NO833350L - TRISUBSTITUTED OCSAZA COMPOUNDS - Google Patents

Description

The invention relates to new trisubstituted oxaza compounds, in particular compounds of the general formula

in which one of the radicals R-^ and R2 means heteroaryl and the other carbocyclic aryl or heteroaryl and A means a divalent hydrocarbon residue and R- means carboxy, esterified or amidated carboxy, as well as their isomers and their salts, as well as methods for their preparation, pharmaceutical preparations containing such compounds as well as the use of the compounds of formula I, their isomers and their salts as active substances in medicines and/or for the production of pharmaceutical preparations.

Carbocyclic aryl is, for example, monocyclic carbocyclic aryl as optionally substituted phenyl.

Heteroaryl is, for example, monocyclic, preferably 5- or 6-membered heteroaryl, with at least one ring member being a heteroatom such as a nitrogen, oxygen or sulfur atom, with a nitrogen atom optionally also present in oxidized form. Such 5-membered residues are e.g. pyrrolyl as 2-pyrrolyl.

As a 6-membered heteroaryl, there is e.g. namely pyridyl as 2-, 3- or 4-pyridiyl, 1-oxidopyridyl as 1-oxido-3-pyridyl or 1-oxido-4-pyridyl and pyrimidyl as 2^pyrimidyl.

As substituents of carbocyclic aryl such as phenyl or heteroaryl such as pyridyl or 1-oxido-pyridyl, for example halogen, lower alkyl, hydroxy, lower alkoxy and/or aceloxy come into consideration. Acyloxy is, for example, derived from an organic carboxylic acid and means e.g. lower alkanoyloxy.

A hydrocarbon residue A is, for example, a divalent aliphatic, cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon residue.

As divalent, aliphatic hydrocarbon residues, there are e.g. in terms of lower alkylene, lower alkylidene, lower alkenylene or lower alkenylidene. Divalent cycloaliphatic hydrocarbons are, for example, monocyclic 3- to 8-membered cycloalkylenes or cycloalkylidenes. Cycloaliphatic-aliphatic hydrocarbon residues are, for example, those which have as cycloaliphatic residue a monocyclic 3- to 8-membered cycloaliphatic residue and as aliphatic residue lower alkylidene such as cycloalkyl-lower alkylidene.

Esterified carboxy is, for example, carboxy esterified with

an optionally substituted aliphatic, cycloaliphatic or aromatic alcohol. An aliphatic alcohol is, for example, a lower alkanol such as methanol, ethanol, propanol, isopropanol, n-butanol, sec- or tert-butanol, while a cycloaliphatic alcohol is, for example, a 3- to 8-membered cycloalkanol, such as cyclopentanol, -hexanol or -heptanol. Substituents of such lower alkanols and cycloalkanols include, for example, hydroxy, mercapto, optionally substituted phenyl, lower alkoxy, optionally substituted in the phenyl part phenyl lower real oxy, lower alkylthio, optionally substituted in the phenyl part phenyl lower alkyl thio, hydroxyl lower real oxy, lower alkyl lower real oxy, optionally substituted in the phenyl part phenyl lower real oxyla lower real oxy, hydroxy- hydroxylavereal oxylavereal oxy, lower-alkdxyl lavereal oxy-lavereal oxy, optionally in the phenyl part substituted phenyl lowerareal oxylavereal oxylavereal oxy, .carboxylavereal oxy, lower alkoxycarbonyl-lowerareal oxy, optionally substituted phenyl-containing lower alkoxycarbonyl-lowerareal oxy or lower alkanoyloxy. An aromatic alcohol is, for example, a phenol or heterocyclic alcohol which can each optionally be substituted with lower alkyl, lower alkoxy, halogen and/or trifluoromethyl, especially hydroxypyridine, e.g. 2-, 3- or 4-hydroxypyridine.

Amidated carboxy is, for example, carbamoyl, monosubstituted

with hydroxy, amino or optionally substituted phenyl, with lower alkyl mono- or disubstituted or with 4- to 7-membered alkylene resp. 3-aza-, 3-lower alkylaza-, 3-oxo-

or 3-thiaalkylene disubstituted carbamoyl. Examples include carbamoyl, N-mono- or N,N-dilaverealkyl-carbamoyl such as N-methyl-, N-ethyl-, N,N-dimethyl-, N,N-diethyl- or N,N-dipropylcarbamoyl, pyrrolidino- or piperidino-carbonyl, morpholino-, piperazino- or 4-methylpiperazino and thiomorpholinocarbonyl, anilinocarbonyl or with lower alkyl, lower alkoxy and/or halogen substituted anilinocarbonyl.

Above and below there are "lower" organic residues

and compounds preferably to be understood as containing up to and including 7, above all up to and including 4 carbon atoms (C atoms).

The above and below mentioned general definitions have

within the framework of the invention primarily the following meanings: Halogen is e.g. halogen up to and including atomic no. 35 as fluorine, chlorine or bromine, further iodine.

Lower alkyl is e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, further a pentyl, hexyl or heptyl residue.

Low-area coke is e.g. methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, isobutyloxy, sec-butyloxy or tert-butyloxy.

Lower alkylthio is - e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butylthio.

Phenylaveral oxy is e.g. phenylmethoxy, phenylethoxy or phenylpropyloxy.

Phenyl lower alkylthio is e.g. benzyl, phenylethyl or phenylpropylthio.

Hydroxylavereal oxy is e.g. hydroxyethoxy, hydroxypropyloxy or 1,2-dihydroxypropyloxy.

Low-real oxylave-real oxy is e.g. methoxyethoxy, ethoxy-ethoxy, methoxypropyloxy or methoxybutyloxy.

Phenyllavereal oxylavereal oxy is e.g. 2-benzyloxyethoxy or 2-(2-phenylethoxy)ethoxy.

Lower alkanoyloxy is e.g. acetyl-, propionyl-, butyryl-, iso-, sec- or tert-butyryloxy.

The lower alkylene is e.g. straight like methylene, ethylene, 1,3-propylene or 1,4-butylene or branched like 1,2-propylene, 1,2- or 1,3-(2-methyl)-propylene or 1,2-butylene.

The lower alkylidene has a tertiary or especially a quaternary C atom and is e.g. ethylidene or 1,1- or 2,2-propylidene, further 1,1- or 2,2-butylidene or 1,1-, 2,2- or 3,3-pentylidene.

The lower alkenyl is e.g. ethenylene, 1,2- or 1,3-propenylene or 1,2-, 1,3- or 1,4-buten-2-ylene.

The lower alkenylide is e.g. ethenylidene, 1,1-propen-1-ylidene, 1,1-propen-2-ylidene, further a butenylidene such as 1,1-buten-3-ylidene.

The cycloalkylene is e.g. cyclopropylene, 1,2- or 1,3-cyclobutylene, 1,2-, 1,3- or 1,4-cyclopentylene, further et'~~cyclohexylene.

The cycloalkylidene is e.g. cyclopropylidene, cyclobutylidene, cyclopentylidene or cyclohexylidene.

The cycloalkyl-lower alkylidene is e.g. a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl methylene, ethylene or propylene, further a cyclohexylbutylidene. Carboxylavereal oxy is e.g. carboxymethoxy, 2-carboxyethoxy, 2-, 3-carboxypropyloxy, 1-carboxy-2-propyloxy,

2-, 3- or 4-carboxy-n-butyloxy, 1-carboxy-2-methyl-propyl-3-oxy or 1-carboxy-2-methyl-propyl-2-oxy.

Lower oxycarbonyl-lower oxy contains each time in the lower alkoxy part independently of each other the meanings listed above under lower alkoxy.

Salts of the compounds according to the invention with formula I are preferably pharmaceutically usable salts such as pharmaceutically usable acid addition salts and/or when R 1 means carboxy, internal salts or salts with bases. Suitable acid addition salts are, for example, salts with inorganic acids such as mineral acid, with sulfamic acids, such as cyclohexylsulfamic acid, with organic carboxylic acids such as lower alkane carboxylic acids, possibly unsaturated dicarboxylic acids, with hydroxy and/or oxo substituted carboxylic acids or with sulfonic acids, for example sulfates or hydrohalides such as hydrobromides or hydrochlorides, oxalates, malonates, fumarates or maleates, tartrates, pyruvates or citrates, sulphonates such as methane, benzene or p-toluene sulphonates.

