WO2020122341A1 - Novel cinnamic acid derivative and antibacterial composition comprising same - Google Patents

Abstract

The present invention relates to a novel cinnamic acid derivative having an excellent antibacterial effect and an antibacterial composition comprising same. Specifically, the present invention relates to an antibacterial composition comprising a cinnamic acid derivative having antibacterial activity against bacteria contaminating cosmetic products and, more specifically, to an antibacterial composition comprising a cinnamic acid derivative as an active ingredient against microorganisms contaminating cosmetic products and a cosmetic composition comprising same. The cinnamic acid derivative exhibits a broad spectrum of antibacterial activities against various bacteria and thus, the antibacterial composition comprising same can be advantageously used for sterile, antibacterial, and antiseptic purposes in various fields such as cosmetic products, medicines, daily supplies, agricultural chemicals, etc.

Description

New cinnamon acid derivative and antimicrobial composition comprising the same

This application claims priority based on Republic of Korea Application No. 10-2018-0162125 filed on December 14, 2018, and all contents disclosed in the specification and drawings of the application are incorporated in this application.

The present invention relates to a novel cinnamic acid derivative having excellent antibacterial effect. More particularly, the present invention relates to a novel cinnamic acid derivative having an antimicrobial effect and excellent water solubility and a composition comprising the same.

Many products, such as foods, medicines, household goods, and cosmetics, which are widely used in our lives, contain various materials such as moisturizers, oils, surfactants, inorganic powders, organic water-soluble polymers, and fragrances, and are suitable for growing microorganisms. to be. Therefore, it is common to add a chemical preservative to prevent product decay by microorganisms and to kill microorganisms over time to prevent product degradation. As such a chemical preservative, paraben, imidazolidinyl urea, phenoxy ethanol, paraoxybenzoic acid ester or benzalkonium chloride is generally used.

However, as new additives such as proteins, gums, vitamins, and medicinal plants have recently been added to the product, changes that occur due to the action of microorganisms are diversified and the preservative effect by chemical preservatives is weakened, and as the content of chemical preservatives increases, the skin Human irritation problems such as stimulation and allergic symptoms are being raised.

Accordingly, there is a need for new products that do not contain chemical preservatives or contain small amounts, which are not contaminated by microorganisms.

On the other hand, cinnamic acid and cinnamon aldehydes, which are natural products, are known to have antibacterial effects and are used in part, but first, they have low solubility (0.05% cinnamic acid and 0.2% 4-hydroxy cinnamic acid), and secondly, the applied pH changes from acidic to neutral. As it has a problem of losing activity, it has been difficult to apply for preservation in cosmetics and human products. It is also characteristic of preservatives in the general acid form. Ethyl ferulate among cinnamic acid derivatives is listed as a cosmetic raw material for antioxidant and preservative use, but it is hardly soluble in water and no examples have been used as product preservatives.

Numerous references are cited and cited throughout this specification. The disclosure content of the cited documents is incorporated by reference herein in its entirety and the level of the technical field to which the present invention pertains and the content of the present invention are more clearly described.

The present inventors synthesized cinnamic acid amide derivatives of a novel structure as a result of research efforts to provide a compound derived from natural substances that can be prescribed for cosmetics and human products, and can replace preservatives, and these compounds have excellent antibacterial effects and excellent Since it has solubility, the present invention was completed by confirming that it is applicable to cosmetics and human products as a preservative.

Accordingly, an object of the present invention is to provide a novel cinnamic acid derivative compound having both antibacterial activity and water solubility.

Another object of the present invention is to provide a composition comprising the novel cinnamic acid derivative compound.

Another object of the present invention is to provide products such as food, pharmaceuticals, quasi-drugs, household goods, and cosmetics containing the novel cinnamic acid derivative compounds.

Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.

One aspect of the present invention is to provide a cinnamic acid derivative compound represented by Formula 1 below.

<Formula 1>

In the above formula,

R ₁ is hydrogen, C ₁ -C ₂ alkyl, OH, OCH ₃ , Cl or Br,

R ₂ is hydrogen, C ₁ -C ₂ alkyl, OH, OCH ₃ , Cl or Br, R ₃ is hydrogen, C ₁ -C ₂ alkyl, OH, OCH ₃ , Cl or Br; Or R ₂ and R ₃ are connected to each other to form a heterocycle containing an oxygen atom,

A is NHR ₂₁ ,

or

ego,

Where R ₂₁ is (CH ₂ ) _m R ₂₁₁ , m is an integer from 1 to 2, and R ₂₁₁ is

ego;

R ₂₂ is hydrogen, C ₁ -C ₂ alkyl, or

Wherein R ₂₂₁ is hydrogen, C ₁ -C ₂ alkyl, OH, OCH ₃ , Cl or Br.

