HU188308B - Process for producing trisubstituted oxazole derivatives and pharmaceutical compositions containing them - Google Patents

Abstract

The present invention relates to a novel tris-substituted oxazole derivative represented by the general formula (I): wherein one of R 1 and R 2 is a heteroaryl group and the other is a carbocyclic aryl or heteroaryl group, A is a divalent hydrocarbon group and R 3 is a carboxy group, an esterified or amidated carboxy group, for their isomers and salts thereof. It applies. The compounds of formula I can be used as skin flogistics. A to R3 -1-

Description

The present invention provides novel trisubstituted oxazole derivatives, compounds of formula I, wherein

One of the substituents R 1 and R a is phenyl and the other is pyridyl or 1-oxidopyridyl,

A is C 1-4 alkylene or C 2-5 alkylidene and

R ₃ is carboxy, C 2 -C 5 alkoxycarbonyl, hydroxy (C 1 -C 4) alkoxy (C 1 -C 4) alkoxycarbonyl, hydroxy (C 1 -C 4) alkoxy (1-4) C 1 -C 4 alkoxy (C 1 -C 4) -alkoxy-carbonyl or C 1 -C 4 alkoxy (C 1 -C 4) -alkoxy (C 1 -C 4) -alkoxy (C 1 -C 4) -alkoxycarbonyl - a process for its preparation and a process for the preparation of a pharmaceutical composition containing them as an active ingredient.

Examples of pyridyl are 2-, 3- or 4-pyridyl, 1-oxido-pyridyl is for example 1-oxido-3-pyridyl or 1-oxido4-pyridyl.

As used herein, the term "lower" refers to organic groups and compounds having up to 4 carbon atoms.

The general definitions used hereinbefore and hereinafter, in the context of the present invention, are in particular:

Halogen is a halogen of up to 35, such as fluorine, chlorine or bromine, and iodine.

Examples of lower alkoxy groups include methoxy, ethoxy, η-propyloxy, isopropyloxy, η-butyloxy, isobutyloxy, sec-butyloxy or tert-butyloxy.

An example of a hydroxy (lower) alkoxy group is a hydroxyethoxy or a hydroxypropyloxy group.

Examples of lower alkoxy (lower) alkoxy include methoxyethoxy, ethoxyethoxy, methoxypropyloxy or methoxy butyloxy.

A lower alkylene group is, for example, a straight chain such as methylene, ethylene, 1,3-propylene or 1,4-butylene, or a branched chain such as 1,2-propylene, 1,2 or

1,3- (2-methyl) propylene or 1,2-butylene.

The C 2 -C 5 alkylidene group has a tertiary or in particular a quaternary carbon atom and is, for example, ethylidene or 1,1- or 2,2-propylidene, and also 1,1- or 2,2-butylidene or 1,1-, , 2 or 3,3-pentylidene.

The novel compounds of formula (I) and their pharmaceutically acceptable salts possess valuable pharmacological properties, in particular, for example, when applied topically, with significant anti-inflammatory activity.

This property is, for example, demonstrated by the method developed by G. Tonelli, L. Thibault (Endoerinology 77, 625 (1965)), by inhibiting croton oil-induced edema in rats in a dose range of about 100 mg / ml to normal rats. For example, for the ethyl ester of 2- [4-phenyl-5- (3-pyridyl) imidazol-2-yl] acetic acid, an ED _SO value of 17 mg / ml was determined in the above test.

The compounds of formula (I) are thus useful as pharmaceutical active substances, in particular as external topical anti-inflammatory agents for the treatment of inflammatory dermatoses of various origins, such as mild skin irritations, contact dermatitis, rashes, burns, and as an anti-inflammatory agent for mucous membranes, lips inflammation and genital and anal inflammation. The compounds of the formula I can also be used as sunscreens.

In particular, the present invention relates to a process for the preparation of a compound of formula I wherein:

Rj is phenyl,

R ₂ is 1-oxido-pyridyl, such as 1-oxido-3-pyridyl,

A is 2,2-propylidene and

R ₃ is a lower alkoxycarbonyl group having up to 5 carbon atoms, such as ethoxycarbonyl.

In particular, the invention relates to processes for the preparation of the novel compounds named by the Examples and to the methods of preparation listed therein.

One process for the preparation of compounds of formula (I) is characterized in that a compound of formula (II), a tautomer and / or a salt thereof, wherein

One of X ₁ and X _{2 represents} an optionally substituted imino group and the other represents an oxy (if X ₁ ) or oxo (if X ₂ ) or optionally substituted imino group, or

X is oxy and

X ₂ is oxo, in which case a compound of formula IIa or its salt is cyclized by condensation with ammonia or an ammonia releasing agent, provided that when X 1 is oxy, X ₂ is oxo, R 1, R ₂ and A are R ₃ other than carboxy and C 2 -C 5 alkoxycarbonyl is as defined above.

For example, the tautomers of the compounds of formula (II) are those in which the partial enol and enmyril moieties are present in the corresponding tautomeric keto or ketintin forms and vice versa, and the respective tautomers are in equilibrium with each other.

Compounds of formula II, their tautomers and / or salts thereof, are cyclized in a conventional manner, particularly for reactions analogous to those in the literature, optionally under heating, for example at temperatures of from about 20 ° C to about 250 ° C, under pressure and / or in the presence of a catalyst, preferably an acid or an anhydride. As the acid, for example, inorganic acids such as mineral acids such as sulfuric acid, polyphosphoric acid or hydrogen halides such as hydrochloric acid or organic acids such as lower alkanecarboxylic acids such as acetic acid can be used. Suitable acid anhydrides are, for example, mineral acid anhydrides, such as sulfuryl or phosphorus (oxy) halides, such as phosphorus oxychloride. This may be done, if necessary, in an inert solvent such as an optionally halogenated hydrocarbon such as chloroform, chlorobenzene, hexane, pyridine or toluene, a lower alkanol such as methanol, dimethylformamide or formamide, or a lower alkanoic acid or in acetic acid -

-2188 308 and / or using an inert gas such as nitrogen gas.

The starting materials of formula (II), their tautomers and / or salts thereof are predominantly formed in situ in known manner and further reacted, without isolation, under the reaction conditions to the compounds of formula (I). This can be accomplished by coupling the cyclization to a preconditioning.

Thus, for example, in a preferred embodiment of the preceding process, a compound of formula IIa

Y 1 is an optionally functionally modified hydroxy group, its tautomer and / or salt thereof with a compound of formula Hb

Y ₂ is a reacting carboxyl group with at least one nitrogen atom, or a salt thereof, or a compound of formula IIa wherein Y 1 is amino, or a tautomer or salt thereof with a compound of formula 11b

Y ₂ is optionally reacted with a functionally modified carboxy group or a salt thereof, optionally in the presence of a condensing agent. During the reaction, for example, a suitable compound of formula II or a tautomer thereof may be formed, which is further reacted under the reaction conditions.

In a particularly preferred embodiment of the above process, for example, a compound of formula (IIa) wherein

Y 1 is an optionally reactively esterified hydroxy group, which is reacted with a carboxylic acid of formula IIc, a salt or a functional derivative thereof and ammonia, or a compound of formula IId which is given to a compound of formula IIa by a compound of formula IIc In this case, it is prepared by condensation with its functional derivatives by reaction with ammonia.

Salts of the compounds of the formulas II and IIa are, for example, acid addition salts such as hydrogen halides. For example, the functionally modified hydroxy group in Yj is, for example, an amino group or a reactively esterified hydroxy group such as an inorganic mineral acid such as hydrogen halide or an organic sulfonic acid.

- e.g. an hydroxy group esterified with an optionally substituted benzenesulfonic acid. Examples of a reactively esterified hydroxy group include, in particular, a halogen atom such as a chlorine or bromine atom or a sulfonyloxy, e.g. p-toluenesulfonyloxy may be mentioned. Y ₂ as a functionally converted carboxy group is, for example, an anhydride-converted carboxy group such as a halocarbonyl group, a lower alkanoyloxycarbonyl group or a lower alkoxycarbonyloxycarbonyl group, a carbamoyl group or an amidino group.

For example, the reactively esterified hydroxy group is preferably a strong inorganic or organic acid such as a mineral acid such as hydrogen halide, e.g. hydroxy ester esterified with hydrogen bromide or hydrochloric acid or an organic sulfonic acid such as an optionally substituted benzenesulfonic acid such as p-toluenesulfonic acid. Functionally modified carboxy derivatives of the compounds of formula IIc include, for example, the corresponding optionally esterified, amidated or anhydride carboxyl derivatives such as the corresponding lower alkoxycarbonyl, optionally substituted carbamoyl or halocarbonyl, lower alkanoyloxy, lower alkoxycarbonyloxy carbonyl derivatives.

Suitable condensing agents include, for example, strong protonic acids such as mineral acids such as sulfuric acid, hydrogen halogen dec, phosphoric acids, sulfonic acids such as optionally substituted benzenesulfonic acids, or carboxylic acids such as lower alkane carboxylic acids such as carboxylic acids such as fatty acids; suitable anhydrides of sulfuric acid, such as phosphorus pentachloride, phosphorus oxychloride, phosphorus pentoxide, thionyl chloride or phosgene.

The reaction is carried out in the usual manner, if necessary using heating and in an inert solvent such as a halogenated hydrocarbon.

In a preferred embodiment, compounds of formula II wherein X 1 and X ₂ are oxy or oxo are prepared by reacting compounds of formula Jla where Y is hydroxy of formula Hb with an acid derivative of the formula I, in particular with the corresponding acid halides. The compounds of formula (IId) thus prepared can be converted to the corresponding compounds of formula (I) in the presence of ammonia in the presence of an acid such as acetic acid.

Compounds of formula (II) compounds of formula - wherein X, is oxiesoport and _X2 iininocsoport - preferably prepared by reacting the formula (IIa) of formula: - wherein Yj is reactively észteiezett hydroxy, especially halogen, - right (Hb) a compound of formula - wherein Y ₂ represents a carbamoyl group - is reacted under the conditions specified above reaction conditions.

Compounds of formula (H) compounds of formula I, wherein X i is iniinocsoport and X ₂ oxo sign it, preferably prepared by reacting the formula (11) compound of the formula - where Yj amino - cut / a salt thereof and / or a tautomer thereof (III this ) with a compound of formula wherein Y ₂ anhydrized carboxyl group, especially a halogen-carbonyl group; the reaction conditions are the same as those described above.

Compounds of formula (II) wherein X? And X ₂ = NH, preferably prepared to a When the compound of the formula: - wherein Y i represents optionally reactively ész'erezett hydroxy, especially hydroxy -, salts thereof and / or a tautomer thereof with a With a compound of formula (Hb) wherein Y ₂ is an amidino group.

The starting materials of the formulas (IIa), (IIb) and (IIc) are known or can be prepared by methods known per se.

For example, (IIa) Compounds of formula Ri _-CH2 -C00H, and R ₂ -CH ₂ -COOH

The esters of 188,308 can be prepared by ester condensation with esters of the acids R ₁ -COOH and R ₂ -COOH, preferably in the presence of bases. For example, the resulting α-methylene-4-ketone (He) is brominated to give a compound (IIa) or a salt, e.g. hydrogen halide, wherein Y 1 is bromo topic.

The compounds of formula (I) may also be prepared by reducing a compound of formula (III) or a salt thereof to a compound of formula (I).

The reduction is carried out by methods known per se. Thus, a compound of formula (IH) or a salt thereof is treated with hydrogen in the presence of a hydrogenation catalyst or with a dithionite such as sodium dithionite or a phosphorus halide such as phosphorus trichloride.

For example, the hydrogenation catalyst is VIII. elements of the substituent group and their derivatives, such as platinum, palladium or palladium chloride, optionally applied to a conventional carrier such as activated carbon or alkaline earth metal compounds such as barium carbonate; can also be used with Raney nickel. The reduction can also be accomplished using a suitable system of a noble metal and a protonic acid such as zinc and glacial acetic acid.

The reduction may be carried out, if necessary, with cooling or heating, at a temperature in the range of from about 0 ° C to about 150 ° C, in an inert solvent such as a halogenated hydrocarbon such as chloroform, carbon tetrachloride or chlorobenzene, or an ether, For example, dimethoxyethane, diethyl ether, dioxane or tetrahydrofuran and / or an inert gas atmosphere such as nitrogen.

The starting materials of formula (III) or salts thereof may be prepared in a manner known per se, for example by reacting a compound of formula (IIIa), a tautomer or a salt thereof with an aldehyde of formula (IIIb), optionally at a higher temperature and Thus, in the presence of a mineral acid such as hydrochloric acid, a sulfonic acid such as p-toluenesulfonic acid or a carboxylic acid such as acetic acid.

Compounds of formula I wherein R 1, R ₂ and A are as defined above and R _{3 represents a} carboxy group or a C 2 -C 5 alkoxycarbonyl group may also be prepared by reacting a compound of formula IV wherein R 1, R ₂ and A are as defined above, R ₃ is, on the one hand, a hydroxymethyl group, an esterified hydroxymethyl group, a formyl group or an acetalized formyl group, and on the other hand, a C 2 -C 5 alkoxymethyl group; is oxidized to a compound of formula I wherein R _{3 is,} on the one hand, a carboxy group or, on the other, a C 2 -C 5 alkoxycarbonyl group. Optionally, a hydrated or acetalized formyl group, preferably during the oxidation reaction, may be formed in situ from an acyl group of an α-unsaturated or α-dihydroxylated aliphatic carboxylic acid, an optionally esterified hydrated form of the hydroxy group, or functional derivatives thereof, e.g. acetal, acyl, or iminej. Acyl groups of αβ-dihydroxylated carboxylic acids are, for example, acyl groups of α3-unsaturated aliphatic mono- or dicarboxylic acids, such as acryloyl group, crotonoyl group or optionally functionally modified fumaric or maleic acid groups. Esterified hydroxymethyl groups, for example, are esterified on the hydroxy group with a mineral acid such as a hydrogen halide such as hydrochloric acid or bromide or a carboxylic acid such as acetic acid or optionally substituted benzoic acid. Acetylated formyl groups include, for example, formyl groups acetylated with lower alkanols or lower alkanediol, such as dimethoxy, diethoxy or ethylenedioxymethyl. Examples of acylated formyl groups are di (lower) alkanoyloxymethyl or dihalomethyl groups such as diacetoxymethyl or dichloromethyl. Imines of the fornyl groups include, for example, optionally substituted N-benzylimines or imines with N- (2-benzothiazolyl) imine or 3,4-di-tert-butyl-o-quinone. Represented by R ₃ can be oxidized C2-5 alkoxycarbonyl group groups are etherified hydroxymethyl groups, such as lower alkoxymethyl groups.

Such R ₃ groups are oxidized in a known manner, for example by reaction with a suitable oxidizing agent, e.g. , if necessary, using cooling or heating, for example, at about 0 ° C to about 150 ° C. As the oxidizing agent, for example, transition metal compounds having an oxidizing property, in particular compounds I, VI, VII. or VIII. compounds of extension group elements are contemplated. Examples include silver compounds such as silver nitrate, oxide or picolinate, chromium compounds such as chromium trioxide or potassium dichroinate, manganese compounds such as tetrabutylammonium or potassium ferrate. Other oxidizing agents are, for example, the corresponding compounds formed with the main group 4 elements, such as carbon monoxide or halogen oxygen compounds such as sodium iodate or potassium periodate.

For example, oxidation of a hydroxymethyl group or a hydroxymethyl group etherified with a lower alkanol leads to a carbonyl group or a carboxy group R ₃ esterified with a lower alkanol. This reaction is preferably carried out, for example, with potassium permanganate in acetone or aqueous pyridine at room temperature. Accordingly, the optionally hydrated formyl group is oxidized to a R ₃ carboxy group, for example iodine, in methanolic potassium hydroxide solution.

The starting materials of formula (IV) are prepared by known methods. For example, starting from a hydroxy ketone of formula IVa and a compound of formula IVb, or a salt thereof, wherein Y ₂ is a carboxyl group optionally functionally modified, or a compound of formula R ₃ -A-CO 2 OH, with a functional derivative thereof, it is reacted with a salt of salt and ammonia, in an inert solvent and under heating, to give the compound of formula IV in situ without isolation of the intermediates.

In the processes described above, for example in the preparation of compounds of formula IV, ammonia, which is used predominantly in excess,

188,308 may also be added in the form of ammonia-releasing compounds, at which time the release is effected at elevated temperature and optionally under pressure. Examples of ammonia-releasing compounds are ammonium salts of lower alkane carboxylic acids, preferably ammonium acetate, and suitable lower alkane carboxylic acids, in particular formamide.

For example, the aldehyde IHb used in the above process for the preparation of compounds of formula III may be liberated under the reaction conditions from an oxazine derivative of formula lile. For example, the compounds of formula (Iile) may be prepared by reacting 2-methyl-2,4-pentanediol ^or nitrile of formula R ₃ -A-CN in the presence of sulfuric acid. The resulting appropriately substituted dihydro-1H-oxazine in tetrahydrofuran / ethanol is reduced at -45 ° C and about pH 7 with sodium borohydride to give tetrahydra-1,3-oxazine (HIc).

The compounds of the present invention may be converted into other compounds of formula I in conventional manner.

Thus, the free and esterified R ₃ carboxy groups of the compounds of formula (I) according to the invention can be converted into each other.

For the preparation of compounds of formula I wherein R 1, R ₂ and A are as defined above and R ₃ is carboxy, a compound of formula I wherein R 1, R ₂ , A is as defined above and R ₃ is C 2 -C 5 alkoxycarbonyl, hydroxy (C 1 -C 4) alkoxy (C 1 -C 4) alkoxycarbonyl, hydroxy (C 1 -C 4) alkoxy (C 1 -C 4) -alkoxy (C 1 -C 4) alkoxycarbonyl or (C 1 -C 4) alkoxy (C 1 -C 4) -alkoxy (C 1 -C 4) -alkoxy (C 1 -C 4) -alkoxycarbonyl - hydrolyze.

The free carboxy group R _{3 is} conventionally prepared, e.g. with a diazo- (lower) alkane, di- (lower) alkylformamide acetal, alkyl halide or tri- (lower) alkyl-oxonium, tri- (lower) -alkylcarboxonium or di- (lower) alkylcarbonium salts such as hexachloro-antimonate or hexafluorophosphate, or in particular the corresponding alcohol or a reactive derivative of the corresponding alcohol such as a carboxylic acid, phosphoric acid, sulfuric acid or carbonic acid ester, e.g. lower alkanecarboxylic acid ester, tri (lower) alkyl phosphite, di- (lower) alkyl 1-sulfite or pyrocarbonate, or a mineral acid or sulfonic acid ester, e.g. it may be esterified with an esterified R ₃ carboxylic acid by reaction with hydrochloric or bromide or with an ester of sulfuric, benzenesulfonic, toluenesulfonic or methanesulfonic acids, or with an olefin derived from the corresponding alcohol.

The reaction with the corresponding alcohol itself is preferably carried out in the presence of an acidic catalyst such as a protonic acid such as hydrochloric or bromide, sulfuric acid, phosphoric acid, boric acid, benzenesulfonic acid and / or toluenesulfonic acid or a Lewis acid such as boron trifluoride etherate. , in an inert solvent, in particular an excess of the alcohol used and, if necessary, the presence of a water-binding agent and / or distillation, such as azeotropos, to remove water from the reaction and / or at elevated temperatures.

The reaction with the reactive derivative of the corresponding alcohol can be carried out in a conventional manner starting from a carboxylic acid, a phosphate acid, a sulfuric acid or a carbonic acid ester, for example in the presence of an acidic catalyst such as one mentioned hereinbefore in an inert solvent such as an aromatic hydrocarbon. benzene or toluene, or excess alcohol derivatives or the corresponding alcohol. Starting from a mineral acid or sulfonic acid ester, the acid to be esterified is preferably used in the form of a salt such as a sodium or potassium salt, and optionally a basic condensing agent such as an inorganic base such as sodium or potassium or calcium hydroxide or carbonate. in the presence of a nitrogen base such as triethylamine or pyridine and / or at a higher temperature, and / or in an inert solvent such as one of the aforementioned tertiary nitrogen bases or in a polar solvent such as dimethylformamide.

The reaction with di- (lower) alkylformamide acetal, such as dimethylformamide acetal, is optionally carried out while heating, while the alkyl halide is reacted in the presence of a base such as an amine, such as triethylamine.

For example, the olefin is an acidic catalyst, such as a Lewis acid such as boron trifluoride, sulfonic acid. p-toluenesulfonic acid - or, above all, a basic catalyst, e.g. the reaction is carried out in the presence of sodium or potassium hydroxide, preferably in an inert solvent such as an ether such as diethyl ether or tetrahydrofuran.

However, the conversion of the free carboxy group of R ₃ to the esterified carboxy group described above can also be effected by first converting a compound of formula (I) wherein R ₃ is a carboxy group into a reactive derivative, such as a halide of phosphorus or sulfur. , e.g. by reaction with phosphorus trichloride or bromide, phosphorus pentachloride or 'ionyl chloride to give the acid halide or a reactive ester, i.e. an ester with an electron withdrawing structure, such as phenol, thiophenol, p-nitrophen or and converting the resulting reactive derivative to the desired R ₃ group in the usual manner with a suitable alcohol.

Eg <RTIgt; R3 </ _RTI> esterified carboxy group is conventionally employed, e.g. a basic or acidic material. Thus, a strong base such as sodium or potassium hydroxide or a mineral acid, e.g. hydrolyzed in the presence of hydrochloric acid, sulfuric acid or phosphoic acid to the free carboxy group R ₃ .

For the preparation of compounds of formula (I) wherein R 1, R ₂ , A are the above-mentioned C ₃ -C 5 alkoxycarbonyl, hydroxy (C 1 -C 4) alkoxy (I). -C4 -C4 alkoxy-carbonyl, hydroxy- (C1 -C4) -alkoxy (C1 -C4) -alkoxy (C1 -C4) -alkoxycarbonyl or C1 -C4 alkoxy- (C 1 -C 4) -alkoxy (C 1 -C 4) -alkoxy (C 1 -C 4) -alkoxycarbonyl, a compound of formula (I) wherein R 1, R ₂ , A are as defined above and R ₃ is carboxy or a salt thereof is esterified.

Depending on the choice of starting materials and working methods, the compound of formula I

188,308 may be prepared in the form of one of the possible isomers or as a mixture thereof.

The compound of formula (I) may also be obtained in the form of its hydrates or may contain other solvents used for crystallization.

Depending on the choice of starting materials and working methods, the compounds are available in the form of one or a mixture of possible isomers, for example, depending on the number of asymmetric carbon atoms, in the form of pure optical isomers such as antipodes or isomer mixtures such as racemates, diastereomeric mixtures or racemates. .

The resulting diastereomeric mixtures and racemate mixtures may be separated into their pure isomers, diastereomers or racemates, e.g. by chromatography and / or fractional crystallization, according to known physicochemical differences. Further, the resulting racemates may be resolved by known methods, e.g. by recrystallization, by microorganisms, or by reaction of the acidic end product with an optically active base which forms salts with a racemic acid, and the salts thus obtained, for example due to their different solubilities, are broken down into diastereomers to release the antipodes. Preferably, the more effective of the two antipodes is isolated.

The invention also relates to those embodiments of the process wherein the starting material is in the form of a salt.

The pharmaceutical compositions of the present invention comprising at least one active ingredient are preferably those for topical use in warm-blooded individuals which contain the pharmacologically active ingredient alone or in combination with a pharmaceutically acceptable carrier. The daily dosage of the active ingredient depends on age, individual condition and the route of administration. Suitable agents in the concentration range of about 1 to about 10% by weight, for example, in the form of creams, ointments or solutions, for example, twice or three times daily.

Topical pharmaceutical formulations include creams, ointments, pastes, foams, tinctures and solutions containing from about 0.1% to about 10% of the active ingredient.

Creams are oil-in-water emulsions containing more than 50% water. The fatty acids, such as lauryl, cetyl or stearyl alcohol, fatty acids such as palmitic or stearic acid, liquid to solid waxes such as isopropyl myristate, wool grease or beeswax (e.g. or paraffin oil. Suitable emulsifiers include surfactants that are predominantly hydrophilic, such as fatty acid esters of suitable nonionic emulsifiers, such as polyalcohols, or ethylene oxide adducts thereof, such as polyglycerol fatty acid ester or polyoxyethylene fatty ethers or fatty acid esters or suitable ionic emulsifiers, such as alkali metal salts of fatty alcohol sulfates, such as sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate, commonly used in fatty alcohols such as cetyl alcohol or stearyl alcohol. Additives to the aqueous phase include those which prevent the creams from drying out, such as polyalcohols such as glycerol, sorbitol, propylene glycol and / or polyethylene glycols, as well as preservatives, fragrances, and the like.

The ointments are water-in-oil emulsions containing up to 70%, preferably from about 20% to about 50%, water or aqueous phase. The fatty phase two is preferably hydrocarbons, such as petroleum jelly, paraffin oil, and / or hard paraffin, which preferably contain hydroxy derivatives such as fatty alcohols or esters thereof such as cetyl alcohol or wool fatty alcohols, or wool fats to improve water retention. Suitable emulsifiers include suitable lipophilic substances such as sorbitan fatty acid ester (Spans), e.g. sorbitan oleate and / or sorbitan isostearate. Additives for the aqueous phase include wetting agents such as polyalcohols such as glycerol, propylene glycol, sorbitol and / or polyethylene glycol, and preservatives, fragrances and the like. They are.

The fatty ointments contain anhydrous c 'bases containing in particular hydrocarbons such as paraffin, petroleum jelly and / or liquid paraffins and natural or partially synthetic fats such as coconut fatty acid triglyceride or preferably hardened oils such as hydrogenated peanut oil or castor oil, e.g. glycerol mono- and distearate as well as fatty alcohols, emulsifiers and / or additives, for example, mentioned in connection with ointments, which increase the water absorption.

Pastes are creams and ointments that contain exudate adsorbing powder components, such as metal oxides, such as titanium oxide or zinc oxide, and talc and / or aluminosilicates, which are intended to absorb the moisture or secretions present.

The foams are e.g. from pressurized containers; they are aerosol liquid oil-in-water emulsions using propellants such as halogenated hydrocarbons, such as chlorofluorocarbons such as dichlorodifluoromethane and dichlorotetrafluoroethane. Examples of the oil phase include hydrocarbons such as paraffin oil, fatty alcohols, e.g. cetyl alcohol, fatty acid esters such as isopropyl myristate and / or other waxes. Emulsifiers include, but are not limited to, mixtures with predominantly hydrophilic properties such as polyoxyethylene sorbitan fatty acid ester (Tweens) and emulsifiers having a predominantly lipophilic property such as fatty acid ester (Spans). This is accompanied by the usual additives such as preservatives, etc.

Tinctures and solutions are mostly water-ethanol based, for which polyalcohols such as glycerol, glycols and / or polyethylene glycol are used as moisturizing agents to reduce evaporation, and fatty acid esters made from low molecular weight polyethylene glycols are added to the skin, soluble lipophilic substances - and, if necessary, other excipients and additives.

Topical formulations are prepared by methods known per se, for example by:

-6188 308 the active ingredient is dissolved or suspended in the base or, if necessary, in a portion thereof. When the active ingredient is processed as a solution, it is usually dissolved in one of the two phases prior to emulsification; for processing as a suspension, after emulsification, it is mixed with a portion of the base and then added to the rest of the formulation.

The invention described below is exemplified by the following examples; however, the examples do not limit the invention in any way. Temperature data refers to degrees Celsius.

Example 1

To a solution of 39.0 g (freshly distilled) 1-phenyl-2- (3-pyridyl) -glyoxal in 500 ml of methanol is added 2.5 g of sodium borohydride in portions over 5 hours at 0 ° C. After the addition was complete, the mixture was stirred at 0 ° C for a further 2 hours, allowed to stand at 0 ° C for 15 hours, and then mixed with 200 ml of 2N hydrochloric acid. The suspension is evaporated to dryness under reduced pressure, the residue is mixed with ice and made basic by the addition of 2N sodium carbonate solution. The aqueous suspension was extracted with ethyl acetate (3 x 200 mL). The combined ethyl acetate solutions were washed with water (50 mL), dried over magnesium sulfate and concentrated under reduced pressure at 40 ° C. The residual brown oil was chromatographed on 500 g of silica gel. Fractions 1 and 2, eluted with 1000-1000 mL of a 1: 1 mixture of toluene / ethyl acetate, contain the starting material [1-phenyl-2- (3-pyridyl) glyoxal]. Fractions 3 and 4, eluted with 1000-1000 ml (1: 1) toluene / ethyl acetate, were combined and evaporated to dryness under reduced pressure. The residue was crystallized from ether / petroleum ether. The α-hydroxybenzyl (3-pyridyl) ketone melts at 109-111 ° C. Fractions 5 and 6, eluted with 1000-1000 mL of a 1: 1 mixture of toluene and ethyl acetate, are discarded. 7-14. fraction (1000: 1000 ml) eluted with toluene / ethyl acetate (40:60), combined and evaporated to dryness under reduced pressure. The residue was crystallized from ether / petroleum ether. The resulting α-hydroxyphenyl [(3-pyridyl) methyl] ketone melted at 9395 ° C.

Example 2

A mixture of 6.0 g of α-hydroxyphenyl - [(3-pyridyl) methyl] ketone and 1 ml of triethylamine in 80 ml of anhydrous benzene was stirred at 10 ° C for 20 minutes and 6.0 g of dimethyl was added. -Malonic acid monoethyl ester chloride in 30 ml of anhydrous benzene, stirred at room temperature for 3 hours, mixed with 30 ml of ethyl acetate and 90 ml of water and stirred at room temperature for 1 hour. The aqueous layer was separated and washed with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (30 mL), 2N potassium bicarbonate (30 mL), brine (30 mL), dried over magnesium sulfate and evaporated under reduced pressure. The residual oil was chromatographed on 200 g of silica gel. Fractions 1 and 2, eluted with 200-200 mL of chloroform, are discarded. 3-9.

Fractions 1 to 4, eluted with chloroform-methanol (99: 1), combined and evaporated to dryness under reduced pressure. The residue, dimethyl malonic acid monoethyl ester [O-benzoyl (3-pyridyl) methyl] ester, is obtained in the form of an oil.

In an analogous manner, methyl malonic acid monoethyl ester [α-benzoyl (3-pyridyl) methyl] ester (oil), hydroxyphenyl [(3-pyridyl) methyl] ketone and methyl malic acid were prepared. starting from monoethyl ester chloride; and monoethyl ester of [alpha] -benzoyl (3-pyridyl) methyl] (oil), hydroxyphenyl [(3-pyridyl) methyl] ketone, and starting from the monoethyl ester of malonic acid.

Example 3

A mixture of 1 g of dimethyl malonic acid monoethyl ester [α-benzoyl (3-pyridyl) methyl] ester, 2.4 g of ammonium acetate and 24 ml of glacial acetic acid was stirred at 140 ° C for 2 hours. The reaction mixture was cooled, poured into 100 mL of ice water and adjusted to pH 8 with concentrated aqueous ammonium hydroxide. It is then extracted three times with 70 ml of ethyl acetate each time and the ethyl acetate extracts are washed twice with 20 ml of water each time. The combined organic layers were dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel (100 g). 1-7. fraction (100-100 ml) was discarded. Fractions 8 and 9, eluted with 100-100 mL of clone form, were combined and evaporated to dryness under reduced pressure. The residual oil was triturated with petroleum ether. The precipitated crystals are filtered off and rinsed with hide petroleum ether. The resulting 2- [4-phenyl-5- (3-pyridyl) -oxazol-2-yl] -2-methyl-propionic acid ethyl ester is m.p.

In an analogous way,

- [4-phenyl-5- (3-pyridyl) oxazol-2-yl] propionic acid ethyl ester (Formula V),

NMR (CDCl ₃ ): 8.85 (s, br, H-2 '); 8.56 (d, br, H-h ');

7.87 (dt, H-4 '); 7.64 (m, H-2.6); 7.35 -7.45 (other aromatic H); 7.18 (dd, H-5 '); 4.03 (q, _CH-CH3); Starting from 1.70 (d, CH ₃ CH), starting from m-methyl malonic acid monoethyl ester [a-benzoyl (3-pyridyl) methyl] ester, and [4-phenyl-5- (3- pyridyl) oxazol-2-yl] acetic acid ethyl ether,

NMR (CDCl ₃ ): 8.85 (s, br, Η-2'a; 8.56 (d, br, H-6 ');

7.87 (dt, H-4 '); 7.64 (m, H-2, 6); 7.35-7.45 (other aromatic H); 7.18 (dd, H-5 '); 3.92 (s, CH 2 CO), m.p. 7071 ° C m; starting from the mono - ethyl ester of lonic acid [a] benzoyl (3 - pyridyl) methyl ester.

Example 4

A solution of 1.6 g of 2- [4-phenyl-5- (3-pyridyl) -oxazol-2-yl] -2-methyl-propionic acid ethyl ester in 20 ml of ethylene chloride is stirred at 0 ° C. , mixed dropwise with a solution of 1.0 g of m-chloroperbenzoic acid in 20 ml of methylene chloride. The reaction mixture was stirred at 0 ° C for two hours

The reaction mixture was stirred for 30 minutes at 0 ° C. The reaction mixture was washed twice with 10 ml of 2N potassium bicarbonate solution, dried over magnesium sulfate and concentrated under reduced pressure. The residual oil was chromatographed on 40 g of silica gel. 1-3. fraction (50-50 ml) was discarded. 4-11. fractions eluted with 50-50 ml of chloroform are combined and evaporated to dryness under reduced pressure. The residue was ethyl 2- [4-phenyl-5- (1-oxido-3-pyridyl) oxazol-2-yl] -2-methylpropionic acid.

NMR (CDCl 3): 839 (t, H-2 '); 8.03 (dt, H-6 '); 7.10 (dd, H-5 '); 7.2-7.6 (m, other aromatic H); 1.65 (s, bo. CH ₃ ), m.p. 73-75 ° C.

Prepared analogously to a

- [4-phenyl-5- (1-oxido-3-pyridyl) oxazpl-2-yl] propionic acid ethyl ester (oil),

Starting from [4-phenyl-5- (3-pyridyl) oxazol-2-yl] propionic acid ethyl ester and

- [4-Phenyl-5- (1-oxido-3-pyridyl) oxazole-2-yl] -acetic acid ethyl ester (oil),

- [4 - fan! Starting from ethyl 5- (3-pyridyl) oxazol-2-yl] acetic acid.

Example 5

A solution of 2.1 g of 2- [4-phenyl-5- (1-oxido-3-pyridyl) oxazol-2-yl] -2-methylpropionic acid ethyl ester in 10 ml of methanol with stirring was added 7.2 ml of In sodium -hydroxide solution. The solution was stirred for 5 hours at room temperature and evaporated to dryness under reduced pressure. The residue was dissolved in water (50 mL) and the aqueous solution was extracted with methylene chloride (20 mL). The aqueous phase was then separated and adjusted to pH 4.0 with 2N hydrochloric acid. The suspension is stirred at 0 ° C for 5 minutes and filtered. The resulting 2- [4-phenyl- (5-oxo-3-pyridyl) -oxazol-2-yl] -2-methyl-propionic acid m.p. 136137 ° C.

Prepared analogously to a

- [4-phenyl-5- (1-oxido-3-pyridyl) - oxazole-2-yl] -propionic acid

- [4-phenyl-5- (1-oxido-3-pyridyl) oxazole-2-yl] propionic acid ethyl ester and

2- [4-phenyl-5- (l-oxido-3-pyridyl) oxazol-2-yl] acetic acid

Starting from ethyl ethyl [4-phenyl-5- (1-oxido-3-pyridyl) oxazole-2-yl] acetic acid;

- [4-phenyl-5- (3-pyridyl) oxazol-2-yl] -2-methylpropionic acid, m.p. 111-112 ° C (from methanol),

- [4-Phenyl-5- (3-pyridyl) oxazol-2-yl] -2-methylpropionic acid ethyl ester.

6. p ed

11.3 g of α-oxobromobenzyl (3-pyridyl) ketone and 12.2 g of 2 (δ, η-dimethyl-ethoxycarbonylmethyl) -4,4,6-trimethyl-23,5,6-tetrahydro To a suspension of -13-oxazole in 300 ml of glacial acetic acid was added hydrochloric acid gas without cooling, with vigorous stirring. The temperature rises to 45 ° C and a clear solution is formed. In the solution

Hydrochloric acid gas was passed at 115 ° C for 30 minutes, then the solution was heated at 115 ° C for 15 hours, cooled and evaporated to dryness at 50 ° C under reduced pressure. The residue was dissolved in water (300 mL). The aqueous solution was made basic with concentrated aqueous ammonium hydroxide solution and the precipitated crystals were dissolved in 300 ml of ethyl acetate-methylene chloride (1: 1). The organic layer was washed with water (50 mL), dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was crystallized from ether / ether. The resulting 2- [4-phenyl-5- (3-pyridyl) (3-oxido-oxazol) -2-yl] -2-methyl-propionic acid ethyl ester, m.p. 195-210 ° C.

Prepared analogously to a

- [4-Phenyl-5- (3-pyridyl) - (3-oxido-oxazol) -2-yl] -propionic acid ethyl ester, from? -OXimobenzyl- (3-pyridyl) ketone; methyl methoxycarbonylmethyl) -4,4,6-trimethyl-23,5,6-tetrahydro-13-oxazine

- [4-Phenyl-5- (3-pyridyl) - (3-oxido-oxazol) -2-yl] -acetic acid ethyl ester, from a-oximobenzyl- (3-pyridyl) ketone and 2- (ethoxy) -carbonylmethyl) -4,4,6-trimethyl-2,3,5,6-tetrahydro-13-oxazine.

Example 7

A solution of 1.2 g of ethyl 2- [4-phenyl-5- (3-pyridyl) - (3-oxidooxazol) -2-yl] -2-methylpropionic acid in 10 ml of glacial acetic acid at 10 ° C, using blending, in portions

Mix with 1.2 g of zinc powder. After the addition was complete, 0.05 ml of concentrated hydrochloric acid solution was added to the reaction mixture, which was heated at 90 ° C for 1 hour, cooled, filtered and rinsed with 5 ml of glacial acetic acid. The filtrate was evaporated to dryness under reduced pressure at 50 ° C. The residue was dissolved in water (20 mL) and the aqueous solution was made basic with aqueous concentrated ammonium hydroxide. The suspension is extracted three times with 30 ml of ethyl acetate each time. The combined organic layers were washed with water (10 mL), dried (MgSO4) and evaporated to dryness under reduced pressure. The residue is chromatographed on 80 g of silica gel. 1-5. fraction (50-50 ml) was discarded. 6-9. fractions eluted with 50-50 ml of chloroform are combined and evaporated to dryness under reduced pressure. After trituration with the remaining petroleum ether, it becomes crystalline. The received

Ethyl [4- (4-phenyl) -5- (3-pyridyl] -oxazol-2-yl] -2-methylpropionic acid, m.p. 70-71 ° C.

Example 8

A mixture of 3.6 g of α-bromobenzyl (3-pyridyl) ketone, 1.7 g of dimethylmalonic acid monoethyl ester monoamide and 1.3 R collidine in 100 ml of xylene is heated for 15 hours at 120130 ° C. , the resulting water is separated with a water separator. The reaction mixture was evaporated to dryness under reduced pressure and the residue was mixed with water (30 ml) and concentrated ammonium hydroxide solution and extracted three times with ethyl acetate (4040 ml). The combined ethyl acetate solution was washed with water (20 mL), dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was chromatographed on 80 g of silica gel. 1-3. fraction (100100 ml) was discarded. 4-6. fractions eluted with 100-100 ml of chloroform contain 2- [4-phenyl-5- (3-pyridyl) -oxazol-2-yl] -2-methylpropionic acid ethyl ester. The latter fractions were combined and evaporated to dryness under reduced pressure. The residue is triturated with petroleum ether and the precipitated crystals are filtered off. Melting point: 70-71 ° C.

Example 9

A mixture of 3.56 g of α-bromobenzyl (3-pyridyl) ketone hydrobromide and 3.66 g of dimethyl malonic acid monoethyl ester sodium salt in 100 ml of aqueous ethanol is heated to reflux. After addition of 1 ml of concentrated sulfuric acid, the solution was stirred at reflux for 1 hour and at 50 ° C for 15 hours. The reaction mixture was cooled and evaporated to dryness under reduced pressure. The residual oil was chromatographed on 250 g of silica gel. 1-5. fraction 300 ml of chloroform was discarded. 6-8. fraction (300-300 ml) was combined and evaporated to dryness under reduced pressure. The resulting dimethyl malonic acid monoethyl ester [α-nicotinoylbenzyl] ester oil is obtained.

Analogously, the methyl malonic acid monoethyl ester [α-nicotinoyl benzyl] ester (oil) is prepared starting from the sodium salt of α-bromobenzyl (3-pyridyl) ketone hydrobromide and the monoethyl ester of methyl malonic acid. as well as the mono-ethyl ester of malonic acid [α-nicotinoyl-benzyl ester (oil), the hydrobromide of α-bromobenzyl (3-pyridyl) ketone and the monoethyl ester of malonic acid.

Example 10

A mixture of 6.5 g of dimethyl malonic acid monoethyl ester [α-nicotinoylbenzyl] ester, 4.8 g of ammonium acetate and 50 ml of glacial acetic acid was stirred at 140 ° C for 2 hours. The reaction mixture was cooled, poured into ice water (400 mL) and adjusted to pH 8.0 with concentrated aqueous ammonium hydroxide. It is then extracted three times with 100 ml of ethyl acetate each time and the ethyl acetate extracts are washed twice with 30 ml of saturated sodium chloride solution each time. The combined organic layers were dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was chromatographed on 300 g of silica gel. Fraction 1, eluted with 300 ml of chloroform, is discarded. 2-4. fractions eluted with 300-300 ml of chloroform and evaporated to dryness under reduced pressure. The residue was triturated with petroleum ether. The activated crystals are filtered off and rinsed with cold petroleum ether. The received

- [4 - phenyl - 5 - (3 - pyridyl - oxazol - 2 - II] - 2 - methylpropanoic acid, ethyl ester, 70 to 71 ^o C, mp.

5-10. fraction 300-100 ml of chloroform was discarded. 11-15. fractions eluted with 300-300 ml of chloroform are combined and concentrated under reduced pressure. The resulting 2- [4- (3-pyridyl) -5-phenyloxazol-2-yl] -2-methylpropanoic acid ethyl ester crystallizes on trituration with cold petroleum ether. Melting point — 42 ° C.

Prepared analogously to a

- [4-Phenyl-5- (3-pyridyl) -oxazol-2-yl] -propionic acid ethyl ester and 2- [4- (3-pyridyl) -5-phenyl-oxazol-2-yl] -propionic acid dip the ethyl ester (oil)! - malonic acid - mono-ethyl ester -] starting from - benzyl ester of nicotinoyl,

- [4-Phenyl-5- (3-pyridyl) -oxazol-2-yl] -acetic acid ethyl ester (oil) and 2- [4- (3-pyridyl) -5-phenyl-oxazol-2-yl] ethyl acetate, starting from the mono-ethyl ester of malonic acid, [a-nicotinoyl-benzyl ester, and

- [4-phenyl] -5- (3-pyridyl) oxazol-2-yl] -2-methylpropionic acid tert-butyl ester,

NMR (CDCl ₃ ): 8.85 (s, br, H-2 '), 8.56 (d, br, H-6');

7.87 (dt, HM '); 7.64 (m, H-2.6); 7.35-7.45 (other aromatic H); 7.18 (dd, H-5 '); 1.75 (s, bo. CH ₃ ) and a

2- (4- (3-pyridyl) -5-phenyl-oxazol-2-yl) -2-methylpropionic acid tert-butyl ester,

NMR (CDCl ₃ ): 8.90 (s, br, H-2 '); 8.57 (d, br, H-6 '); 8.00 (dt, H-4 '); 7.55 (m, H-2.6); 7.35-7.45 (m, other aromatic H); 7.32 (dd, H-5 '); 1.73 (s, bo. CH ₃ ).

dimethyl malonic acid mono - ter - butyl ester (starting from the nicoyl benzyl ester.

Example 11

In a manner analogous to that described in Example 4, ethyl 2- (4- (1-oxido-3-pyridyl) -5-phenyloxazol-2-yl) -2-methylpropionic acid was prepared.

Starting from [4- (3-pyridyl) -5-phenyl-oxazol-2-yl] -2-methylpropanoic acid ethyl ester, m.p. 85-90 (ether petroleum ether).

2- (4- (1-oxido-3-pyridyl) -5-phenyl-oxazole-2-yl] -propionic acid ethyl ester,

Starting from 2- (4- (3-pyridyl) -5-phenyl-oxazol-2-yl) -propionic acid ester, the

2- (4- (1-Oxido-3-pyridyl) -5-phenyl-oxazol-2-yl) -acetic acid ethyl ester [4- (3-pyridyl) -5-phenyl-oxazole-2-yl] yl] -acetic acid ethyl ester, starting from [4-phenyl-5- (1-oxido-3-pyridyl) oxazol-2-yl] -2-methylpropionic acid terbutyl ester .

NMR (CDCl ₃ ): 8.39 (t, H-2 '); 8.03 (dt, H-6 '); 7.10 (dd, 4-5 '); 7.2-7.6 (m, other aromatic H); 1.65 (s, gem. CH ₃ ) [4-phenyl-5- (3-pyridyl) oxazol-2-yl] -2-methylpropionic acid tert-butyl ester and

2- (4- (1-Oxido-3-pyridyl) -oxazol-2-yl] -2-methyl-propionic acid tert-butyl ester, [4- (3-pyridyl) -5-phenyl-oxazol-2-yl] ] -2-Methylpropyl Starting from Dn-acid tert-butyl ester.

Example 12

A solution of 6.2 g of α-aminobenzyl- (3-pyridyl) ketone in 100 ml of anhydrous tetrofuran was stirred with 8.8 g of dinethyl rnalonic acid inonoethyl ether and 7.2 ml of N, N-. diisopropylethyl amine

188,308 are added. The reaction mixture was stirred for 15 hours and evaporated to dryness under reduced pressure. The residue is chromatographed on 500 g of silica gel. 1-6. fraction 400-400 ml of chloroform was discarded. 7-10. fractions eluted with 400-400 ml chloroform were combined and evaporated to dryness under reduced pressure. The resulting N- [α- (3-pyridyl) -phenacyl] -dimethyl-mononic acid monoethyl ester monoamide oil is obtained.

Prepared analogously to

Starting with N - [o - (3-pyridyl) -phenacyl] -methyl-malonic acid triionoethyl ester monoamide (oil), α-aminobenzyl (3-pyridyl) ketone and methyl malonic acid monoethyl ester chloride , and that

N - [? - (3-pyridyl) phenacyl] malonic acid monoethyl ester monoamide, starting from? -Aminobenzyl (3-pyridyl) ketone and malonic acid monoethyl ester chloride.

Example 13

A solution of 2.1 g of N- [α- (3-pyridyl) phenacyl] dimethylmalonic acid monoethyl ester monoamide in 40 ml of phosphorus oxychloride was heated under reflux for 4 hours. The reaction mixture was then cooled and poured onto ice. The precipitated oil was extracted with ethyl acetate (100 mL). The ethyl acetate solution was extracted twice with water (20 ml), twice with sodium carbonate solution (20 ml each), and finally with water (20 ml), dried over magnesium sulfate and concentrated under reduced pressure. The residue was chromatographed on 70 g of silica gel. 1-5. fraction (80-80 ml chloroform) was discarded. 6-8. fractions eluted with 80-80 ml of chloroform are combined and evaporated to dryness under reduced pressure. The residue was triturated with petroleum ether to give the ethyl 2- [4-phenyl-5- (3-pyridyl) -oxazol-2-yl] -2-methylpropionic acid as a crystalline solid. Melting point: 70-71 ° C.

Prepared analogously to a

- [4-phenyl-5- (3-pyridyl) oxazol-2-yl] propionic acid ethyl ester,

N · [a - (3-pyridyl) -phenacyl] -methyl-malonic acid - monoethyl ester monoamide and starting from

- [4-Phenyl-5- (3-pyridyl) oxazol-2-yl] acetic acid ethyl ester, m.p. 70-71 ° C.

N- [a - (3-pyridyl) -phenacyl] -malonic acid, mono-ethyl ester, mono-amide.

The α-aminobenzyl (3-pyridyl) ketone can be prepared as follows.

A solution of 10.8 g of benzyl (3-pyridyl) -ptone in 40 ml of pyridine and 8 g of hydroxylamine hydrochloride in 15 ml of pyridine is stirred at 100 ° C for 6 hours. The reaction mixture was poured into a mixture of ice and water and stirred for 15 minutes. The precipitated crystals are filtered off with suction, washed with water and dried under high vacuum. The resulting benzyl (3-pyridyl) ketonoxime m.p. 122-126 ° C.

To a solution of 8.5 g of benzyl (3-pyridyl) ketone oxime in 20 ml of pyridine and stirred at -10 ° C is added dropwise a solution of 7.7 g of p-toluenesulfochloride in 15 ml of pyridine over 5 minutes. The reaction mixture was stored in a refrigerator for 24 hours and then poured into a mixture of ice and water. After a few agitations and rubbing, the precipitated oil solidifies into crystals, sucked off, washed with water and dried under high vacuum. The resulting benzenesulfonyl (3-pyridyl) ketone oxime-p-toluenesulfonic acid ester can be used in the following reactions without further purification.

11.6 g of crude benzyl (3-pyridyl) ketone-oxime-p-toluenesulfonic acid ester are suspended in 90 ml of absolute ethanol. A solution of potassium tert-butylate (3.7 g) in dry ethanol (30 ml) was added dropwise with stirring at 0 ° C. The reaction mixture was stirred for 2 hours at 0 ° C. The suspension is filtered off with suction and the filtrate containing the desired α-aminobenzyl (3-pyridyl) ketone is evaporated to dryness under reduced pressure.

Example 14

A 5% ointment containing 2- [4-phenyl-5- (1-oxido-3-pyridyl) oxazol-2-yl] -2-methylpropionic acid can be prepared as follows:

Composition:

active ingredient 5.0% petroleum jelly 45.0% paraffin oil 19.6% cetyl alcohol 5.0% beeswax 5.0% sorbital scvioleate 5.0% p-hydroxybenzoic acid ester 0.2% water (aqua demineralisata) ad 100.0%

Fats and emulsifiers are melted together. The preservative is dissolved in water and the solution is emulsified in the fat melt at a higher temperature. After cooling, a suspension of the active ingredient is incorporated into the emulsion in a portion of the fat melt.

Example 75 A cream containing% 2- [4-phenyl-5- (3-pyridyl) -oxazol-2-yl] -2-methyl-propionic acid can be prepared as follows:

Composition:

active ingredient 10.0% isopropyl palmitate 8.0% cetyl palmitate 1.5% silicone oil 100 0.5% sorbitan monostearate 3.0% polysorbate 60 3.5%

1,2-Propylene Glycol PH 20.0% Acrylic Acid Polymerate 0.5% Triethanolamine 0.7% Water (Aqua Demineralisata) Add 100.0%

The acrylic acid polymerizate is suspended in a mixture of demineralized water and 1,2-propylene glycol. Triethanolamine is then added with stirring to form mucus. A mixture of isopropyl palmitate, cetyl palmitate, silicone oil, sorbitan monostearate, and polysorbate is heated to about 75 ° C and incorporated into the mucus, also heated to about 75 ° C, with stirring. The room temperature-cooled cream stock is used to make the concen trated drug substance 10188 308 needles. The concentrate is homogenized in an apparatus and then added in portions to the starting material.

Example 16

A cream containing 5% 2- [4-phenyl-5- (1-oxido-3-pyridyl) oxazol-2-yl] -2-methylpropionic acid is prepared as follows: Formulation:

active ingredient 5.0% cetyl palmitatePH 2.0% cetyl alcohol PH 2.0% triglyceride mixture of saturated fatty acids 5.0% stearic acid 3.0% glycerol stearate PH 4.0%

Cetomacrogol 1000 1.0% Microcrystalline Cellulose 0.5%

1,2-propylene glycol, dist. 20.0% water (aqua demineralisata) gives 100.0%

Cetyl alcohol, cetyl palmitate, triglyceride mixture, stearic acid and glycerol stearate are fused. The microcrystalline cellulose is dispersed in a portion of the water. The remainder of the water is dissolved in Cetomacrogol and mixed with propylene glycol and mucus. The fat phase is added with stirring to the aqueous phase and stirred cold. Thereafter, the active ingredient is rubbed with a portion of the base and then applied to the rest of the cream.

Example 17

A clear hydrogel containing 5% of 2- [4-phenyl-5- (1-oxido-pyridyl) -oxazol-2-yl] -2-methyl-propionic acid ethyl ester was prepared as follows:

Composition:

active ingredient 5% propylene glycol 10-20% isopropanol 20% hydroxypropylmethylcellulose 2% water 100%

The hydroxypropylmethyl cellulose is swelled in water. The active ingredient is dissolved in a mixture of isopropanol and propylene glycol. A solution of the active ingredient is then mixed with the swollen cellulose derivative and, if desired, perfume is added in an amount of 0.1%.

Example 18 A translucent hydrogel containing% 2- [4-phenyl-5- (1-oxido-pyridyl) -oxazol-2-yl] -2-methyl-propionic acid was prepared as follows:

Composition:

active ingredient 5% propylene glycol 20% isopropanol 20% acrylic acid polymer 2% triethanolamine 3% water 100%

The acrylic acid polymer and water were dispersed and neutralized with triethylamine. The active ingredient is dissolved in a mixture of isopropanol and propylene glycol. Thereafter, the solution containing the active ingredient is mixed with the gel and, if desired, perfume is added in an amount of 0.1%.

Example 19

7 ₀ 2- [4-phenyl-5- (l-oxido-3-pyridyl) oxazol-2-yl] -2-containing foam spray-methylpropionic claims ATO prepared as follows:

total item:

active ingredient 1.00% cetyl alcohol PH 1.70% paraffin oil, dense 1.00% isopropyl myristate 2.00%

Cetomacrogol 1000 2.40% Sorbitan Monostearate 1.50%

1,2-Fropylene glycol PH 5.00% methyl'-paraben 0.18% prop 1-paraben 0.02%

Chemoderm 314 0.10% water (tqua demineralisata) gives 100.00%

Cetyl alcohol, paraffin oil, isopropyl myristate, Cetomacrogol and sorbitan stearate are fused. Methyl and propyl paraben are dissolved in hot water. The melt and solution are then mixed. Incorporate the active ingredient into the base when suspended in propylene glycol. Chemoderm is then added and water is added to the final weight.

Download

An amount of 20 ml of the mixture is filled into an aluminum bottle. The bottle is fitted with a valve and the propellant is filled under pressure.

Example 20

A mixture of 4.0 g of hydroxyphenyl [(3-pyridyl) methyl] ketone and 0.6 ml of triethylamine in 70 ml of anhydrous benzene was stirred at 10 ° C for 20 minutes under a nitrogen atmosphere. A solution of 2-ethoxymethyl-2-methylethylpropionic acid chloride (20 g) in anhydrous benzene (20 ml) was added. The reaction mixture was stirred at room temperature for 3 hours, mixed with ethyl acetate (30 ml) and water (60 ml) and stirred at room temperature for 1 hour. The aqueous layer was separated and washed with ethyl acetate (2 x 20 mL). The combined organic phases are washed with 20 ml of saturated sodium chloride solution, 20 ml of 2N potassium bicarbonate solution and again with 20 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue was 2-ethoxymethyl-2-methyl-propionic acid [a-benzyl]

-11188 308 Oil (3-pyridylmethyl)] ester (oil) was dissolved in glacial acetic acid (40 mL), ammonium acetate (4.1 g) was added and the reaction mixture was heated at 140 ° C for 2 hours with stirring. The reaction mixture was cooled, poured into 150 ml of ice water and adjusted to pH 8.0 with concentrated aqueous ammonium hydroxide. It was then extracted with ethyl acetate (3 x 100 mL) and the ethyl acetate extracts were washed with water (20-20 mL). The combined organic layers were dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is chromatographed on 150 g of silica gel. 1-5. fraction (150-150 ml) was discarded. 6-9. fraction (150-150 ml) was combined and evaporated to dryness under reduced pressure. The residue was 2- [4-phenyl-5- (3-pyridyl) oxazol-2-yl] -2-methyl-1-ethoxy] propane as an oil.

Example 21

A solution of 2.0 g of 2- [4-phenyl-5- (3-pyridyl) -oxazol-2-yl] -2-methyl-letoxy-propane in 40 ml of acetone and 12 ml of water at room temperature with vigorous stirring in portions mix with potassium permanganate until no discoloration is observed.

The reaction mixture was stirred at room temperature for 10 hours and then filtered. The filtrate was evaporated to dryness at 1470 Pa at 50 ° C. The residue was mixed with ice water (15 ml) and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue is chromatographed on 70 g of silica gel. 1-3. fraction (50-50 ml) was discarded. 4-8. fractions eluted with 50-50 ml of chloroform are combined and evaporated to dryness under reduced pressure. The residue was triturated with cold petroleum ether, allowed to stand overnight, and the precipitated crystals were filtered off. The resulting 2- [4- (phenyl) -5- (3-pyridyl) oxazole-2-yl] -2-methyl propionic acid ethyl ester is melted at 70-71 ° C.

Example 22

1.0 g of 2- [4-phenyl-5- (3-pyridyl) -oxazol-2-yl] -2-methylpropionic acid, 0.6 g of triethylene glycol monomethyl ether and 40 mg of 4-dimethylaminopyridine. of methylene chloride (0.7 g) was stirred at room temperature with vigorous stirring and 0.7 g of dicyclohexylcarbodiimide under nitrogen. After stirring at room temperature for 48 hours, toluene (40 mL) was added and filtered. The filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in methylene chloride (20 mL). The methylene chloride solution was washed with 5 ml of 0.1N sodium carbonate solution and 5 ml of water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. 2- [4-phenyl-5- (3-pyridyl) -oxazol-2-yl] -2-methyl-propionic acid -2- (2- (2-methoxy-ethoxy) -ethoxy) -ethyl ester is obtained as an oil, m.p.

NMR (CDCl ₃ ): 8.85 (s, br, H-2 '); 8.56 (d, br, H-h ');

7.87 (dt, HA '), 7.64 (m, H-2, 6j; 7.35-7.45 (other aromatic H); 7.18 (dd, H-5'), 1.75 (s, heron. CH ₃ ).

Prepared analogously to a

- [4-Phenyl-5- (1-oxido-3-pyridyl) oxazol-2-yl] -2-methylpropionic acid -2- (2- (2-methoxyethoxy) ethoxy] ethyl ester (oil) )

NMR (CDCl ₃ ); 8.39 (t, H-2 '); 8.03 (dt, H-6 '); 7.10 (dd, H-5 '); 7.2-7.6 (m, other aromatic H); 1.65 (s, heron. CH ₃ ) and a

- [4-Phenyl-5- (1-oxido-3-pyridyl) oxazol-2-yl] -2-methylpropionic acid 2- (2- (2-hydroxyethoxy) ethoxy] ethyl ester (oil) )

NMR (CDCl ₃ ): 8.39 (t, H-2 '); 8.03 (dt, H-6 '); 7.10 (dd, H-5 '); 7.2-7.6 (m, other aromatic H); 1.65 (s, heron CH ₃ ),

- starting from [4-phenyl-5-1-oxido (3-pyridyl) oxazol-2-yl] -2-methylpropionic acid and triethylene glycol monomethyl ether and triethylene glycol;

- [4-Phenyl-5- (3-pyridyl) oxazol-2-yl] -2-methylpropionic acid 2- [2- (2-hydroxyethoxy} ethoxy] ethyl ester (oil),

NMR (CDCl ₃ ): 8.85 (s, br, H-2 '); 8.56 (d, br, 6 H ^5);

7.87 (dt, H-4 '); 7.64 (m, H-2.6); 7.35-7.45 (other aromatic H); 7.18 (dd, H-5 '); 1.75 (s, cm -1 CH ₃ ),

Starting from (4-phenyl-5- (3-pyridyl) oxazol-2-yl) -2-methylpropionic acid and triethylene glycol.

Example 23

A solution of 1.43 g of diethylene glycol monochlorohydrin in 6 ml of hexamethylphosphoric triamide at 50-60 [deg.] C. with stirring at 3.46 g of 2- (4-phen; 1-5 <3'-oxidopyridyl) oxazol-2-yl]. Mix with 2-methylpropionic acid sodium salt. The reaction mixture was stirred for 4 hours at 100 ° C, cooled and poured into 50 ml of ice water. The precipitated oil was extracted with 100 ml of ether. The ether layer was washed with water (20 mL), 2N potassium bicarbonate solution (20 mL), water (20 mL), dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed on 100 g of silica gel. 1-3. fraction (80-80 ml) was discarded. 4-6. fractions eluted with 80-80 ml of chloroform are combined and evaporated to dryness under reduced pressure. The residue is obtained in the form of an oil, 2- (4-phenyl-5- (1-oxido-3-pyridyl) -oxazol-2-yl) -2-methyl-propionic acid 2- (2-hydroxy-ethoxy) -ethyl ester.

NMR (CDCl 3): 839 (t, H-2 '); 8.03 (dt, H-6 '); 7.10 (dd, H-5 '); 7.2-7.6 (m, other aromatic H); 1.65 (s, gcm. CH ₃ ).

Prepared analogously to a

- [4-phenyl-5- (3-pyridyl) oxazol-2-yl] -2-methylpropionic acid 2- (2-hydroxyethoxy) ethyl ester (oil),

NMR (CDCl 3): 8.85 (s, br, H-2 '); 8.56 (d, br, H-6 ');

7.87 (dt, HA '); 7.64 (m, H-2.6); 7.35-7.45 (m, other aromatic H); 7.18 (dd, H-5 '); 1.75 (s, gcm. Cl ₁₃ ),

Starting from the sodium salt of [4-phenyl-5- (3-pyridyl) oxazol-2-yl] -2-methylpropionic acid and diethylene glycol inonochlorochlorohydrin.

The yield is, in all examples, approx. 40% and approx. 90% and can be further improved.

Claims (13)

Claims A process for the preparation of a trisubstituted oxazole derivative of formula (I): wherein: R ₂ or R one of the substituents is phenyl and the other represents pyridyl or 1-oxidopiridil moiety, A. is C 1-4 alkylene or C 2-5 alkylidene and R ₃ is carboxy, C 2 -C 5 alkoxycarbonyl, hydroxy (C 1 -C 4) alkoxy (C 1 -C 4) alkoxycarbonyl, hydroxy (C 1 -C 4) alkoxy (1) -C 4 -C 4 alkoxy-C 1 -C 4 -alkoxycarbonyl or C 1 -C 4 -alkoxy (C 1 -C 4) -alkoxy (C 1 -C 4) -alkoxy (C 1 -C 4) alkoxycarbonyl group, characterized in that: a) a compound of formula II, a tautomer and / or a salt thereof, in the formula _{One of the} substituents X ₁ and X _{2 represents} an optionally substituted imino group and the other represents oxy (if X ₁ ) or oxo (if X ₂ ) or optionally substituted imino, optionally when heated in the presence of an acid or an anhydride, or Xi is oxy and X ₂ is oxo - in this case a compound of formula II and / or a salt thereof is cyclized in the presence of an acid or anhydride, if necessary with heating, by condensation with ammonia or an ammonia-releasing agent, with a partial enol or enamine or ketimine to form and vice present, with the proviso that when X) is oxygen, X ₂ is oxo, R j, R ₂ and A are as defined, R ₃ is carboxy, alkoxycarbonyl of 2-5 carbon atoms as defined above and or b) reducing a compound of formula (III) wherein R 1, R ₂ , R ₃ and A are as defined above, or a salt thereof, with the aid of a reducing agent, preferably under cooling or heating, or c) for the preparation of compounds of formula I wherein R 1, R ₂ and A are as defined above and R _{3 represents a} carboxy group or a C 2 -C 5 alkoxycarbonyl group, a compound of formula IV: wherein R 1, R 2 ₂ and A are as defined above, R ₃ is, on the one hand, a hydroxymethyl group, an esterified hydroxymethyl group, a formyl or acetalized formyl group, or on the other hand a C 2 -C 5 alkoxymethyl group, or a salt thereof using a suitable oxidizing agent. is oxidized to compounds of the general formula wherein R _{3 is,} on the one hand, carboxy or, on the other hand, C 2 -C 5 alkoxycarbonyl, or d) for the preparation of compounds of the formula I in which R _1; R ₂ and A are as defined above and R ₃ is a carboxy group which is a compound of formula (I) wherein R 1, R ₂ , A are as defined above and R ₃ is C 2 -C 5 alkoxycarbonyl, hydroxy (I). (C4-C4) -alkoxy (C1-C4) -alkoxycarbonyl, hydroxy (C1-C4) -alkoxy (C1-C4) -alkoxy-C1-C4) -alkoxycarbonyl- or a 1-4 carbon atom alkoxy (C 1-4) alkoxy (C 1-4) alkoxy (C 1-4) alkoxycarbonyl group, or e) for the preparation of compounds of formula I. wherein R 1, R ₂ , A are as defined above and R ₃ is C 2 -C 5 alkoxycarbonyl, hydroxy (C 1 -C 4) alkoxy (C 1 -C 4) alkoxycarbonyl, hydroxy (C 1 -C 4) -alkoxy (C 1 -C 4) -alkoxy (C 1 -C 4) -alkoxycarbonyl or C 1 -C 4 -alkoxy (C 1 -C 4) -alkoxy (1-) A (C 4) -alkoxy (C 1 -C 4) -alkoxycarbonyl group, esterifying a compound of formula (I) wherein R 1, R ₂ , A are as defined above and R ₃ is carboxy, or a salt thereof, or fj for the preparation of compounds (I) of formula wherein one of R and R ₂ substituents, a phenyl group and another 1-oxido-pyridyl signal strength, is as defined above and R ₃ is hydroxy (C, -C4) alkoxy - (C 1-4) alkoxycarbonyl, hydroxy (C 1-4) alkoxy (C 1-4) alkoxy (C 1-4) alkoxycarbonyl a powder or a C1-C4 alkoxy (C1-C4) alkoxy (C1-C4) alkoxy (C1-C4) alkoxycarbonyl group, a compound of formula (I) wherein R @ 1 is hydrogen; and one of the substituents R ₂ is pyridyl, R ₃ is as defined in this process, and A is as defined above - or a salt thereof is N-oxidized with an oxidizing agent. Process (a) according to claim 1, characterized in that the excess ammonia is added in the form of an ammonia-releasing agent, such as an ammonium salt of a lower alkane carboxylic acid or a suitable lower alkane carboxylic acid amide, especially formamide. Process b) according to claim 1, characterized in that the reducing agent is hydrogen, in the presence of a hydrogenation catalyst or a noble metal and potonic acid system. A), b), c), e) according to claim 1 or 2 or 3. A method according to any one of claims of Formula (I) compounds, which digs one of the substituents R, and R ₂ is phenyl wherein the other represents pyridyl or 1-oxido-pyridyl, A is a C2-4 alkylidene group and R ₃ is an alkoxycarbonyl group having from 2 to 5 carbon atoms, characterized in that the appropriately substituted starting materials are used. A), b), c), e) according to claim 1 or 2 or A process for preparing 2- [4-phenyl-5- (3-pyridyl) -oxazol-2-yl] -acetic acid ethyl ester according to any one of claims 3 to 5, characterized in that it is an appropriately substituted starting material; g. A process according to claim 1, a), b), c), e), f) or any of claims 2 or 3, 2- [4-phenyl-5- (1-oxido-3-pyridyl) - oxazol-2-yl] -2-methyl-propionsav13 -131 188,308 ethyl ester, characterized in that appropriately substituted starting materials are used. The process according to claim 1 a), b), e) or any of claims 2 or 3 2-F4-phenyl-5- (3-pyridyl) oxazol-2-yl] -2-methylpropionic acid - 2- [2- (2-methoxyethoxy) ethoxy] ethyl ester, characterized in that appropriately substituted starting materials are used. A), b), e), f) according to claim 1 or 2 or The process according to any one of claims 3 to 2, 2- [4-phenyl-5- (1-oxido-3-pyridyl) oxazol-2-yl] -2-methylpropionic acid 2- [2- (2-methoxyethoxy) - in the preparation of ethoxy] ethyl ester, characterized in that appropriately substituted starting materials are used. The process according to claim 1, a), b), e) or any of claims 2 or 3, 2- [4-phenyl-5- (3-pyridyl) oxazol-2-yl] -2-methyl - Propionic acid -2- (2-hydroxyethoxy) ethyl ester, characterized in that the starting materials are suitably substituted. The a), b), e), f) or claim 2 of claim 1. A process for the preparation of 2- [4-phenyl-5- (1-oxido-3-pyridyl) -oxazol-2-yl] -2-methyl-propionic acid 2- (2-hydroxy-ethoxy) -ethyl ester according to any one of claims 1 to 3, characterized in that appropriately substituted starting materials are used. A), b), e) according to claim 1 or 2 or A process according to any one of claims 3 to 2- (4-phenyl-5- (3-pyridyl) -oxazol-2-yl) -2-methyl-propionic acid 2- [2- (2-hydroxy-ethoxy) -ethoxy] -ethyl- The ester is characterized in that it uses appropriately substituted starting materials. 0 12. The method according to claim 1, which is a), b), e), f) or 2. A process according to any one of claims 1 to 3 or 2- [4-phenyl-5- (1-oxido-3-pyridyl) oxazol-2-yl] -2-methylpropionic acid 2- [2- (2-hydroxyethoxy) ethoxy] ] ethyl ester, characterized in that it is suitably substituted Starting materials are used. 13. A process for the preparation of a pharmaceutical composition comprising the steps of 1 to 12. At least one compound according to any one of claims 1 to ₃ , wherein R 1, R ₂ , A and R ₃ are as defined in claim 1. as defined in Claim 0, optionally using conventional excipients and carriers, creams, ointments, pastes, foams, tinctures, solutions, or other forms of formulation.