JP5718065B2 - Antibacterial agent and external preparation for skin containing the same - Google Patents

Description

  The present invention relates to an antibacterial agent effective for skin troubles such as acne and atopic dermatitis, and a skin external preparation containing the antibacterial agent.

On the human skin surface, resident skin bacteria such as Staphylococcus epidermidis exist and form a flora. Due to the action of the resident bacteria, the pH of the skin surface is kept weakly acidic, and the skin homeostasis is maintained by its barrier function. When the balance of the flora due to this resident skin bacterium is lost, it is thought to cause skin diseases such as acne and inflammation.

Acne (acne vulgaris) is said to be caused by an increase in sebum secretion, infection with Propionibacterium acnes, and the like.

In addition, in the skin lesions of patients with skin diseases such as atopic dermatitis, dermatitis, and contact dermatitis, in addition to Staphylococcus epidermidis , which is abundant on healthy human skin, Staphylococcus aureus is noticeably proliferating, causing aggravation of symptoms and itching.

  Therefore, antibacterial agents having antibacterial activity against these causative bacteria have been conventionally used for the prevention / improvement of acne and the treatment / prevention of skin diseases such as atopy. However, when such an antibacterial agent is applied, staphylococcus epidermidis that has the role of preventing the invasion of pathogenic microorganisms into the skin is often sterilized, and the bacterial distribution on the skin becomes unhealthy. There was also a problem.

  On the other hand, fatty acids having an ether bond in the main chain (about 10 to 30 carbon atoms) are used as intermediates for fine chemicals such as pharmaceuticals, agricultural chemicals, and fragrances, but some have antibacterial activity. For example, those reported to be effective against acne (Patent Document 1) and those having antibacterial activity against Staphylococcus aureus (Non-Patent Document 1) have been reported.

JP 2005-539093 A

Yoshiro Abe, Lipids, 1 (2), 141-5 (1966)

  The present invention relates to providing an antibacterial agent useful for the prevention, improvement or treatment of acne and the prevention or treatment of skin diseases such as atopic dermatitis.

As a result of investigations on various fatty acids, the present inventors have found that the fatty acid derivative having an ether bond in the main chain represented by the following formula (1), Propionibacterium acnes , and Staphylococcus aureus It has been found that it has excellent antibacterial activity and hardly exhibits antibacterial activity against Staphylococcus epidermidis and is useful as an antibacterial agent against skin diseases.

That is, the present invention relates to the following 1) to 4).
1) The following general formula (1):

[In formula, X shows a C2-C14 alkyl group, and y shows the integer of 5-15. ]
The antibacterial agent which uses the fatty acid derivative represented by these, or its salt as an active ingredient.
2) The antibacterial agent according to 1) above, wherein X is an alkyl group having 6 to 10 carbon atoms, and y is 5 to 7.
3) The antibacterial agent according to 1) or 2) above, which has antibacterial activity against at least one kind of bacteria selected from acne and Staphylococcus aureus.
4) A skin external preparation containing the antibacterial agent of 1) to 3) above.

  According to the antibacterial agent of the present invention, prevention or treatment of acne infectious skin diseases such as acne and seborrheic dermatitis, atopic dermatitis, skin, while maintaining a healthy distribution of skin resident bacteria It is possible to prevent or treat skin diseases such as pruritus and contact dermatitis.

The graph which shows the antimicrobial effect with respect to Staphylococcus epidermidis . The graph which shows the antimicrobial effect with respect to Staphylococcus epidermidis . The graph which shows the antimicrobial effect with respect to Staphylococcus aureus . The graph which shows the antibacterial action with respect to Propionibacterium acnes .

  In the formula (1) of the present invention, the alkyl group having 2 to 14 carbon atoms represented by X may be either branched or linear, for example, ethyl group, n-propyl group, isopropyl group, n- Butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, isooctyl, 2-ethylhexyl, 1,1,3 , 3-tetramethylbutyl group, 1-isopropyl-1,2-dimethylpropyl group, n-nonyl group, 3,5,5-trimethylhexyl group, n-decyl group, isodecyl group, n-undecyl group, n- Examples include dodecyl group, 1-isopropyl-1,2,4,4-tetramethylpentyl group, n-tridecyl group, n-tetradecyl group, etc., of which linear or branched one In particular, an alkyl group having 6 to 10 carbon atoms is preferable, and an n-hexyl group, an n-octyl group, a 2-ethylhexyl group, an n-decyl group, and the like are more preferable.

  As for the integer of 5-15 shown by y, 5-10 are more preferable, and 5-7 are more preferable.

Among these, X is an alkyl group having 6 to 10 carbon atoms and y is more preferably 5 to 7 from the viewpoint of antibacterial activity against acne bacteria, and X is X from the viewpoint of antibacterial activity against Staphylococcus aureus. Is an alkyl group having 2 to 10 carbon atoms, and y is more preferably 5 to 14.
Therefore, from the viewpoint of antibacterial activity against two strains of acne and Staphylococcus aureus, X is preferably an alkyl group having 6 to 10 carbon atoms, y is preferably 5 to 7 and X is 6 to 10 carbon atoms. More preferably, y is 5.

  The fatty acid derivative represented by the above formula (1) can be converted into a pharmacologically acceptable salt by a conventional method. Examples of such salts include salts with alkali metals such as sodium salts and potassium salts. Examples thereof include salts with alkaline earth metals such as calcium and magnesium, or amino acid salts such as ammonium salts, lysine salts, and arginine salts containing various amine salts, guanidine salts, aluminum salts, and zinc salts.

  Some compounds of the fatty acid derivative represented by the formula (1) are known compounds and can be produced by a known synthesis method.

For example, as shown in the following reaction formula, it is produced by a method in which an alcohol represented by formula (2) and a carboxylic acid having a halogenated alkyl chain represented by formula (3) are reacted in the presence of a basic substance. can do.
In the following formula, examples of the halogen atom represented by Z include a fluorine atom, a chlorine atom, and a bromine atom, and among these, a bromine atom is preferable.

[Wherein, X and y are the same as defined above, and Z represents a halogen atom. ]
The reaction can be performed in the presence or absence of a solvent.
The solvent in the case of using a solvent is not particularly limited as long as it does not affect the reaction. For example, ethers such as tetrahydrofuran, diethyl ether, dimethyl ether, methoxyethane, t-butyl methyl ether, isopropyl ether, dioxane and the like. Hydrocarbons such as hexane, cyclohexane, heptane, isooctane and decane; aromatic hydrocarbons such as benzene, toluene and xylene, and mixtures thereof.

Examples of basic substances include NH ₄ OH (ammonia water), alkali metal hydroxides (KOH, NaOH, etc.) and carbonates (Na ₂ CO ₃ , K ₂ CO ₃ etc.). Moreover, you may use a quaternary ammonium salt.

  The reaction is preferably carried out under a nitrogen atmosphere, usually at 0 ° C. to 120 ° C., preferably 40 ° C. to 100 ° C., for 20 minutes to 48 hours, preferably 60 minutes to 4 hours.

  After completion of the reaction, the means for isolating and purifying the obtained fatty acid derivative represented by the formula (1) can be carried out by appropriately combining neutralization, washing, extraction, recrystallization, various chromatography and the like.

The fatty acid derivative represented by the formula (1) or a salt thereof exhibits an excellent antibacterial action against acne ( Propionibacterium acnes ) and Staphylococcus aureus , as shown in the examples described later, and the epidermis. It does not show antibacterial activity against Staphylococcus epidermidis .
Here, having antibacterial activity means, for example, reducing the number of bacteria to 1/10 or less compared to control in antibacterial evaluation, and having no antibacterial activity is compared with control in antibacterial evaluation, for example. Thus, the number of bacteria is not reduced to 1/10 or less.

  Therefore, the fatty acid derivative represented by the formula (1) or a salt thereof itself prevents or treats acne-infectious skin diseases such as acne and seborrheic dermatitis, and prevents skin diseases such as atopic dermatitis. Or it can be an antibacterial agent for treatment. In addition, the antibacterial agent can be used as a composition containing other components generally used for pharmaceuticals and cosmetics, which will be described later, or as a skin external preparation.

When the above composition or external preparation for skin is used as a medicine, it can be in the form of tablets, capsules, ointments, sticks, liquids, extracts, lotions, emulsions, cataplasms, etc. Use as a topical medicine is preferred. For example, in the case of an ointment, it may be one based on an oily base, or one based on an oil-in-water or water-in-oil emulsified base. Examples of oily bases include: Examples include vegetable oils, animal oils, synthetic oils, fatty acids and natural or synthetic glycerides.
In addition, other medicinal ingredients such as analgesic / anti-inflammatory agents, bactericidal / disinfectants, astringents, emollients, hormones, antibiotics, and the like can be appropriately added to the medicament as needed.

  When used as a cosmetic, various forms such as water-in-oil or oil-in-water emulsified cosmetics, facial cleansers, skin lotions, emulsions, skin creams, foundations, lipsticks, scalp cosmetics ( Lotion, scalp refresher, etc.) and hair cosmetics (shampoo, hair tonic, hair restorer, etc.).

  The cosmetics further include oils, ceramides, pseudoceramides, sterols, humectants, antioxidants, singlet enzyme erasers, powder components, colorants, UV absorbers that are commonly used as cosmetic ingredients. , Whitening agents, alcohols, chelating agents, pH adjusters, preservatives, thickeners, pigments, fragrances, plant extracts, various skin nutrients, and the like can be added in any combination.

  In addition, pH 4-8 is preferable from the point of an effect, and pH 4-7 is more preferable from the point of an effect.

  The content of the fatty acid derivative represented by the formula (1) or a salt thereof in the composition or the external preparation for skin is preferably 0.001 to 20% by mass, and more preferably 0.01 to 5% by mass.

  The dose of the antibacterial agent of the present invention varies depending on the administration form, the animal species to be treated, individual body weight and condition, but 0.1 to 0.1 per day as the fatty acid derivative represented by formula (1) or a salt thereof 2000 mg, preferably 1 to 500 mg.

Production Example 1 Synthesis of 6-decyloxy-hexanoic acid Under a nitrogen atmosphere, 2.4 g (40 mmol) of potassium hydroxide was added to 20 mL of decanol and heated and stirred at 80 ° C. After the potassium hydroxide was dissolved, 6-bromohexanoic acid 2.0 g (10 mmol) was added and the temperature was raised to 100 ° C. After confirming the disappearance of the raw material 6-bromohexanoic acid by GC analysis, 50 mL of chloroform and 25 mL (50 mmol) of 1N sulfuric acid were added, acidified, and washed with water. After concentration, the main fraction was obtained by distillation (GC purity 94%). Since it was colored, silica gel column purification was performed, and the following 6-decyloxy-hexanoic acid (compound 1) 1.7 g (GC purity 98%, Yield 64%).

White solid, mp 31 ° C;
IR (cm ^-1 , ATR method): 2924, 2854, 1709, 1465, 1114;
¹ H-NMR (CDCL ₃ , ppm): 0.85 (t, J = 7Hz, 3H), 1.20-1.47 (m, 16H), 1.52-1.70 (m, 6H), 2.33 (t, J = 8Hz, 2H) , 3.35-3.45 (m, 4H).

Production Example 2 Synthesis of 8-octyloxy-octanoic acid In the same manner as in Production Example 1, octanol and 6-bromohexanoic acid were changed to 8-bromooctanoic acid instead of decanol, and the following 8-octyloxy-octanoic acid ( Compound 2) 1.1 g (GC purity 99%, yield 40%) was synthesized.

White solid, mp 31 ° C;
IR (cm ⁻¹ , ATR method): 2927, 2855, 1709, 1465, 1114;
¹ H-NMR (CDCL ₃ , ppm): 0.85 (t, J = 7Hz, 3H), 1.18-1.38 (m, 16H), 1.49-1.66 (m, 6H), 2.32 (t, J = 8Hz, 2H) , 3.33-3.43 (m, 4H).

Production Example 3 Synthesis of 8- (2-ethyl-hexyloxy) -octanoic acid In the same manner as in Production Example 1, instead of decanol, 2-ethylhexanol and 6-bromohexanoic acid were changed to 8-bromooctanoic acid, The following 8- (2-ethyl-hexyloxy) -octanoic acid (compound 3) 1.0 g (GC purity 99%, yield 36%) was synthesized.

Colorless oil;
IR (cm ⁻¹ , ATR method): 2957, 2929, 2857, 1709, 1462, 1109;
¹ H-NMR (CDCL ₃ , ppm): 0.80-0.90 (m, 6H), 1.18-1.40 (m, 14H), 1.45-1.65 (m, 5H), 2.32 (t, J = 8Hz, 2H), 3.20 -3.3.30 (m, 2H), 3.32-3.40 (m, 2H).

Production Example 4 Synthesis of 11- (2-ethyl-hexyloxy) -undecanoic acid In the same manner as in Production Example 1, instead of decanol, 2-ethylhexanol and 6-bromohexanoic acid were changed to 11-bromoundecanoic acid, The following 11- (2-ethyl-hexyloxy) -undecanoic acid (compound 4) 1.4 g (GC purity, 98%, yield 46%) was synthesized.

Colorless oil;
IR (cm ⁻¹ , ATR method): 2925, 2855, 1709, 1463, 1111;
¹ H-NMR (CDCL ₃ , ppm): 0.80-0.90 (m, 6H), 1.18-1.40 (m, 20H), 1.45-1.65 (m, 5H), 2.32 (t, J = 8Hz, 2H), 3.20 -3.3.30 (m, 2H), 3.32-3.40 (m, 2H).

Production Example 5 Synthesis of 11-isobutyroxy-undecanoic acid In the same manner as in Production Example 1, isobutanol and 6-bromohexanoic acid were changed to 11-bromoundecanoic acid instead of decanol, and the following 11-isobutyroxy-undecanoic acid was used. (Compound 5) 1.8 g (GC purity, 98%, yield 68%) was synthesized.

White solid, mp 42 ° C;
IR (cm ⁻¹ , ATR method): 2951, 2918, 2853, 1696, 1472, 1112;
¹ H-NMR (CDCL ₃ , ppm): 0.85-0.95 (m, 6H), 1.20-1.40 (m, 12H), 1.50-1.68 (m, 4H), 1.78-1.92 (m, 1H), 2.34 (t , J = 7Hz, 2H), 3.17 (q, J = 7Hz, 2H), 3.39 (t, J = 7Hz, 2H).

Production Example 6 Synthesis of 15-ethoxy-pentadecanoic acid In the same manner as in Production Example 1, ethanol and 6-bromohexanoic acid were replaced with methyl 15-iodopentadecanoate instead of decanol, and methyl 15-ethoxy-pentadecanoate. Thereafter, hydrolysis was performed to synthesize 1.3 g of 15-ethoxy-pentadecanoic acid (Compound 6) (GC purity 98%, yield 78%).

White solid, mp 53 ° C;
IR (cm ⁻¹ , ATR method): 2979, 2915, 2849, 1698, 1471, 1111;
¹ H-NMR (CDCL ₃ , ppm): 1.20 (t, J = 7Hz, 3H), 1.22-1.42 (m, 20H), 1.50-1.70 (m, 4H), 2.35 (t, J = 7Hz, 2H) , 3.38-3.58 (m, 4H).

Production Example 7 Synthesis of 6-octyloxy-hexanoic acid As in Production Example 1, 1.2 g of the following 6-octyloxy-hexanoic acid (compound 7) (GC purity, 98%, Yield 50%) was synthesized.

Pale yellow oil;
IR (cm ⁻¹ , ATR method): 2931, 2858, 1708, 1113;
¹ H-NMR (CDCL ₃ , ppm): 0.85 (t, J = 7Hz, 3H), 1.20-1.34 (m, 10H), 1.35-1.43 (m, 2H), 1.50-1.60 (m, 4H), 1.60 -1.67 (m, 2H), 2.34 (t, J = 7Hz, 2H), 3.34-3.40 (m, 4H).

Reference Production Example 1 Synthesis of 6- (2-hexyloxy-ethoxy) -hexanoic acid In the same manner as in Production Example 1, instead of decanol, 2-hexyloxy-ethanol was used and 6- (2-hexyloxy-ethoxy)- 0.9 g of hexanoic acid (Comparative Compound 1) (GC purity 99%, yield 36%) was synthesized.

Colorless oil;
IR (cm ⁻¹ , ATR method): 2931, 2860, 1736, 1708, 1458, 1115;
¹ H-NMR (CDCL ₃ , ppm): 0.86 (t, J = 7Hz, 3H), 1.20-1.50 (m, 10H), 1.50-1.75 (m, 4H), 2.32 (t, J = 7Hz, 2H) , 3.39-3.54 (m, 4H), 3.55 (bs, 4H).

Reference Production Example 2 Synthesis of 8- (2-hexyloxy-ethoxy) -octanoic acid In the same manner as in Production Example 1, instead of decanol, 2-hexyloxy-ethanol and 6-bromohexanoic acid were changed to 8-bromooctanoic acid. Thus, 1.9 g of 8- (2-hexyloxy-ethoxy) -octanoic acid (Comparative Compound 2) (GC purity 98%, yield 65%) was synthesized.

Colorless oil;
IR (cm ⁻¹ , ATR method): 2930, 2857, 1737, 1709, 1457, 1113;
¹ H-NMR (CDCL ₃ , ppm): 0.86 (t, J = 7Hz, 3H), 1.20-1.38 (m, 12H), 1.50-1.65 (m, 6H), 2.32 (t, J = 7Hz, 2H) , 3.39-3.48 (m, 4H), 3.55 (bs, 4H).

Test Example (1) Strain used Staphyllococus epidermidis NBRC12993 as Staphylococcus epidermidis , Staphyllococus aureus NBRC13276 as Staphylococcus aureus , and Propionibacterium acnes JCM6425 as acne.

(2) Media used SCD agar (Daigo) is used for culturing Staphylococcus epidermidis and Staphylococcus aureus, modified GAM agar (Nissui) is used for acne, and malassezia is used for culture. YM agar medium (manufactured by DIFCO) or YMOLP agar medium (YM agar 4.1%, LP diluent (manufactured by Daigo) 3.0%, olive oil 1.0%) was used. For measuring the number of cells, the above-mentioned agar medium added with an LP diluent was used.

(3) Antibacterial evaluation against Staphylococcus epidermidis
Sorbitan monostearate was added to 4.5 mL of 50 mM phosphate buffer (1 potassium and 2 potassium) adjusted to pH = 6 to a final concentration of 0.1% and a sample concentration of 0.01% (control is sorbitan monostearate only). Added at a final concentration of 0.01%). Staphylococcus epidermidis cultured at 30 ° C. for 2 days was suspended in physiological saline to a final concentration of 10 ⁵ to 10 ⁷ cells / mL, and 0.5 mL of this suspension was inoculated into the prepared solution. After thoroughly mixing and leaving at 30 ° C. for a predetermined time, 50 μL was taken from the solution. After inactivation with 5 mL of LP diluent, the solution was appropriately diluted with LP diluent and applied to an agar medium for counting the number of cells. After culturing at 30 ° C., the number of colonies grown was counted.
As a result, none of the compounds showed antibacterial activity against Staphylococcus epidermidis (Figs. 1 and 2).

(4) Evaluation of antibacterial activity against Staphylococcus aureus In the same manner as in Example 1, the antibacterial activity was evaluated by changing Staphylococcus epidermidis to Staphylococcus aureus (all sample concentrations were evaluated at 0.01%).
As a result, compounds 1, 2, 3, 4, 5, 6, and 7 showed a high antibacterial effect (FIG. 3).

(5) Antibacterial evaluation against acne
Sorbitan monostearate was added to 4.5 mL of 50 mM phosphate buffer (1 potassium and 2 potassium) adjusted to pH = 6 so that the final concentration was 0.01% and the sample concentration was 0.01% (control was only sorbitan monostearate). Added at a final concentration of 0.01%). Acne bacteria cultured for 5 days at 37 ° C. under anaerobic conditions were suspended in physiological saline to a final concentration of 10 ⁵ to 10 ⁷ cells / mL, and 0.5 mL of this suspension was inoculated into the above preparation. After thoroughly mixing and leaving under anaerobic conditions at 37 ° C. for a predetermined time, 50 μL was collected from the solution. After inactivation with 5 mL of LP diluent, the solution was appropriately diluted with LP diluent and applied to an agar medium for counting the number of cells. After culturing at 37 ° C under anaerobic conditions, the number of colonies grown was counted.
As a result, compounds 1, 2, 3, and 7 were found to have a high inhibitory effect against acne bacteria (FIG. 4).

Claims (2)

The following general formula (1):

[In formula, X shows a C2-C14 alkyl group, and y shows the integer of 5-15. ]
The antibacterial agent with respect to 1 or more types chosen from the acne bacteria and Staphylococcus aureus which use the fatty acid derivative represented by these, or its salt as an active ingredient.   The antibacterial agent according to claim 1, wherein X is an alkyl group having 6 to 10 carbon atoms, and y is 5 to 7.

Images