Suitable salts with bases are, for example, alkali or alkaline earth metal salts, e.g. sodium, potassium or magnesium salts, pharmaceutically usable transition metal salts such as zinc or copper salts, or salts with ammonia or of substituted organic amines, such as cyclic amines, e.g. morpholine, thiomorpholine, piperidine, pyrrolidine, as mono-, di- or resp. trilower alkylamines or mono-, di-^resp. trihydroxy lower alkylamines, e.g. mono- di- resp. triethanolamine. Monol-averealkylamines are, for example, ethyl or tert-butylamine. Dilave alkylamines are e.g. diethyl or diisopropylamine, and as tri-lower alkylamine, e.g. triethylamine.

The new compounds of formula I and their pharmaceutically usable salts have valuable pharmacological properties. In particular, they have e.g. with local application a pronounced anti-inflammatory effect.

This property can be demonstrated, for example, according to the method developed by G. Tonelli, L. Thibault, "Endocrinology", 77, 625 (1965) by inhibiting croton oil-induced rat ear edema in normal rats in a dose range from approx. 1 to approx. 100 mg/ml. Thus, for example, for the compound 2-[4-phenyl-5-(3-pyridyl)-imidazol-2-y1]-acetic acid ethyl ester in the above-mentioned sample, an ED^Q value of 17 mg/ml was determined.

The compounds according to the invention with formula I are therefore suitable as drugs, especially external (topical) skin phlogistics for the treatment of inflamed dermatoses of any genesis, such as in light skin irritations, contact dermatitis, exanthems, burns and as mucosal skin phlogistics for the treatment of mucosal inflammations, e.g. in the eye, nose, lips, genital, anal region. Furthermore, the compounds can be used as a sun protection agent.

The invention concerns e.g. compounds of formula I, in which one of the radicals R 1 and R 2 means a 5- or 6-membered,

as heteroatom or atoms nitrogenous heteroaryl which may be unsubstituted or substituted with halogen, lower alkyl, hydroxy, lower alkoxy and/or lower alkanoyloxy and the other means unsubstituted or with halogen, lower alkyl, hydroxy, lower alkoxy and/or lower alkanoyl substituted phenyl, or a 5- or the 6-member as a heteroatom or atoms nitrogenous heteroaryl residue which may be unsubstituted or substituted with halogen, lower alkyl", hydroxy, lower alkoxy and/or lower alkanoyl, A means lower alkylene, lower alkylidene, lower alkenylene, lower alkenylidene, cycloalkylene, cycloalkylidene or cycloalkyl-lower alkylidene and R ^ means carboxy, carboxy esterified with a lower alkanol, 3- to 8-membered cycloalkanol, phenol, a hydroxypyridine, a substituted phenol or hydroxypyridine further means carbamoyl or with hydroxy, amino,

phenyl or substituted phenyl mono-substituted, with lower alkyl mono- or di-substituted or with 4- to 7-membered alkylene resp. 3-aza-, 3-lower alkylaza-, 3-oxa- or 3-thiaalkylene disubstituted carbamoyl, wherein a lower alkanol can be unsubstituted or substituted with hydroxy, mercapto, optionally substituted phenyl, lower alkoxy, optionally in the phenyl part substituted phenyl lower alkylthio, optionally in the phenyl part substituted phenyl lower alkylthio, hydroxy lave real oxy, lower alkoxy lave real oxy, optionally in the phenyl part substituted phenyl lave real oxy lave real oxy, hydroxyl lave real oxy lave real oxy, lower alkyl lave real oxy lave real oxy, optionally in the phenyl part substituted phenyl lave real oxy lave real oxy lave real oxy, carboxy lave real oxy, lower alkoxycarbonyl-lave real oxy, optionally substituted phenyl-containing lower alkoxycarbonyl-lower phenol, and resp. hydroxypyridine, each time can be substituted with lower alkyl, lower alkoxy, halogen and/or trifluoromethyl as well as their isomers as well as their salts, especially pharmaceutically usable salts.

The invention relates, for example, to compounds with the formula

I, in which one of the radicals R-^ and R£ means pyridyl or 1-oxido-pyridyl, which may be unsubstituted and/or each time substituted by halogen, hydroxy, lower alkyl, lower alkoxy and/or lower alkanoyloxy and the other means phenyl, pyridyl or 1-oxidopyridyl which may be unsubstituted and/or each substituted by halogen, hydroxy, lower alkyl, lower alkoxy and/or lower alkanoyloxy, A means the lower alkylene with up to and including 4 C atoms such as methylene, the lower alkylidene with up to and including 7 C atoms such as 2,2-propylidene, lower alkenylene with up to and including 4 C atoms such as 1,3-propen-2-ylene, lower alkenylidene with up to and including 7 C atoms such as 1,1-buten-3-ylidene, 3- to 8-membered cycloalkylene, such as cyclopropylene,

The 3- to 8-membered cycloalkylidene such as cyclopentylidene or cycloalkyl-lower alkylidene with up to 7 C atoms in the alkylidene moiety and with a 3- to 8-membered cycloalkyl moiety such as

2-cyclohexyl-1,1-ethylidene and means carboxy, with a lower alkanol, a 3- to 8-membered cycloalkanol, phenol or a substituted phenol esterified carboxy, carbamoyl, N-mono-, N,N-di-lower alkylcarbamoyl, pyrrolidino -, piperidino-, morpholino-, piperazino-, 4-lower alkyl-piperazino-, thiomorpholino-, anilino- or with lower alkyl, lower alkoxy and/or halogen substituted anilinocarbonyl, the lower alkanol may be unsubstituted or may be substituted with hydroxy, mercapto, phenyl , substituert fenyl, laverealkoksy, fenyllaverealkoksy, i fenyldelen substituert fenyllaverealkoksy, laverealkyltio, fenyllaverealkyltio, i fenyldelen substituert fenyllaverealkyltio, hydroksylavérealkoksy, laverealkoksylaverealkoksy, fenyllaverealkoksylaverealkoksy, i fenyldelen substituert fenyllaverealkoksylaverealkoksy, hydroksylavérealkoksy la ver ealkoksy , laverealkoksylaverealkoksylaverealkoksy, eventuelt i fenyldelen substituert fenyllaverealkoksylaverealkoksylaverealkoksy, karboksylaverealkoksy, la verealkoxy-carbonyl-lowerealoxy, optionally substituted phenyl-containing lower-alkoxycarbonyl-lowerealoxy or loweralkanoyloxy and substituted phenol resp. phenyl can each be substituted with lower alkyl, lower alkoxy, halogen and/or trifluoromethyl as well as their isomers as well as their salts.

The invention relates, for example, to compounds with the formula

I, in which one of the radicals R 1 and R 2 means unsubstituted or

in another row with halogen with atomic no. up to 35 such as chlorine, hydroxy, lower alkyl of up to 4 C atoms, such as methyl, and/or lower alkoxy of up to 4 C atoms such as methoxy, substituted phenyl and the other means pyridyl, such as 3- pyridyl or 1-oxido-pyridyl or 1-oxido-3-pyr±dyl which can each be unsubstituted or alternatively substituted by halogen with atomic no. up to and including 35 as chlorine, hydroxy and/or lower alkoxy with up to 4 C atoms as methoxy, A means the lower alkylene with up to 4 C atoms as methylene, the lower alkylidene with up to 7 C atoms as 2,2 -propylidene, the lower alkenylidene with up to 7 C atoms such as 1,1-buten-3-ylidene or the 3- to 8-membered cyclolower alkylidene such as 1,1-cyclopentylidene and R^ means carboxy,

lower alkoxycarbonyl with up to and including 5 C-atoms such as ethoxycarbonyl, where lower alkoxycarbonyl can be substituted with lower alkanoyloxy with up to and including 5 C-atoms such as pivaloyloxy further means hydroxy-lower-alkoxy-lower-alkoxycarbonyl as 2-(2-hydroxyethoxy)-ethoxycarbonyl, lower-alkyl-lower-alkoxy-lower-alkoxycarbonyl as 2 -(2-Methoxyethoxy)-ethoxycarbonyl, hydroxylaverealoxylaverealoxy-laverealoxycarbonyl as 2-[2-(2-hydroxyethoxy)-ethoxy]-ethoxycarbonyl or loweralkyllaverealoxylaverealoxy-laverealoxycarbonyl as 2-[2-(2-methoxyethoxy)-ethoxy]-ethoxycarbonyl, each times with up to 4 C atoms in the lower alkoxy part as well as their isomers as well as their salts.

