DE2327959A1 - ANTI-INFLAMMATORS FOR COSMETIC PREPARATIONS - Google Patents

Description

"Anti-inflammatory agents for cosmetic preparations"

Subject of. Invention are anti-inflammatory agents for cosmetic preparations, especially for sun protection and sunburn control agents based on benzoxazol-2-yl-acetic acid derivatives.

It has been found that benzoxazol-2-yl-acetic acid derivatives the general formula

Ε — CH.-I

in which R, for a hydrogen atom, a halogen atom, a lower alkyl, a lower alkoxy, a nitro, an amino, a carboxyl, a carbon ester or an optionally substituted carbonamide group, A for the groups -CN, -CO 0 «R ₂ , -CON-RyR ₂ J. or -CO-NH-NR-, · R ^, in which R is hydrogen or a lower alkyl group with 1-4 carbon atoms and Rz and R ₂ , independently of one another, are hydrogen, a lower alkyl-, a lower acyl- * a hydroxyalkyl-j an aralkyl group a heterocycle or an aryl group optionally substituted one or more times by alkyl and / or alkoxy groups and R ^ and R ₂ , together with the stick

Henkel & Cie GmbH su 2 »» Pei »nionm» id «n _e d 4726

substance atom can mean a heterocyclic ring system, are excellent as anti-inflammatory agents are suitable for cosmetic preparations.

The products are of particular importance as anti-inflammatory Agents in sunscreen or sunburn control agents.

The manufacture of most of the benzoxazol-2-yl-acetic acid derivatives can be carried out according to methods known per se. The benzoxazol-2-yl-acetic acid esters can be passed through Implementation of the appropriately substituted ο-aminophenols with malonic acid dialkyl esters and subsequent acid-catalyzed Cyelo condensation of the ο -hydroxy-malonic ester anilides formed obtain. Alkaline hydrolysis, aminolysis or hydrazinolysis turn the esters into benzoxazol-2-yl-acetic acids, -acetamide or -acethydrazide obtained. The benzoxazol-2-yl-acetonitrile can be according to new Process by reacting the appropriately substituted ο-aminophenols with malonitrile or alkyl cyanoacetimidate hydrochloride produce. The N-unsubstituted benzoxazol-2-yl-acetamides are also by implementation of the appropriately substituted ο-aminophenols with Cy.anacetamid accessible with ammonia elimination. In addition, N-substituted amides can be prepared by transamidation will.

Compounds to be used according to the invention are, for example Benzoxazol-2-yl-acetic acid, benzoxazol-2-ylacetic acid acetyl ester, 5-methyl-benzoxazol-2-yl-acetic acid methyl ester, 5-chloro-benzoxazol-2-yl-acetic acid ethyl ester, S-bromo-benzoxazol ^ -yl-acetic acid butyl ester, benzoxazol-2-yl-acetamide, 5-methyl-benzoxazol-2-yl-acetamide, 5-chloro-

409881/1250

Henkel & CIe GmbH since. 3 to Poi <mionm.idun _fl ο 4 726

benzoxazol-2-yl-acetamide, S-methyl-benzoxazol - ^ - yl-acetic acid methylamide, 5-methoxy-benzoxazol-2-yl-acetic acid-npropylamide, S-bromobenzoxazol - ^ - yl-acetic acid methylamide, S-diethylaminocarbonyl-benzoxazole- ^ -yl-acetic acid-n-butylamide, -S-methoxy-benzoxazole ^ -yl-acetic acid-cyclohexylamide, 5-ethoxy-benzoxazol-2-yl-acetic anilide, 5-acetylaminobenzoxazol-2-yl-acetic acid-3'-methoxy -n-propylamide, 5-trifluoromethyl-benzoxazol-2-yl-acetic acid-n-propylamide, 5-methylbenzoxazol-2-yl-acetic acid-2'-hydroxyethylamide, 5-methylbenzoxazol-2-yl-acetic acid-benzylamide, 5-methyl-benzoxazol-2-yl-acetic acid 2 '-phenylathylamid, 5-methyl-benzoxazol-2-yl-acetic acid ⁱ i ^t -picolylamid, 5-methyl-benzoxazol-2-ylacetic acid ^1-4 -toluidide , S-methyl-benzoxazol - ^ - yl-acetic acid dimethylaraid, 5-methyl-benzoxazol-2-yl-acetic acid-di-n-butylamide, S-methyl-benzoxazol ^ -yl-acetic acid-pyrrolidide * 5-methylbenzoxazol-2- yl-acetic acid-piperidide, 5-methyl-benzoxazol ~ 2-yl-acetic acid-piperazid, S-methyl-benzoxazol ^ -yl-acetic acid-morph olide, S-methyl-benzoxazol ^ -yl-acetic acid-N-methylaynilide, benzoxazol-2-yl-acetic acid hydrazide, benzoxazol-2-yl-acetic acid-N-benzylamide, benzoxazol-2-yl-acetic acid-N-phenylamide, benzoxazole -2-yl-acetic acid-.ß-pyridylamide, benzoxazol-2-yl-acetic acid-o-fluoroanilide, benzoxazol-2-ylacetic acid-p-anisidide, benzoxazol-2-yl-acetic acid-o-toluidide, benzoxazol-2- yl-acetic acid-m-trifluoromethylanxlide, benzoxazol-2-yl-acetic acid-o-anisidide, benzoxazol-2-yl-acetic acid-omethyl-p-anisidide, benzoxazol-2-yl-acetic acid-3 ' Λ * -dioxymethylene-anilide , Benzoxazol-2-yl-acetic acid diethanolamide, benzoxazol-2-yl-acetonitrile.

