WO1991002515A1

WO1991002515A1 - Anti-inflammatory substances for cosmetic preparation

Info

Publication number: WO1991002515A1
Application number: PCT/EP1990/001322
Authority: WO
Inventors: Hinrich Möller; Matthias Potokar
Original assignee: Henkel Kommanditgesellschaft Auf Aktien
Priority date: 1989-08-19
Filing date: 1990-08-10
Publication date: 1991-03-07
Also published as: AU6070790A; DE3927460A1

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 -Cn?H2n?-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 $i(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 -Cn?H2n?-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 -Cn?H2n?-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

"Anti-inflammatory agents for cosmetic preparations"

The invention relates to the use of 1,3-dioxolanes as anti-inflammatory agents for the production of topical pharmaceutical and cosmetic agents.

It is known to expand the action of cosmetic and pharmaceutical preparations, in particular those for use on skin which is stressed as a result of strong light radiation, by adding anti-inflammatory substances.

The anti-inflammatory properties of 1,3-dioxolanes are known from German Offenlegungsschriften 2519161, 2526312 and 2526 675. Although the addition of these compounds already achieves a significant inhibition of inflammation, these 1,3-dioxolanes do not show all the desired properties. Thus, the compounds disclosed in DE 2529161 and DE 2526312 do not have the necessary hydrolysis stability in all formulations. Although this hydrolysis stability is given for the compounds according to DE 2526675, there is still a need for substances with a higher activity at the same or lower application concentrations. It has now been found that certain 1,3-dioxolanes of the general formula (I)

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ independently of one another are hydrogen, alkyl groups with 1-4 carbon atoms, alkoxy groups with 1-4 carbon atoms or a group -C _n H2n ~ 0-Y, where Y is a phenyl group, a mono- or dialkylphenyl, a mono- or dialkoxyphenyl, an alkyl inophenyl, a dialkylrinophenyl or an alkylthiophenyl group, each with 1-4 carbon atoms in the alkyl or alkoxy group, or represents a mono- or dihalophenyl group and n is an integer from 1 to 4, with the proviso that at least one and at most two of the radicals R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} a group -C _n H2 _n -0-Y, or that Rl and R ² together with the carbon atom carrying them represent a carbonyl group, R ^{3 is} a group -C _n H2n-0-Y and R ⁴ , R5 and RÖ have the meaning given, are characterized by a significantly greater anti-inflammatory effect. These compounds can be easily incorporated into common pharmaceutical and cosmetic foundations for topical applications; they can be easily combined with the other customary ingredients of such preparations and have no or only a minimal intrinsic odor. The invention thus relates to the use of 1,3-dioxolanes of the general formula (I) as anti-inflammatory active substances for the production of topical pharmaceutical and cosmetic agents.

The compounds of the formula (I) can be prepared from readily available starting products using known chemical reactions.

One possibility is the known ketalization processes in which oxo compounds are reacted with 1,2-diols in the presence of an acidic catalyst such as p-toluenesulfonic acid, sulfuric acid, zinc chloride or iron (III) chloride, the water of reaction being reacted with a suitable entrainer such as toluene or cyclohexane is continuously removed during the reaction. Another possibility is the reaction of oxo compound and 1,2-diol in the presence of a trialkyl ortho-formate and an acidic catalyst at temperatures between 50 and 150 ° C, at which the lower-level reaction products formic acid ester and alcohol are continuously distilled off .

Another production process is the alkylation of appropriately substituted phenols with 2-haloalkyl-1,3-dioxolanes in the presence of a phase transfer catalyst such as, for example, tetraalkyl monium chloride, bromide or iodide in an inert solvent at temperatures between 50 and 150 ° C.

The following groups can appear as substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 in the} compounds to be used according to the invention: hydrogen

Alkyl groups with 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 with 1-4 carbon atoms, such as methoxy,

Ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-n-butoxy and tert-butoxy groups. The methoxy group is the preferred alkoxy group in the context of the teaching according to the invention.