The invention primarily relates to compounds of formula I, in which one of the radicals R-^ and R- means unsubstituted or

in another row with halogen with atomic no. up to 35 as chlorine, hydroxy or lower alkoxy with up to 4 C atoms as methoxy substituted phenyl, the other means pyridyl as 3-or 4-pyridyl or 1-oxido-pyridyl as 1-oxido-3-pyridyl or l -oxido-4-pyridyl, A means the lower alkylidene with up to and including 4 C atoms such as 2,2-propylidene and R₁ means lower alkoxycarbonyl with up to and including 5 C atoms such as ethoxycarbonyl as well as their isomers and their salts.

The invention primarily relates to compounds of formula I, in which one of the radicals R-^ and R£ means unsubstituted or, alternatively, with halogen with atomic no. up to 3 5 as chlorine, hydroxy or lower alkoxy with up to 4 C atoms as methoxy substituted phenyl and the other means pyridyl as 3- or 4-pyridyl or 1-oxido-pyridyl as 1-oxido-3-pyridyl or 1-oxido-4-pyridyl, A means a quaternary C-atom-containing lower alkylidene with even 4-C atoms such as 2,2-propylidene, the quaternary C atom being attached directly to the imidazole ring and R₂ means lower alkoxycarbonyl with up to 5 C atoms such as ethoxycarbonyl as well as their isomers as well as their salts.

The invention primarily relates to a compound of formula I, in which phenyl means, R£ means 1-oxidopyridyl such as 1-oxido-3-pyridyl, A means 2,2-propylidene and R^ means lower alkoxycarbonyl with up to and including 5 C atoms such as ethoxycarbonyl as well as their isomers as well as their salts.

The invention relates in particular to the new compounds mentioned in the examples and their salts, in particular pharmaceutically usable salts of such compounds with salt-forming groups, as well as the manufacturing methods listed in the examples.

A method for producing the compounds of formula I is characterized, for example, by a compound of formula

a tautomer and/or a salt thereof, in which one of the residues X-^ and X2 means optionally substituted imino and the other oxy or optionally substituted imino is cyclized or in which X^ means oxy and X2 means oxo is cyclized during condensation and, if desired, a compound obtained according to the method is transferred with formula I in another compound, a free compound obtained according to the method is transferred into a salt or a salt obtained according to the method is transferred into another salt or into a free compound and, if desired, an isomer mixture obtained according to the method is divided into its components.

Tautomers of compounds with formula II are, for example, those where a partial enol or enamine grouping exists in the form of the corresponding tautomeric keto- or ketimine form and vice versa, the possible tautomers being in equilibrium with each other.

The cyclization of a compound of formula II, a tautomer and/or salt thereof takes place in the usual way, especially in the manner known from the literature for analogous reactions, if necessary under heating, such as in a temperature range from approx. 20°C to approx. 250°C under pressure and/or in the presence of a catalytic agent, preferably an acid or an acid anhydride. Suitable acids are, for example, inorganic acids such as mineral acids, e.g. sulfuric acid, polyphosphoric acid or halogen hydrogen acids such as hydrochloric acid or organic acids such as lower alkane carboxylic acids, e.g. acetic acid. As acid anhydrides, there are e.g. in consideration of mineral anhydrides such as sulphuryl or phosphorus (oxy) halides, e.g. phosphorus oxychloride. Thereby, if necessary, one works in an inert solvent, for example a possibly halogenated hydrocarbon such as chloroform, chlorobenzene, hexane, pyridine or toluene, a lower alkanol such as methanol, e.g. dimethylformamide or formamide, or a lower alkane carboxylic acid such as formic or acetic acid and/or under an inert gas such as nitrogen.

The starting substances with formula II, their tautomers and/or salts are formed according to methods known in and of themselves for a predominant part in situ, reacted under the reaction conditions without isolation further to the compounds with formula I. The cyclization can thereby take place in connection with the preceding condensation .

Thus, in a preferred embodiment of the above-mentioned method, for example, a compound of formula

a tautomer and/or salt thereof, wherein optionally means

functionally modified hydroxy reacts a compound of formula R^-A-Y2(IIb), in which Y2 means at least a nitrogen-containing functionally modified carboxy or a salt thereof, or a compound of formula IIa, a tautomer and/or salt thereof, in which Y-^ means amino, is reacted with a compound of formula IIb, in which Y2 means optionally functionally modified carboxy or a salt thereof, optionally in the presence of a condensing agent. Thereby, for example, a corresponding compound with formula II or a tautomer thereof can be formed, which, according to the invention, reacts further during the reaction to form the ice.

In a particularly preferred embodiment of the above-mentioned method, for example, compounds with formula are reacted

in which Y^means optionally reactive esterified hydroxy, with carboxylic acid of formula R^-A-COOH (lic), their salts or functional derivatives and with ammonia, or compounds of formula

which is obtainable by condensation of compounds of formula IIa with optionally "functional derivatives of compounds

with formula lic is reacted with ammonia.

Salts of compounds of formula II and IIa are, for example, acid addition salts such as hydrohalides. Functionally modified hydroxy Y-^ is, for example, amino or reactive esterified hydroxy such as hydroxy esterified with an inorganic mineral acid, e.g. hydrohalic acid or with an organic sulphonic acid, e.g. optionally substituted benzenesulfonic acid. As examples of reactive esterified hydroxy, mention should first be made of halogen, e.g. chlorine or bromine, or sulphonyloxy, e.g. p-toluenesulfonyloxy. Functionally modified carboxy Y2 is, for example, anhydridized carboxy such as halocarbonyl, lower alkanoyloxycarbonyl or lower alkoxycarbonyloxycarbonyl, carbamoyl or amidino.

Reactive esterified hydroxy is, for example, hydroxy, esterified with a preferably strong inorganic or organic acid, such as mineral acid, e.g. hydrohalic acid, e.g. hydrobromic or hydrochloric acid or organic sulphonic acids,

as optionally substituted benzenesulfonic acids, e.g. p-toluenesulfonic acid. Functionally modified carboxy derivatives with formula lic are, for example, equivalent to any esterified amidated or anhydridized carboxy compounds that correspond to lower alkoxycarbonyl, optionally substituted carbamoyl or halocarbonyl, lower alkanoyloxycarbonyl or lower alkoxycarbonyloxycarbonyl derivatives.

Suitable condensing agents include, for example, strong protonic acids, such as mineral acids, e.g. sulfuric acid, hydrohalic acid, phosphoric acid, sulphonic acids,

as optionally substituted benzenesulfonic acids, or carboxylic acids such as lower alkane carboxylic acids or anhydrides of mineral acids, such as corresponding anhydrides of phosphoric acids, carbonic acid or sulfuric acid, e.g. phosphorus pentachlorideT'""' phosphorus oxychloride, phosphorus pentoxide, thionyl chloride or phosgene.

The reaction takes place in the usual way, if necessary, under heating and in an inert solvent, such as a halogenated hydrocarbon.

In a preferred method, compounds of formula II, in which X 1 and X 2 each mean oxy, are obtained, while compounds of formula IIa, in which Y means hydroxy, are reacted with acid halides of formula 11, especially the corresponding acid halides. Of the thus obtainable compounds of formula Ild, the corresponding compounds of formula I can be formed with ammonia in the presence of an acid such as acetic acid.

In particular, compounds of formula II are obtained, in which

X-^ means oxy and Y,^ means imino, since a compound of formula IIa, in which Y^ means reactive esterified hydroxy, primarily means halogen, is reacted with a corresponding compound of formula IIb, in which means carbamoyl under the reaction conditions indicated above.

In particular, one comes to a compound of formula II, in which

X-^ means imino and Y.^ means oxo, by reacting a compound of formula Ila, in which Y^ means amino, a salt and/or tautomers thereof with a compound of formula IIb,

in which Y2 denotes anhydridized carboxy primarily halocarbonyl under the stated reaction conditions.