The compounds to be used according to the invention are colorless to pale yellowish colored crystalline substances, which are characterized by a good anti-inflammatory effect with good physiological tolerance.

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Henkel & CIe GmbH su 4 » _r rot.ntanm.iduna d 4726

When used as anti-inflammatory substances, the benzoxazol-2-yl-acetic acid derivatives according to the invention can be incorporated into liquid, pasty or solid cosmetic preparations, such as aqueous solutions, aqueous Suspensions, emulsions, solutions in organic solvents, oils, ointments, creams, pens or powders. the Preparations can serve a wide variety of purposes, such as general skin waters with anti-inflammatory properties Aftershave, water, pens or lotions against insect bites, shaving powder, baby powder, creams or lotions, but especially as aqueous, emulsion-like, oily or pasty sunscreen or sunburn-combating agents.

When used as anti-inflammatory substances, the benzoxazol-2-yl-acetic acid derivatives according to the invention are used used in amounts of 0.01 to 10 percent by weight, based on the total formulation of the cosmetic agent.

The following examples are intended to explain the subject matter of the invention in more detail without, however, restricting it thereto.

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Henkel & CIa GmbH s.it. 5 ^lur M «nwnm.idun _e d 4726

Examples

Preparation of benzoxazol-2-yl-acetic acid-ethy-ester compound A.

109 g (1 mol) of o-amionophenol were added in portions to a boiling mixture of 801 g (5 mol) of malonic acid diethyl ester and 3 * 5 1 of P-HYlol with stirring over the course of 1.5 to 2 hours. The ethanol formed was distilled off via a: column until a vapor temperature of 135 ° C. was reached (approx. 2 hours). After cooling, the resulting malonic acid monoethyl ester-o-hydroxyanilide was filtered off and recrystallized from ethyl acetate "193 g were obtained from the molten product hydroxyanilide 128- 130 ⁰ C.

190 g (0.85 mol) of the malonic acid monoethyl ester-o-hydroxyanilide prepared as described above and a spatula tip of p-toludsulfonic acid were heated to the boil in p-xylene until the separation of water had ceased. After the p-xylene had been distilled off, the residue was distilled in vacuo. 100 g (59 # of theory) benzoxazol-2-yl-acetic acid ethyl ester with a boiling point _Q o 121-122 ° C and melting point 55-56 ° C were obtained.

Manufacture of benzoxazol-2- yl-acylic acid

4.1 g (20 m mol) benzoxazol-2-yl-esslgsäureäthy! Ester were added to 40 ml of 10 $ aqueous sodium hydroxide solution and stirred for 30 minutes at ² ^ ⁰ C · The resulting solution was stirred at 0 to 5 ° C with 2 η-hydrochloric acid acidified * the precipitate formed is filtered off, washed and dried. The yield of benzoxazol-2-yl-acetic acid voj
( $ 85> de theory).

2-yl-acetic acid with a melting point of 114-115 ° C. was 3.0 g

409SS1 / 12S0

6 -

Henkel & CIe GmbH StIt * 6 xvr Patantanmildung D 4726 Preparation of benzoxazol-2-yl-acetic acid amide. Compound B

A solution of 37.7 g (0.18 mol) of benzoxazol-2-yl-acetic acid ethyl ester in 150 ml of methanol was saturated with ammonia and heated to the boil for 11 hours while passing in ammonia. After cooling, filtering off the precipitate with suction and recrystallization from methanol, 16.5 g (52 % of theory) of benzoxazol-2-yl-acetic acid amide were obtained.

Preparation of benzoxazol-2-yl-acetic acid hydrazide. Compound C

20.5 S (0.1 mol) benzoxazol -2-yl-acetic acid ethyl ester,

5 g (0.1 mol) of hydrazine hydrate and 100 ml of methanol were

Stirred for 6 hours at room temperature. After cooling to 0-5 ° C., the deposited precipitate was filtered off with suction. There were 16.5 g (86% of theory.) Benzoxazol-2-yl-acetic acid of melting point 147 - 149 ⁰ C obtained. After recrystallization from benzene / ethanol, the analytically pure substance melts at 149 - 150 ^° C.

Production of benzoxazol-2-yl-acetic acid nitrile. Connection D

82.1 g (0.75 mol) of O-aminophenol and 112 g (0.75 mol) of ethyl cyanacelimidate hydrochloride were stirred in 750 ml of chloroform for 4-5 hours at room temperature. It was then extracted with cold sodium hydroxide solution and the aqueous phase extracted with chloroform. The combined chloroform extracts were dried with sodium sulfate and evaporated. After recrystallization of the residue from benzene, 77/8 g (66 # of theory) of benzoxazol-2-yl-acetic acid nitrile with a melting point of 65 ° -66 ° C. were obtained. After repeated recrystallisation from petrol (bp. 80 - 110 ⁰ C) the melting point was the substance anälysenreinen 68 ..- 70 C.

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Henkel & CIe GmbH su ¹ J zurp _a t.nion _m .idun ₀ d 4726

According to another method of preparation, 19 * 3 g (0.3 mol) of malononitrile were introduced into a boiling solution of 21.8 g (0.2 mol) of o-aminophenol in 100 ml of xylene over the course of one hour while stirring. The mixture was then heated to boiling for a further 3 hours and then cooled. After filtration, the solution was chromatographed on silica gel (eluent benzene / chloroform / methanol 7: 2: 1). The first fractions were combined and evaporated. By recrystallizing the residue from gasoline (sol. 80 - HO ⁰ C), 15.8 g (50 % of theory) benzoxazol-2-yl-acetic acid nitrile with a melting point of 68-70 ⁰ C were obtained.

Manufacture of benzoxazol-2-yl-acetic acid diethanolamide . ' Connection E -

To a solution of 8.9 g (50 m mol) benzoxazol-2-yl-acetic acid and 5 * 3 S (5o m mole) diethanolamine in 150 ml of tetrahydrofuran were added at -5 to -10 ° C 11 ² I-g (55 m mol) of N, N ¹ -dicyclohexyl-carbodiimide. After stirring for two hours at this temperature, the mixture was left to stand at room temperature for 96 hours. The deposited precipitate was filtered off with suction, washed with 30 ml of tetrahydrofuran and the solution was strongly concentrated in vacuo. After cooling to room temperature, the deposited precipitate was recrystallized from benzene / chloroform. 7 * 6 g (58 % of theory) of benzoxazol-2-yl-acetic acid diethanolamide with a melting point of 95 ° -98 ° C. were obtained. Another recrystallization from benzene / chloroform increased the melting point to 97-99 ° C.

409881/1250

Henkel & CIe GmbH since »8 xur Poiantonmnung d 4726

Production of N-benzyl-benzoxazol-2-yl-acetic acid amide Connection F

52.9 g (0.3 mol) of benzoxazol-2-yl-acetic acid amide, 42.9 g (0.4 mol) of benzylamine and 200 ml of p-cymene were added under nitrogen until the evolution of ammonia ceased (about 4 hours) stirred 170 ⁰ C - at I60. After cooling to room temperature, suctioning off and washing the precipitate with ether and recrystallizing from dimethylformamide / ethanol, 71 g (89% of theory) of N-benzylbenzoxazol-2-yl-acetic acid amide with a melting point of 179-181 ° C. were obtained .