Furthermore, at least one and at most three of the named substituents are a group -C _n H2n-0-Y.

The index n stands for an integer from 1 to 4; a substituted methyl group, an ethyl group substituted in the 2-position or an n-propyl group substituted in the 3-position are preferred here. In the context of the teaching according to the invention, substituted methyl groups are preferred.

Y can stand for

a phenyl group, a monoalkylphenyl group having 1-4 carbon atoms in the alkyl group. Monoalkylphenyl groups in which the alkyl substituent is in the 4-position are preferred. Preferred alkyl substituents are methyl, ethyl and tert-butyl. 4-Methylphenyl, 4-ethylphenyl and 4-tert-butylphenyl groups represent particularly preferred monoalkylphenyl groups. A dialkylphenyl group each having 1-4 carbon atoms in the alkyl group. Dialkylphenyl groups in which the alkyl substituents are in the 3- and 4-position are preferred. Preferred alkyl substituents are methyl and ethyl. The 3,4-dimethylphenyl group is a particularly preferred dialkylphenyl group. a monoalkoxyphenyl group having 1-4 carbon atoms in the alkoxy group. Monoalkoxyphenyl groups in which the alkoxy substituent is in the 4-position are preferred. Preferred alkoxy substituents are methoxy and ethoxy. 4-methoxyphenyl and 4-ethoxyphenyl groups are particularly preferred monoalkoxyphenyl groups. A dialkoxyphenyl group each having 1-4 carbon atoms in the alkoxy group. Dialkoxyphenyl groups in which the alkoxy substituents are in the 3- and 4-position are preferred. Preferred alkoxy substituents are methoxy and ethoxy. The 3,4-dimethoxyphenyl group is a particularly preferred dialkoxyphenyl group. an alkylaminophenyl group having 1-4 carbon atoms in the alkyl group. Alkylaminophenyl groups in which the alkyl ino substituent is in the 4-position are preferred. Preferred alkyl substituents are methyl and ethyl. a dialkylaminophenyl group with 1 to 4 carbon atoms in each of the alkyl groups. Preferred groups are those in which the dialkylamino substituent is in the 4-position. The 4-dimethylaminophenyl group is particularly preferred. an alkylthiophenyl group having 1-4 carbon atoms in the alkyl group. Alkylthiophenyl groups in which the alkylthio substituent is in the 4-position are preferred. Preferred alkyl substituents are methyl and ethyl. a monohalophenyl group. Monohalophenyl groups in which the halogen substituent is in the 4-position are preferred stands. Fluorine, chlorine, bromine and iodine are preferred halogen substituents, chlorine is particularly preferred, a dihalophenyl group. Preference is given to dihalophenyl groups in which the halogen substituents are in the 4-position and in the 3- or 2-position. Fluorine, chlorine, bromine and iodine are preferred halogen substituents, and chlorine is particularly preferred.

Furthermore, the substituents R and R ² together with the carbon atom carrying them can represent a carbonyl group. R ³ in this case is a group -C _n H2 _n -0-Y; R ⁴ , R ^ and R6 have the meaning given above.

Compounds of the general formula (I) which are preferred according to the invention are 4- (4-methoxyphenoxymethyl) -1, 3-dioxolane, 4- (4-methoxyphenoxymethyl) -2-methyl-1,3-dioxolane, 4- (4-chlorophenoxymethyl) ) -2-methyl-1,3-dioxolane, 4- (4-methoxyphenoxymethyl) -l, 3-dioxolan-2-one and 2_ (4-methoxyphenoxymethyl) -4,4,5,5-tetramethyl-1,3 -dioxolane.

The compound 4- (4-methoxyphenoxymethyl) -2-methyl-1,3-dioxolane and 4- (4-chlorophenoxymethyl) -2-methyl-l _f 3-dioxolane are new and therefore also an object of the invention. Manufacturing processes for these compounds can be found in the example section.