Compounds of formula II, in which X^ and X2 are imino, are preferably obtainable when a compound of formula IIa, in which Y^ is possibly a reactive esterified hydroxy,

primarily hydroxy, a salt thereof and/or tautomers thereof are reacted with a compound of formula IIb, in which Y2 means amidino.

The starting substances with formulas Ila, Ilb and lic are known or can be prepared according to methods known per se.

Thus, for example, compounds with formula IIa can be obtained, for example, by ester condensation of esterified acids with formulas R-^Cr^-COOH or R2-CH2-COOH with esterified acids with the formulas R-^-COOH resp. R 2 -COOH, preferably in the presence of a base. The resulting α-methylene ketone of formula

brominated, for example, and thus transferred to a compound of formula IIa or a salt e.g. hydrohalide thereof in which Y-^ means bromine. Compounds of formula I or salts thereof can further be prepared as, for example, a compound of formula

or a salt thereof is reduced to a compound of formula I and, if desired, the free compound of formula I obtained according to the method is transferred to another free compound,

a free compound obtainable according to the method is transferred to a salt or a salt obtained according to the method is transferred to the free compound or to another salt and, if desired, an isomer mixture obtained according to the method is divided into its components.

The reduction takes place according to methods known per se. Compounds of formula III or

their salts with hydrogen in the presence of a hydrogenation catalyst or with a dithionite, e.g. sodium ditibnite, or with a phosphorus halide, e.g. phosphorus trichloride. As a hydrogenation catalyst, it is possible to use, for example, elements from the VIII-subgroup as well as derivatives thereof such as platinum, palladium or palladium chloride, which are possibly drawn onto a common support material such as activated carbon or an alkaline earth metal compound, e.g. barium carbonate, or Raney nickel is used. Likewise, the reduction can through

lined with a system of a suitable base metal and protonic acid, for example with zinc/glacial vinegar.

If necessary, the reduction can be carried out during cooling or heating, for example in a temperature range from approx. 0 to approx. 150°C, in an inert solvent such as a halogenated hydrocarbon, e.g. chloroform, carbon tetrachloride or chlorobenzene or an ether such as dimethoxyethane, diethyl ether, dioxane or tetrahydrofuran and|or under inert gas, e.g. nitrogen.

The starting substances with formula III or their salts can be obtained in a manner known per se, for example as a compound of formula

a tautomer or a salt thereof, is reacted with an aldehyde of the formula R-^-A-C (=0)-H (Illb), optionally at elevated temperature and in the presence of an acid such as mineral acid, e.g. hydrochloric acid, sulphonic acid, e.g. p-toluenesulfonic acid or carboxylic acid, e.g. acetic acid.

Compounds of formula I can be further prepared in this manner

in a connection with formula

in which R^' means a residue transferable to R^, the residue R3<1> is transferred to the residue R^ and, if desired, the free compounds of formula I obtained according to the method are transferred to another free compound, a free compound obtained according to the method is transferred to a salt or a

the salt obtained in this way is transferred to a free compound or to another salt, and if desired, an isomer mixture obtained according to the method is divided into its components.

Such groups 1 are, for example, by means of solvolysis or oxidation to optionally esterified or amidated carboxy R^transferable groups. As solvolytically transferable groups to R^, different functionally modified carboxys are mentioned by R^, which are primarily cyano, anhydridized carboxy such as halocarbonyl, lower alkanoyloxycarbonyl or lower alkoxycarbonyloxycarbonyl, optionally substituted amidino such as lower alkylamidino, optionally esterified thiocarboxy, such as lower alkylthiocarbonyl, optionally esterified dithiocarboxy, optionally substituted thiocarbamoyl, as mono- or dilaverealkyl-thiocarbamoyl, optionally esterified or anhydridized carboximidoyl as lower alkoxy or haloiminocarbonyl, or esters derived from orthoformic acid esters such as trilavereal oxy- or trihalo-methyl. Such groups can by means of solvolysis, e.g. hydrolysis or alcoholysis, further ammono- or aminolysis, is transferred in a residue R^.

Solvolytic agents are, for example, water, alcohol corresponding to the desired esterified carboxy group, ammonia or amines corresponding to the desired amidated carboxy group.

The treatment with a corresponding solvolytic agent is optionally carried out in the presence of an acid or base, optionally during cooling or heating or, if necessary, in an inert solvent or diluent. Suitable acids are, for example, inorganic or organic protonic acids such as mineral acid, e.g. sulfuric acid or hydrohalic acid such as sulphonic acid, e.g. lower alkane or optionally substituted benzenesulfonic acid or as carboxylic acids such as lower alkane carboxylic acids. For example, hydroxides such as alkali metal hydroxides can be used as bases.

Thus, for example, cyano groups, optionally esterified thiocarboxy, optionally esterified dithiocarboxy, optionally substituted thiocarbamoyl, optionally esterified or anhydridized carboxyimidoyl, or residues derived from orthoformic acid, can optionally be hydrolyzed in the presence of a protonic acid to carboxy R^ , while for example cyano, optionally S-esterified thiocarboxy or anhydrided carboxy'

can be alcoholized with a suitable alcohol, optionally in the presence of a protonic acid to esterified carboxy R^- Amidated carboxy R^ can e.g. also obtained by aminolysis or by treatment with a suitable amine of cyano, for example working in the presence of a Lewis acid such as aluminum chloride or anhydridized carboxy.

Further to carboxy or esterified carboxy R^transferable groups are, for example, oxidative to these transferable residues which may be hydrated or acetalized formyl. These can preferably be formed in situ during the oxidation reaction, e.g. of the acyl group of an ot, e-unsaturated or a,B-dihydroxylated aliphatic or araliphatic carboxylic acid, a formyl group optionally esterified to the hydroxy group, or set free from one of their functional derivatives, e.g. one of their acetals, acylals or imines. Acyl groups of α,B-unsaturated or α,B-dihydroxylated carboxylic acids are, for example, acyl groups of α,B-unsaturated aliphatic mono- or dicarboxylic acids, e.g. acryloyl, crotonyl or the acyl group of the optionally functionally modified fumaric or maleic acid, acyl groups of a,B-unsaturated araliphatic carboxylic acids, e.g. optionally substituted cinnamoyl or acyl groups of aliphatic α,β-dihydroxydicarboxylic acids such as tartaric acid or monofunctional carboxy derivatives such as esters or amides thereof. Esterified hydroxymethyl groups are e.g. groups esterified to the hydroxy group with a mineral acid, such as a halohydrogen acid, e.g. with hydrochloric or hydrobromic acid or with a carboxylic acid, e.g. with acetic acid or an optionally substituted benzoic acid. Acetalized formyl groups are, for example, formyl groups acetalized with lower alkanols or a lower alkanediol such as dimethoxy, diethoxy or ethylenedioxymethyl. Acylated formyl groups are e.g. dilave alkanoyloxymethyl or dihalomethyl groups such as diacetoxymethyl or dichloromethyl. Imines of formyl groups are, for example, optionally substituted N-benzylimine or N-(2-benzothiazolyl)-imines thereof or imines with 3,4-di-tert-butyl-o-quinone. Further oxidatively transferable residues to the carboxy group are e.g. optionally substituted as in the 5-position of an acetalized formyl group such as diethoxymethyl-containing 2-furoyl groups. For esterified carboxyl groups, oxidizable groups are preferred hydroxymethyl or dihydroxymethyl groups such as lower alkoxymethyl or dilavereal oxymethyl groups.

The oxidation of such groups R^' takes place in a manner known per se, for example by reaction in a suitable oxidizing agent, for example in an inert solvent such as a lower alkane carboxylic acid, e.g. acetic acid, a ketone, e.g. acetone, an ether, e.g. tetrahydrofuran, a heterocyclic aromatic, e.g. pyridine or water or a mixture thereof, if necessary during cooling or heating, e.g. of approx. 0°C

to approx. 150°C. Oxidizing agents include, for example, oxidizing transition metal compounds, especially those with elements from subgroups I, CI, VII or VIII.