Since the compound of the present invention has been little structurally studied, it was possible to significantly increase the solubility by introducing an alkylamide group or a cyclic amide group to cinnamic acid, and loses its activity when an acidic cinnamic acid compound is added to a neutral composition. Unlike it, it was confirmed that the compound of the present invention does not lose its activity even under a neutral pH condition and can be used by prescribing various pH conditions of cosmetics and human products.

A preferred example of the cinnamic acid derivative of Formula 1 according to the present invention is a compound selected from Formulas 2 to 3 below.

<Formula 2>

<Formula 3>

In addition, the novel cinnamic acid derivative according to the present invention may be exemplified by the following compounds, but the following compounds are not intended to limit the present invention.

An example of the synthetic reaction of the cinnamic acid derivative compounds of Formula 1 according to the present invention is shown in Scheme 1 below.

<Scheme 1>

As shown in Reaction Scheme 1, the compound of Formula 1 may be synthesized through a coupling reaction between a cinnamic acid derivative and a primary or secondary amine derivative.

In the present invention, the cinnamic acid derivative is used as a preservative, and can exhibit excellent antibacterial and antiseptic effects. Specifically, the antimicrobial composition of the present invention may preferably have antibacterial activity against bacteria, fungi or yeast, more preferably Escherichia coli, Pseudomonas aeruginosa, Candida albicans, Black mold (Aspergillus niger) may have antibacterial activity at the same time, but is not limited thereto.

In the present invention, the term "antibacterial" refers to the ability to resist bacteria, and means all mechanisms that are made to defend against the action of microorganisms such as bacteria, fungi, mold, yeast, and the like. It was confirmed that the composition containing the cinnamic acid derivative of the present invention has excellent antibacterial activity against microorganisms including bacteria, fungi and yeast.

In the present invention, the term "bacteria" is a creature belonging to bacteria, the most prosperous species among living organisms, most of which are pathogenic bacteria and have the characteristics of prokaryotes, but do not have a nuclear membrane, mitochondrial, chloroplast-like structure. Sizes range from 0.5 μm to 0.5 mm. Such bacteria include, but are not limited to, Staphylococcus aureus ATCC 6538, Pseudomonas aeruginosa ATCC 15522, Escherichia coli ATCC10536, and the like. no.

In the present invention, the term, "fungus" collectively refers to a group of microorganisms composed of more than 72,000 species including fungi, yeast, mushrooms, belongs to eukaryotic organisms with a nuclear membrane, and cell organelles such as mitochondria, vesicles are developed, There are cell walls composed of chitin and glucan. Most of them are characterized by forming a mycelium that is cellular, renal, developing, and sexual and asexual reproduction. It forms a spore as a propagation body, but some fungi have unicellular proliferation. As a by-product, it is mainly involved in organic decomposition in nature, but some parasitic or symbiotic with plants and animals. The fungi include, but are not limited to, Aspergillus niger ATCC 9642 and Candida albicans ATCC 10231, for example.

In the present invention, cinnamic acid derivative is used as a preservative, it can exhibit excellent antibacterial and antiseptic effect, and the content of the cinnamic acid derivative for this is 0.1 to 10% by weight (w/v) or 0.5 to 2% by weight of the total composition %(w/v). It has excellent antibacterial and preservation effect in the above content range. This is because if the content of the cinnamic acid derivative is less than 0.1% by weight, it does not greatly help the antibacterial and antiseptic effect, and when it exceeds 10% by weight, there is no increase in the apparent effect of increasing the content.

In addition, the human body composition of the present invention may further include a chemical preservative in addition to the cinnamic acid derivative. In this case, the cinnamic acid derivative may be used together with a chemical preservative to produce a synergistic effect, thereby exhibiting more excellent antibacterial and antiseptic effects. Specifically, the cinnamic acid derivative exhibits excellent antibacterial and antiseptic effects, and thus, even when a small amount of a chemical preservative is used, it can exhibit excellent antibacterial and antiseptic effects. Therefore, unlike the conventional cosmetic composition using an excessive amount of chemical preservatives causes skin side effects such as skin irritation and allergies, the human body composition of the present invention hardly causes skin side effects such as skin irritation and allergies.

The chemical preservatives include, for example, 3-hexyloxy-1,2-propanediol, 1,2-hexanediol, polyols such as octanediol, parabens such as methylparaben, ethylparaben or propylparaben, And it may be used by mixing one, or two or more selected from the group consisting of phenoxyethanol and the like.

