JPS625884B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is a light-screening agent.
Regarding. More particularly, the present invention relates to a light-screening agent, a method for making the same, and a method for protecting the skin from harmful rays using the agent. Furthermore, the present invention relates to some of the essential active ingredients of the agent and a process for their preparation. The light screening agent provided by the present invention comprises as an essential active ingredient the general formula [In the formula, when n represents 1, R ₁ represents hydrogen, alkyl, alkali metal, ammonium, or ammonium substituted with one or more alkyl or hydroxyalkyl groups, and R ₂ represents hydroxymethyl or alkoxymethyl and R ₃ represents hydrogen, or R ₁ and R ₂ together represent a methylene group and R ₃ represents hydrogen, methyl or ethyl; when n represents 2, R ₁ represents an alkaline earth R ₂ is hydroxymethyl or alkoxymethyl and R ₃ is hydrogen] and/or one or more acid addition salts thereof; and compatible cosmetic groups. Contains cosmetic base. The shielding action of the compounds of formula is that they are absorbed into living epidermal cells by specific absorption.
The sun's erythema-generated ultraviolet rays (erythema-
It is based on the fact that it shields from producing ultraviolet rays (290 nm to 340 nm). A compound of formula, for example 4-pyridoxic acid (4
-pyridoxic acid) or 4-pyridoxic acid lactone is a metabolite of pyridoxine (vitamin _B6 ) or a derivative thereof. The compounds of the formula thus contain exogenous substances (exogeno-us
It cannot be considered as a substance. The compounds of formula therefore have very good tolerability on the skin. Further advantages of the light screening agent provided by the present invention are its selective absorption, its odorlessness and its good chemical and photochemical stability. Additionally, compounds of the formula in which R ₃ represents hydrogen re-emit a large portion of the absorbed skin-toxic UV light as long wavelength fluorescent irradiation (420 nm). This fluorescent radiation is in the brown light range, converting radiation that is harmful to the skin into radiation that is actually useful for browning. As used herein, "alkyl" by itself or "alkoxy" or "hydroxyalkyl"
In combinations such as, it means a straight or branched hydrocarbon group having up to 20 carbon atoms.
"Lower alkyl" groups having up to 7 carbon atoms are preferred. Compounds of the formula in which R ₂ is hydroxymethyl or alkoxymethyl, R ₃ is hydrogen and R ₁ is hydrogen, alkali metal, alkaline earth metal or substituted ammonium are preferred. In this case, sodium and potassium are particularly preferred alkali metals, calcium and magnesium are particularly preferred alkaline earth metals, and diethanolammonium and triethanolammonium are particularly preferred substituted ammonium groups. Particularly preferred compounds are sodium 4-pyridoxine, potassium 4-pyridoxate, and triethanolammonium 4-pyridoxate. The maximum absorption wavelengths (measured in ethanol) of some compounds of formula are shown in the table below:

[In the formula, R′ ₁ represents an alkali metal, ammonium, or ammonium substituted with one or more alkyl or hydroxyalkyl groups, and m represents 1, or R′ ₁ represents an alkaline earth metal. And m indicates 2]

(c) where n is 1, R′ ₁ is alkyl, and R′ ₂
When producing a compound of the formula in which R represents hydroxymethyl or alkoxymethyl and R′ ₃ represents hydrogen, an acid or a salt thereof of the formula in which R′ ₂ represents hydroxymethyl or alkoxymethyl is prepared using the general formula R′ ₁ X () [Wherein, X is fluorine, chlorine, bromine, iodine or p-
represents toluenesulfonic acid ester and
R′ ₁ represents alkyl] or (d) in preparing a compound of the formula in which R′ ₁ and R′ ₂ together represent a methylene group and R′ ₃ represents ethyl. , 4-pyridoxine acid lactone is reacted with diazoethane and, if desired, the resulting compound of formula is converted to its acid addition salt. In embodiment (a) of the above method, a compound of formula is oxidized to the corresponding acid. The compound of formula is new and has the following formula can be prepared from known compounds of the formula according to: Oxidation is carried out using conventional methods, e.g. Am. Chem. for the production of 4-pyridoxic acid from pyridoxine.
It can be carried out according to a method similar to that of Soc. 70 , 3434 (1948). In embodiment (b) of the above method, the acid of formula is converted into a salt with an equivalent amount of base according to conventional methods.