Examples include: silver compounds such as silver nitrate, silver oxide or picolinate, chromium compounds such as chromium trioxide or potassium dichromate, manganese compounds such as potassium ferrate, tetrabutylammonium or benzyl (triethyl)ammonium permanganate. Further oxidizing agents are, for example, suitable compounds with the elements from the 4th main group such as lead dioxide or halogen-oxygen compounds such as sodium iodate or potassium periodate.

Thus, for example, the oxidation of hydroxymethyl resp. of with a lower alkanol etherified hydroxymethyl to carboxy resp. to with a lower alkanol esterified carboxy. This turnover is carried out e.g. advantageously with potassium permanganate in acetone or aqueous pyridine at room temperature. Correspondingly, the oxidation of optionally hydrated formyl to carboxy R^ takes place, e.g. with iodine in a methanolic potassium hydroxide solution. For the oxidation of acetalized formyl to esterified carboxy R, bromine or N-bromosuccinimide in particular is used as oxidizing agent.

The starting substances with formula IV are prepared according to methods known per se. For example, one starts from a hydroxy ketone with formula

and reacts this with a compound of formula R^'- A- Y^'

(IVb) or a salt thereof, in which Y^' optionally means functionally modified carboxy, resp. R^'-A-COOH, a functional derivative or salt thereof and ammonia in an inert solvent and under heating in situ to the compound of formula IV without isolation of intermediates.

In the above-mentioned methods for producing e.g. compounds of formula IV, ammonia which is predominantly added in excess can also be used in the form of an ammonia-releasing agent, the release taking place at an elevated temperature and possibly under pressure. As an ammonia-releasing agent, there is e.g. namely ammonium salts of lower alkane carboxylic acids, preferably ammonium acetate, further a suitable lower alkane carboxylic acid amide, especially formamide.

The aldehyde with formula R3-A-C(=0)-H (Illb) can, in the above-mentioned method for compound with formula I, also be released under the reaction conditions from an oxazine derivative with formula

The compounds of formula III can be prepared, for example, by reacting 2-methyl-2,4-pentanediol with a nitrile of the formula R^-A-CN in the presence of sulfuric acid. The correspondingly substituted dihydro-1,3-oxazine thus formed is reduced in a mixture of tetrahydrofuran and ethanol at -45°C and a pH value of approx. 7 under the influence of sodium borohydride to tetrahydro-1,3-oxazine of formula Ille.

A compound obtained according to the invention can be transferred in the usual way into another compound with formula I.

Thus, compounds of formula I obtained according to the invention can be converted into free and esterified carboxy groups R

in each other.

A free carboxyl group R^ can for example be esterified in the usual way to an esterified carboxyl group R^, for example by treatment with a diazolaveralkane, dilaverealkyl formamidacetal, alkyl halide or trilaverealkyloxonium, trilaverealkylcarboxonium or dilaverealkylcarbonium salts such as hexachloroantimonate or hexafluorophosphate or above all by reaction with the corresponding alcohol or a reactive derivative such as a carboxylic, phosphoric acid, sulfuric acid or carboxylic acid ester. E.g. a lower alkane carboxylic acid ester, tri-lower alkyl phosphite, di lower alkyl sulphite or the pyrocarbonate or a mineral acid or sulphonic acid ester, e.g. chloro or hydrobromic acid or sulfuric acid, benzenesulfonic acid, toluenesulfonic acid or methanesulfonic acid ester of the corresponding alcohol or an olefin derived therefrom.

The reaction with the corresponding alcohol itself can preferably take place in the presence of an acidic catalyst such as a protonic acid, e.g. of chloro or bromohydrogen, sulphur, phosphoric, boric, benzenesulfonic and/or toluenesulfonic acid, or a Lewis acid, e.g. of boron trifluoride etherate in an inert solvent, especially an excess of the alcohol used and if necessary in the presence of a water-binding agent and/or under distillation, e.g. azeotropic removal of the water of reaction and/or at elevated temperature.

The reaction with a reactive derivative of the corresponding alcohol can be carried out in the usual way, starting from a carboxyl, phosphoric acid, sulfuric acid or carboxylic acid ester, for example in the presence of an acid catalyst such as one of those mentioned above in an inert solvent as an aromatic hydrocarbon, e.g. in benzene or toluene or an excess of the alcohol derivative used or of the corresponding alcohol. Starting from a mineral acid or sulphonic acid ester, the acid to be esterified is preferably used in the form of a salt, e.g. of the sodium or potassium salt and working, if necessary, in the presence of a basic condensing agent such as an inorganic base e.g. of sodium or potassium or calcium hydroxide or

-carbonate, or a tertiary organic nitrogen base, e.g.

of triethylamine or pyridine, and/or in an inert solvent such as one of the above tertiary nitrogen bases or a polar solvent, e.g. in dimethylformamide and/or at elevated temperature.

The reaction with a dilower alkyl formamide acetal such as dimethyl formamide acetal takes place optionally under heating, while the reaction with an alkyl halide is carried out in the presence of a base such as an amine, e.g. triethylamine.

The reaction with an olefin can, for example, take place in the presence of an acidic catalyst, e.g. a Lewis acid such as boron triflubride, a sulphonic acid e.g. of p-toluenesulfonic acid or above all of a basic catalyst, e.g. of sodium or potassium hydroxide, preferably in an inert solvent such as an ether such as diethyl ether or tetrahydrofuran.

The above-mentioned conversions of free to esterified carboxyl groups R^ can, however, also be re-converted so that a compound of formula I is transferred, in which R^ means carboxyl primarily in the usual way into a reactive derivative, for example by means of a halide of phosphorus or sulphur, e.g. by means of phosphorus trichloride or bromide, phosphorus pentachloride or thionyl chloride, to an acid halide and by reacting a corresponding alcohol to a reactive ester, i.e. ester with an electron-attracting structure such as esters with phenol, thiophenol, p-nitrophenol or cyanomethyl alcohol and reacting it formed reactive derivatives then in the usual way, e.g. as discussed below for transesterification or interconversion" of esterified carboxyl groups with a corresponding alcohol to the desired group R^.

An esterified carboxyl group R^ can be transferred in the usual way to a free carboxyl group R^, e.g. by hydrolysis in the presence of a catalyst, for example a basic or acidic agent such as a strong base, e.g. of sodium or potassium hydroxide, or a mineral acid, e.g. hydrochloric acid, sulfuric acid or phosphoric acid.

An esterified carboxyl group R^ can be transesterified in the usual way to another esterified carboxyl group R^, e.g. by reaction with a metal salt of sodium or potassium salt of a corresponding alcohol or with this even in the presence of a catalyst, for example a strong base, e.g. of sodium or potassium hydroxide or a strong acid, such as a mineral acid, e.g. of hydrochloric, sulfuric or phosphoric acid or an organic sulphonic acid, e.g. of p-toluenesulfonic acid or a Lewis acid, e.g. of bridge trifluoroidetate.

Furthermore, one can transfer carboxy resp. reactive functional carboxy derivatives to a desired amidated form by solvolysis with ammonia or a primary resp. secondary amine, as also the hydroxylamine resp. hydrazines can be used in the usual way during dehydration, possibly in the presence of a condensing agent. Bases are preferably used as condensation agents, for example inorganic bases such as alkali metal hydroxides, e.g. sodium or potassium hydroxide, organic nitrogen bases, such as tert-amines, e.g. pyridine, tributyl-

amine or N-dimethylaniline or tetrahalosilanes such as tetrachlorosilane. Likewise, compounds of formula I obtained according to the invention, in which R., means amidated carboxy, can be cleaved according to methods known per se to cleave the amide bond and thus transfer the carbamoyl to free carboxy. Here, one works in the presence of a catalyst, for example a base such as an alkali metal or alkaline earth metal hydroxide or carbonate, e.g. sodium, potassium or potassium hydroxide or carbonate, or an acid such as a mineral acid, e.g. hydrochloric acid, sulfuric acid or phosphoric acid.

