US3895022A - Anti-inflammatory agents, cosmetic preparations and method of preventing inflammation - Google Patents

Abstract

Anti-inflammatory benzoxazole compounds of the formula

WHEREIN X is -C*N or

Y is O, S or NH, R is a hydrocarbon or when Y is O, H, alkali metal, ammonium or organic ammonium and R1 to R4 are H, halogen, lower alkyl, lower alkoxy, nitro, carboxyl, carbamyl or a carboxylic acid ester, as used in cosmetic preparations for the prevention and control of inflammation, and methods for the prevention and control of inflammation.

Description

United States Patent 1191 Moller et al.

[ ANTI-INFLAMMATORY AGENTS,

COSMETIC PREPARATIONS AND METHOD OF PREVENTING INFLAMMATION [75] Inventors: Hinrich Miiller, Dusseldorf-Benrath;

Christian Gloxhuber, Haan, Rhineland; Harald Schnegelberger, Leichligen, all of Germany [73] Assignee: Henkel & Cie GmbI-I, Dusseldorf,

Germany [22] Filed: Dec. 27, 1972 [21] Appl. No.: 318,757

[30] Foreign Application Priority Data Dec. 27, 1971 Germany 2164851 [52] US. Cl 260/307 D; 424/59; 424/69;

[51] Int. Cl C07d 85/48 [58] Field of Search ..260/307 D [56] References Cited UNITED STATES PATENTS 3,641,029 2/1972 Wright et al 260/268 BC [451 July 15,1975

c. A. 76, 126996g, 1972 Abstract of Ger. Offen., 2,021,679.

0. A. 76, 7250'6m, 1972), Abstract of Get. Offen, 2,024,052.

Sycheva et al., C. A. 66, l04936p, (1967).

Primary Examiner-Donald G. Daus Assistant Examiner-Raymond V. Rush Attorney, Agent, or FirmI-Iammond & Littell [57] ABSTRACT Anti-inflammatory benzoxazole compounds of the formula C-X R 9 N wherein X is C E N or Y ll Y is O, S or NH, R is a hydrocarbon or when Y is O, H, alkali metal, ammonium or organic ammonium and R to R are H, halogen, lower alkyl, lower alkoxy, nitro, carboxyl, carbamyl or a carboxylic acid ester, as used in cosmetic preparations for the prevention and control of inflammation, and methods for the prevention and control of inflammation.

6 Claims, No Drawings 1 ANTI-INFLAMMATORY AGENTS, COSMETIC PREPARATIONS AND METHOD OF PREVENTING INFLAMMATION OBJECTS OF THE INVENTION An object of the present invention is the obtaining of an anti-inflammatory cosmetic preparation consisting essentially of from 0.01% to by weight of an antiinflammatory benzocazole compound having the formula wherein X represents a member selected from the group consisting of C E N and Y !OR,

Y represents a member selected from the group consisting of =0, =8, and =NH, R represents a member selected from the group consisting of alkyl having from I to 22 carbon atoms, alkenyl having from 3 to 22 carbon atoms, phenyl, alkylphenyl having from 7 to 18 carbon atoms, phenylalkyl having from 7 to 18 carbon atoms, and when Y is =0, hydrogen, alkali metal, -NH lower alkylammonium and lower alkanolammonium, and R,, R R and R represent members selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, nitro, carboxyl', alkali metal salts of carboxy, carabamyl and carbo-lower alkoxy, and the remainder inert cosmetic excipients.

Another object of the present invention is the development of a process for the prevention or alleviation of inflammation of the skin consisting essentially of applying to the skin to be protected a safe but effective amount of an anti-inflammatory benzoxazole compound having the formula 3 I R M wherein X represents a member selected from the group consisting of C a! N and Y represents a member selected from the group consisting of =0, =8, and =NI'I, R represents a member selected from the group consisting of alkyl having from 1 to 22 carbon atoms, alkenyl having from 3 to 22 carbon atoms, phenyl, alkylphenyl having from 7 to l8 carbon atoms, phenylalkyl having from 7 to 18 carbon atoms, and when Y is =0, hydrogen, alkali metal, NI-l lower alkylammonium and lower alkanolammonium, and R R R and R represent members selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, nitro, carboxyl; alkali'metal salts of carboxy, carbamyl and carbo-lower alkoxy.

A further object of the present invention is the development of an anti-inflammatory benzoxazole compound having the formula wherein X represents a member selected from the group consisting of C E N and Y ll Y represents a member selected from the group consisting of =0, 8 and =NI-I, R represents a member selected from the group consisting of alkyl having from 1 to 22 carbon atoms, alkenyl having from 3 to 22 carbon atoms, phenyl, alkylphenyl having from 7 to 18 carbon atoms, phenylalkyl having from 7 to 18 carbon atoms, and, when Y is 0, hydrogen, alkali metal, -NI-I lower alkylammonium and lower alkanolammonium, R represents a member selected from the group consisting of chloro, lower alkyl, lower alkoxy, nitro, carboxy, alkali metal salts of carboxy, c'arbamyl, carbo-lower alkoxy, and, when Y is S or NH, hydrogen, and R represents a member selected from the group consisting of hydrogen, and, when R is nitro, chloro.

A yet further object of the present invention is the development of processes for the production of the anti-inflammatory benzoxazole compounds.

These and other objects of the invention will become more apparent as the description thereof proceeds.

DESCRIPTION OF THE INVENTION The invention relates to inflammation preventatives for use in cosmetic preparations, especially for compositions for protection against the sun and sunburn con- I trol.

in which X represents a group of the formula E N in which Y represents an oxygen atom, a sulfur atom or a =NH residue, R represents an aliphatic, aromatic aliphatic-aromatic or aromatic-aliphatic hydrocarbon residue, and when Y represents an oxygen atom, may also represent a hydrogen atom, an alkali metal, anammonium ion or an organic nitrogen base, andR, to R if desired each individually represents a hydrogen or, halogen atom, a short-chain alkyl, short-chain alkoxy, nitro, carboxylic acid, carboxylic acid ester or carboxylic acid amide group, are outstandingly suitable as inflammation preventatives for cosmetic preparations.

