DE3927460A1 - ANTI-INFLAMMATORY ACTIVITIES FOR COSMETIC PREPARATIONS - Google Patents

Abstract

1,3-dioxolanes of general formula (I), in which R<1>, R<2>, R<3>, R<4>, R<5> and R<6> are independently hydrogen, alkyl groups with 1-4 carbon atoms, alkoxy groups with 1-4 carbon atoms or a -CnH2n-O-Y group where Y is a phenyl group, a mono or dialkoxy phenyl, an alkylamino phenyl, a dialkylamino phenyl or an alkyl thiophenyl group, with 1-4 carbon atoms in the alkyl or alkoxy group, or a mono or dihalogen phenyl group and n is a whole number from 1 to 4, with the proviso that at least one and at most two of the residues R<1>, R<2>, R<3>, R<4> R<5> and R<6> are a -CnH2n-O-Y group, or that R<1> and R<2> together with the carbon atom bearing them are a carbonyl group, R<3> is a -CnH2n-O-Y group and R<4>, R<5> and R<6> have the meaning stated, are anti-inflammatory substances suitable for the manufacture of topical pharmaceuticals and cosmetics.

Description

The invention relates to the use of 1,3-dioxolanes as ent anti-inflammatory agents for the preparation of topical pharma cosmetic and cosmetic products.

It is known the effect of cosmetic and pharmaceutical Prä parate, especially those for use due to strong Light irradiation strained skin, by adding inflammatory expand inhibitory substances.

The anti-inflammatory properties of 1,3-dioxolanes are out German published patent applications 25 19 161, 25 26 312 and 25 26 675 known. Although by the addition of these compounds be already a clear anti-inflammatory effect is achieved, so show these 1,3-dioxolanes do not all have the desired properties. So have the compounds disclosed in DE 25 29 161 and DE 25 26 312 not in all formulations the necessary Hydrolysestabi quality. This hydrolytic stability is indeed in the compounds according to DE 25 26 675, but there is still a need for substances with a higher efficacy in the same or lower application concentrations.

It has now been found that certain 1,3-dioxolanes of the general my formula (I),

in the R¹, R², R³, R⁴, R⁵ and R⁶ are independently hydrogen, alkyl groups having 1-4 carbon atoms, alkoxy groups having 1-4 carbon atoms or a group -C _n H _2n -OY, where Y is a phenyl group, a mono- or dialkylphenyl, a mono- or di-alkoxyphenyl, an alkylaminophenyl, a dialkylaminophenyl or an alkylthiophenyl group each having 1-4 carbon atoms in the alkyl or alkoxy group, or a mono- or dihalo genphenyl group and n is an integer from 1 to 4, provided that at least one and at most two of R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} a group -C _{n H} 2n -OY, or that R ¹ and R ² together with the carbon atom carrying them represent a carbonyl group, R ^{3 is} a group -C _n H _2n -OY and R ⁴ , R ⁵ and R ^{6 have} the meaning given, by a significantly greater anti-inflammatory effect distinguished. These compounds can be easily incorporated into conventional pharmaceutical and cosmetic bases for topical applications; They are easy to combine with the other usual ingredients of such preparations and have no or only a minimal odor.

The invention thus relates to the use of 1,3-dioxo lanen of the general formula (I) as an anti-inflammatory agent materials for the manufacture of topical pharmaceutical and cosmetic products technical means.

The compounds of formula (I) are known with the aid of che Mixer reactions from readily available starting materials produced.

One possibility is the known ketalization process in which oxo compounds with 1,2-diols in the presence of a acid catalyst such as p-toluenesulfonic acid, p be reacted with rock acid, zinc chloride or iron (III) chloride, wherein the water of reaction by means of a suitable Schleppmitmit such as toluene or cyclohexane during the reac tion is continuously removed. Another possibility is the Reaction of oxo compound and 1,2-diol in the presence of a ortho-formic acid trialkyl ester and an acidic catalyst Temperatures between 50 and 150 ° C, at which they are low The reaction products formic acid esters and alcohol are ongoing be distilled off.

Another preparation process is the alkylation of ent correspondingly substituted phenols with 2-haloalkyl-1,3-dioxo lanen in the presence of a phase transfer catalyst such as Example tetraalkylammonium chloride, bromide or iodide in one inert solvents at temperatures between 50 and 150 ° C.

