DE2129864A1 - New 1,2,3-triazoles and their use as UV absorbers - Google Patents

Description

The present invention relates to new compounds which are strong TJV absorbents, particularly to their use as a protective agent against erythema or sunburn.

The radiation energy of the wavelength from 285 to 325 ni / u. is the main cause of burns from radiation or erythema. If the sun is the source of radiation, it is so called the resulting skin burns are called sunburn. As most people spend a good part of their free time spend outdoors, i.e. at the. Sun, on the beach, in the boat or other recreational areas, especially when skiing,

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is a protection against these burning wavelengths of UV light s very welcome. To provide maximum protection against erythenu or sunburn, the exposed skin should be coated with a material that contains a is a strong absorber for UV light, especially in the range from 285 to 325 myu .. However, since the brown skin is dated From a cosmetic point of view, it is desirable to use the longer wavelengths, i.e. those between 320 and 350 m / rev, cannot be completely filtered out. Through this you can achieve a nice, even tan while completely preventing burning.

There are many known sunscreens that are beneficial Have the ability to filter out the burning rays of UV light, while the rays of tanning Area can penetrate the skin of the protected person »

To be particularly effective as a cosmetic sunscreen, the compounds must have the ability to act on the skin keep the protected person active for a long time. The two The main sources of error with sunscreens are the following: (1) They get knocked off your skin, either by Swimming or perspiration} (2) they are unstable when exposed to UV light, i.e. they are broken down by it.

There are some connections that have a high level of stability

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■■ ..- ■■ ■ -3- 212986 k

have against UV light; however, these compounds showed that
Property of skin substantivity, that is, they cannot be easily washed off with water.

It has now been found that 2H-1,2,3-triazoles with an o-hydroxy substituent in the phenyl ring are suitable as sunscreens because they are skin substantive and not when bathing to be washed off.

The substances according to the invention are also inexpensive to produce, since the relatively inexpensive ß-aminocrotonic acid ethyl ester or the ethyl acetoacetate or mixtures thereof can be used as the starting coupling component. These connections. are considerably less expensive than the starting materials
the previously used UV absorbers.

The invention accordingly relates to new compounds following formula:

N = C-CH ₃ N = CR ₃

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in which R, hydrogen, halogen, a lower alkyl or alkoxy, acylamido, sulfo or carboxy group, R ^ hydrogen, halogen, a lower alkyl or alkoxy group, R, a carboxy group or the radical COR ₆ , where R _{2 is} a lower alkoxy or amino group and where one of the radicals R and R is to be a carboxy or sulfo group.

The new compounds of the present invention are obtained by diazotizing o-aminophen oil in a conventional manner, whereupon one coupling with about the equivalent amount of a lower alkyl ester of ß-aminocrotonic acid or acetoacetic acid. It has It has been found to be advantageous that the lower alkyl ester of ß-aminocrotonic acid or acetoacetic acid is used in the coupling dissolves in an alkaline solvent, e.g. pyridine, picoline, dimethylformamide, sodium acetate, sodium carbonate, etc. The reaction proceeds easily even at room temperature. A solution or slurry of the reaction product in the above-mentioned alkaline reacting solvent is then treated with gaseous ammonia to convert the ketone group to the imino group. The received The product is then subjected to the ring closure to form 2H-1,2,3 - fr? Iazole in the usual way, e.g. by treatment with copper (II) chloride. The entire reaction proceeds according to the following scheme: '

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.OH

OH

NH,

HCl NaNO,

N = N ⁺ Cl "

NH

N = N + H CC-CH ₂ -C

O OEt

OH COOEt 0

N = N-CH C CH

OH

COOEt

N = N-

Sh c -gh.

NH ₃ (g)

COOEt

_N = N CH C CH,

NH

OH

COOEt

CH

OH

Nc

NH \ ^ C-COOEt N

For explanation: Et means the ethyl residue

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Reaction I) is a customary diazotization of an o-aminophenol. When the diazotization reaction has ended, the diazo solution is added to a mixture of picoline, water and a lower alkyl ester of β-aminocrotonic acid or acetoacetic acid at room temperature. After the mixture has been stirred overnight at room temperature and the mixture has been filtered off, the coupling reaction (reaction 2) has ended. The product obtained in reaction 2) is then dissolved in picoline. Gaseous ammonia is then passed through the solution and left to stand overnight. Now anhydrous copper-II-chloride is added into the mixture and allowing the temperature to about 80 to 100 ⁰ G rise; the reaction mixture is kept at this temperature for a few hours.

After heating, the mixture is cooled, whereupon the copper salts are precipitated with sodium sulfide flakes. After filtering and distilling off the picoline, the residue is allowed to cool further, filtered and then distilled in vacuo. The solid obtained is the product of the rearrangement reaction W (reaction 4). The ester group can then either be hydrolyzed to the free acid or converted to the amide, or it can be left as it is, depending on which product is desired.

Suitable o-aminoph.enols for this reaction are the following: o-aminophenol, 4-chloro-o-aminophenol, ^ -chloro-o-aminoplienol, 4,6-dichloro-o-aminophenol, 4 ~ meth.yl-O-aminoph.enol, 5-methyl-oaminophenol, 6-Ch.lor-4-methyl-o-aminoph.enol, 4,6-dimethyl-oaminophenol, 5-methoxy-o-aminophenol, 4-methoxy-o-aminophenol,

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5-methoxy-3-methyl-o-aminoplienol, ^ -chloro-G-methyl-o-aminophenol, ö-chloro - ^ - methyl-o-aminophenol, 4 ~ acetamino-o-aminophenol, 3-amino-4 ~ hydroxybenzoic acid, ^ -Ami methyl! benzoic acid, 4-hydroxymetanilic acid, jpmetanilic acid, 3-hydroxysulfanilic acid, G-chloro ^ -hydroxysulfanilic acid, 4-bromo-o-aminophenol, 5-bromo-o-aminophenol, 4-, G-dibromo-aminophenol _T 6-bromo-o-aminophenol, 4-butyl-o-aminoplienol, 5-butyl-o-aminoplienol, 6-butyl-o-aminoplienol, 6-chloro-4-butylo-aminophenol, 6-bromo-A -Äthyl-o-aminoplienol, '^ -Ohlor-e-butoxy-0-aminoph.enol.

The esters of ß-aminocrotonic acid and acetoacetic acid can be use the methyl, ethyl, propyl, isopropyl, and butyl esters. The methyl and ethyl esters are particularly preferred because they are the most easily accessible.

In connection with the present invention, the means The term "lower alkyl" means an alkyl group having 1 to 6 carbon atoms. Similarly, the term "lower alkoxy" is intended to mean an alkoxy group having 1 to 6 carbon atoms.

The UV absorbing compounds of the present invention can be used alone as sunscreens, or they can be incorporated into conventional, cosmetically acceptable carriers, E.g. as creams, lotions, emulsions or alcoholic solutions etc. as they are common with sunscreens. Watery Solutions of the new compounds of the present invention

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are also effective as sunscreens. These solutions may also contain small amounts of weakly alkaline salts, e.g., sodium carbonate, and polymeric binders such as polyvinylpyrrolidone or polyvinylpyrrolidone-vinyl acetate copolymers, as well as other compounds such as sodium alginate and starch.

Special components for the production of cosmetically usable ointment bases for the compounds according to the invention are the following materials: hardened oils of vegetable origin, Animal fats, semi-solid petroleum hydrocarbons, stearic acid, as well as their esters and salts, getyl alcohol, polyoxyl-40-stearate, Polysorbate-80, cholesterol, waxes, higher ethylene glycol polymers etc. These compounds can be used alone or in combination with usual mixtures, so that • you get an ointment base that is cosmetically compatible Represents carriers for the new sunscreens of the present invention.

Cosmetically acceptable lotion bases which can be used for the compounds according to the invention are used many of the compounds listed above as ointment bases are in question; other typical lotion components are triethanolamine, Glycerin, alcohol, boric acid, water, Garbopol 95 ^ - » liquid vegetable oils, liquid petroleum hydrocarbons, etc.

Water-in-oil emulsion creams can also be used as cosmetically

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convenient carriers for the novel compounds of the present invention can be used. These emulsion creams generally contain a combination of the above-mentioned ointment components, as well as water and perfume.

The substances according to the invention can also be used together with the usual petroleum hydrocarbons and vegetable oils that are used in liniments, bath oils, etc. ■ "

Since the new compounds of the present invention are skin substance because they stain the skin and can only be removed with soap and water, the compounds can too can be used with such ointments, creams or lotions that are water soluble without causing any noticeable adverse effects Can determine the effect on the protective power of the new compounds according to the invention.

The effective amount of the substances according to the invention which is required for excellent protection depends on the desired one Level of protection. The concentration of the 1,2,3-triazole compounds according to the invention in conventional sun protection preparations is usually about 0.01 to 10% by weight (based on the preparation); but you can also if desired, use larger or smaller amounts of the 1,2,3-triazole compounds according to the invention. Generally lies however, the preferred concentration range of the new compounds

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fertilize the present invention between 1 Ms 5 wt .-% (based on the cosmetic preparation).

• The absorption maximum of the compounds according to the invention in UV range, lies within the main combustion range, i.e. between 260 and 320 m / u, and the absorption increases slowly on both sides of this maximum. The absorption profile of the novel compounds of the present invention is shown in FIG sufficient absorption so that the burning short-wave Sun rays are filtered out, while at the same time a sufficient amount of the longer-wave, stronger tanning Rays can penetrate.

The following examples illustrate the new compounds and compositions containing them, as well as processes for their use. All parts are based on weight and all temperatures are based on ⁰ G.

Example 1: Establishing the connection between the molds.!:

OH

N = C-COOH

125.1 g (0.696 moles) of ^ -chloro-o-aminophenol hydrochloride, 100 ecm Water and 119 ecm concentrated hydrochloric acid are mixed and

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stirred in a steam bath for an hour; then cooled, the mixture from the outside to ⁰ ° C and admixed with 129> 8 cc of sodium nitrite solution (38.5 wt .-% / vol.), followed by stirring for two hours at O to 5 ⁰ G. The excess nitrite is then destroyed by treatment with sulfamic acid and the diazo solution obtained is added to a mixture of 2000 ecm picoline, 1080 ecm water and 94.4 g ß-aminocrotonic acid ethyl ester at room temperature. After stirring overnight, the mixture is filtered, washed with water and dried; 187.7 g of a dye cake are obtained from a compound of the following formula:

I ^{2 5}

N = N-CHCOCH ₃

0.13 mol of this product are dissolved in 600 ecm picoline, whereupon gaseous ammonia at atmospheric pressure and room temperature initiates and the mixture is stirred overnight. Now add 4-3 * 8 g of anhydrous copper (II) chloride to the mixture and the temperature is allowed to rise to 90 to 95 ° 0, whereupon the mixture is heated for four hours. The mixture is now cooled to 80 ° C and the copper salts are precipitated with sodium sulfide flakes. After filtering off the picoline is distilled off with steam, the residue is cooled and filtered. The filter cake will now 'washed with water, dried and placed in a' distillation

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piston given; it is distilled at a temperature of 153 to 158 ° G in a vacuum of 0.34 to 0.44 mm. In this way 22.3 g of a solid are obtained which are recrystallized from isopropanol and represents a compound of the following formula: - ·

N = C-CH

Cl

The product melts at 110.6 to 111.2 ⁰ G; K »30.6 at

IUcLjC

515 nyu. "'.. -

Analysis C ₁₂ H ₁₂ GlW ₅ O ₅ ;

calculated 51.22 % C; 4.29 % H; 14.92 % N;

found 51.19 % G; 4.69 % H; 15.03 % N 51.19 % 4.53 % 14.86 %

0.05 mol of the above product are mixed with 150 ecm of water and 44 ecm a 5% aqueous sodium hydroxide solution heated with stirring for 1 hour. The mixture is then allowed to cool to 10 ° C. and neutralized with dilute acetic acid to pH delta neutral. The plague is filtered off, washed acid-free and dried. The filter cake is recrystallized from glacial acetic acid and this is obtained desired product of the following formula:

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OH

N = C-COOH

Cl

The compound melts at 314.5-315.0 C; K = 37.4 at 315 HIyU.

Analysis. G-jqHoGIN-, 0 ,:

calculated: 47.43 % C; 3.18 % H; 16.59 % N;

found: 48.50 % C; 3.18 % H; 16.62 % N ··. 48.76 % 3.18 % , 16.62

Example 2:

A 2% aqueous solution of the compound of Example 1 one weight equivalent of sodium carbonate is added.

This solution is applied to the skin and left to dry.

After the skin had been exposed to the summer sun for 4 hours, the protected areas of the skin showed no noticeable burns and a weak tan compared to completely covered areas of the skin.

After the irradiation, the skin was washed with warm water, dried and exposed to the sun for an additional four hours. The protected areas showed no signs of sunburn, just a slight tan, while the unprotected areas Parts were noticeably burned.

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Example 3

The composition of Example 2 is mixed with 2% by weight of polyvinylpyrrolidone (K = JO). This composition will be similar in Tested like the composition according to Example 2 and similar results are obtained.

Example 4:

The composition according to Example 2 is mixed with the following substances: A) 2 % vinylpyrrolidone (70 %) , B) vinyl acetate (30%) copolymer (K = 45), G) 2% sodium alginate and D) 2 % starch. The test described in Example 2 is carried out with these compositions, and results similar to those in Example 2 are obtained.

Example 5: Preparation of the compound of the formula:

12 g of 4,5-dimethyl-o-aminophenol (0.087 mol), 33 ecm of glacial acetic acid, 50.6 ecm of water and 14.8 ecm of concentrated hydrochloric acid are mixed and heated until a solution is obtained; then it is cooled to 5 ° 0. 15.7 ecm of sodium nitrite solution (38.5% by weight / vol.) Are then added at 5 to 10 ^{0 g, whereupon the mixture is stirred for 45 minutes.} The excess nitrite is then taken with

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Destroyed dilute aqueous sulfamic acid and the diazo compound obtained is added to a mixture of 500 ecm picoline, 135 ecm water and 11.8 g ß-amino crotonic acid ethyl ester. The mixture is stirred for 7 to 10 days at room temperature and the mixture is then poured into 8 liters of ice water. After leaving the stirrer overnight, the solid is filtered off, washed with water and dried. 19.2 g of a dye cake are obtained, ^K max ⁼ 73.75 at 395 nyu; Sp. - 138.4 to 14-2 ⁰ C. The product has the following formula:

CH-

COOC ₂ H ₅ O

N = N-CH

-C-CH.

0.05 mol of this product is dissolved in 300 ecm picoline, whereupon gaseous ammonia is introduced into the mixture at atmospheric pressure until it is saturated. The solution is left Stir overnight and remove the excess ammonia and picoline under reduced pressure; this gives a mixture of the above keto dye and the following intermediate:

CH,

COOC ₂ H

N = N-CH

NH Il C-CH.

CH

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-Ιο

12.1 g of the above mixture (about 0.0435 mol) are added to 250 ecm picoline which contains 14.8 g copper (II) chloride. The mixture is heated for 3 hours at 90 to 95 ° C and then cooled to 80 ⁰ G. The copper salts are precipitated with sodium sulfide flakes, the slurry obtained is clarified, the picoline is distilled off with steam and the residue is cooled and filtered. The filter cake is washed with water and dried, then wird'im vacuum (0.47 to 0.50 mm) distilled at 172-182 ⁰ C. 6.7 g of a solid are obtained, which is recrystallized from methanol and has the following structure:

CH.

COOC ₂ H ₅

The product melts at 86.8-87.2 ° C; K _max = 57.5 "at 315 m./U. Analysis (G ₁₄ H ₁₇ N ₅ O ₅ ).

calculated: 61.15% G; 6.24% H; 15.29 % F;

found: 61.72 % C; 6.22 % H; 15.32 % N; 61.72 % 6.22 % 15.32 %

0.02 mol of this product is added to 60 ecm of water and 17.6 ecm of 5% strength aqueous sodium hydroxide solution, whereupon the mixture is heated for 1 hour while stirring. Allow to cool the mixture to 10 ⁰ G and neutralized with dilute acetic acid to neutral pH Delta.

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The solid is filtered off and washed acid-free with water and dried. The filter cake is recrystallized from glacial acetic acid and yields the desired product of the following formula

Example 6: Preparation of the compound of the formula:

»: C ^J

\ ^ s * CONH ₂

N

SO ₃ Na

0.0696 mol of the sodium salt of ^ - hydroxymetanilic acid diazotized in a manner analogous to that described in Example 1 and at room temperature with the ethyl ester of ß-aminocrotonic acid coupled in a picoline / water mixture. The mixture is stirred overnight and the mixture is subjected to steam distillation, to remove the picoline; this way you get a aqueous mixture of the following keto dye:

OH COOC ₂ H ₅ Q

N = N-CH C-CH ₃

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The aqueous mixture is saturated with gaseous ammonia, whereupon 2.5 equivalents of copper (II) chloride dihydrate are added and the mixture is refluxed for 24 hours. Now allowed to cool to 80 ⁰ G and the copper salts precipitated with sodium sulfide flakes. The resulting slurry is marked with an equi. valent sodium hydroxide brought to pH 1.2 and filtered. The aqueous filtrate is ^{cooled to 0} ° C. and brought to pH 5 with concentrated hydrochloric acid, the desired product of the following formula being obtained after filtration:

SO ₃ Na

Example 7 » Preparation of the compound of the formula:

™ ■

N ^L COSC ₂ H ₅

0.05 mol of the intermediate keto dye according to Example 6 is suspended in 200 ecm of a 5: 1 mixture of isopropanol and 29% aqueous ammonia. so

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2.5 equivalents of copper (II) chloride dihydrate are added and the mixture is heated. Reflux for 24 hours. The mixture is allowed to cool to 60 ⁰ G and the copper salts precipitated with 20% aqueous Natriuinsulfid solution. The resulting slurry is brought to pH 12 with one equivalent of sodium hydroxide and then filtered. The aqueous filtrate is allowed to cool and the pH is adjusted to 5 with hydrochloric acid. Filtering off gives the desired product of the following formula:

SO ₃ Na

Example 8: Preparation of the compound of the formula;

0.05 mol of the product prepared according to Example 7 is hydrolyzed in a manner analogous to that of the chlorine analog of Example 1, the desired product being obtained.

Example 9: Preparation of the compound of the formula:

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0.696 mol of 5-methoxy-o-aminophenQl hydrochloride Chem. Ber., 46, 3382 (1913) are diazotized in an analogous manner and coupled as in Example 1 for the ^ - chloro-o-aminophenol hydrochloride is described; a keto dye is obtained here of the following formula:

I 2 5

N = N-CH

C-CH

0.13 moles of this product will result in an analogous ring closure subjected as in Example 1 for the 4-chloro analog is described, giving the desired triazole of the following formula:

CH ₃ O

0, -0.5 mol of this product are hydrolyzed in an analogous manner, as described in Example 1 for the chlorine analogue;

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the desired product of the following formula is obtained:

Example 10:

! "lan repeats Example 1, but using the 94.4 · 'g of the ß-aminocrotonic acid ethyl ester by 94.5 g of the ethyl acetoacetate replaced. The reaction proceeds in the same way as in Example 1 and gives a corresponding reaction product.

Examples 11-18:

The following compounds are prepared according to the procedure described in Example 1:

N = C-CH ^

N = C-COOH example starting o-aminophenol R- ^ Rp

11 4-Butyl-o-aminophenol "" ^ Α- ^ α "" ^

12 4-, 6-dibutoxy-o-aminophenol -OC ^ EL

13 4-Bromo-o-aminophenol -Br. -H

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Example starting o-aminophenol 14 15 16 17 18

4-, 6-dibromo-o-aminophenol ^ -acetamino-o-aminophenol

ο-aminophenol

4-, 6-dibutyl-o-aminophenol

3-amino-4-hydroxybenzoic acid

-Br 21 29864 ^R l -KH-C ^
-H E ₂ ~ ^G 4 ^H 9 -Br .0
^ CH _x -H
-H ~ ^G 4- ^H 9

-COOH

-H

Example 19:

According to process example 7, using 3-Amino-4-hydroxybenzoic acid as the starting material is as follows Product:

COOH

N = C-CH.

N = C-COOC ₂ H ₅

/ Claims: 109853/1977

Claims (1)

Claims' in which R _{1 is} hydrogen, halogen, a lower alkyl or alkoxy, acylamido, sulfo or carboxy group, R ^ is hydrogen, halogen, a lower alkyl or alkoxy group, S, a carboxy group or the radical COR ^ , where R ^ is a lower alkoxy or amino group and where one of the radicals R ₁ and R ^ should be a carboxy or sulfo group. 2.) 1,2,3-Ti "iazole compound according to claim 1 of the following Formula: N = C-CH. N = C-COOH 1,2, ^ - 'i'riazole compound according to claim 1 of the following Formula: 10 9 8 5 3/1977 OH CH CH. N = C-CH. N = C-CQOH 4-.) 1,2,3-Triazole compound according to claim 1 of the following Formula: OH SO ₃ Na N = C-CONHr 5.) 1,2,3-triazole compound according to claim 1 of the following Formula: pH N = C-CH SO ₃ Na N = C-COOC H 2 5 6.) 1,2,3-Triazole-Vert) indung according to claim 1 of the following Formula: ■ OH N = C-CH- N = C-COOH SO ₃ Na 109853/1977 ?.) 1,2,3-Triazole compound according to claim 1 of the following Formula: N = C-CH- N = C-COOH S.) Method of protecting the skin against sunburn under simultaneous tanning, characterized by treating the skin with an effective amount (so that the burning Rays of UV light are filtered out) a 1,2,3-triazole compound of the following formula: OH N = C-CH N = C-R, in which E _{1 is} hydrogen, halogen, a lower alkyl or alkoxy, acylamido, sulfo or carboxy group, R _{2 is} hydrogen, halogen, a lower alkyl or alkoxy group, IU is a carboxy group or the radical COR ^, where R ^ is a lower alkoxy or amino group and where one of the radicals R and R ^ is to be a carboxy or sulfo group. 9.) Method according to claim 8, characterized in that 109853/1977 the 1,2,3-triazole compound is a substance of the following Formula used: N = C-CH. N = C-COOH 10.) Method according to claim 8, characterized in that
a substance of the following formula is used as the 1,2,3-triazole compound: OH CH. N = C-CH- N = C-COOH 11.) Process according to claim 8, characterized in that Wk is used as the 1,2,3-triazole compound, a substance of the following formula: .OH .N = C-CH. 'N = C-CONH ₂ 12.) Method according to claim 8, characterized in that the 1,2,3-triazole compound is a substance of the following 109853/1977 uses the formula: N = C-CH N = C-COOC ₂ H ₅ 13 ·) Method according to claim 8, characterized in that the 1,2,3-triazole compound is a substance of the following Formula used: N = C-CH N = C-COOH 14-.) Method according to claim 8, characterized in that the 1,2,3-triazole compound is a substance of the following Formula used: N = C-COOH 15 ·) Cosmetic composition to protect the skin against sun 10 9 8 5 3/1977 brand with simultaneous browning, consisting of one cosmetically acceptable carrier and an effective Mengo (sod3ns the burning rays of UV light heraUKgo a sunscreen of the formula below N. N = C-CH. -N = C-R in which R _{1 is} hydrogen, halogen, a lower alkyl or alkoxy, .Acylamido, SuIfο or carboxy group, Rp is hydrogen, halogen, a lower alkyl or alkoxy group, R-, a carboxy group or the radical COR ^ mean, where R ^ is a lower alkoxy or amino group and where one of the radicals R-, and E, should be a carboxy or sulfo group. ■ - 109853/1977