More particularly, an anti-inflammatory cosmetic preparation consisting essentially of from 0.01% to by weight of an anti-inflammatory benzoxazole compound.having the formula 3 c-x R2 N wherein X represents a member selected from the group consisting of C I N and Y represents a member selected from the group consisting of =0, =S, and=NH, R represents a member selected from the group consisting of alkyl having from 1 to 22 carbon atoms, alkenyl having from 3 to 22 carbon atoms, phenyl, alkylphenyl having from 7 to 18 carbon atoms, phenylalkyl having from 7 to 18 carbon atoms, and when Y is =0, hydrogen, alkali metal, NH lower alkylammonium and lower alkanolammonium, and R R R and R represent members sewherein X represents a member selected from the group consisting of C E N and Y it,

Y represents a member selected from the groupconsisting of =70, =8, and =NH, R represents a member selected from the group consisting of alkyl having from 1 to 22 carbon atoms,,alkenyl having from 3 to 22 carbon atoms, phenyl, alkylphenyl having from 7 to 18 carbon atoms, phenylalkyl having from 7 to 18 carbon atoms, and when Y is =0, hydrogen, alkali metal, NH.,, lower alkylammonium and lower alkanolammonium, and R R R and R, represent members selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, nitro, carboxyl', alkali metal salts of carboxy, carbamyl and carbo-lower alkoxy.

Some of the anti-inflammatory benzoxazole compounds are, in addition, novel compounds. Among these novel compounds are benzoxazole compounds having the formula wherein X represents a member selected from the group consisting of C i N and p a I a, a l

Y represents a member selected from the group consi'sting of =0, =8 and ''NH, R represents a member selected from the'g'roup consisting of alkyl having from v l to 22 car bonatoriis, alkenyl having from 3 to 22 carpreventing substances in compositions for protection of the skin against the sun and for sunburn control, since, in addition to an excellent anti-inflammatory action, they also have a good absorption action with respect to ultra-violet radiation.

When X in the above general Formula I is a cyano group 2-cyano-benzoxazoles to be used according to' the invention are obtained. These include, for example, 2-cyano-benzoxazole, 2-cyano-5-methyl-benzoxazole, 2-cyano-5-ethyl-benzoxazole,2-cyano-5-isopropylbenzoxazole, i I 2-cyano-5-chloro-benzoxazoie, 2-cyano-5-nitro-ben2oxazole, 2-cyano-4,5,7-trichlorobenzoxazole, 2-cyan o- 5-carboxybenzoxazole, 2- cyano-S-methoxy-bniopkazole, 2-cyano-5-ethoxybenzoxazole, and also 2-cyano-benzoxazoles substituted in the 5-position by a carboxylic acid ester or carboxylic acid amide (carbamyl) group.

The preparation of Lcyano-benzoxazole is described by Jones et al in the Journal of the Chemical Society", London (196 page 4393. According to this procedure, the substance was obtained in 23% yield by reacting 2-chloro-benzoxazole with sodium cyanide in dimethylsulfoxide at 90 to 100C.

The yield of Z-cyano-benzoxazole can be raised to over 50% by the modification of the process described in the literature, which comprises lowering the reaction temperature and addition of solvent to the dimethylsulfoxide.

The generally nuclear-substituted 2-cyanobenzoxazoles, most of which have not as yet been prepared and described in the literature, can also be prepared in good yield by this modified process.

For the preparation of the substances to be used according to the invention, 1 mol of-a 2-halogeno-, preferably Z-chlorobenzoxazole or the corresponding 2- chloro-benzoxazole derivatives undiluted or dissolved in dimethylsulfoxide, is reacted, at a temperature between and 30C with cooling, with a suspension of l to 1.5 mols of sodium cyanide in dimethylsulfoxide, which contains 1 to 50% of another solvent, as for example, dimethylformamide, benzene, pyridine, etha nol, isopropanol, triethylamine or a mixture of several of these solvents. Pyridine, isopropanol and dimethylformamide are preferably used as additives to the solvent. The most favorable reaction temperature is generally 18 to 20C. The reaction mixture is then treated with water and extracted with benzene or chloroform. The residue obtained from the solvent phase on evaporation may be purified by column chromatography or sublimation.

2-chloro-benzoxazole and the derivatives thereof may be prepared in known way from the corresponding 2-mercapto-benzoxazoles by reaction with chlorine or with thionyl chloride or disulfur dichloride.

If in the above-mentioned general Formual l, X is the group in which Y represents a =NH residue and R represents a hydrocarbon residue, the benzoxazole-Z- carbimide acid esters to be used according to the invention are obtained. These include, for example, benzoxazole-Z-carbimide acid methyl ester, -ethyl ester, -isopropyl ester, -octyl ester, -d0decyl ester, -0leyl ester, 5-methyl-, S-chloro, 5-nitro-, 4,5 ,7-trichloro-, 5- methoxy-, S-ethoxy, 5-carboxy-benzoxazole-2- carbimide acid-methyl ester, 5-chloro-benzoxazole-2- carbimide acid-ethyl ester, S-methyhbenzoxazole-L carbimide acid-isopropyl ester, benzoxazole-Z- carbimide acid-phenyl ester, S-methyl-benzoxazole-2- carbimide acid-benzyl ester, and also benzoxazole-2- carbimide acid-methyl ester substituted in the 5- position by a carboxylic acid ester or carboxylic acid amide (carbamyl) group.

For the preparation of the benzoxazole-Z-carbimide -acid esters according to the invention, 2-cyanobenzoxazole or the corresponding 2-cyanobenzoxazole derivative is suspended or dissolved in 5 to times its amount by weight of the aliphatic alcohol, aromatic, aliphatic-aromatic or aromatic-aliphatic alcohol to be reacted, possibly with addition of inert solvents such as, for example, hydrocarbons, halogenated hydrocarbons, ethers (alkoxyalkane) or ketones (alkanones), at room temperature, treated with 0.1% to 10% by weight, referred to the 2-cyano-benzoxazole, of a basic catalyst, and stirred at a temperature between 20 and l00C. After a reaction time of a few minutes to several hours, and cooling of the reaction mixture to 0C or below, the carbimide acid ester is filtered off. A further portion of the reaction product can be obtained by concentrating the mother liquors. The carbimide acid esters are obtained pure or may be recrystallized from alcohol-water mixtures.