In the compounds to be used according to the invention, the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 may be the} following groups:

• - hydrogen
• Alkyl groups having 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-n-butyl and tert-butyl Groups. The methyl group is within the scope of the invention Teach the preferred alkyl group.
• Alkoxy groups having 1-4 carbon atoms, such as methoxy, Ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-n-butoxy and tert-butoxy groups. The methoxy group is under the teachings according to the invention the preferred alkoxy group.

Furthermore, at least one and at most three of the genann th substituents is a group -C _n H _2n -OY.

The index n is an integer from 1 to 4; are preferred here a substituted methyl group, one in 2-position substi ethyl group or a 3-substituted n-Pro pylgruppe. In the context of the teaching of the invention are substituted te methyl groups preferred.

Y can stand for

• a phenyl group,
• a monoalkylphenyl group having 1-4 carbon atoms in the Alkyl group. Preference is given to monoalkylphenyl groups in which the alkyl substituent is in the 4-position. Preferred Al kylsubstituenten are methyl, ethyl and tert-butyl. 4-methyl phenyl, 4-ethylphenyl and 4-tert-butylphenyl groups particularly preferred monoalkylphenyl groups.
• a dialkylphenyl group each having 1-4 carbon atoms in the alkyl group. Preference is given to dialkylphenyl groups, in de NEN the alkyl substituents in the 3- and 4-position.  Preferred alkyl substituents are methyl and ethyl. The 3,4- Dimethylphenyl group is a particularly preferred dialkylphene nylgruppe.
• a monoalkoxyphenyl group having 1-4 carbon atoms in the Alkoxy. Preference is given to monoalkoxyphenyl groups, in de NEN the alkoxy substituent is in the 4-position. preferred Alkoxy substituents are methoxy and ethoxy. 4-methoxyphenyl and 4-ethoxyphenyl groups are particularly preferred mono alkoxyphenyl groups.
• a dialkoxyphenyl group each having 1-4 carbon atoms in the alkoxy group. Dialkoxyphenyl groups are preferred where the alkoxy substituents are in the 3- and 4-position. Preferred alkoxy substituents are methoxy and ethoxy. The 3,4-Dimethoxyphenyl group is a particularly preferred dialk oxyphenylgruppe.
• an alkylaminophenyl group having 1-4 carbon atoms in the Alkyl group. Preference is given to alkylaminophenyl groups in which the alkylamino substituent is in the 4-position. preferred Alkyl substituents are methyl and ethyl.
• a dialkylaminophenyl group each having 1 to 4 carbon atoms in the alkyl groups. Preferred are such groups, in where the Dialkylaminosubstituent is in the 4-position. Particularly preferred is the 4-dimethylaminophenyl group.
• an alkylthiophenyl group having 1-4 carbon atoms in the Alkyl group. Preferred are alkylthiophenyl groups in which the alkylthio substituent is in the 4-position. preferred Alkyl substituents are methyl and ethyl.
• a monohalophenyl group. Preference is given to monohalogeno nylgruppen, in which the halogen substituent in the 4-position  stands. Fluorine, chlorine, bromine and iodine are preferred halo sub substituents, chlorine is particularly preferred.
• a dihalophenyl group. Preference is given to dihalophenyl groups in which the halogen substituents in the 4-position so as in the 3- or 2-position. Fluorine, chlorine, bromine and iodine are preferred halogen substituents, chlorine is particularly be vorzugt.

Further, the substituents R ¹ and R ² together with the carbon atom carrying them may represent a carbonyl group. R ³ in this case is a group -C _n H _2n -OY; R ⁴ , R ⁵ and R ⁶ have the meaning given above.

Preferred compounds of the general formula (I) according to the invention are 4- (4-methoxyphenoxymethyl) -1,3-dioxolane, 4- (4-methoxyphenoxy methyl) -2-methyl-1,3-dioxolane, 4- (4-chlorophenoxymethyl) -2-methyl- 1,3-di-oxolane, 4- (4-methoxyphenoxymethyl) -1,3-dioxolan-2-one and 2- (4-methoxyphenoxymethyl) -4,4,5,5-tetramethyl-1,3-dioxolane.

New and therefore also the subject of the invention are the verbin 4- (4-methoxyphenoxymethyl) -2-methyl-1,3-dioxolane and 4- (4- Chlorophenoxymethyl) -2-methyl-1,3-dioxolane. production method for these compounds, see the example section.

According to the invention, the 1,3-dioxolanes of the general formula (I) preferably in amounts of 0.01-10 wt .-%, in particular in amounts from 0.5-5 wt .-%, based on the total agent used. Be the compounds of the general formula are particularly preferred (I) in amounts of 2-5 wt .-%, in particular in amounts of about 3 Wt .-%, used.  

Particularly advantageous is the use of the compounds of all common formula (I) for the production of sunscreens and suns fire-fighting agents. The 1,3-dioxolanes can be used both in Means before as well as in those after sunbathing the skin are applied, find use.

The 1,3-dioxolanes according to the invention have erythema-producing UV-B range of about 300-320 nm itself no absorption band on. For the preparation of funds before sunbathing on the Skin be applied, it is therefore preferred to use them in combination tion with conventional UV filter substances.

Suitable UV filter substances are, for example:

• Salicylic acid derivatives, such as the esters of menthol, of homo menthol, fenchol, borneol, glycerine, ben cyl alcohol, phenol, ethylene glycol, 2-ethylhexa nols and tert. Butanols and the triethanolammonium salt salicylic acid,
• Cinnamic acid esters, such as p-methoxy, p-amino and p-dimethylamino cinnamic acid esters, for example p-methoxycinnamic acid 3-ethoxy ethyl ester, p-methoxycinnamic acid 2-ethylhexyl ester and p-acet amidozimtsäure isopropyl,
• p-aminobenzoic acid and its derivatives, such as p-aminobenzoic acid ethyl, -propyl, -butyl, -isobutyl, -monoglycerol and -dipropylene glycol ethyl ester, p-dimethylaminobenzoic acid ethyl and -amyl esters and p-Diethylaminobenzoesäureethyl- and amyl esters,  
• - substituted benzophenones, such as 2,2'-dihydroxy-4,4'-dimethoxy benzophenone, 2-hydroxy-4-n-octoxybenzophenone, 4-phenylbenzo phenone, 2-hydroxy-4-methoxy-benzophenone-5-sulfonic acid and 4-phenylbenzophenone-2-carboxylic acid isooctyl ester,
• Coumarin derivatives, such as 4-methylcoumarin, 6-methoxycoumarin, 7-ethylamino-4-methyl-coumarin, 7,8-dihydroxycoumarin, 6,7-dihy droxycumarin, 7-hydroxycoumarin, 4-methyl-7-hydroxycoumarin and 3-phenylcoumarin,

furthermore, 2-phenylbenzimidazole-5-sulfonic acid, sodium 3,4-di-methoxyphenylglyoxylate, butylbenzalacetone, benzalacetophenone, 3-toluylidene-D, L-camphor, 3- benzylidene-D, L-camphor, 3- (p-methylbenzylidene ) -D, L-camphor, urocanic acid and its salts, benzimidazole derivatives, digalloyl trioleate, sulfonamides, hydrazones, condensation products of tannin with ethylene oxide and, as natural products, extracts of cinnamon bark, ratanhia and licorice.

A list of suitable UV filter substances can be found also in the German Cosmetics Regulation (Appendix 7 to § 3b).

The UV filter substances mentioned are usually in quantities from 1-10 wt .-%, based on the total agent used. Men of 2-6 wt .-% are preferred.

Furthermore, it is preferred according to the invention according to claim 1 to produce antioxidants. Especially before In this case, the uses of natural or natural identity are granted shear compounds such as tocopherols. The mentioned Antioxidants are in the inventive compositions in  Quantities of 0.1-5 wt .-%, in particular of 0.5-2 wt .-%, based on the entire remedy, included.

The agents according to the invention can be used as liquid, pasty or solid formulations are formulated, for example as aqueous or alcoholic solutions, aqueous suspensions, emulsions, Ointments, creams, oils, powders or pens. Depending on the desired formulation, the 1,3-dioxolanes in pharmazeu tables and cosmetic bases for topical applications be incorporated, which as other components, for example Oil components, fats and waxes, emulsifiers, anionic, cat ionic, ampholytic, zwitterionic and / or nonionic Surfactants, lower mono- and polyhydric alcohols, water, Konser vierungsmittel, buffers, thickeners, fragrances, Dyes and opacifiers included.