According to the invention, the 1,3-dioxolanes of the general formula (I) are preferably used in amounts of 0.01-10% by weight, in particular in amounts of 0.5-5% by weight, based on the total agent. The compounds of the general formula (I) are particularly preferably used in amounts of 2-5% by weight, in particular in amounts of about 3% by weight. The use of the compounds of the general formula (I) is particularly advantageous for the preparation of sunscreens and sun-fighting agents. The 1,3-dioxolanes can be used both in compositions which are applied to the skin before and in those which are applied after sun exposure.

The 1,3-dioxolanes according to the invention themselves have no absorption band in the erythema-producing UV-B range of approximately 300-320 nm. For the preparation of agents which are applied to the skin before sunbathing, it is therefore preferred to use them in combination with conventional UV filter substances.

Suitable UV filter substances are, for example:

Salicylic acid derivatives, such as the esters of menthol, homo-enthol, fenchol, borneol, glycerol, benzyl alcohol, phenol, ethylene glycol, 2-ethylhexanol and tert-butanol, as well as the triethanolammonium salt of salicylic acid ,

Cinnamic acid esters, such as p-methoxy, p-amino and p-dimethylamino cinnamic acid esters, for example ethyl p-methoxy cinnamic acid 3-ethoxy, p-methoxy cinnamic acid 2-ethylhexyl ester and p-acetamido cinnamic acid isopropyl ester,

p-aminobenzoic acid and its derivatives, such as p-aminobenzoic acid, ethyl, propyl, butyl, isobutyl, onoglycerol and dipropylene glycol ethyl ester, p-dimethylaminobenzoic acid, ethyl and ayl ester, and p-diethylaminobenzoic acid, ethyl and amyl ester, substituted benzophenones, such as 2,2'-dihydroxy-4,4'-dimethoxy-benzophenone, 2-hydroxy-4-n-octoxy-benzophenone, 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-methylcoumarin, 7,8-dihydroxycoumarin, 6,7-dihydroxycoumarin, 7-hydroxycoumarin, 4-methyl-7-hydroxycoumarin and 3-phenylcoumarin,

further 2-phenylbenzimidazole-5-sulfonic acid, sodium 3,4-dimethoxyphenylglyoxylate, butylbenzalacetone, benzalacetophenone, 3-tolylidene-D, L-camphor, 3-benzylidene-D, L-camphor, 3- (p-methylbene - Cylidene) -D, L-camphor, urocanic acid and its salts, benzimidazole derivatives, digalloyl trioleate, sulfona ide, hydrazones, condensation products of tannin with ethylene oxide and as natural products extracts of cinnamon bark, ratanhia and licorice.

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

The UV filter substances mentioned are usually used in amounts of 1-10% by weight, based on the total agent. Amounts of 2-6% by weight are preferred.

Furthermore, it is preferred according to the invention to add antioxidants to agents prepared according to claim 1. The use of natural or nature-identical compounds such as tocopherols is particularly preferred. The antioxidants mentioned are in the agents according to the invention in amounts of 0.1-5% by weight, in particular 0.5-2% by weight, based on the total agent.

The agents according to the invention can be formulated as liquid, pasty or solid preparations, for example as aqueous or alcoholic solutions, aqueous suspensions, emulsions, ointments, creams, oils, powders or sticks. Depending on the desired formulation, the 1,3-dioxolanes can be incorporated into pharmaceutical and cosmetic foundations for topical applications which, for example, include oil components, fats and waxes, emulsifiers, anionic, cationic, ampholytic, zwitterionic and / or contain nonionic surfactants, lower mono- and polyhydric alcohols, water, preservatives, buffer substances, thickeners, fragrances, dyes and opacifiers.

B E I S P I E L E

The following examples serve to explain the invention further, without restricting it thereto.