The basic catalysts which may be used are, for example, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium cyanide, sodium alcoholate, potassium or sodium acetate, trimethylamine, triethylamine, triisopropylamine. Of these, potassium carbonate, sodium hydroxide, potassium cyanide and triethylamine have proved the best.

If in the above-mentioned general Formula I, X is the group in which Y represents an oxygen atom and R represents a hydrocarbon residue or hydrogen or a cation, the benzoxazole-Z-carboxylic acid esters to be used according to the invention or the free benzoxazole-2- carboxylic acid or its salts are obtained. Benzoxazole-2- carboxylic acid esters according to the invention which may be mentioned are, for example, benz0xazole-2- carboxylic acid-methyl ester, -ethyl ester, -isopropyl ester, -octyl ester, -dodecyl ester, -oleyl ester, 5- methyl-, 5-chl0ro-, 5-nitro-, 4,5,7-trichloro-, 5- methoxy-, 5-ethoxy-, S-carboxy-benzoxazole-Z- carboxylic acid-methyl ester, 5-chloro-benzoxazole-2- carboxylic acid-ethyl ester, S-methyl-benzoxazole-Z- carboxylic acid-isopropyl ester, benzoxazole-2- carboxylic acid-phenyl ester, 5-methylbenzoxazole-2- carboxylic acid-benzyl ester, and also the benzoxazole- Z-carboxylic acid-methyl ester substituted in the 5- position by a carboxylic acid ester or carbamyl group.

Unsubstituted or substituted benzoxazole-Z- carboxylic acids according to the invention are, for example, 5-methyl-, 5-chloro-, 5'nitro-, 4,5,7-trichloro-, 5-methoxy-, 5-ethoxy-, S-carboxy-benzoxazole-Z- carboxylic acid as well as their alkali metal salts such as potassium, sodium, ammonium, monoethanolamine, diethanolamine and triethanolamine salts, (lower alkanolammonium), and monoethylamine salts (lower alkylammonium), and also benzoxazole-Z-carboxylic acid and its salts substituted in the 5-position by a carboxylic acid ester or carbamyl group.

For the preparation of the benzoxazole-2-carboxylic acid esters, the corresponding benzoxazole-2- carbimide acid esters are introduced into dilute, for example 2N hydrochloric acid. The precipitated benzoxazole-Z-carboxylic acid esters are recovered, e.g. by filtering off, dried and, if desired, purified.

For the preparation of the salts of the benzoxazole-2- carboxylic acid the corresponding benzoxazole-2- carboxylic acid esters are saponified with a suitable base. For example, the substituted or unsubstituted benzoxazole-2-carboxylic acid ester is introduced into N caustic soda solution and the mixture is then stirred for 1 hour at room temperature. The sodium salt of the desired benzoxazole-Z-carboxylic acid derivative or of 5 the benzoxazole-2-carboxylic acid is obtained by working up the reaction mixture. If on the other hand, the reaction mixture is acidified with dilute hydrochloric acid to a pH value of 1-2, the corresponding unsubstituted or substituted free benzoxazole-Z-carboxylic acid is precipitated, which can be worked up in the usual way.

If in the above-mentioned general Formula I, X is the group in which Y represents a sulfur atom, the benzoxazole-2-thio-carboxylic acid esters to be used according to the invention are obtained. Benzoxazole-2-thio-carboxylic acid esters according to the invention include, for example, benzoxazole-Z-thiocarboxylic acid-O-methyl ester, -O-ethyl ester,-O- isopropyl ester, -O- octyl ester, -O-dodecyl ester, oleyl ester, 5-methyl-, 5-chloro-, 5-nitro-, 4,5,7- trichloro, 5-methoxy-, 5-ethoxy-, S-carboxybenzoxazole-2-thio-carboxylic acid-O-methyl ester, 5- chloro-benzoxazole-2-thio-carboxylic acid-O-ethyl ester, 5-methyl-benzoxazole-2-thio-carboxylic acidO- isopropyl ester, benzoxazole-2-thio-carboxylic acid-O- phenyl ester, 5-methyl-benzoxazole-2-thio-carboxylic acid-O-benzyl ester, and also benzoxazole-Z-thiocarboxylic acid-O-methyl ester substituted in the 5- position by a carboxylic acid ester or carbamyl group. For the preparation of the benzoxazole-2-thiocarboxylic acid esters, the corresponding benzoxazole- 2-carbimide acid esters are treated in inert solvents such as, for example, ether or benzene, with gaseous hydrogen chloride at temperatures of from about 0 to -l0C. Their corresponding hydrochlorides are thus formed which are precipitated. The precipitate is introduced in pyridine containing hydrogen sulfide and the desired thio-carboxylic acid esters are Obtained. The benzoxazole derivatives substituted by a carboxylic acid group or carboxylic acid alkali metal salts have good solubility in water, which makes them specially suitable for use in aqueous sunburn control compositions or compositions for protecting against the sun and those based on emulsions. The benzoxazole derivatives substituted by a carboxylic acid amide group show the highest anti-inflammatory activity of all the derivatives, which enables them to be used in smaller concentrations in the anti-inflammatory cosmetic preparations.

When used as anti-inflammatory substances, the benzoxazole derivatives according to the invention may be incorporated in liquid, pasty or solid cosmetic preparations as, for example, aqueous solutions, aqueous suspensions, emulsions, solutions in organic solvents, oils, salves, creams, pencils or powders. The preparations may serve a large variety of purposes such as a general skin cleansing lotion with an anti-inflammatory action, shaving lotion, lotions, pencils or lotions for insect bites or stings, shaving powders, baby powders, creams or lotions, but especially as aqueous, emulsionlike, oily or pasty compositions for protection against the sun or sunburn control compositions.

For use as inflammation preventatives, the benzoxazole derivatives according to the invention are preferably used in amounts from 0.01% to 10% by weight, especially 0.1 to 5% by weight, referred to the total charge of the cosmetic compositions.