Contains at least one of the substituents R^, R2 and R^as

additional substituents hydroxy, then this can be preferred on

in and of itself known manner. The turnover with an alcohol component, e.g. with a lower alkanol such as ethanol, in the presence of acids, e.g. mineral acid such as sulfuric acid, or of dehydrating agents such as dicyclohexylcarbodiimide, leads to lower alkoxy. Phenols or their salts can be transferred into corresponding lower alkyl phenyl ethers or aryl phenyl ethers, e.g. in the presence of bases such as alkali metal hydroxides or

-carbonates e.g. sodium hydroxide or potassium carbonate,

by means of dilave alkyl sulfates, diazaolave alkanes or alkyl resp. aryl halides. Conversely, ethers can be split into alcohols. Thus, e.g. of alkoxyaryl compounds aromatic alcohols, carrying out the ether cleavage with the help of acids such as mineral acids, e.g. hydrohalic acids, such as hydrobromic acid or as a Lewis acid, e.g. halides of the elements from the 3rd main group such as boron tribromide or with the help of bases e.g. lower alkyl amines such as methylamine.

Furthermore, hydroxy can be converted into lower alkanoyloxy, for example by reaction with a desired lower alkane carboxylic acid such as acetic acid or a reactive derivative thereof, for example in the presence of an acid such as a protonic acid e.g. chlorine-,

hydrobromic, sulphurous, phosphoric or a benzene sulphonic acid,

in the presence of a Lewis acid e.g. of boron trifluoride etherate or in the presence of a water binding agent. Conversely, esterified hydroxy, e.g. by base catalysis is solvolysed to hydroxy.

Formed free compounds of formula I can be transferred to salts in a manner known per se. Hydroxy-containing groups or R2 and carboxy R^ are converted to corresponding bases such as alkali metal hydroxides in the initially listed salts with bases or by treatment with an acid addition salt-forming acid as listed above to acid addition salts.

Formed salts can be converted in a manner known per se into

the free connections e.g. by treatment with an acidic reagent such as a mineral acid or a base, e.g. alkali hydroxide.

Due to the narrow relationship between the compound in free form or in the form of their salts, in the preceding and following, free compounds and their salts are also possibly also

the corresponding salts resp. the free connection.

Depending on the choice of starting materials and working methods, the compounds can exist in the form of one of the possible isomers or as mixtures of these.

The compounds including their salts can also be obtained in form

of their hydrates or contain other solvents used for crystal lysis.

Depending on the choice of starting materials and working method, the compounds can exist in the form of one of the possible isomers or as mixtures of these, e.g. depending on the number of asymmetric carbon atoms as pure optical isomers, as antipodes or as isomeric mixtures such as racemates, diastereomer mixtures or racemate mixtures, further as tautomers.

Formed diastereomer mixtures and racemate mixtures can, due to the physico-chemical differences of the components, be separated in a known manner into the pure isomers, diastereomers or racemates, for example by chromatography and/or fractional crystallization. Formed racemates can be further cleaved by known methods by optical antipodes, for example by recrystallization of an optically active solvent, with the help of microorganisms or by reaction of an acidic final substance with an optically active base that forms salts with the racemic acid and separation of the salts formed in this way, e.g. due to their different solubilities, are split into the diastereomers, from which the antipodes can be released by the action of suitable agents. The most effective of the two antipodes is preferably isolated.

The invention also relates to the embodiments of the method according to which one proceeds from one or the other step of the method as an intermediate formed compound and carries out the missing steps or uses the starting material in the form of a salt or especially forms it under the reaction conditions.

The starting substances with formulas II, III and IV which were especially developed for the production of the compounds according to the invention, the methods for their production and their use are also covered by the invention.

The pharmaceutical preparations which at least contain an active substance or a pharmaceutically usable salt thereof are preferably those for topical use on warm-blooded animals, the pharmacologically active substance being contained alone or together with a pharmaceutically usable carrier material. The daily dosage of the active substance depends on the age of the individual condition as well as on the method of application. Corresponding means with a concentration range from approx. 1 to approx. 10% weight/weight, e.g. in the form of creams, ointments or solutions, can for example apply

res 2-3 times daily.

As topically applicable pharmaceutical preparations it comes

primarily creams, ointments, pastes, foams, tinctures or solutions containing from approx. 0.1 to approx. 10% of the active substance.

Creams are oil-in-water emulsions that have more than 50% water. Fatty alcohols are primarily used as an oily base, e.g. lauryl, cetyl or stearyl alcohol, fatty acid, e.g. palmitic or stearic acid, liquid to solid waxes, e.g. isopropyl myristate, wool wax or beeswax and/or hydrocarbons e.g. petroleum jelly (Petrolatum) or paraffin oil. Emulsifiers include surface-active substances with predominantly hydrophilic properties such as corresponding non-ionic emulsifiers, e.g. fatty acid esters of polyalcohols or ethylene oxide adducts thereof such as polyglycerol fatty acid esters or polyoxyethylene fatty acid esters (Tweens), further polyoxyethylene fatty alcohol ethers or fatty acid esters or corresponding ionic emulsifiers such as alkali metal salts of fatty alcohol sulfates, e.g. sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate, which are usually used in the presence of fatty alcohols, e.g. cetyl alcohol or stearyl alcohol. Additions to the water phase include agents that prevent the cream from drying out, e.g. polyalcohols such as glycerol, sorbitol, propylene glycol and/or polyethylene glycols, further preservatives, fragrances, etc.

Ointments are water-in-oil emulsions containing intii;"70%, preferably however from approx. 20% to approx. 50% water or aqueous phases. Fat phases are primarily hydrocarbons, e.g. . vaselines, paraffin oil and/or hard paraffins which, to improve the water-binding capacity, preferably contain suitable hydroxy compounds such as fatty alcohols or esters thereof, for example cetyl alcohol or wool wax alcohols or wool wax. Emulsifiers are corresponding lipophilic substances such as sorbitan fatty acid esters (Spans), e.g. eg sorbitan oleate and/or sorbitan isostearate Additions to the water phase include humectants, such as polyalcohols, eg glycerol, propylene glycol, sorbitol and/or polyethylene glycol as well as preservatives, fragrances etc.

Fatty ointments are anhydrous and contain hydrocarbons in particular as a basis, e.g. paraffin, vaseline and/or liquid paraffin, further natural or partially synthetic fats, e.g. coconut fatty acid triglyceride or preferably hardened oils, e.g. hydrogenated peanut or castor oil, further fatty acid partial esters of glycerol, e.g. glycerol mono- and

-distearate, as well as e.g. those in connection with the salves mentioned

■water absorption increasing fatty alcohols, emulsifiers and/or additives.

Pastes are creams and ointments with secretion-absorbing powder ingredients such as metal oxides, e.g. titanium oxide or zinc oxide, further talc and/or aluminum silicates which have the task of binding the moisture or secretions present.

Foam is administered e.g. from pressure vessels and are liquid oil-in-water emulsions present in aerosol form, halogenated hydrocarbons such as chlorofluorolower alkanes, e.g. dichlorodifluoromethane and dichlorotetrafluoroethane are used as propellants. Hydrocarbons are used as the oil phase, e.g. paraffin oil, fatty alcohols, e.g. cetyl alcohol, fatty acid esters, e.g. isopropyl myristate and/or other waxes. As an emulsifier, mixtures of those with predominantly hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters (Tweens), and those with predominantly lipophilic properties, such as sorbitan fatty acid esters (Spans), are used as emulsifiers. In addition, there are the usual additives such as preservatives etc.

Tinctures and solutions mostly have an aqueous-ethanolic basis such as polyalcohols, e.g. glycerol, glycols and/or polyethylene glycol as a humectant to reduce evaporation and fattening substances such as fatty acid esters with lower polyethylene glycols, e.g. soluble in an aqueous mixture, lipophilic substances as a substitute for the fatty substances removed from the skin with the ethanol and, if necessary, other auxiliaries and additives are added.

Production of the topically applicable pharmaceutical preparations takes place in a manner known per se, e.g. by dissolving or suspending the active substance in the base or in a part thereof, if necessary. When processing the active substance as a solution, this is usually dissolved before emulsification in one of the two phases; when processing as a suspension, it is mixed after emulsification with part of the base and then the rest is added to the formulation.

The invention will be described in more detail with the help of some examples where the temperature is indicated in degrees Celsius.