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) propane-1,2-diol, 17.7 g (0.15 mol) of 1,1-diethoxyethane and 0.1 g of p-toluenesulfonic acid was heated at 95 ° C. for 4 hours, the alcohol formed during the reaction being distilled off. The residue was then taken up in toluene, washed with water, dried with sodium sulfate and evaporated. The remaining residue was finally subjected to fractional distillation. 2Q, 7 g (92% of theory) of a colorless liquid with a boiling point of 116-118 ° C. at 0.06 mbar were obtained, whose refractive index nn ^{20 was} 1.5160.

The following connections were made analogously:

b) 4- (4-methoxyphenoxymethyl) -2,2-dimethyl-l, 3-dioxolane boiling point: 118 ° C at 0.06 mbar; nn ²⁰ : 1.5060.

c) 4- (4-methoxyphenoxymethyl) -2-ethyl-1,3-dioxolane n _D ² 0: 1.5098.

d) 4- (4-methoxyphenoxymethyl) -l, 3-dioxolan-2-one melting point: 98-100 ° C. e) 4- (4-methoxyphenoxymethyl) -l, 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; nn ²⁰ : 1.5092.

g) 4- (4-tert-butylphenoxymethyl) -2-methyl-l, 3-dioxolane boiling point: 105-107 ° C at 0.1 mbar;

1.4993.

h) 4- (4-ethylphenoxymethyl) -2-methyl-1,3-dioxolane boiling point: 90-91 ° C at 0.09 mbar; np ²⁰ : 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; np ²⁰ : 1.5250.

k) 4- (3,4-dichlorophenoxymethyl) -2-methyl-1,3-dioxolane boiling point: 122 ° C at 0.08 mbar; np ²⁰ : 1.5389.

1) 4- (2,4-dichlorophenoxymethyl) -2-methyl-1,3-dioxolane boiling point: 166 ° C at 0.09 mbar; nn ²⁰ : 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 tetrabutylam onium iodide and 100 ml of diethylene glycol dimethyl ether were heated to 120 ° C. and, after the methanol had been distilled off, the mixture was stirred at 150 ° C. for 12 hours. After filtering, concentrating the mother liquor under reduced pressure, taking up the residue in methylene chloride, washing with water until the solution was neutral, drying and evaporating the solution, the residue was fractionally distilled. 37.1 g (83% of theory) of a colorless oil with a boiling point of 111 ° C. at 0.08 mbar were obtained, which had a refractive index np ² 0 of 1.5166.

The following connections were made analogously:

n) 2- (4-methoxyphenoxymethyl) -4,5-dimethyl-1,3-dioxolane Boiling point: 123-124 ° C at 0.08 mbar; n _D 0: 1.5166.

0) 2- (4-methoxyphenoxymethyl) -4,4,5,5-tetramethyl-1,3-dioxolane The purification was carried out here by column chromatography (SiO 2 / eluent: methylene chloride).

Boiling point: 128-130 ° C at 0.09 mbar; n _D ²⁰ : 1.5058.

1) 2- (4-methoxyphenoxymethyl) -l, 3-dioxolane boiling point: 128-129 ° C at 0.08 mbar; ΠQ ²⁰ : 1.5278.

2. Test procedure for the anti-inflammatory effect

To determine the anti-inflammatory effects of the substances, a test was carried out on hairless mice for skin damage by UV light.

The hairless mice were irradiated on the back with a UV lamp (Ultravitalux lamp, OSRAM) from a distance of 45 cm for 3 minutes, which triggered a measurable skin inflammation (edema). Immediately after the end of the irradiation and 1, 2 and 3 hours later, the test substances were applied in the form of an ethanolic solution (2 × 20 μl per application using an automatic pipette) and gently massaged in using a glass rod. As a comparison test, aftertreatment with the carrier ethanol (control) was carried out on mice irradiated in the same way. After 30 hours, the degree of edema formation was determined by measuring the skin fold thickness. The degree of edema inhibition was determined by comparing the change in the skin fold thickness due to the radiation in treated animals and animals treated only with the carrier.