Since the application of the cosmetic preparations is topical, the dosage amounts of the anti-inflammatory benzoxazole compounds can vary widely.

The following examples are illustrative of the practice of the invention without being limitative in any respect.

EXAMPLE 1 2-Cyano-5 -methoxy-benzoxazole A solution of 50 gm (0.273 mol) of 2-chloro-5- methoxy-bezoxazole in 280 ml of dimethylformamide was introduced (over a period of about 8 minutes) into a stirred suspension of 16 gm (0.327 mol) of sodium cyanide in 428 ml of dimethylsulfoxide, 143 ml of dimethylformamide and 100 ml of isopropanol at 18C. After stirring for 1 hours, the reaction mixture was poured into a mixture of 750 ml of benzene and 750 ml of water and the mixture was acidified with dilute hydrochloric acid so that it was weakly acid. The aqueous phase was separated and extracted with benzene. After washing with water and drying over calcium chloride, the extract was evaporated to dryness. The residue was moistened with a little methanol and filtered by suction. 35.7 gm of theory) of 2-cyano-5-methoxybenzoxazole, having a melting point of 9799C, were obtained. After recrystallizing from methanol/water, the colorless substance melted at 98 to 100C.

The 2-chloro-5-methoxy-benzoxazole required was prepared as follows: 75 gm (0.415 mol) of 2-mercapto- 5methoxy-benzoxazole were suspended in 370 ml of methylene chloride at 0C and treated with stirring with gm (0.456 mol) of phosphorus pentachloride. The mixture was stirred for a further 1 /2 hours at 0 and 4% hours at 22C, then heated to boiling over a period of half an hour and kept at the boil for 15 minutes. After distilling off the methylene chloride, the residue was triturated with cyclohexane and filtered by suction. 55.9 gm (74% of theory) of 2-chloro-5-methoxybenzoxazole, having a melting point of 6770C, were obtained after purification, together with the product obtained from the mother liquors, by concentration and recrystallization from petroleum ether. The melting point was raised to 687lC by recrystallization from cyclohexane.

The 2-cyano-benzoxazole derivatives mentioned below and Z-cyano-benzoxazole were prepared in a corresponding way, as described in German Published Patent Application (DOS) No. P20216799:

Melting Point Z-cyano-benzoxazole 75-77C 2cyano-5-chlorobenzoxazole 9496C 2-cyano-5-nitro-benzoxazole 84-86C 2 :yano-4,5 ,7-trichloro-benzoxazole 8385C EXAMPLE 2 2-Cyano-S-carboxy-benzoxazole in this case the preparation of the compound was carried out by the process described by Dickore et al., Liebigs Chem., pp. 70-87 (1970), via the -carboxybenzooxazole-Z-aldoxime. a. 5-Carboxy-benzoxazole-Z-aldoxime 100 gm (0.65 mol) of 3-amino-4-hydroxy-benzoic acid were dissolved in the hot in 1000 ml of water and 210 ml of concentrated hydrochloric acid. The solution was filtered with active charcoal, adjusted to pH 3 with concentrated caustic soda solution. Thereafter, at 60C while stirring simultaneously a solution of 83.2 gm 1.2 mol) of hydroxylamine hydrochloride in 200 ml of water and a solution of 198.6 gm (1.2 mol) of chloral hydrate in 300 ml of water was added. The pH value was adjusted to 4 by portionwise addition of sodium acetate and was maintained at this value during two hours of stirring at 60C. After cooling, filtering off the precipitate by suction, washing with water and drying at 80C in vacuo, 124 gm (92% of theory) of 5-carboxybenzoxazole-Z-aldoxime, having a melting point of 268-269C, were obtained. After recrystallizing from dioxan, the melting point was raised to 269 -270C. b. 2-Cyano-benzoxazole-Scarboxylic acid chloride A mixture of 51.5 gm (0.25 mol) of 5-carboxybenzoxazole-2-aldoxime and 238 gm (2 mol) of thionyl chloride was slowly heated to boiling. After boiling for 3 /2 hours, the excess thionyl chloride was distilled off in vacuo and the residue was extracted several times with boiling cyclohexane. After distilling off the solvent, 43.7 gm (85% of theory) of yellowish 2-cyanobenzoxazole-S-carboxylic acid chloride, having a melt ing point of 6465C were obtained from the cyclohexane extracts. After further purification, the melting point was raised to 68 to 69C. c. 2-Cyano-5-carboxy-benzoxazole A solution of 10.3 gm (0.05 mol) of 2- cyanobenzoxazole-S-carboxylic acid chloride in 100 ml of dioxan was introduced within in a period of minutes into a stirred solution of 12.6 gm (0.15 mol) of sodium hydrogen carbonate. The resulting suspension was stirred for 2 A: hours at room temperature. After filtering, the solution was acidified with dilute hydrochloride acid and the precipitated 2-cyano-5-carboxybenzoxazole was filtered off. After drying, 6 gm (64% of theory) of the colorless acid having a melting point of 217-2 19C were obtained. On recrystallization from isopropanol/water, the melting point was raised to 220-221C.

EXAMPLE 3 2-Cyano-5-carbomethoxy-benzoxazole A solution of 20.7 gm (0.1 mol) of 2- cyanobenzoxazole-S-carboxylic acid chloride in 60 ml of benzene was introduced while cooling with icewater, into a stirred solution of 4 gm (0.12 mol) of methanol and 8 gm (0.1 mol) of pyridine in 30 ml of benzene. The mixture was then boiled for a further 2 hours and after cooling, the solution was filtered off from the pyridine hydrochloride formed. The benzene phase was then washed with water, dried over calcium chloride and the solvent was distilled off. 19 gm (94% of theory) of 2-cyano-5-carbomethoxy-benzoxazole having a melting point of 9899C were obtained.

After recrystallizing from cyclohexane, the ester melted at 9910lC.

