid derivative having a polyamine of the following chemical formula (1), a stereoisomer thereof, a salt thereof, or a solvate thereof:
[Chemical Formula 1]
. An ascorbic acid derivative having a polyamine of the following chemical formula (1), a stereoisomer thereof, a salt thereof, or a solvate thereof, and
Physiologically acceptable cosmetic base
Cosmetic composition comprising:
[Chemical Formula 1]
. A quasi-drug comprising an ascorbic acid derivative, a stereoisomer thereof, a salt thereof, or a solvate thereof, to which a polyamine of the following chemical formula (1) is bound:
[Chemical Formula 1]
. A medical device comprising an ascorbic acid derivative, a stereoisomer thereof, a salt thereof, or a solvate thereof, to which a polyamine of the following chemical formula (1) is bound:
[Chemical Formula 1]
. A method for producing an ascorbic acid derivative bound to a polyamine of chemical formula (1), wherein the compound of chemical formula 9 is reacted with 1Boc-putrescine, 2Boc-spermidine or 3Boc-spermine to produce a compound of chemical formula 10, 11 or 12, and then the protecting group is removed to produce a compound of chemical formula 1, as in the following reaction scheme 6:
[Reaction Formula 6]
. In claim 5,
A method for producing an ascorbic acid derivative bound to a polyamine of chemical formula (1), characterized in that the molar number of 1Boc-putrescine, 2Boc-spermidine or 3Boc-spermine reacting with 1 mol of the compound of chemical formula 9 is 0.8 to 2.0 mol, or 1 to 1.5 mol.