Examples

The following examples serve to further explain the Invention, without limiting it.

1. Preparation of 1,3-dioxolanes

• a) 4- (4-methoxyphenoxymethyl) -2-methyl-1,3-dioxolane A mixture of 19.8 g (0.1 mol) of 3 - (4-methoxyphenoxy) -pro pan-1,2-diol, 17 , 7 g (0.15 mol) of 1,1-diethoxyethane and 0.1 g of p-toluenesulfonic acid was heated for 4 hours at 95 ° C, wherein the alcohol formed during the reaction was distilled off. Thereafter, the residue was taken up in toluene, washed with water, dried with sodium sulfate and evaporated. The remaining residue was finally subjected to fractional distillation. There were obtained 20.7 g (92% of theory) of a colorless liquid having a boiling point of 116-118 ° C. at 0.46 mbar, whose refractive index n was 1.5160.

Analogously, the following compounds were prepared:

• b) 4- (4-methoxyphenoxymethyl) -2,2-dimethyl-1,3-dioxolane boiling point: 118 ° C at 0.06 mbar; n: 1.5060.
• c) 4- (4-Methoxyphenoxymethyl) -2-ethyl-1,3-dioxolane: 1.5098.
• d) 4- (4-Methoxyphenoxymethyl) -1,3-dioxolan-2-one
  Melting point: 98-100 ° C.
• e) 4- (4-Methoxyphenoxymethyl) -1,3-dioxolane
  Melting point: 45-46 ° C.
• f) 4- (4-methylphenoxymethyl) -2-methyl-1,3-dioxolane boiling point: 81-82 ° C at 0.1 mbar; n: 1.5092.
• g) 4- (4-tert-butylphenoxymethyl) -2-methyl-1,3-dioxolane boiling point: 105-107 ° C at 0.1 mbar; n: 1.4993.
• h) 4- (4-ethylphenoxymethyl) -2-methyl-1,3-dioxolane boiling point: 90-91 ° C at 0.09 mbar; n: 1.5062.
• i) 4- (3,4-dimethylphenoxymethyl) -2-methyl-1,3-dioxolane
  Melting point: 40-41 ° C.
• j) 4- (4-chlorophenoxymethyl) -2-methyl-1,3-dioxolane boiling point: 98-100 ° C at 0.08 mbar; n: 1.5250.
• k) 4- (3,4-dichlorophenoxymethyl) -2-methyl-1,3-dioxolane boiling point: 122 ° C at 0.08 mbar; n: 1.5389.
• l) 4- (2,4-dichlorophenoxymethyl) -2-methyl-1,3-dioxolane boiling point: 166 ° C at 0.09 mbar; n: 1.5380.
• m) 2- (4-Methoxyphenoxymethyl) -4-methyl-1,3-dioxolane
• A mixture of 34 g (0.25 mol) of 2-chloromethyl-4-methyl 1,3-dioxolane, 24.8 g (0.20 mol) of hydroquinone monomethyl ether, 11.3 g (0.21 mol) of sodium methoxide solution (30% in methanol),  1.3 g of tetrabutylammonium iodide and 100 ml of diethylene glycol diol methyl ether was heated to 120 ° C and after the Abdestil The methanol was stirred at 150 C for 12 hours. After this Filtration, concentration of the mother liquor under reduced pressure, Take up the residue in methylene chloride, wash with Water until neutrality of the solution, drying and evaporation the solution was the residue fractionally distilled. It were 37.1 g (83% of theory) of a colorless oil with a Boiling point of 111 ° C at 0.08 mbar obtained a Bre index of 1.5166.

Analogously, the following compounds were prepared:

• n) 2- (4-methoxyphenoxymethyl) -4,5-dimethyl-1,3-dioxolane boiling point: 123-124 ° C at 0.08 mbar; n: 1.5166.
• o) 2- (4-Methoxyphenoxymethyl) -4,4,5,5-tetramethyl-1,3-dioxolane
• The purification was carried out here by column chromatography (SiO 2 / mobile phase: methylene chloride). Boiling point: 128-130 ° C at 0.09 mbar; n: 1.5058.
• l) 2- (4-Methoxyphenoxymethyl) -1,3-dioxolane boiling point: 128-129 ° C at 0.08 mbar; n: 1.5278.