Example 1

A solution of 39.0 g of 1-phenyl-2-(3-pyridyl)-glyoxal (freshly distilled) in 500 ml of methanol is mixed with stirring at 0°C in portions over the course of 5 hours with 2.5 g of sodium borohydride. After the addition has been completed, the mixture is stirred for a further 2 hours

at 0°C, leave for 15 hours at 0°C and then mix with 200 ml of 2N hydrochloric acid. The suspension is evaporated under reduced pressure to dryness, the residue is mixed with ice and made alkaline by the addition of 2N sodium carbonate solution. The aqueous suspension is extracted three times with 200 ml of ethyl acetate each time. The combined ethyl acetate solutions are washed with 50 ml of water, dried over magnesium sulphate and evaporated under reduced pressure at 40°C. The residue, a brown oil, is chromatographed on 500 g of silica gel. Fractions 1 and 2, eluted with each 1000 ml of toluene ethyl acetate (1:1), contain the starting material (1-phenyl-2-(3-pyridyl)glyoxal). Fractions 3 and 4, eluted each time with 1000 ml of toluene-ethyl acetate (1:1), are combined and evaporated under reduced pressure to dryness. The residue is crystallized from ether-petroleum ether. a-hydroxy-

the benzyl-(3-pyridyl) ketone melts at 109-111°C. Fractions 5 and 6 eluted with each time 1000 ml of toluene-ethyl acetate (1:1) are discarded. Fractions 7-14, eluted each time with 1000 ml of toluene-ethyl acetate (40:60), are combined and evaporated to dryness under reduced pressure. The residue is crystallized from ether-petroleum ether. α-Hydroxy-phenyl-[(3-pyridyl)-methyl]-ketone melts at 93-95°C.

Example 2

A mixture of 6.0 g of α-hydroxy-[(3-pyridyl)-methyl]-ketone

and 1 ml of triethylamine in 80 ml of anhydrous benzene are mixed with stirring and introduction of nitrogen at 10°C with a solution of 6.0 g of dimethyl-malonic acid mono-ethyl ester chloride in 30 ml of anhydrous benzene during 20 minutes, stirred for 3 hours at room temperature, mixed with 30 ml ethyl acetate and 90 ml water and stirred again for one hour at room temperature. The aqueous phase is separated and washed twice with 20 ml of ethyl acetate each time. The combined organic phases are washed with 20 ml of saturated sodium chloride solution, 30 ml of 2N potassium bicarbonate and again 30 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue, an oil, is chromatographed on 200 g of silica gel. Fractions 1 to 2 eluted with each time 200 ml of chloroform are discarded. The fractions 3 to 9 eluted with chloroform-methanol (99:1) are combined and evaporated under reduced pressure to dryness. The residue, dimethyl malonic acid monoethyl ester [α-benzoyl-(3-pyridyl-methyl)-ester] is present as an oil.

Analogously, starting from a-hydroxy-phenyl-[(3-pyridyl)-methyl]-ketone is obtained: methyl-malonic acid mono-ethyl ester [α-benzoyl-(3-pyridyl-methyl)-ester (oil) and methylmalonic acid mono-ethyl ester chloride.

Malonic acid mono-ethyl ester [α-benzoyl-(3-pyridyl-methyl)-ester (oil) based on

α-hydroxy-phenyl-[(3-pyridyl)-methyl]-ketone and malonic acid mono-ethyl ester chloride.

Example 3

A mixture of 3.1 g of dimethylmalonic acid mono-ethyl ester [α-benzoyl-(3-pyridyl-methyl)-ester, 2.4 g of ammonium acetate and 24

ml of glacial acetic acid are mixed with stirring for 2 hours at a bath temperature of 140°C. The entire reaction mixture is cooled on

100 ml ice water and adjust with concentrated aqueous ammonia solution at pH 8.0. Extract three times with 70 ml of ethyl acetate each time and wash the ethyl acetate extracts twice with 20 ml each time. The combined organic phases are dried over magnesium sulfate and evaporated under reduced pressure to dryness. The residue is chromatographed on 100 g of silica gel. Fractions 1-7 eluted with each time 100 ml of chloroform are discarded. Fractions 8 and 9, eluted each time with 100 ml of chloroform, are combined and evaporated under reduced pressure to dryness. The residue, an oil, is expelled with petroleum ether. The separated crystals are filtered off and washed with cold petroleum ether. 2-[4-Phenyl-5-(3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid ethyl ester melts at 70-71°C.

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

NMR (CDCl 3 ): 8.85 "(s, br, H-2'), 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'), 4.03 (q, 'CH-CH3), 1, 70 (d, CH3CH), starting from methyl malonic acid mono-ethyl ester [α-benzoyl-(3-pyridyl-methyl)-ester.

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

NMR (CDCl 3 ): 8.85 (s, br, H-2'), 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, C|2,CO),

starting from malonic acid mono-ethyl ester [α-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 methylene chloride is mixed with stirring at 0°C dropwise with a solution of 1.0 g of m-chloroperbenzoic acid in 20 ml of methylene chloride. The mixture is stirred for 2 hours at 0°C, mixed again with 0.1 g of m-chloropenbenzoic acid and stirred for 30 minutes at 0°C. The mixture is washed twice with each time 10 ml of 2N potassium bicarbonate solution, dried over magnesium sulphate and evaporated under reduced pressure to dryness. The residue, an oil, is chromatographed on 40 g of silica gel. The fractions 1-3 eluted with each time 50 ml of chloroform are discarded. Fractions 4-11 eluted with 50 ml of chloroform each time are combined and evaporated to dryness under reduced pressure. The residue, 2-[4-phenyl-5-(1-oxido-3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid ethyl ester is present as an 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), d.65 (s, according to CH3).

Analogously, 2-[4-phenyl-5-(1-oxido-3-pyridyl)-oxazol-2-yl]-propionic acid ethyl ester (oil) is obtained, starting from 2-[4-phenyl-5- (3-Pyridyl)-oxazol-2-yl]-propionic acid ethyl ester.

2-[4-phenyl-5-(1-oxido-3-pyridyl)-oxazol-2-yl]-acetic acid ethyl ester (oil), assuming

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

Example 5

A solution of 2.1 g of 2-[4-phenyl-5-(1-oxido-3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid ethyl ester in 10 ml of methanol is mixed with stirring with 7.2 ml IN caustic soda. The solution is stirred for 5 hours at room temperature and evaporated under reduced pressure to dryness. The residue is dissolved in 50 ml of water and the aqueous solution is extracted with 20 ml of methylene chloride. The aqueous phase is then separated and adjusted to exactly pH 4.0 with 2N hydrochloric acid. The suspension is stirred for 5 minutes at 0°C and filtered off. 2-[4-Phenyl-5-(1-oxido-3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid melts at 136-137°C.

Analogously: 2-[4-phenyl-5-(1-oxido-3-pyridyl)-oxazol-2-yl]-propionic acid is obtained from 2-[4-phenyl-5-(1-oxido-3-pyridyl)- oxazol-2-yl]-propionic acid ethyl ester.

2-[4-phenyl-5-(1-oxido-3-pyridyl)-oxazol-2-yl]-acetic acid assuming

2-[4-Phenyl-5-(1-oxido-3-pyridyl)-oxazol-2-yl]-acetic acid ethyl ester.

2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid, melting point 111-112°C (from methanol), starting from 2-[4-phenyl -5-(3-pyridyl)-oxazol-2-yl]-2-methylpropionic acid ethyl ester.

Example 6

In a suspension of 11.3 g of α-oximobenzyl-(3-pyridyl) ketone

and 12.2 g of 2-(2,2-dimethyl-carbethoxymethyl)-4,6,6-trimethyl-2,3,5,6-tetrahydro-1,3-oxime in 300 ml of glacial acetic acid are introduced without cooling and under good stirring hydrochloric acid gas. The temperature thereby increases to 45°C and a clear solution occurs.

Hydrochloric acid gas is fed into the solution at 115°C for 30 minutes, then the solution is heated for 15 hours at 115°C, cooled and evaporated under reduced pressure at 50°C to dryness. The residue is dissolved in 300 ml of water. The aqueous solution is made alkaline with concentrated aqueous ammonia solution and the separated crystals are dissolved with 300 ml of ethyl acetate-methylene chloride (1:1). The organic phase is washed with 50 ml of water, dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue is crystallized from methanol-ether. 2-[4-Phenyl-5-(3-pyridyl)-(3-oxido-oxazol)-2-yl]-2-methyl-propionic acid ethyl ester melts at 195-210°C.