The content of the chemical preservative may be 0.01 to 30% by weight, 0.1 to 10% by weight or 0.5 to 5% by weight based on the total weight of the total composition. In the above range, the synergistic effect with the cinnamic acid derivative is excellent, and if it exceeds 30% by weight, skin side effects such as skin irritation and allergy may occur.

In addition, the cinnamic acid derivative compound of the present invention may have antibacterial activity and water solubility at the same time. In this case, the water solubility of the cinnamic acid derivative compound at room temperature (15 to 25°C) is 1 to 10%, preferably 1.5 to 5%, and 100 g of room temperature water contains 1 to 10 g of compounds, preferably 1.5 to 5 g. Can dissolve.

Another aspect of the present invention is to provide a composition characterized in that it comprises the cinnamic acid derivative compound, or a salt, hydrate or solvate thereof.

The salts include inorganic acids such as hydrochloride, hydrobromide or hydroiodide, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, p-toluenesulfonate, bisulfate, sulfamate, sulfate, Naphthylate, butyrate, citrate, camphorate, camposulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, hep Formed with organic acids such as tanoate, hexanoate, 2-hydroxyethanesulfate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, tosylate or undecanoate Can be.

Hydrate refers to a substance in which water is added to the compound or water enters as a constituent substance of the molecule, and a solvate refers to a higher-order compound formed between a molecule or ion of a solute and a molecule or ion of a solvent. The hydrate or solvate may be prepared using the above-described acids.

The composition may be an antimicrobial composition, in which case it may be used with other ingredients, and may be appropriately formulated according to conventional methods. These other ingredients may be optionally selected and formulated according to the formulation or purpose of use of the antibacterial composition. For example, it may include a thickening agent, a stabilizer, a solubilizing agent, conventional adjuvants such as vitamins, pigments and fragrances, and a carrier.

The antimicrobial composition of the present invention can be added to the cosmetic composition, antiseptic composition, pharmaceutical composition and quasi-drug composition for antibacterial. The antimicrobial composition containing the cinnamic acid derivative of the present invention as an active ingredient can be applied to any formulation, such as, for example, liquid, creamy, pasty, and solid phases, and its use can be applied to various fields. For example, it can be applied to various cosmetic compositions such as human body-related cleaners such as whole body, skin, oral cavity, and hair.

When the composition of the present invention is a cosmetic composition, it may be variously formulated in the form of cosmetics known in the art, and additional ingredients may be arbitrarily selected according to the formulation and purpose of use and appropriately formulated. For example, it may include conventional ingredients such as thickeners, surfactants, moisturizers, abrasives, sweeteners, pH adjusting agents, preservatives, binders, wetting agents, foaming agents, stabilizers, solubilizing agents, vitamins, pigments and flavoring agents.

Another aspect of the present invention is to provide a product selected from the group consisting of food, pharmaceuticals, quasi-drugs, household products and cosmetics, as a product comprising the aforementioned composition.

The food includes, but is not limited to, general 　 food, health supplement food, health functional food, functional 　 food, skin beauty 　 food, animal food, and the like. The addition of the composition of the present invention to natural foods, processed foods, general food materials, etc. is also included in the scope of the foods of the present invention.

The above medicine means a product used to treat diseases or relieve symptoms, including over-the-counter medicines, specialty medicines, oriental medicines, and animal medicines.

Quasi-drugs include, but are not limited to, oral preparations, pesticides, pesticides, fungicides, disinfectants, anti-odor agents, soaking agents, contact lens care products, ointments, external disinfectants, vitamins and nutrient toners.

Household goods include, but are not limited to, cleaning agents, laundry detergents, fabric softeners, dishwashing agents, fragrances, waxes, emulsifiers, lubricants, and the like.

Cosmetics are products that are used in a similar way to clean and beautify the human body, add attractiveness, change the appearance brightly, or apply, rub, or spray on the human body to maintain or promote the health of the skin and hair. It refers to cosmetics for infants and toddlers, bath products, human body cleaning products, eye cosmetic products, fragrance products, hair dye products, color makeup products, hair products, nail products, shaving products, basic makeup products, And products for preventing body odor, but are not limited thereto.

Since the novel cinnamic acid derivative compound of the present invention has excellent water solubility with antibacterial activity, it has the advantage that it can be widely prescribed in various products, including water-based food, pharmaceuticals, quasi-drugs, household goods and cosmetics.

The novel cinnamic acid derivative according to the present invention has improved solubility, so it can be easily prescribed without the use of separate emulsifiers and solubilizers. It has stability under various pH conditions and excellent resistance to microorganisms. It can be used in various ways in the field of human products.