The following values were found:

Substance inhibition of UV edema after 30 hours 4- (4-methoxyphenoxymethyl) -l, 3-dioxolane 19%

4- (4-methoxyphenoxymethyl) -2-methyl-

1,3-dioxolane 35%

4- (4-methoxyphenoxymethyl) -l, 3-dioxolan-2-one 21% 2- (4-methoxyphenoxymethy1) -4,4,5,5-tetramethyl-l, 3-dioxolane 23%

4- (4-chlorophenoxymethyl) -2-methyl-1,3-dioxolane 33%

4- (3,4-dichlorophenoxymethyl) -2-methyl-1,3-dioxolane 22%

3. Composition of a sun protection emulsion

Component: parts by weight

Cutina GMS ( ^R H 10.0

Peanut oil 10.0

Eumulgin (R) B 3 ² 4.0

Glycerin 5.0

Phenonip ( ^R ) ³ 0.2

Active ingredient according to formula (I) 3.0

3-tolylidene-D, L-camphor 2.0

α-D-tocopherol 1.0

Dyes, fragrances, water ad 100.0 Glycerol monostearate DAB 8 (HENKEL)

Cetylstearyl alcohol with approx. 30 moles of ethylene oxide (HENKEL)

Mixture of hydroxybenzoic acid methyl ester, hydroxybenzoic acid ethyl ester, hydroxybenzoic acid propyl ester, hydroxybenzoic acid butyl ester and phenoxyethanol (NIPA).

Claims

PATENT CLAIMS

1. Use of 1,3-dioxolanes of the general formula (I),

in which R ¹ , R ² , R ³ , R ⁴ and Rß independently of one another are hydrogen, alkyl groups with 1-4 carbon atoms, alkoxy groups with 1-4 carbon atoms or a group -C _n H2n-0-Y, where Y is a phenyl group, a mono- or dialkylphenyl, a mono- or dialkoxyphenyl, an alkylaminophenyl, a dialkylaminophenyl or an alkylthiophenyl group, each with 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, with the proviso that at least one and at most two of the radicals R *, R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are} a group -C _n H2 _{n are} -0-Y, 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 H2n ~ 0-Y and R ⁴ , and Rß have the meaning given have, as anti-inflammatory agents for the manufacture of topical pharmaceutical and cosmetic products.

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 , Rß and Rß is a p-alkoxyphenoxyalkyl group.

3. Use according to one of claims 1 or 2, characterized gekenn¬ 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 , Rß and R ⁶ one p-methoxyphenoxymethyl group and at least one further radical is a methyl group.

4. Use according to one of claims 1 to 3, characterized gekenn¬ characterized in that the 1,3-dioxolanes of the general formula (I) in an amount of 0.01 to 10 wt .-%, in particular from 0.5 to 5 % By weight, based on the total agent, are used.

5. Use according to one of claims 1 to 4, characterized gekenn¬ characterized in that the pharmaceutical and cosmetic agents are sunscreen and sunburn control agents.

6. Use according to any one of claims 1 to 5, characterized gekenn¬ characterized in that the 1,3-dioxolanes are used in combination with conventional UV filter substances.

7. Use according to claim 6, characterized in that the UV filter substances in amounts of 1 to 10 wt .-%, in particular 2 to 6 wt .-%, based on the total agent, are used.

8. Use according to one of claims 1 to 7, characterized gekenn¬ characterized in that the 1,3-dioxolanes are used in combination with antioxidants.

9. Use according to claim 8, characterized in that the antioxidants are used in amounts of 0.1 to 5% by weight, in particular 0.5 to 2% by weight, based on the total agent.

10. 4- (4-methoxyphenoxymethyl) -2-methyl-1,3-dioxolane.

11. 3- (4-chlorophenoxymethyl) -2-methyl-1,3-dioxolane.