Acids of the formula in which R' ₂ represents alkoxymethyl are novel and can be obtained as described in Example (a) above. In embodiment (c) of the above method, an acid of formula or a salt thereof is reacted with a compound of formula. The reaction is preferably carried out under basic conditions at room temperature using an inert organic solvent such as dimethylformamide (DMF). In example (d) of the above method, 4-pyridoxine acid lactone is reacted with diazoethane.
The reaction is preferably carried out by adding an ethereal solution of diazoethane in an inert organic solvent such as methanol. This reaction is advantageously carried out at temperatures between 0 and 20°C. The following examples illustrate the invention. Examples 1-4 illustrate the preparation of compounds of formula, and Examples 5-11 illustrate specific examples of light screening agents provided by the present invention. Example 1 D. Heyl, J. Amer. Chem. Soc. 70 , 3434 (1948)
7.32 g of 4-pyridoxic acid prepared according to
(40 mmol) was dissolved in 20 ml (40 mmol) of freshly prepared 2N sodium hydroxide solution. The resulting solution was subsequently diluted with ethanol, substantially concentrated on a rotary evaporator, and water was removed by azeotropic distillation. The solution was finally treated with ethyl acetate to crystallize. The result is a colorless sodium salt of 4.96
g as initial crystals, while a further 2.11 g of the colorless sodium salt were obtained from the mother liquor after decolorization with Norit. 7.07 g of the sodium salt obtained in this way was present as a hydrate. Anhydrous sodium 4-pyridoxinate was obtained directly by using sodium methylate as base in methanol; mp 250-252°C (decomposition).
This salt was very soluble in water, ethanol, and sparingly ethyl acetate. Example 2 1.10 g (5 mmol) of the sodium salt of pyridoxic acid prepared in Example 1 were dissolved in 15 ml of dimethylformamide at room temperature and treated dropwise with stirring with 784 mg (5 mmol) of methyl iodide. After a few minutes, fine crystals began to separate. After the addition is complete,
The mixture was stirred for a further 2 hours at room temperature, then the crystals were filtered off with suction. Furthermore, crystals were further separated from the liquid by cooling. Recrystallization of the crude product from methanol/water gave 875 mg of weak yellow crystals of methyl 4-pyridoxinate; melting point 256°C.
(Disassembly). Following a similar method, n-hexyl 4-pyridoxic acid was obtained from chloroform/hexane by reacting the sodium salt of pyridoxic acid with n-hexyl iodide for 4 hours at 80°C and treating the reaction mixture with water/chloroform. Melting point: 154-155
℃. Example 3 1.18 g of sodium methylate in 20 ml of methanol
3-O-4-O-isopropyritenepyridoxine [W.Ko-
rytnik) and M.IKawa,
Methods of Enzymology, Volume, Part A,
Page 527, Academic Press (Aca-demic
Press (1970)] was converted into the sodium salt and the crystalline salt obtained after removal of methanol was dried at room temperature and 0.01 Torr. Dissolve the salt thus obtained in 50 ml of dimethylformamide and add cetyl iodide while stirring.
8.426 g (22 mmol) was treated dropwise. After the addition was complete, the mixture was stirred overnight (15 hours) at room temperature. The mixture was subsequently treated with water and benzene and the organic phase was dried over sodium sulfate. The evaporated organic phase was then diluted with benzene/ethyl acetate (1:
2.56 g of pure 3-O-4-O-isopropylidene-5-(O-cetyl)-pyridoxine was obtained by treatment with silica gel chromatography in step 1).
was obtained in colorless crystalline form. This was converted to 5-(O-cetyl)-pyridoxine hydrochloride by heating under reflux for 90 minutes in a mixture of 10 ml dioxane and 10 ml 1N hydrochloric acid. After recrystallization from ethanol/ether, 2.5 g of hydrochloric acid with a melting point of 120-122 DEG C. were obtained.
Oxidation of this free base (melting point 91-92°C) with manganese dioxide in chloroform for 3 hours at room temperature yielded 5-(O-cetyl)-pyridoxal (melting point 48.5-49.5°C) almost quantitatively. Obtained. 1.0 g of 5-(O-cetyl)-pyridoxal was dissolved in methanolic potassium hydroxide (1.0 g of potassium hydroxide in 80 ml of absolute methanol) and stirred with 7.0 g of activated manganese dioxide at room temperature for 6 days. 30%
The dissolved manganese salt was oxidized to manganese dioxide by adding 5 ml of hydrogen peroxide. The hot mixture was immediately filtered and the separated manganese dioxide was washed with methanolic potassium hydroxide. The yellow liquid was then acidified to pH 4 with 1N hydrochloric acid, thereby allowing the acid produced to be properly separated.