Hereinafter, the present invention will be described in more detail through examples. These examples are only for explaining the present invention in more detail, it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples.

Example

1. Synthesis of cinnamonic acid derivatives

Among the cinnamic acid derivatives represented by [Chemical Formula 1] according to the present invention, CA-9, which is a representative example, was prepared as follows.

Specifically, according to <Scheme 2>, 4-methoxy cinnaaldehyde (1) (5 g, 28 mmol, 1 eq) and thionyl chloride (3 mL, 42 mmol, 1.5 eq) were added to 30 mL of diclomethane and 50 The mixture was stirred for 4 hours. After completion of the reaction, the residual thionyl chloride and solvent were removed under reduced pressure to obtain 4-methoxy cinnamic acid chloride (2) in a liquid state with a dark yellow high viscosity. The 4-methoxy cinnamic acid salt (2) obtained in the above reaction was dissolved in 50 mL of dichloromethane, methyl piperazine (8.4 g, 84 mmol) was slowly dropped, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the resulting amine salt solid was removed with a celite filter, and the organic layer was washed twice with purified water. The combined organic layers were dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain CA-9 as a pale yellow solid (6.9 g, 94.7%). 1H NMR (400 MHz, CDCl3-d3) δ 2.3 (s, 3H), 2.42-2.44 (m, 4H), 3.68-3.71 (m, 4H), 3.78 (s, 3H), 6.73 (d, J = 15.2 , 1H), 6.85 (d, J=8.4, 2H) 7.43 (d, J=8.4, 2H), 7.61 (d, J=15.2, 1H).

<Reaction Scheme 2>

Cinnamic acid derivatives containing different substituents represented by [Chemical Formula 1] according to the present invention were prepared by the same reaction principle as the preparation example of CA-9, and compounds synthesized by nuclear magnetic resonance analysis were confirmed. The cinnamic acid derivatives of the present invention thus prepared and their NMR data are summarized in Table 1 below.

2. Minimum microbial inhibitory concentration ( MIC ) evaluation

The minimum inhibitory concentration (MIC) of cinnamic acid derivative was measured. Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa pre-cultured in liquid medium were cultured at 37° C. for 24 hours in 5 ml of brain heart infusion broth. , Candida albicans, Aspergillus niger were prepared by incubating potato dextrose broth in 5 ml at 30°C for 48 hours. A 2-fold dilution method was used to measure the MIC of the fermentation culture. Table 2 shows the results of the measurement of the minimum inhibitory concentration.

Sample	Bacteria (ppm)			Fungi (ppm)
	S. aureus	E. coli	P. aeruginosa	C. albicans	A. niger
CA-9	313	313	625	313	313
CA-12	1250	625	625	313	313
CA-13	1250	>2500	1250	313	313
CA-16	625	625	625	313-	313
CA-17	625	625	625	313	313

As a result of the experiment, it was confirmed that the cinnamic acid derivative compounds of the present invention have excellent antibacterial effects.

3. Water solubility test

(1) logP value analysis

The logP (partition coefficient between octanol and water) is a property commonly used in new drug development. The lower the value, the higher the polarity and the higher the water solubility. The logP values of various types of cinnamic acid derivative compounds were analyzed and the results are shown in Table 3 below.

As a result of evaluating the logP value for physical properties having a high water solubility with respect to the above compounds, the logP value of compounds 11 to 14 (CA-2, CA-14, CA-9 and CA-17 compounds) is 1.4 or less. As a result, it was confirmed that it has properties that can be easily prescribed to cosmetics and household products containing water as a main component. Compound 5 was evaluated to have a logP value of 1.35, but the MIC was not able to be measured because of poor water solubility. The water solubility was 0.005%, and the water solubility was significantly lower than that of CA-9, which was 2%.

(2) Water solubility measurement

The water solubility of cinnamic acid and cinnamic acid derivatives was measured and compared to Table 4 below. CA-9 developed in the present invention has 2% water solubility at room temperature, and when heated to 40°C, it showed excellent results in that it dissolves well up to 5%.

	Cinnamon	Cinnamic acid methyl ester	Cinnamic acid aldehyde	CA-9
Water solubility (%)	0.05	Insolubls	Slightly soluble	2

4. Preparation of shampoo containing cinnamonic acid derivatives and confirmation of antibacterial effect

Emulsion-type shampoo was prepared by a conventional method using the composition components and contents shown in Table 5 below. The CA-9 and CA-12 compounds of the present invention were prepared using these two compounds because they were found to have high water solubility enough to produce an emulsion-type shampoo based on water.