Analogous to the manufacturing methods listed above were obtained the products listed in the table below.

link N-phenyl-benzoxazol-2-yl-vinegar
acid hydrazide M.p. ⁰ ° C Yield % G N-hydroxyethyl-benzoxazol-2-yl-
acetic acid amide 176-178 10 H N-ß-pyridyl-benzoxazol-2-yl-
acetic acid amide 119 - 121 14th I. Benzoxazol-2-yl-acetic acid-o-
fluoranilide 121-122 19th K Benzoxazole - ^ - yl-acetic acid ^ -p-
anisidid 149-151 43 L. Benzoxazol-2-yl-acetic acid-o-
toluidid 166-168 81 M. Benzoxazol-2-yl-acetic acid-m-
tri fluoromethylanilide 172-174 60 N Benzoxazol-2-yl-acetic acid-o-
anisidid 163-165 68 O Benzoxazol-2-yl-acetic acid-o-
methyl-p-anisldide 117 75 ρ Benzoxazol-2-yl-acetic acid-3 '> 4 ^f -
methylenedioxy anilide 202-203 64 Q Benzoxazol-2-yl-acetic? Iure-2 ', 4' -
dimethoxy anilide 185 61 R. 164 - I65 60

0 9 8 81/12 BO ₉ _

Henkel & CIe GmbH string 9 for the pot tone report D 4726

Some of the benzoxazol-2-ylacetic acid derivatives listed above has not yet been described in the literature.

The following statements are intended to describe the anti-inflammatory properties of the substances to be used according to the invention Compounds and their suitability for cosmetic preparations, in particular sunscreen or sunburn control agents, point out.

In the investigations listed below, the benzoxazol-2-yl-acetic acid derivatives to be used according to the invention were used tested for their anti-inflammatory properties. Previously there was an exploratory study of her Toxicity carried out in order to be able to determine the test dosages for further investigations.

As a test to assess the compounds with regard to their suitability for inhibiting those caused by sunburn Inflammation, the rat paw test was used, as described by P. Kemper in the journal "Arzneimittel If or schung "10 (1960), p. 777 is described Generation of the 'edema was given to the test animals 0.1 ml of 6% Dextran solution is injected into the right hind paw approx. 5 mm deep between the second and third toe. While the control animals were given only the dextran solution, the test animals received 30 minutes before their injection the various test substances are injected or administered orally in the amount given in the table. The volume der Pfoten was published with that of P. Kemper and G. Amelin in the "Journal for the entire experimental medicine" 131 (1959), 'page 407 described in more detail electrical Volume measuring device determines “The measurements were made for 30 minutes before injections of the dextran solution, i.e. at the time of administration

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Henkel & CIe GmbH S.It. 10 to Patantanm.lduiii D ^ 6

presentation of the test substances to the test animals and 30 minutes after the injection of the dextran solution. To the For comparison, the left untreated paw was always measured at the times mentioned. From the values for the swelling in animals that had been treated with the test substance and untreated animals for 30 minutes after the dextran injection, the degree of was calculated Inhibition of edema as a percentage of those swelling that occurred in animals that had not received the test substance.

Based on general experience, the results of the rat paw test can be used as a basis for the assessment a compound serve as a sunburn control agent.

In addition, a UV test was carried out on hairless mice, which also allows a statement to be made about the usefulness of the substances as sunburn control agents. The back of the hairless mice was irradiated with a UV lamp from a distance of 60 cm for 30 minutes, causing skin inflammation. In the test animals, the test substances were administered by interperitoneal injection or per os following the irradiation, while the control animals received no after-treatment. The dosage of the test substances was the same as in the rat paw test. The degree of edema formation was determined by measuring the thickness of the skin folds after JO hours. By comparing the change in the thickness of the skin folds due to the irradiation in treated test animals with the change in the thickness of the skin folds in animals which were irradiated but not treated, the degree of the percentage inhibition of the erythema, which is given in the table below, was determined.

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409881/1250

Henkel & CIe GmbH

Fed up"

for patent application D

4726

In the investigations carried out - as described above - for the individual substances, those in the following Table - listed values determined.

Tabel

Test orienting substance toxicity

L _D 50
g / kg

Dextran Edema ^ O 'UV Irradiation

on the rat hairless mouse

paw dosage inhibition

Dosage inhibition mg / kg #

tion mg / kg % .

A.
B.
C.
D.
E.
F.
G
H
I.
K
L.
M.
N
0
P.
Q

2.25

1.75

1.75

0.07

1.52

1.0

2.5

1.57

0.75

5
1.0

2.5
5

1.0
1.0
1.0

1000 po

500 po

1000 po

75 po

1000 po

1000 po

1000 pb

1000 po

200 po

1000 po

1000 po

1000 po

1000 po

1000 po

500 po

500 po 21.2

10.5 22.1 14.4

11.0

13.0 9.0 12.6 23.1 10.0 24.2 17.6 11.3 31.5 25.9 21.9

1000 po

500 po

1000 po

75 po

1000 po 1000 po

1000 po 1000 po

1000 po 500 po 500 po

30.4 24.5 35.3 18.9

1000 po 23.9

25.0 34.1

51.6 35.0

59.6 53.2 45.7

A few examples of cosmetic preparations containing the substances according to the invention are given below listed.