After standing at 0° C. for 30 minutes, the mixture was filtered through a glass filter and the white-yellow residue was washed successively with water, ethanol and ether. The last traces of aldehyde were removed from 5-(O-cetyl)-4-pyridoxic acid by dissolving the product in ethanolic potassium hydroxide (1%) followed by precipitation with 1N hydrochloric acid. Yield of pure acid is 0.41g
It was equivalent to The melting point of the acid was 250°C (decomposition). Example 4 102 mg (0.25 mmol) of 5-(O-cetyl)-4-pyridoxic acid in 5 ml of absolute methanol for 1 hour
Sodium methylate 13.5 mg (0.25 mmol)
and boiled under reflux. After evaporating the solvent on a rotary evaporator, the yellow 5-(O-cetyl)-4
- Sodium pyridoxate was dried under high vacuum overnight. The yield was equivalent to 70 mg. Example 5

Table: The cream was prepared by melting together the various components of the fatty phase at 45-50°C with gentle stirring. Sodium 4-pyridoxinate 5
g and 0.3 g of Dowisil 200 were dissolved in 58.5 ml of cold water and the resulting solution was heated to 45-50° C. and mixed with the fat phase with continuous stirring. The mixture was stirred for an additional 3 hours while cooling to room temperature. The pH value of the finally obtained cream was adjusted to 6 with ascorbic acid. Example 6 Cream fat phase: Emulgade 1000NI (saturated aliphatic alcohol polyglycol ether) 2.5g Cetyl alcohol 1.0g Vaseline (white) 2.0g Hydrogenated Nanjing bean fat 2.0g Glycerin monostearate 1.5g Softisan 100 (hard fat) 2.0g Cremophor O (alkyl- or acyl-substituted polyaddition product of ethylene oxide) 1.0 g Emulgin C700 (saturated aliphatic alcohol polyglycol ether) 1.0 g Cetiol HE (fatty acid ester) 1.0 g Aqueous phase: sodium pyridoxate 6.0 g Tris buffer solution, 1% (PH with citric acid
8.1) 20ml Carbopol 940, 1 in water
% (pH adjusted to 8 with Tris) 54.0 g Fat phase was mixed into the aqueous phase at 80°C. The following solutions were introduced at 50°C: Perfume 0.2 g Pantyl 0.5 g Dawisil 200 [1-(3-chlorallyl)-3.
5,7-triaza-1-azonia-adamantane trichloride] 0.3g Water 2.0g Example 7 Cream fat phase: Pyridoxic acid 5.0g Triethanolamine 8.15g Propylene glycol 6.0g Amphisol 3.55g Stearic acid 1.2g Cetyl Alcohol 1.2g Deltyl extra
(Isopropyl mystearate) 3.0g Arachis oil 1.2g Diethylene glycol monostearate
1.2g Lantrol (purified lanolin) 3.55g PCL-Liquid (branched chain fatty acid ester)
0.1g Aqueous phase: 2% Carbopol in water 50.0g Dawisil 0.2g Water 15.65g Example 8

[Table] Thearyl alcohol)

[wherein R′ ₁ represents an alkali metal, ammonium or ammonium substituted with one or more alkyl or hydroxyalkyl groups and m represents 1 or R′ ₁ represents an alkaline earth metal and m indicates 2]

(c) n is 1 and R′ ₁ is alkyl;
In order to prepare compounds of the formula in which R' ₂ represents hydroxymethyl or alkoxymethyl and R' ₃ represents hydrogen, an acid or a salt thereof of the formula in which R' ₂ has the abovementioned meaning is converted into a compound of the general formula R' ₁ () [wherein, X is fluorine, chlorine, bromine, iodine or p
-toluenesulfonic acid ester and R′ ₁ represents alkyl], or (d) R′ ₁ and R′ ₂ taken together represent a methylene group and R′ ₃ represents ethyl. Compounds of the formula and their acids characterized in that 4-pyridoxine acid lactone is reacted with diazoethane to prepare compounds of the formula and, if desired, the resulting compound of formula is converted into an acid addition salt. Method for producing addition salts. 2. A method for producing sodium 4-pyridoxinate according to the above embodiment 1, in which 4-pyridoxic acid is treated with sodium hydroxide. 3. A method for producing methyl 4-pyridoxate according to the above embodiment 1, in which sodium 4-pyridoxate is reacted with methyl iodide. 4 4-4-According to the above embodiment 1 when sodium 4-pyridoxine is reacted with n-hexyl iodide
A method for producing n-hexyl pyridoxine. 5-(O-cetyl)- according to the above embodiment 1 when oxidizing 5-(O-cetyl)-4-pyridoxine
Method for producing 4-pyridoxic acid. 6 General formula as an essential active ingredient [In the formula, when n represents 1, R ₁ represents hydrogen, alkyl, alkali metal, ammonium, or ammonium substituted with one or more alkyl or hydroxyalkyl groups, and R ₂ represents hydroxymethyl or alkoxymethyl and R ₃ represents hydrogen, or R ₁ and R ₂ together represent a methylene group and R ₃ represents hydrogen, methyl or ethyl; when n represents 2, R ₁ represents an alkaline earth R ₂ is hydroxymethyl or alkoxymethyl and R ₃ is hydrogen] and/or one or more acid addition salts thereof; and compatible cosmetic groups. A method of protecting the skin against harmful rays, comprising applying to the skin a light-shielding agent containing a light-blocking agent. 7. The method of embodiment 6 above, wherein the light screening agent contains up to 25% by weight of one or more compounds of formula. 8. The method of embodiment 6 or 7 above, wherein the light-screening agent contains 2 to 6% by weight of one or more compounds of formula. 9. The method according to any of embodiments 6 to 8 above, wherein the light-screening agent contains one or more para-type compounds as an essential active ingredient. 10. The method of any of embodiments 6-8 above, wherein the light-screening agent also contains one or more other organic compounds having a maximum absorption between 290 and 340 nm. 11. The method according to any of aspects 6 to 10 above, wherein the light shielding agent also contains an anti-inflammatory substance. 12 The light-screening agent is characterized in that n represents 1 and R ₁ represents hydrogen, alkali metal or ammonium substituted with an alkyl or hydroxyalkyl group, R ₂ represents hydroxymethyl or alkoxymethyl and R ₃ represents hydrogen. 12. The method of any of embodiments 6 to 11 above, comprising a compound of the formula represented. 13 The light-screening agent is characterized in that n represents 2, R ₁ represents an alkaline earth metal, R ₂ represents hydroxymethyl or alkoxymethyl, and R ₃
12. The method according to any of embodiments 6 to 11 above, comprising a compound of the formula where represents hydrogen. 14. The method according to any one of Embodiments 6 to 12 above, wherein the light shielding agent contains 4-pyridoxic acid. 15. The method according to any one of Embodiments 6 to 12 above, wherein the light shielding agent contains sodium 4-pyridoxine. 16. The method according to any one of Embodiments 6 to 12 above, wherein the light shielding agent contains potassium 4-pyridoxinate. 17. The method according to any one of Embodiments 6 to 12 above, wherein the light shielding agent contains triethanolammonium 4-pyridoxinate. 18. The method according to any one of Embodiments 6 to 12 above, wherein the light shielding agent contains 5-(O-cetyl)-4-pyridoxic acid. 19. The method according to any one of Embodiments 6 to 11 above, wherein the light shielding agent contains methyl 4-pyridoxinate. 20. The method according to any one of Embodiments 6 to 11 above, wherein the light shielding agent contains n-hexyl 4-pyridoxine acid. 21. The method according to any one of Embodiments 6 to 11 above, wherein the light shielding agent contains 4-pyridoxine acid lactone hydrochloride. 22 The light shielding agent is 4-pyridoxine acid lactone 3
- The method according to any one of the above embodiments 6 to 11, containing methyl ether. 23 Embodiments 6 to 11 above, wherein the light shielding agent contains sodium 5-(O-cetyl)-4-pyridoxinate.
Either way. 24. The method according to any of embodiments 6 to 11 above, wherein the light shielding agent contains tris(hydroxymethyl)amino-methane-4-pyridoxynel. 25 One or more compounds of the formula according to embodiment 6 above and/or one or more acid addition salts thereof and optionally 290-340 nm
A light-screening agent according to any of the above embodiments 5 to 24, consisting of admixing one or more further organic compounds with maximum frontal absorption and/or anti-inflammatory substances with a compatible cosmetic base. manufacturing method. 26 General formulas as essential active ingredients [In the formula, when n represents 1, R ₁ represents hydrogen, alkyl, alkali metal, ammonium, or ammonium substituted with one or more alkyl or hydroxyalkyl groups, and R ₂ represents hydroxymethyl or alkoxymethyl and R ₃ represents hydrogen, or R ₁ and R ₂ together represent a methylene group and R ₃ represents hydrogen, methyl or ethyl; when n represents 2, R ₁ represents an alkaline earth metal, R ₂ represents hydroxymethyl or alkoxymethyl and R ₃ represents hydrogen] and/or one or more acid addition salts thereof; and compatible cosmetic bases. A light shielding agent characterized by containing. 27. The light-screening agent of embodiment 26 above, wherein the light-screening agent contains up to 25% by weight of one or more compounds of formula. 28. The light-screening agent of embodiment 26 or 27 above, wherein the light-screening agent contains 2 to 6% by weight of one or more compounds of formula. 29. The light-screening agent according to embodiments 26 to 28 above, wherein the light-screening agent contains one or more para-type compounds as an essential active ingredient. 30. The light-screening agent of any of embodiments 26-28 above, wherein the light-screening agent also contains one or more other organic compounds having a maximum absorption between 290 and 340 nm. 31. The light shielding agent according to any one of aspects 26 to 30 above, wherein the light shielding agent also contains an anti-inflammatory substance. 32 The light-screening agent is characterized in that n represents 1 and R ₁ represents hydrogen, alkali metal or ammonium substituted with an alkyl or hydroxyalkyl group, R ₂ represents hydroxymethyl or alkoxymethyl and R ₃ represents hydrogen. 32. The light shielding agent according to any of the above embodiments 26 to 31, containing a compound of the formula represented. 33 The light-screening agent is characterized in that n represents 2, R ₁ represents an alkaline earth metal, R ₂ represents hydroxymethyl or alkoxymethyl, and R ₃
32. The light shielding agent according to any one of the above embodiments 26 to 31, which contains a compound of the formula in which represents hydrogen. 34. The light shielding agent according to any one of the above embodiments 26 to 32, wherein the light shielding agent contains 4-pyridoxic acid. 35. The light shielding agent according to any one of embodiments 26 to 32 above, wherein the light shielding agent contains sodium 4-pyridoxine. 36. The light shielding agent according to any one of embodiments 26 to 32 above, wherein the light shielding agent contains potassium 4-pyridoxinate. 37. The light shielding agent according to any one of the above embodiments 26 to 32, wherein the light shielding agent contains triethanolammonium 4-pyridoxine acid. 38. The light shielding agent according to any one of embodiments 26 to 32 above, wherein the light shielding agent contains 5-(O-cetyl)-4-pyridoxic acid. 39. The light shielding agent according to any one of the above embodiments 26 to 32, wherein the light shielding agent contains methyl 4-pyridoxinate. 40. The light shielding agent according to any one of the above embodiments 26 to 32, wherein the light shielding agent contains n-hexyl 4-pyridoxine acid. 41. The light shielding agent according to any one of embodiments 26 to 32 above, wherein the light shielding agent contains 4-pyridoxine acid lactone hydrochloride. 42 The light shielding agent is 4-pyridoxine acid lactone 3
- The light shielding agent according to any one of the above embodiments 26 to 32, which contains methyl ether. 43 Embodiments 26 to 32 above, wherein the light shielding agent contains sodium 5-(O-cetyl)-4-pyridoxine.
Any light shielding agent. 44. The light shielding agent according to any one of embodiments 26 to 32 above, wherein the light shielding agent contains tris(hydroxymethyl)amino-methane-4-pyridoxinate.

Claims (1)

[Claims] 1. General formula as an essential active ingredient [In the formula, when n represents 1, R ₁ represents hydrogen, alkyl, alkali metal, ammonium, or ammonium substituted with one or more alkyl or hydroxyalkyl groups, and R ₂ represents hydroxymethyl or alkoxymethyl and R ₃ represents hydrogen, or R ₁ and R ₂ together represent a methylene group and R ₃ represents hydrogen, methyl or ethyl; if n represents 2,
R ₁ represents an alkaline earth metal, R ₂ represents hydroxymethyl or alkoxymethyl, and R ₃
represents hydrogen] A light shielding agent characterized in that it contains one or more of the compounds and/or one or more of its acid addition salts.