Ingredient name	Example 1	Example 2	Example 3	Example 4
CA-9	0.5	1.0	2.0
CA-12				2.0
Purified water	To 100	To 100	To 100	To 100
Sodium laureth-2 sulfate	20	20	20	20
Cocamidopropyl Betaine	20	20	20	20
Polyquaternium-10	0.5	0.5	0.5	0.5
IDT 4 Sodium	0.05	0.05	0.05	0.05
Citric acid	0.04	0.4	0.04	0.04

To test the antimicrobial and antiseptic effect of the compositions of Examples 1 to 4 prepared above, bacteria or fungi were added to the sample and the change in the number of inoculum bacteria was checked, and the number of fungi or bacteria started to be 20 CFU/g or less. Recorded and shown in Table 6 below. Measurements were made up to 28 days, and the test procedure is as follows.

First, after containing the cosmetic composition 40 g each, bacteria, that is, Staphylococcus aureus (Staphylococcus aureus ATCC 6538), Sedmonas aeruginosa (Pseudomonas aeruginosa ATCC 15522) and Escherichia coli (Escherichia coli ATCC10536) The mixture was added to the sample so that the number of 106 animals per 1 g of the sample was mixed and stored for 4 weeks. Then, the change in the number of inoculum bacteria was checked every time 1 day, 7 days 14 days, 21 days, and 28 days elapsed from the day of inoculation.

The test procedure using fungi is the same as the test procedure using bacteria, and Aspergillus niger ATCC 9642 and Candida albicans ATCC 10231 were used as fungi.

Evaluation items	The day the number of inoculum bacteria started to reach 20 CFU/g or less
	Example 1	Example 2	Example 3	Example 4
Germ	14 days	7 days	7 days	7 days
Fungi	14 days	14 days	7 days	14 days

As a result of the experiment, Example 1 of the present invention was found to have excellent antibacterial and antiseptic effect by showing the number of fungi or bacteria below 20 CFU/g from the 14th day even though no chemical preservative was used. In particular, in the case of Example 3 containing more than 2% by weight of cinnamic acid derivatives, the number of fungi and bacteria rapidly decreased, indicating the number of fungi or bacteria of 20 CFU/g or less from the 7th day, and it was confirmed that the antibacterial and antiseptic effect was much better. Can be.

Claims (11)

1. Cinnamic acid derivative compound represented by the following formula (1):

   <Formula 1>

   

   In the above formula,

   R ₁ is hydrogen, C ₁ -C ₂ alkyl, OH, OCH ₃ , Cl or Br,

   R ₂ is hydrogen, C ₁ -C ₂ alkyl, OH, OCH ₃ , Cl or Br, R ₃ is hydrogen, C ₁ -C ₂ alkyl, OH, OCH ₃ , Cl or Br; Or R ₂ and R ₃ are connected to each other to form a heterocycle containing an oxygen atom,

   A is NHR ₂₁ ,

   

   or

   

   ego,

   Where R ₂₁ is (CH ₂ ) _m R ₂₁₁ , m is an integer from 1 to 2, and R ₂₁₁ is

   

   ego;

   R ₂₂ is hydrogen, C ₁ -C ₂ alkyl, or

   

   Wherein R ₂₂₁ is hydrogen, C ₁ -C ₂ alkyl, OH, OCH ₃ , Cl or Br.
2. The compound of claim 1, wherein the cinnamic acid derivative compound is selected from the group consisting of the following Chemical Formulas 2 to 14:

   

   .
3. The compound of claim 1 or 2, wherein the cinnamic acid derivative compound is represented by the following Chemical Formula 2, Chemical Formula 3 or Chemical Formula 13:

   
4. The compound according to any one of claims 1 to 3, wherein the compound has antibacterial activity.
5. The compound according to any one of claims 1 to 4, wherein the compound has antibacterial activity and water solubility at the same time, and the water solubility of the compound at room temperature is 1 to 10%.
6. An antibacterial composition comprising the compound of any one of claims 1 to 5, or a salt, hydrate or solvate thereof, or an antibacterial use thereof.
7. The composition of claim 6, wherein the composition comprises the compound, or a salt, hydrate or solvate thereof, in an amount of 0.1 to 10% by weight.
8. The composition or use thereof according to claim 6 or 7, wherein the composition is a pharmaceutical composition for antibacterial use.
9. The composition or use thereof according to any one of claims 6 to 8, wherein the composition is an antibacterial cosmetic composition.
10. A product comprising the composition of any one of claims 6 to 9, characterized in that it is selected from the group consisting of food, pharmaceuticals, quasi-drugs, household goods and cosmetics.
11. A method for inhibiting microbial growth by using the composition of any one of claims 6 to 9.