EXAMPLE 4 2-Cyano-5-carbamyl-benzoxazole A solution of 10.6 gm (0.22 mol) of ammonium carbonate in 50 m1 of water was introduced into a solution of 20.7 gm (0.1 mol) of 2-cyano-benzoxazole-5- carboxylic acid chloiide in 50 ml of dioxan while stirring and cooling, so that the temperature did not rise above 20C. After the evolution of CO had ceased, the precipitate was filtered off and dried. 138 gm (74% of theory) of Z-cyano-S-carbamyl-benzoxazole having a melting point of 199200C were obtained. After recrystallizing from chloroform, the melting point of the substance, found to be pure on analysis, was 202203C.

2-Cyano-7-chloro-5-nitro-benzoxazole was prepared corresponding to the process described for the preparation of 2-cyano-benzoxazole-5-carboxylic acid chloride, with use of suitable corresponding starting materials. The melting point of the compound was 79-81C.

EXAMPLES S-Methoxy-benzoxazole-Z-carbimide acid-methyl ester 15 gm (0.086 mol) of 2-cyano-5-methoxybenzoxazole and 500 mg of potassium carbonate were stirred in 125 ml of methanol for 1 hour at 20C. The precipitated substance was then filtered off by suction and purified, together with the product obtained from the mother liquor by evaporation and recrystallization from cyclohexane. 14.7 gm (83% of theory) of 5 methoxy-benzoxazoie-2-carbimide acid-methyl ester having a melting point of 99l0lC were obtained. After repeated recrystallizations from cyclohexane, the melting point was raised to l00lO3C.

The following benzoxazole-Z-carbimide acid esters were prepared in a corresponding way:

Benzoxazole-2-carbimide acid-methyl ester having a melting point of 103104C in 92% yield,

Benzoxazole-Z-carbimide acid-n-propyl ester having a melting point of 59-61C in 28% yield, Benzoxazole-Z-carbimide acid-isopropyl ester having a melting point of -7lC in 19% yield, 5-Chloro-benzoxazole-2-carbimide acid-methyl ester having a melting point of l35l 38C in 58% yield, 5-Methyl-benzoxazole-Z-carbimide acid-methyl ester having a melting point of 9093C in 84% yield. The potassium salt of 5-carboxy-benzoxazole-2- carbimide acid-methyl ester having a melting point of 305-320C with decomposition in 97% yield,

5-Carbomethoxy-benzoxazole-2-carbimide acidmethyl ester having a melting point of l38139C in 80% yield.

With use of sodium hydroxide instead of potassium carbonate as catalyst, benzoxazole-Z-carbimide acidethyl ester having a melting point of 76C in 41% yield was prepared in an analogous way.

Benzoxazole-2carbimide acid-octyl ester with a yield of 28% and a melting point of 35-37C was prepared by a method corresponding to method used for the ethyl ester. In an analogous method of preparation, only with replacement of the potassium carbonate as catalyst by sodium acetate and lengthening of the reaction time to 16 hours, 5-nitrobenzoxazole-Z-carbimide acid-methyl ester having a melting point of 178l 8 1C was obtained in a yield of 90.5%.

EXAMPLE 6 Benzoxazole-Z-carbimide acid-phenyl ester hydrochloride A solution of 10 gm (0.0695 mol) of 2- cyanobenzoxazole and 6.5 gm (0.0695 mol) of phenol in 200 ml of ethyl ether was saturated at C with dry hydrogen chloride and allowed to stand at this temperature for 20 hours. The precipitate was filtered off by suction and dried in vacuo over potassium hydroxide. 15.6 gm (82% of theory) of benzoxazole2-carbimide acid-phenyl ester hydrochloride having a melting point of 128C were obtained.

EXAMPLE 7 Methyl -methoxy-benzoxazole-2-carboxylate 41 gm (0.199 mol) of 5-methoxy-benzoxazole-2- carbimide acid-methyl ester were introduced with stirring into 350 ml of dilute hydrochloric acid at room temperature. After stirring for one hour, the precipitate was filtered off by suction and then washed with water. It was then triturated in a little warm methanol, neutralized with sodium hydrogen carbonate, cooled, filtered by suction and dried. 34.5 gm (85% of theory) of methyl 5-methoxybenzoxazole-2-carboxylate having a melting point of 107-110C were obtained. After recrystallizing from methanol, the melting point was raised to 1 10-l 12C.

The other benzoxazole-Z-carboxylic acid esters mentioned below were prepared in a corresponding way:

Methyl benzoxazole-Z-carboxylate having a melting point of 99l00C in 92% yield,

Methyl 5-methyl-benzoxazole-Z-carboxylate having a melting point of 9799C in 85% yield,

Methyl 5-chloro-benzoxazole-Z-carboxylate having a melting point of ll22C in 86% yield,

Methyl 5-nitro-benzoxazole-Z-carboxylate having a melting point of 156l58C in 83% yield.

EXAMPLE 8 Phenyl benzoxazole-2-carboxylate With reference to the method of preparation described by Dickore et al, Liebigs Ann. Chem. 733, 70 (1970), the ester was obtained in good yield on replacement of sodium hydrogen carbonate by pyridine.

10 gm (0.055 mp1) of 3-chloro-2-oxo-l,4- benzoxazine were heated to the boiling point together with 5.7 gm (0.061 mol) of phenol and 4.35 gm (0.055 mol) of pyridine in 200 ml of benzene for 16 hours. After filtration (pyridine hydrochloride) and distillation of the solvent, the residue was recrystallized from cyclohexane. 9.3 gm (71% of theory) of phenyl benzoxazole-2-carboxylate having a melting point of l53-157C were obtained.

EXAMPLE 9 Further, oleyl benzoxazole-2-carboxylate and octyl benzoxazole-2-carboxylate were prepared from methyl benzoxazole-2-carboxylate by interesterification. Oleyl benzoxazole-Z-carboxylate was a light yellow oil with a refractive index with n of 1,4992. Octyl benzoxazole-2-carboxylate was also a light yellow oil, the refractive index n of which was 1,4863.

EXAMPLE 10 Benzoxazole-Z-carboxylic acid 8' gm (0.045 mol) of methyl benzoxazole-Z- carboxylate were stirred into 87 ml of water, which contained 3.6 gm (0.09 mol) of sodium hydroxide, at room temperature. After stirring for 1 hour at 20C, a little insoluble matter was filtered off and the filtrate was acidified with dilute hydrochloric acid while cooling with ice. The precipitate was filtered off, washed with a little water and benzene and dried in a dessicator over potassium hydroxide. 6.3 gm (91% of theory) of benzoxazole-Z-carboxylic acid having a melting point of 83C were obtained.

Using the corresponding starting esters, the following benzoxazole-Z-carboxylic acid derivatives were prepared in an analogous way:

5-Chloro-benzoxazoleQ-carboxylic acid having a melting point of 100103C in 95% yield,

S-Methyl -benzoxazole-2-carboxylic acid having a melting point of l00103C in 85% yield, 5-Nitro-benzoxazole-2-carboxylic acid, which decomposed on heating to 240C, in 60% yield,

5-Methoxy-benzoxazole-2-carboxylic acid having a melting point of -97C in 88% yield.

EXAMPLE 1 l Di-ethanolammonium salt of 5-methoxybenzoxazole-2-carboxylic acid 7.8 gm of 5-methoxy-benzoxazole-2-carboxylic acid were stirred in ml of methanol with 5.0 gm of diethanolamine at room temperature. The methanol was distilled off from the solution formed, the oily residue was taken up in a little acetone, cooled to 0to 5C, and the di-ethanolammonium salt which crystallized out was filtered off. 9.7 gm (80.5% of theory) of the salt of melting point 95-99C were obtained.

The salts of the benzoxazole-Z-carboxylic acid and its derivatives mentioned below were prepared in an analogous way, using corresponding starting compounds.

Benzoxazole-2-thiocarboxylic acid-O-methyl ester A solution of 75 gm (0.426 mol) of benzoxazole-Z- carbimide acid-methyl ester in 400 ml of benzene was saturated at 0C with hydrogen chloride; the precipitate formed was filtered off and introduced while stirring into 400 ml of pyridine, which had been saturated at 20C with hydrogen sulfide. After stirring for a further 5 minutes at 20C, the reaction mixture was introduced while stirring into a mixture of 1 liter of half concentrated hydrochloric acid and 700 gm of ice. The precipitate formed was filtered off and recrystallized from methanol/water. 70 gm (85% of theory) of benzoxazole-Z-thiocarboxylic acid-OOester of a yellow color and a melting point of l l4l 15C were obtained. After repeated recrystallization from methanol/water, the melting point was raised to 11s 119c.

5-Methyl-benzoxazole-2-thiocarboxylic acid-- methyl ester was prepared with 82% yield from methyl-benzoxazole-Z-carbamide acid-methyl ester according to the method given above. The compound had a yellow color and after repeated recrystallization from methanol/water, had a melting point of lll1l4C.

EXAMPLE l3 5-Chloro-benZoxazole-2-thiocarboxylic acid-O-methyl ester A solution of 20 gm (0.095 mol) of S-chlorobenzoxazole-2carbimide acid-methyl ester in 300 ml of absolute ether was saturated at -5C with dry hydrogen chloride. After filtering off the precipitate formed, the solution was introduced while stirring into a solution of 3.5 gm (0.106 mol) of hydrogen sulfide in 100 ml of pyridine at 18C. The mixture was cooled for a further 15 minutes at this temperature and then poured with stirring into a mixture of 200 gm of ice and 150 ml of water. It was then neutralized with half concentrated hydrochloric acid and the yellow precipitate formed was filtered off by suction. 16.8 gm (78% of theory) of 5-chloro-benzoxazole-2-thiocarboxylic acid-O-methyl ester having a melting point of ll7-l20C were obtained. On recrystallization from cyclohexane the melting point was raised to 120123C.

The following benzoxazole-2-thiocarboxylic acid esters were prepared analogous to the abovementioned process, using corresponding benzoxazole-Z-carbimide acid esters:

5-Nitro-benzoxazole-2-thiocarboxylic acid-O-methyl ester, a yellow product having a melting point of l59-l62C. The yield was 51% of theory, and after repeated recrystallization from methanol/water, the melting point was raised to 162165C.

5-Methoxy-benzoxazole-Zacid- O-methyl ester was obtained as a yellow product with a melting point of l27130C in 56% yield.

5-Carboxy-benzoxazole-2-thiocarboxylic acid'O- methyl ester was obtained in a yield of 17% of theory. The yellow compound melted with decomposition at 268-269C.

5-Carbomethoxy-benzoxazole-2-thiocarboxylic acid- ()-methyl ester, a yellow product with a melting point of l52l53C in 77% yield.

A large number of the above-mentioned benzoxazole derivatives have not previously been described in the literature. In addition, some of the methods of preparation described, such as the preparation of most benzoxazole-Z-carboxylic acid esters, benzoxazole-2- carboxylic acids (derivatives) and benzoxazole-2- thiocarboxylic acid esters and the 2-cyanobenzoxazoles are not known from the literature.

The following shows the inflammation-preventing properties of the compound to be used according to the invention as well as their suitability for cosmetic preparations, especially compositions for protecting against the sun and sunburn control compositions.

1n the following examples the benzoxazole derivatives to be used according to the invention were tested for thier inflammation-preventing properties, especially in the case of UV erythema. First an orienting experiment was carried out to determine their toxicity, in order to be able to determine the test dosages for the further experiments.

As a first test for the estimation of the suitability of the compounds for preventing the inflammation caused by sunburn, the rats paw test was used, as described by Kemper in Arzneimittelforschung l0 1960), p. 777. To produce the edema the test animals were injected with 0.1 ml of 6% dextran solution in the right hind paw about 5 mm deep between the second and third pads. While the control animals were only given the dextran solution, the test animals obtained the various test substances suspended of dissolved in a physiological solution injected in the amount indicated in the following Table l, 30 minutes before the dextran injection. The volume of the paw was determined by the electrical volume measuring device further described by Kemper et a1, Zeitschrift fur die gesamte Experimentelle Medizin, 131 (1959), p. 407. The measurements took place 30 minutes before injection of the dextran solution, i.e., at the time of the injection of the test substances in the case of the test animals, and 30 minutes after the injection of the dextran solution. For comparison, the left untreated paw was always measured as well at the stated times. From the values for the swelling in animals which had been treated with the test substance and untreated animals 30 minutes after the dextran injection, the degree of checking of the edema as a percentage of that swelling which occurred with animals which had been given no test substance was calculated.

As a further test for the estimation of the substance with regard to its usefulness as a sunburn control means, the guinea pig UV erythema test was used. It was carried out according to the test method given by Wilhelmi in the Schweizerischen Medizinischen Wochenschrift, 79 1949), p. 577. Dehaired guinea pigs were irradiated for 8 minutes with UV light. Then the experimental animals were given the same dosage of the test substance as in the rats paw test. The evaluation of the degree of reddening is effected by a point system, in which a complete erythema was indicated by 2 points, a suggested reddening by one point. Control experiment and test experiment were carried out on the same animal at different points on the back on two consecutive days. The different degrees of reddening were measured at different times at an interval of 30 minutes, and the left-hand number in the table indicates the degree of the reddening on treatment with the experimental substance, and the right-hand number the degree of reddening without a corresponding injection.

Further, a UV test was carried out on hairless mice, which also allowed a statement on the utility of the substances as sunburn control means. The hairless mice were irradiated for 30 minutes on the back with a UV lamp at a distance of 60 cm, thus causing a skin inflammation. In the case of the test animals the administration of the test substances was effected by intraperitoneal injection following the irradiation, while the region producing erythema, which extends from 280 to 320 mu, these, besides their inflammation-preventing action as sunburn control substances, show themselves simultaneously as useful means for protection from the sun.

scribed, the values given in the following Table I were determined for the individual substances. Under the heading Test Substance, Bo signifies the benzoxazole 10 ring system:

In addition, the absorption maxima of the test sub- X 2 stances 1n the ultraviolet region are given in the follow- 6 o ing Table I. Since with some of the test substances the a H & absorption maxirna lie conveniently in the ultraviolet TABLE I Dextran Edema 8' UV Irradia- Orienting of Rats Paw tion of Dehaired UV Irradi- Toxicity Guinea Pigs ation of Hair- UV Spectrum Ip. less Mice L 50 Dosage Check- Time Reddening yrnax. mp. Test Substance gm/kg mg/kg ing Min. Unit 0-2 Checking (Log 6) BoCN 0.3 75 41 60 0.6/0.8 270 (4.04

240 1.6/1.8 Bo-CN 120 0.8/1.0 46 5C1 0.92 24 240 1.6/1.8 297 (3.78 Bo-CN 0.04 10 21 35 307 (3.65) 5-110 296 (3.76) Bo-CN 0.18 50 29 30 0.6/1.0 96 283 (4.06) .1, 5 7 180 1.0/1.6 274 (4.11)

240 1.4/2.0 Bo-CN 0.3 50 43 30 0.2/0.6 78.3 291 (3.86) 5 COQH 180 1.0/1.4 264 (3.96)

240 1.4/2.0 Bo-CN 1.75 75 18 300 (3.68) 5-coo on, 290 (3. Bo--CN 0.2 50 72.4 30 0.0/0.2 100.0 286 (3.21) 5CO NH 120 1.0/1.6 276 (3.29)

180 1.0/1.8 Bo-CN 0.35 50 20.5 5-0C1-1 NH Bo-C 0.5 75 41 00/04 61 275 (4.04)

ggI-I 240 1.2/2.0 Bo-C 0.69 9.6

OCI I 5-Cl NH Bra-Cf 0.6 75 10.6 180 1.4/1.8 22 303 (3.81)

OCH 5NO Bo-C 0.4 75 18 60 0.6/0.8 52 298 (3.79)

OCH 180 1.2/l.8 5-COOH OCH 5COOCl-I NH Bo-C 0.75 24 34 gC H 1-1 Bo-C 0.9 100 38 1.0/1.2 63

gSH(CH 180 1.4/1.8 Bo-C 0.75 37.3

OCH 5-OCH o Bo-C 0.9 75 33 120 0.6/1.0 57 276 (4.06)

gCH 1.0/1.4 Bo-C 2 92 50 27.3 49

ocH, S-NO O BoC 0.75 100 36.6

OCH, 5 0CH 0 BoC 0.35 75 58 60 0.4/0.8 65 286 (3.48) H 180 0.6/1.2 276 (3.52

In the experiments carried out, as previously de- TABLE 1 Dextran Edema 8' UV Irradia- Orienting of Rat's Paw tion of Dehaired 30' UV lrradi- Toxicity Guinea Pigs ation of Hair- UV Spectrum 1p. less Mice L,,50 Dosage Check Time Reddening ymax. mu Test Substance gm/kg mg/kg ing Min. Unit -2 Checking 70 (Log 6) O B c 1.9 250 28 OK 0 Bo-C 3.75 250 24.2 180 1.0/1.4 280 (3.89) gNH. 258 (3.92) Bo-C 2.9 250 22.9

OH Diethanolammonium O Bo-C 3.75 250 36.7 180 0.8/1.4 35.4 279 (3.85) or-i Triethanol- 257 (3.88)

ammonium /0 Bo-C 0.3 75 36.4 0.2/0.6 81 284 (3.72) OH 180 0.6/1.2 247 (3.78) 5-CH; 0 Bo-C 1.75 250 57.7 48.3 290 (3.85) 0 Diethanol- 257 (3.96)

ammonium 5-CH,

O Bo-C 0.5 45.3 180 0.8/1.6 71.2 290 (3.59) 240 1.4/2.0 247 3.78 5-Cl BO-Cf 1.6 250 47.8 60 0.4/0.8 19.4 288 (3.79) O Triethanol- 0.8/1.2 251 (3.95) ammonium 5-CI O Bo-C 1.75 39.1 75 285 (3.87) OH 244 4.07 5-NO ,0 Bo-C 1.56 100 46.0 60 0.6/0.8 48 288 (3.85) O Monoethanol 240 1.6/2.0 242 (4.29)

ammonium 5 N0 S BoC 0.3 75 45 60 0.0/1.0 32 317 (4.01)

OCl-l 0.6/20 0 Bo-C 0.58 50 63.3

5-OCH;, Bo-C 2.25 250 40.8

0 Diethanolammonium 5-OCH S BoC 0.35 75 16.1 18 335 (4.03) 316 (4.10) .1 302 (4.12)

S BoC 0.3 75 29 60 0.2/0.6 37 315 (4.21)

OCH; 120 1.0/1.4 5-COO (H 240 1612.0 Bo-C 0.35 50 13.6

OCH, 5 0cn The cosmetic preparations of the present invention, especially where sunburn preparations are concerned, may include a component which will impart suppleness to the skin and/or keep it from drying up as much as possible. Such a component is a fatty component, such as a derivative of a long chain fatty acid especially an ester thereof whose alcohol moiety is derived from a shortor long-chain monoor multi-hydric alcohol.