2. Test method for the anti-inflammatory effect

To determine the anti-inflammatory effect of the substances was a test on hairless mice on skin damage caused by UV Light performed.

The hairless mice were treated on the back with a UV lamp (Ultravi talux lamp, OSRAM) irradiated for 3 minutes from a distance of 45 cm, whereby a measurable dermatitis (edema) was triggered. Un Immediately after the end of the irradiation, the test substances were dissolved in Form of an ethanolic solution with the help of a glass rod carry. As a comparative experiment was be in the same way be mice were given a post-treatment with the carrier ethanol (Control) performed. After 30 hours, the degree of edema became formation determined by measuring the skin fold thickness. By Ver equal to the change in the skin fold thickness due to the Bestrah treated and treated only with the vehicle Animals were determined the degree of inhibition of the edema.

The following values were found:

substance Inhibition of UV edema after 30 hours 4- (4-methoxyphenoxymethyl) -1,3-dioxolane | 19% 4- (4-methoxyphenoxymethyl) -2-methyl-1,3-dioxolane 35% 4- (4-methoxyphenoxymethyl) -1,3-dioxolan-2-one 21% 2- (4-methoxyphenoxymethyl) -4,4,5,5-tetramethyl-1,3-dioxolane 23% 4- (4-chloro-phenoxymethyl) -2-methyl-1,3-dioxolane 33% 4- (3,4-Dichloro-phenoxymethyl) -2-methyl-1,3-dioxolane 22%

3. Composition of a sunscreen emulsion

Claims (11)

1. Use of 1,3-dioxolanes of the general formula (I), in the R ¹ , R ² , R ³ , R ⁴ R ⁵ and R ^{6 are} independently hydrogen, alkyl groups having 1-4 carbon atoms, alkoxy groups having 1-4 carbon atoms or a group -CnH _2n -OY, wherein Y is a phenyl group represents a mono- or dialkylphenyl, a mono- or dialkoxyphenyl, an alkylaminophenyl, a dialkylaminophenyl or an alkylthiophenyl group each having 1-4 carbon atoms in the alkyl or alkoxy group, or a mono- or dihalophenyl group and n is an integer from 1 to 4, provided that at least one and at most two of R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} a group -C _n H _2n -OY or that R ¹ and R ^{2 together} with the carbon atom carrying them represent a carbonyl group, R ^{3 is} a group -C _n H _2n -OY and R ⁴ , R ⁵ and R ^{6 have} the meaning given, as anti-inflammatory agents for the preparation of topical pharmaceutical and cosmetic agents. 2. Use according to claim 1, characterized in that in the 1,3-dioxolanes of the general formula (I) one of the radicals R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 is} a p-Alkoxyphenoxyalkyl group is. 3. Use according to one of claims 1 or 2, characterized in that in the 1,3-dioxolanes of the general formula (I) one of the radicals R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 is} a p-Methoxyphe noxymethyl group and at least one further radical is a methyl group. 4. Use according to one of claims 1 to 3, characterized marked characterized in that the 1,3-dioxolanes of the general formula (I) in in an amount of 0.01 to 10 wt .-%, in particular from 0.5 to 5 Wt .-%, based on the total agent used. 5. Use according to one of claims 1 to 4, characterized marked records that the pharmaceutical and cosmetic means Sunscreen and sunscreen are. 6. Use according to one of claims 1 to 5, characterized marked characterized in that the 1,3-dioxolanes in combination with conventional UV filter substances are used. 7. Use according to claim 6, characterized in that the UV filter substances in amounts of 1 to 10 wt .-%, in particular from 2 to 6% by weight, based on the total agent be set. 8. Use according to one of claims 1 to 7, characterized marked records that the 1,3-dioxolanes in combination with Antioxi danties are used.   9. Use according to claim 8, characterized in that the Antioxidants in amounts of 0.1 to 5 wt .-%, in particular from 0.5 to 2% by weight, based on the total agent be set. 10. 4- (4-Methoxyphenoxymethyl) -2-methyl-1,3-dioxolane. 11. 3- (4-Chlorophenoxymethyl) -2-methyl-1,3-dioxolane.