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409881/1250

Henkel & CIS GmbH SU 12 for Pa..n. _a nm.l <i «n _e O 4726

1. To be used in the manufacture of a sun protection oil

20 g benzoxazol-2-yl-acetic acid ethyl ester

finely suspended in 100 g of paraffin oil with heating, and then wii

Components

and then at approx. 25 ° C with the following others

300 g vegetable oil containing lecithin

400 g of olive oil

100 g isopropyl myristinate

100 g purcellin oil

intimately mixed.

2. To produce a sunburn puäers

hO g benzoxazol-2-yl-acetic acid hydrazide in a powder mixer intensively with

400 g rice starch 400 g colloidal clay 100 g Lycopodium 100 g talc

brought into homogeneous distribution.

5 · To make an anti-inflammatory aftershave will

50 g benzoxazol-2-yl ~ acetic acid-Q-anisidide along with a solution of

5 g citric acid 30 g glycerine in g witch hazel water

with a perfumed 80 $ alcoholic preparation combined to a total of 1000 g »

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Henkel & CIO GmbH SU X ^ aurPeH.ntannwtöuiig D

4. Be used to make a sunscreen

40 g glycerine monostearate l60 g beeswax 420 g mineral oil 50 g ceresin 50 g of an absorption base based on

Cholesterol, beeswax, stearyl alcohol and petroleum jelly

30 g of benzoxazol-2-yl-acetic acid-3 ^f Λ ¹ -dioxyraethylenaiilid

melted together at 65 C. In this warm mixture will be a device heated to the same temperature by

247 g water 13 g borax 2 g of methyl p-oxybenzoate

incorporated with vigorous stirring and the obtained · The cream is stirred further until it has reached room temperature.

5. To produce a sun protection emulsion, a mixture of heated ^{to approx. 80 ° C. is added}

20 g glycerol monostearate

70 grams of stearic acid

50 g oleic acid

20 g of cetyl alcohol

4Qg benzoxazol-2-yl-acetic acid-o-methyl-panisidide

a mixture of 800 g of water with vigorous stirring, g glycerine and 9 S triethanolarain given. The lotion obtained is then stirred while cold «,

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Henkel & CIe GmbH s.it · 1Λ zurrot.ntonm.idun «ο 4726

The above emulsion can also be used using a propellant gas in a ratio of 80 parts lotion: 20 parts Pack propellant in aerosol form.

409881/1250 " ¹⁵ "

Claims (1)

Claims 1) Use of benzoxazol-2-yl-acetic acid derivatives der - general formula in which R * stands for a hydrogen atom, a halogen atom, a lower alkyl, a lower alkoxy, a nitro, an amino, a carboxyl, a carbon ester or an optionally substituted carbonamide group, A for the groups -CN, -COORg , -CONR ^ R ^ or ^ CONH-NR, Rjj. » in which R «is hydrogen or a lower alkyl group with 1-4 carbon atoms and R_ and Rj, independently of one another hydrogen, a lower alkyl, a lower acyl, a hydroxyalkyl, an aralkyl group, a heterocycle or optionally one or more times Aryl group substituted by alkyl and / or alkoxy groups, and R and R ₂ , together with the nitrogen atom, can represent a heteroyclic ring system, are used as anti-inflammatory agents in cosmetic preparations. 2) Use of compounds according to claim 1 as anti-inflammatory agents in sunscreen or sunburn control agents. 5) Use of compounds according to claims 1 and 2 as anti-inflammatory agents ■ in cosmetic preparations, in particular sunscreens and / or »sunburn control agents in an amount of 0 ₉ oil to 10 percent by weight, preferably 0 * 1-5 percent by weight, based on the total preparation, 409881/1250 - 16 - HENKEL & CIE GMBH S.U. l6 for Pot.n.anm.ldung D '(726 4) Benzoxazol-2-yl-acetic acid hydrazide 5) N-phenyl-benzoxazol-2-yl-acetic acid hydrazide 6) N-ß-pyridyl-benzoxazol-2-yl-acetic sureamide 409881/1250