Further the cosmetic preparations of the present invention may have a content of an emulsifying agent, for

0 example, one or more of a partial ester or soap of a long chain fatty acid, higher fatty alcohol natural wax, fat or oil and glycerine.

Specific examples of cosmetic preparations accord- 65 ing to the present invention are as follows EXAMPLE l4 Suntan Oil A suntain oil was produced as follows:

gm of 2-cyano-S-carboxy-benzoxazole were heated while suspended in a very fine state in 100 gm of paraffin and then thoroughly mixed at about C with the following other ingredients:

300 gm of vegetable oil containing lecithin 400 gm of olive oil 100 gm of isopropyl myristate, and

100 gm of purcellin oil.

EXAMPLE l5 Suntan Powder A suntan powder was produced as follows:

40 gm of 2-cyano-5-carbamyl-benzoxazole were introduced into a powder mixing applicance together with 400 gm of rice starch 400 gm of colloid clay 100 gm of lycopodium, and

100 gm of talcum, and the mixture was intensively mixed to obtain a powder having a uniform distribution.

EXAMPLE 16 After-Shave Lotion An anti-inflammation after-shave lotion was prepared as follows:

gm of S-methoxy-benzoxazole-2-carbimide acidmethyl ester and a solution of:

5 gm of citric acid 30 gm of glycerine in 100 gm of witch hazel, were incorporated into a perfumed 80% alcoholic preparation.

EXAMPLE 17 Sun Barrier Cream A sun barrier cream was produced as follows: 40 gm of glycerine monostearate 160 gm of beeswax 420 gm of mineral oil 50 gm of ceresine 50 gm of an absorption base prepared from cholesterin, beeswax, stearyl alcohol and Vaseline, 30 gm of methyl S-methoxy-benzoxazole-Z- carboxylate were melted together at a temperature of 65C. A mixture of:

247 gm of water 13 gm of borax, and 2 gm of methyl para-hydroxybenzoate, heated to the same temperature, was then incorporated into the warm mixture under strong agitation and the cream thus obtained agitated further until it reached room temperature.

EXAMPLE 18 Sun Barrier Emulsion A sun barrier emulsion was produced by adding a mixture of:

800 gm of water,

10 gm of glycerine, and

9 gm of triethanolamine, under strong agitation to a mixture (heated to about 80C) of the following:

20 gm-of glycerine monostearate gm of stearicacid 30 gm of oleic acid 20 gm of cetylic alcohol, and

40 gm of the diethanolammonium salt of S-methoxybenzoxazole-Z-carboxylic acid. The lotion thus obtained was agitated until smooth.

The emulsion so produced can also be packed in aerosol form by combining it with a propellant in the ratio of parts of lotion to 20 parts of propellant.

Any of the other listed anti-inflammatory benzoxazole compounds may be employed in place of those actually employed in Examples 14 to 18 with comparable results. Similarly other customary pharmaceutical preparations for sunburn protection and antiinfiammation cosmetic preparations may be employed containing from 0.01% to 10% by weight of the antiinflammatory benzoxazole compounds of the invention.

The preceding specific embodiments are illustrative of the practice of the invention. It is to be understood, however, that other expedients known to those skilled in the art or disclosed herein may be employed without departing from the spirit of the invention or the scope of the appended claims.

We claim:

1. An anti-inflammatory benzoxazole compound having the formula 6 N (Hi1 wherein X, represents a member selected from the group consisting of C E N and Y represents a member selected from the group consisting of =0, =S and =NH, R represents a member selected from the group consisting of alkyl of from 1 to 22 carbon atoms, alkenyl of from 3 to 22 carbon atoms, phenyl, alkylphenyl of from 7 to 18 carbon atoms, phenylalkyl of from 7 to 18 carbon atoms, and, when Y is 0, hydrogen, alkali metal, NH lower alkylammonium and lower alkanolammonium, R represents a member selected from the group consisting of carboxy, alkali metal salts of carboxy, carbamyl, and carbolower alkoxy, and R represents hydrogen.

2. The anti-inflammatory benzoxazole compound of claim 1 wherein X is C E N, R; is carboxy and R is hydrogen.

3. The anti-inflammatory benzoxazole compound of claim 1 wherein X, is C N, R is carbamyl and R is hydrogen.

4. The anti-inflammatory benzoxazole compound of claim 1 wherein X is C 2 N, R is carbo-methoxy and R is hydrogen.

5. The anti-inflammatory benzoxazole compound of claim 1 wherein X, is claim 1 wherein X is Y is NH, R is methyl, R is the potassium salt of car- Y is 1 is methyL R6 is carbo'methoxy and is yboxy and R is hydrogen. drogen.

6. The anti-inflammatory benzoxazole compound of 10

Claims (6)

1. AN ANTI-INFLAMMATORY BENZOXAZOLE COMPOUND HAVING THE FORMULA

2. The anti-inflammatory benzoxazole compound of claim 1 wherein X1 is - C*N, R6 is carboxy and R5 is hydrogen.

3. The anti-inflammatory benzoxazole compound of claim 1 wherein X1 is - C*N, R6 is carbamyl and R5 is hydrogen.

4. The anti-inflammatory benzoxazole compound of claim 1 wherein X1 is - C*N, R6 is carbo-methoxy and R5 is hydrogen.

5. The anti-inflammatory benzoxazole compound of claim 1 wherein X1 is

6. The anti-inflammatory benzoxazole compound of claim 1 wherein X1 is