Analogously, 2-[4-phenyl-5-(3-pyrido)-(3-oxido-oxazol)-2-yl]-propionic acid ethyl ester is obtained, when starting from α-oximo-benzyl-(3-pyridyl)- ketone and 2-(2-methyl-carbethoxymethyl)-4,4,6-trimethyl-2,3,5,6-tetrahydro-1,3-oxazine,

2-[4-phenyl-5-(3-pyrido)-(3-oxido-oxazol)-2-yl]-acetic acid ethyl ester, when proceeding from α-oximo-benzyl-(3-pyridyl)-ketone and 2-(carbethoxymethyl)-4,4,6-trimethyl-2,3,5,6-tetrahydro-1,3-oxazine.

Example 7

A solution of 1.2 g of 2-[4-phenyl-5-(3-pyrido)-(3-oxido-oxazol)-2-yl]-2-methyl-propionic acid ethyl ester in 10 ml of glacial acetic acid is mixed at 10°C under stirring in portions with 1.2 g of zinc dust. After the addition is complete, 0.05 is also added

ml of concentrated hydrochloric acid. The mixture is heated for one hour at 90°C, cooled, filtered and washed with 5 ml of glacial acetic acid. The filtrate is evaporated under reduced pressure at 50°C to dryness. The residue is dissolved in 20 ml of water. The aqueous solution is made alkaline with aqueous concentrated ammonia solution. The suspension is extracted three times with 30 ml of ethyl acetate each time. The combined organic phases are washed with 10 ml of water, dried over magnesium sulphate and evaporated under reduced pressure to dryness. The residue is chromatographed at 80

g silica gel. Fractions 1-5 eluted with each time 50 ml of chloroform are discarded. Fractions 6-9 eluted with 50 ml of chloroform each time are combined and evaporated to dryness under reduced pressure. The residue crystallizes after expulsion with petroleum ether. 2-[4-Phenyl-5-(3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid ethyl ester melts at 70-71°C.

Example 8

A mixture of 3.6 g of α-bromo-benzyl-(3-pyridyl)-ketone, 1.7

g of dimethylmalonic acid mono-ethyl ester-mono-amide and 1.3 g of collidine in 100 ml of xylene are heated for 15 hours at 120-130°C, the water formed being separated with a water separator. The reaction mixture is then evaporated under reduced pressure to dryness. The residue is mixed with 30 ml of water and concentrated aqueous ammonia solution and extracted three times with 40 ml of ethyl acetate each time. The combined ethyl acetate solutions are washed with 20 ml of water, dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue is chromatographed on 80 g of silica gel. The fractions 1-3 eluted with each time 100 ml of chloroform are discarded. Fractions 4-6 eluted each time with 100 ml of chloroform contain 2-[4-phenyl-4-(3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid ethyl ester. They are combined and evaporated under reduced pressure to dryness. The residue is expelled with petroleum ether and the separated crystals are filtered off. Melting point 70-71°C.

Example 9

A mixture of 3.56 g of α-bromo-benzyl-(3-pyridyl)-ketone hydrobromide and 3.66 g of dimethyl malonic acid monoethyl ester sodium salt in 100 ml of aqueous ethanol is heated with stirring to reflux. After adding 1 ml of concentrated sulfuric acid, the solution is stirred for one hour under reflux and 15 hours at 50°C. Cool and evaporate under reduced pressure to dryness. The residue, an oil, is chromatographed on 250 g of silica gel. Fractions 1-5 eluted with each time 300 ml of chloroform are discarded. Fractions 6-8 are eluted each time with 300 ml of chloroform, combined and evaporated to dryness under reduced pressure. The residue, dimethyl-malonic acid mono-ethyl ester [α-nicotinoyl-benzyl]-ester is present as ol j-e.

Analogously, methyl-malonic acid mono-ethyl ester [α-nicotinoyl-benzyl]-ester (oil) is obtained, when starting from α-bromo-benzyl-(3-pyridyl)-ketone hydrobromide and methyl-malonic acid mono -ethyl ester sodium salt. Malonic acid mono-ethyl ester [α-nicotinoyl-benzyl]-ester (oil), starting from α-bromo-benzyl-(3-pyridyl)-ketone hydrobromide and malonic acid mono-ethyl ester sodium salt.

Example 10

A mixture of 6.5 g of dimethyl-malonic acid mono-ethyl ester [α-nicotinoyl-benzyl]-ester, 4.8 g of ammonium acetate and 50 ml of glacial acetic acid are mixed with stirring for 2 hours at a bath temperature of 140°C. It is cooled, the reaction mixture is poured into 400 ml of ice water and adjusted to pH 8.0 with concentrated aqueous ammonia solution. It is 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 phases are dried over magnesium sulfate and evaporated under reduced pressure to dryness. The residue is chromatographed on 300 g of silica gel. Fraction 1 eluted with 300 ml of chloroform is discarded. Fractions 2-4 eluted with 300 ml of chloroform each time are combined and evaporated under reduced pressure to dryness. The residue is expelled with petroleum ether. The separated crystals are filtered off and washed with cold petroleum ether. 2-[4-Phenyl-5-(3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid ethyl ester melts at 70-71°C.

The fractions 5-10 eluted with each time 300 ml of chloroform are discarded. Fractions 11-15, eluted each time with 300 ml of chloroform, are combined and evaporated to dryness under reduced pressure. The residue, 2-[4-(3-pyridyl)-5-phenyl-oxazol-2-yl]-2-methyl-propionic acid ethyl ester, is crystallized by extraction with cold petroleum ester. Melting point 41-42°C.

Analogously available: 2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl]-propionic acid ethyl ester (oil) and 2-[4-(3-pyridyl)-5-phenyl-oxazol-2-yl ]-propionic acid ethyl ester (oil), starting from methyl-malonic acid mono-ethyl ester [α-nicotinoyl-benzyl]-ester.

2-[4-Phenyl-5-(3-pyridyl)-oxazol-2-yl]-acetic acid ethyl ester (oil) and 2-[4-(3-pyridyl-5-phenyl-oxazol-2-yl]-acetic acid-

ethyl ester (oil) starting from malonic acid mono-ethyl ester [α-nicotinoyl-benzyl) ester.

2-[4-Phenyl-5-(3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid tert-butyl ester, oil.

NMR (CDCl 3 ): 8.85 (s, br. H-2'), 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' ), 1.75 (s, according to CH3) and

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

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, according to CH3),

starting from malonic acid mono-tert-butyl ester [α-nicotinoyl-benzyl] ester.

Example 11

Analogous to example 4 is obtained: 2-[4-(1-oxido-3-pyridyl)-5-phenyl-oxazol-2-yl]-2-methyl-propionic acid ethyl ester (oil), starting from 2-[4- (3-Pyridyl)-5-phenyl-oxazol-2-yl]-2-methyl-propionic acid ethyl ester. Melting point 85-90°C (ether-protrol ether).

2-[4-(1-oxido-3-pyridyl)-5-phenyl-oxazol-2-yl]-propionic acid ethyl ester, starting from 2-[4-(3-pyridyl)-5-phenyl-oxazol- 2-yl]-propionic acid ethyl ester.

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

2-[4-Phenyl-5-(1-oxido-3-pyridyl)-oxazol-2-yl]-2-methylpropionic acid tert-butyl 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 , according to CH3), starting from 2-(4-phenyl-5-(3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid-

tert-butyl ester,

2-[4-(1-oxido-3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid tert-butyl ester, oil, assuming

2-[4-(3-pyridyl)-5-phenyl-oxazol-2-yl]-2-methyl-propionic acid tert-butyl ester.

Example 12

A solution of 6.2 g of α-aminobenzyl-(3-pyridyl) ketone in 100 ml of anhydrous tetrahydrofuran is mixed with stirring and the introduction of nitrogen gas with 8.8 g of dimethylmalonic acid monoethyl ester chloride and 7.2 ml of N,N -diisopropyl-ethylamine. The mixture is stirred for 15 hours and evaporated under reduced pressure to dryness. The residue is chromatographed on 500 g of silica gel. Fractions 1-6 eluted with each time 400 ml of chloroform are discarded. