JP4210573B2 - Substituted phenoxypropanolamines - Google Patents

Description

  The present invention relates to substituted phenoxypropanolamines having excellent tyrosinase inhibitory activity and useful as a whitening agent.

Various hydroquinone alkyl ethers and the like (Patent Documents 1 to 6) are known as whitening agents having tyrosinase inhibitory activity. However, these hydroquinone alkyl ethers have low solubility in water, and it may be difficult to mix them in a high-concentration skin external preparation. Arbutin has a high solubility in water and is a whitening agent actually used in cosmetics. However, arbutin is a glycoside, and there is a concern that the glycoside is generally chemically unstable.
JP-A-1-269498 JP-A-6-192062 Japanese Patent Laid-Open No. 61-159943 Japanese Patent Laid-Open No. 63-246311 JP-A-2-270812 JP-A-4-54109

  Accordingly, an object of the present invention is to provide a compound having excellent tyrosinase inhibitory activity, chemically stable and good water solubility, a whitening agent using the compound, and a skin external preparation containing the compound.

  The present inventors have synthesized various compounds using tyrosinase inhibitory activity as an index, and substituted phenoxypropanolamines represented by the following formula (1) have strong tyrosinase inhibitory activity and are chemically stable. And it was found to be useful as a whitening agent because of its excellent water solubility.

  That is, the present invention relates to the general formula (1)

(Wherein X ¹ represents a hydroxy group or a carboxyl group;
R ¹ represents a hydrogen atom or an alkyl group having 2 to 12 carbon atoms which may be substituted with 1 to 3 hydroxy groups;
R ² represents an alkyl group having 2 to 12 carbon atoms substituted with 1 to 3 hydroxy groups), and a method for producing the same.
Moreover, this invention provides the skin external preparation and whitening agent containing the said substituted phenoxypropanolamine or its salt.

  The substituted phenoxypropanolamines or salts thereof of the present invention are useful as a skin external preparation typified by whitening cosmetics because they are chemically stable, have excellent water solubility, and have excellent tyrosinase inhibitory activity. It is.

In general formula (1), the alkyl group having 2 to 12 carbon atoms which may be substituted with 1 to 3 hydroxy groups represented by R ¹ is a linear or branched alkyl group having 2 to 12 carbon atoms. And a straight chain or branched chain alkyl group having 2 to 12 carbon atoms substituted with 1 to 3 hydroxy groups. Here, as the alkyl chain part of the linear or branched alkyl group having 2 to 12 carbon atoms and the linear or branched alkyl group having 2 to 12 carbon atoms substituted with 1 to 3 hydroxy groups, , Ethyl group, n-propyl group, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, n-butyl group, n-pentyl group, n-hexyl group, n-octyl group, n-decyl group, n-dodecyl group etc. are mentioned, Among these, a C2-C6 linear or branched alkyl group is preferable, Furthermore, a C2-C4 linear or branched alkyl group is preferable.

From the viewpoint of water solubility, R ² is preferably a linear or branched alkyl group having 2 to 12 carbon atoms substituted with 1 to 3 hydroxy groups. As such an alkyl group substituted with a hydroxy group, one in which 1 to 3 hydroxy groups are substituted on the above-described linear or branched alkyl group is preferable. Specifically, a 2-hydroxyethyl group 2-hydroxy-1-methylethyl group, 3-hydroxypropyl group, 4-hydroxybutyl group, 2-hydroxy-1-hydroxymethylethyl group, 2-hydroxy-1,1-bishydroxymethylethyl group, etc. It is done.

R ¹ is a hydrogen atom or an alkyl group having 2 to 6 carbon atoms substituted with 1 to 3 hydroxy groups, and R ² is 2 carbon atoms substituted with 1 to 3 hydroxy groups. More preferred is an alkyl group of ˜6.

R ¹ is a hydrogen atom or a linear or branched alkyl group having 2 to 4 carbon atoms substituted with 1 to 3 hydroxy groups, and R ² is substituted with 1 to 3 hydroxy groups More preferably, it is a linear or branched alkyl group having 2 to 4 carbon atoms.

  Furthermore, a compound represented by the following formula is particularly preferable.

Salts of substituted phenoxypropanolamines (1) include mineral acid salts such as phosphoric acid, hydrochloric acid, sulfuric acid and nitric acid; organic acid salts such as citric acid, tartaric acid and lactic acid; alkali metals such as sodium, potassium and calcium Alkaline earth metal salts; amphoteric metal salts such as aluminum and zinc; amino acid salts; amine salts and the like. Further, since it has both a phenolic hydroxyl group or carboxyl group and an amino group of X ^1, inner salt may be formed. Furthermore, although the compound of the present invention may have an optical isomer depending on the types of R ¹ and R ² , both the optically active substance and the optically inactive substance are included in the present invention.

  The substituted phenoxypropanolamines (1) or salts thereof of the present invention can be produced, for example, according to the following reaction formula.

(Wherein, X ² represents a protected hydroxy group or a protected carboxyl group, and R ¹ , R ² and X ¹ are the same as above)

  That is, the substituted phenoxypropanolamine of the present invention or a salt thereof is prepared by reacting the oxirane compound represented by the general formula (2) with the amine (3) and then removing the protective group for the hydroxy group or carboxyl group. Is manufactured.

In the protected hydroxy group or carboxyl group represented by X ² , the protective group used is not particularly limited as long as it can withstand the reaction conditions of the oxirane compound and the amine. Aralkyl groups such as benzyl group, methoxymethyl group, ethoxymethyl group and the like, and examples of the protecting group for carboxyl group include benzyl ester group, alkyl ester groups such as methyl and ethyl, and the like.

  The reaction of the oxirane compound (2) and the amines (3) may be performed at room temperature to reflux temperature in a solvent such as no solvent or lower alcohol for 1 to 48 hours. Further, the removal reaction of the protective group for the hydroxy group or the carboxyl group may be carried out according to a conventional method. For example, when a benzyl group is used as the protective group for the hydroxy group, a normal hydrogenation reaction is preferred, When an alkyl ester group is used as the group, it is preferably carried out by an alkali hydrolysis reaction.

  After completion of the reaction, the target product can be isolated and purified from the reaction mixture by conventional methods such as washing, extraction, distillation or recrystallization, various chromatographies and the like. The conversion to the desired salt may be performed according to a conventional method.

  The substituted phenoxypropanolamines or salts thereof of the present invention have a tyrosinase activity inhibitory action and are useful as whitening agents. Moreover, the solubility with respect to neutral or acidic aqueous solution is also favorable, and it is chemically stable, and can be applied to various forms of external skin preparations.

  The skin external preparation of the present invention contains the substituted phenoxypropanolamines (1) or a salt thereof, and the content thereof is usually 0.001 to 20% by mass in the total amount of the external preparation from the viewpoint of whitening effect, and is further preferably 0.00. 001 to 10% by mass, particularly 0.005 to 5% by mass is preferable.

  The external preparation for skin of the present invention includes other components usually used in cosmetics and pharmaceuticals in addition to the above components, such as oils, ultraviolet absorbers, antioxidants, surfactants, moisturizers, fragrances, water, alcohols, thickening agents. Agents, coloring materials, etc. can be blended as necessary. The form is not particularly limited, and examples thereof include cosmetics, hair cosmetics, quasi drugs, and pharmaceuticals.

Synthesis example 1
Synthesis of 4- [2-hydroxy-3- (2-hydroxyethylamino) -propoxy] -phenol:
(1) 2-Aminoethanol (10.7 g, 175.5 mmol) and ethanol (6 g) were placed in a 100 mL two-necked flask equipped with a dropping funnel and stirred at 80 ° C., and 2- (4-benzyloxyphenoxy) was added thereto. A solution of methyl) oxirane (3.0 g, 11.7 mmol) in ethanol (30 g) was added dropwise over 1 hour, and the mixture was further stirred at that temperature for 1.5 hours. After completion of the reaction, unreacted 2-aminoethanol was distilled off using Kugelrohr (140 ° C./<0.1 mmHg), and the resulting residue (3.6 g) was re-reused with ethanol (21.6 g). Purification by crystals gave 1- (4-benzyloxyphenoxy) -3- (2-hydroxyethylamino) propan-2-ol (2.7 g, mp 115.2 ° C.) as white crystals.

¹ H-NMR (CDCl ₃ , 200 MHz) δ: 2.29 (br, 3H), 2.84 (m, 4H), 3.70 (t, 2H, J = 5.10Hz), 3.93 (d, 2H, J = 4.49Hz), 4.07 (m, 1H), 5.01 (s, 2H), 6.81-6.93 (m, 4H), 7.31-7.44 (m, 5H)

(2) Next, the obtained 1- (4-benzyloxyphenoxy) -3- (2-hydroxyethylamino) propan-2-ol (2.0 g) was dissolved in methanol (20 g), and 5% Pd -C (0.2 g) was added, and the mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. Pd—C was removed by filtration, followed by concentration under reduced pressure to obtain a crude product (1.4 g). A part (1.1 g) of the obtained crude product was purified by recrystallization using ethanol (5 g) to obtain the desired product (0.5 g, m.p. 125.1 ° C.) as yellow crystals.

¹ H-NMR (CD ₃ OD, 200 MHz) δ: 2.71-2.92 (m, 4H), 3.72 (t, 2H, J = 5.48Hz), 3.91 (d, 2H, J = 5.34Hz), 4.07 (m, 1H), 4.07 (m, 1H), 6.71-6.85 (m, 4H)
¹³ C-NMR (CD ₃ OD, 200 MHz) δ: 52.45, 53.27, 61.63, 69.95, 72.72, 116.77, 116.83, 152.59, 153.65

Synthesis example 2
Synthesis of 4- {3- [bis- (2-hydroxyethyl) amino] -2-hydroxypropoxy} -phenol:
(1) 2- (4-Benzyloxyphenoxymethyl) oxirane (5.0 g, 19.5 mmol), diethanolamine (4.2 g, 40 mmol) and t-BuOH (20 g) were placed in a 100 mL round bottom flask at 80 ° C. Stir for 6 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, ethyl acetate (50 mL) was added to the residue, and the ethyl acetate layer was washed with saturated brine (50 mL × 3). After drying over magnesium sulfate and filtration, the filtrate was concentrated under reduced pressure, and the resulting residue (5.8 g) was purified by silica gel column chromatography (ethyl acetate to CH ₃ Cl: MeOH = 9: 1) to give 1- (4- Benzyloxyphenoxy) -3- [bis- (2-hydroxyethyl) amino-propan-2-ol (4.6 g) was obtained as white crystals.

¹ H-NMR (CDCl ₃ , 200 MHz) δ: 2.42-2.85 (m, 6H), 3.52-3.79 (m, 4H), 3.89 (d, 2H, J = 4.93 Hz), 4.11 (m, 1H), 4.84 (br, 3H), 4.99 (s, 2H), 6.80-6.91 (m, 4H), 7.27-7.43 (m, 5H)

(2) Next, the obtained 1- (4-benzyloxyphenoxy) -3- [bis- (2-hydroxyethyl) amino-propan-2-ol (3.8 g) was dissolved in 30 g of methanol. % Pd—C (0.4 g) was added, and the mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere. Pd—C was removed by filtration, followed by concentration under reduced pressure to obtain the desired product (2.9 g, m.p. 82.5 ° C.) as a solid.

¹ H-NMR (CD ₃ OD, 200 MHz) δ: 2.63-2.85 (m, 6H), 3.56-3.72 (m, 4H), 3.75-4.07 (m, 3H), 6.71-6.86 (m, 4H)
¹³ C-NMR (CD ₃ OD, 200 MHz) δ: 58.70, 59.51, 60.85, 69.41, 72.20, 116.77, 116.80, 152.49, 153.70

Synthesis example 3
Synthesis of 2- [2-hydroxy-3- (4-hydroxyphenoxy) propylamino] -2-hydroxymethylpropane-1,3-diol:
(1) 2- (4-Benzyloxyphenoxymethyl) oxirane (5 g, 19.5 mmol), 2-amino-2-hydroxymethylpropane-1,3-diol (2.5 g, 20.5 mmol) in a 100 mL round bottom flask ) And t-BuOH (20 g), and stirred at 80 ° C. for 15 hours. After completion of the reaction, 50 mL of distilled water was added and extracted with ethyl acetate (50 mL × 3). The organic layer was washed with saturated brine (50 mL × 3), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue (7.2 g) was purified by recrystallization using a mixed solvent of ethanol (3.6 g) / ethyl acetate (22 g) to give 2- [3- (4-benzyloxyphenoxy) -2- Hydroxypropylamino] -2-hydroxymethylpropane-1,3-diol (4.7 g) was obtained as white crystals.

¹ H-NMR (CD ₃ OD, 200 MHz) δ: 2.76-2.97 (m, 2H), 3.54-3.63 (m, 6H), 3.94-4.06 (m, 3H), 5.05 (s, 2H), 6.88-6.98 (m, 4H), 7.32-7.48 (m, 5H)

(2) Next, the obtained 2- [3- (4-benzyloxyphenoxy) -2-hydroxypropylamino] -2-hydroxymethylpropane-1,3-diol (4.0 g) was dissolved in 40 g of methanol. 5% Pd—C (0.4 g) was added, and the mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere. Pd—C was removed by filtration, followed by concentration under reduced pressure to obtain the desired product (3.0 g) as an oil.

¹ H-NMR (CD ₃ OD, 200 MHz) δ: 2.76-2.97 (m, 2H), 3.54-3.66 (m, 6H), 3.73-4.01 (m, 3H), 6.71-6.86 (m, 4H)
¹³ C-NMR (CD ₃ OD, 200 MHz) δ: 45.19, 61.05, 62.79, 71.03, 72.63, 116.80, 116.80, 152.47, 153.65

Synthesis example 4
Synthesis of 4- [2-hydroxy-3- (2-hydroxyethylamino) -propoxy] -benzoic acid:
(1) 2-Aminoethanol (13.2 g, 216 mmol) and ethanol (6 g) were placed in a 100 mL two-necked flask equipped with a dropping funnel, and 4-oxiranylmethoxybenzoic acid methyl ester (3 (0.0 g, 14.4 mmol) in ethanol (18 g) was added dropwise over 1 hour, and the mixture was further stirred at that temperature for 1.5 hours. After completion of the reaction, ethanol used as a solvent was distilled off under reduced pressure. Unreacted 2-aminoethanol was distilled off from the resulting residue using Kugelrohr (140 ° C./<0.1 mmHg), and the resulting residue (4.0 g) was re-recycled with ethanol (12 g). Purification by crystals gave 4- [2-hydroxy-3- (2-hydroxyethylamino) propoxy] -benzoic acid methyl ester (2.4 g, mp 117.9 ° C.) as white crystals.

¹ H-NMR (CDCl ₃ , 200 MHz) δ: 2.02 (br, 3H), 2.76-2.95 (m, 4H), 3.71 (t, 2H, J = 5.10Hz), 3.89 (s, 3H), 4.02-4.14 (m, 3H), 6.93 (d, 2H, J = 8.94Hz), 7.99 (d, 2H, J = 8.94Hz)

(2) Next, the obtained 4- [2-hydroxy-3- (2-hydroxyethylamino) propoxy] -benzoic acid methyl ester (2.0 g) was dissolved in 8 g of methanol. -Aqueous NaOH (8 g) was added and stirred at 50 ° C for 3 hours. After completion of the hydrolysis, the mixture was concentrated, and 1N HCl (50 mL) was added to the obtained residue (3.1 g), and then purified using a cation exchange resin (Mitsubishi Chemical DIAION SK1B 15 mL) to obtain a crude product (1 .2 g) was obtained. The crude product was purified by recrystallization using a mixed solvent of ethanol (4.6 g) / distilled water (2.3 g) to obtain the desired product (0.4 g, m.p. 100.9 ° C.) as white crystals.

¹ H-NMR (D ₂ O, 200 MHz) δ: 3.10-3.25 (m, 4H), 3.74 (t, 2H, J = 5.18Hz), 3.91-4.06 (m, 2H,), 4.18-4.25 (m, 1H), 6.84 (d, 2H, J = 8.68Hz), 7.68 (d, 2H, J = 8.94Hz)
¹³ C-NMR (D ₂ O + CD ₃ OD, 200 MHz) δ: 50.28, 50.41, 57.42, 66.23, 70.45, 114.94, 130.39, 131.91, 161.24, 175.95

Synthesis example 5
Synthesis of 4- [2-hydroxy-3- (2-hydroxy-1,1-bishydroxymethyl-ethylamino) -propoxy] -benzoic acid:
In a 100 mL round bottom flask was 4-oxiranylmethoxybenzoic acid methyl ester (3.5 g, 16.8 mmol), 2-amino-2-hydroxymethyl-propane-1,3-diol (1.8 g, 15 mmol) and t-BuOH (14 g) was added and refluxed for 17 hours. Then, MeOH (20 g) and 1.5 M NaOH aqueous solution (20 g) were added, and the mixture was stirred at room temperature for 48 hours. After completion of hydrolysis, the reaction mixture was acidified with 2N-HCl (25 mL), and a by-product derived from unreacted 4-oxiranylmethoxybenzoic acid methyl ester precipitated by distillation of MeOH under reduced pressure was removed by filtration. The filtrate was purified using a cation exchange resin (Mitsubishi Chemical DIAION SK1B 115 mL) to obtain a crude product (4.6 g). Crystals (2.9 g) obtained by purifying the crude product by recrystallization using methanol (30 g) were further purified by recrystallization using methanol (18 g) once more, and the desired product (2.4 g) was obtained. , Mp decomposed at about 250 ° C.) as white crystals.

¹ H-NMR (D ₂ O, 200 MHz) δ: 2.65-2.90 (m, 2H), 3.46-3.61 (m, 6H), 3.99-4.11 (m, 3H), 6.96 (d, 2H, J = 8.61Hz ), 7.79 (d, 2H, J = 8.55Hz)
¹³ C-NMR (D ₂ O + CD ₃ OD, 200 MHz) δ: 44.53, 60.74, 61.88, 70.50, 71.50, 114.84, 130.62, 131.94, 161.69, 175.64

Test Example 1 (Evaluation of water solubility)
Distilled water was added to the sample, and aqueous solutions of 5, 10 and 20% (w / w (%)) were prepared for each compound. Table 1 summarizes the maximum concentrations at which crystals were confirmed not to precipitate even when allowed to stand at room temperature overnight after heating and dissolving at about 50 to 65 ° C.

Test Example 2 (tyrosinase inhibitory activity)
Tyrosinase inhibitory activity test using mushroom tyrosinase.
The test results are summarized in Table 2.

[Preparation of reagents]
(1) L-DOPA solution (A) 10 mg of L-DOPA (special grade reagent) was dissolved at the time of use with 20 mL of the phosphate buffer solution of (3) to obtain a 0.05% L-DOPA solution.
(B) 20 mL of the solution prepared in (A) was diluted to 60 mL with the phosphate buffer of (3) and used.
(2) Tyrosinase solution 6.1 mg of mushroom tyrosinase (50,000 units / 20 mg protein, manufactured by SIGMA) was dissolved in 7.625 mL of distilled water to give a 2000 unit / mL solution.
(3) 0.1 M phosphate buffer The pH was adjusted to 6.8 by a conventional method.

[Preparation of sample solution]
Each sample shown in Table 1 was diluted with distilled water to a concentration of three levels to obtain a sample solution.
[Test Method] L-DOPA was used as a substrate, and the absorbance at 475 nm based on the reaction product dopachrome was measured. When the samples of Synthesis Examples 1 to 3 were evaluated, the L-DOPA solution (A) was used, and when the samples of Arbutin and Synthesis Examples 4 and 5 were evaluated, the L-DOPA solution (B) was used. That is, 1.0 mL of L-DOPA solution and 1.8 mL of phosphate buffer were taken, and 0.1 mL of the sample solution was added thereto. Subsequently, the tyrosinase solution was added and mixed, and it was made to react at room temperature for 1.5 minutes. The absorbance at 475 nm was measured using a spectrophotometer (Hitachi, Ltd. Spectrophotometer U-1100). In addition, 1.0 mL of distilled water was used instead of the L-DOPA solution as a reagent blank, and 1.8 mL of phosphate buffer and 0.1 mL of the sample solution were added and mixed, and the same procedure was followed to measure the absorbance. The value was T ′.
As a control, 0.1 mL of distilled water was added to 1.0 mL of L-DOPA solution [(A) or (B)] and 1.8 mL of phosphate buffer instead of the sample solution. Was C. As a control reagent blank, 1.0 mL of distilled water was used in place of the L-DOPA solution, and 1.8 mL of phosphate buffer and 0.1 mL of distilled water were added thereto. It was. The tyrosinase activity inhibition rate at each sample concentration is calculated by the following formula, the horizontal axis of the semilogarithmic graph is the sample concentration (logarithm), and the vertical axis is the activity inhibition rate. From this graph, the tyrosinase activity 50% inhibition concentration (IC ₅₀ ) Asked.

[Tyrosinase activity inhibition rate calculation formula]
Tyrosinase activity inhibition rate (%) = 100 × [1- (TT ′) / (CC ′)]

  The obtained results are shown in Table 2. The tyrosinase activity 50% inhibitory concentration of arbutin in this evaluation system was a value larger than 100 mM, and all the evaluated compounds showed stronger tyrosinase inhibitory activity than arbutin.

Formulation Example 1 (Lotion)
A lotion having the following composition was produced by a conventional method.
The obtained lotion had a good feeling of use.
(Ingredient) (wt%)
4- [2-Hydroxy-3- (2-hydroxyethylamino) -propoxy] -phenol 0.1
Polyethylene glycol 1.0
1,3-butanediol 8.0
Glycerin 4.0
Sodium hyaluronate 0.1
Ethanol 3.0
Polyoxyethylene (25) 2-octyldodecyl ether 0.5
Trisodium citrate 0.1
Edetate disodium 0.1
Perfume Appropriate amount Preservative (methylparaben) Appropriate amount Ion-exchanged water remaining amount

Formulation Example 2 (Lotion)
(Ingredient) (wt%)
4- [2-Hydroxy-3- (2-hydroxy-1,1-bishydroxymethyl-ethylamino) -propoxy] -benzoic acid 0.1
Polyethylene glycol 1.0
1,3-butanediol 8.0
Glycerin 4.0
Sodium hyaluronate 0.1
Ethanol 3.0
Polyoxyethylene (25) 2-octyldodecyl ether 0.5
Trisodium citrate 0.1
Edetate disodium 0.1
Perfume Appropriate amount Preservative (methylparaben) Appropriate amount Ion-exchanged water remaining amount

Claims (2)

General formula (1)
(Wherein X ¹ represents a hydroxy group or a carboxyl group;
R ¹ represents a hydrogen atom or an alkyl group having 2 to 12 carbon atoms substituted with 1 to 3 hydroxy groups;
R ² represents an alkyl group having 2 to 12 carbon atoms substituted with 1 to 3 hydroxy groups)
A skin external preparation containing a substituted phenoxypropanolamine represented by the formula: General formula (1)
(Wherein X ¹ represents a hydroxy group or a carboxyl group;
R ¹ represents a hydrogen atom or an alkyl group having 2 to 12 carbon atoms substituted with 1 to 3 hydroxy groups;
R ² represents an alkyl group having 2 to 12 carbon atoms substituted with 1 to 3 hydroxy groups)
The whitening agent containing substituted phenoxypropanolamines represented by these, or its salt .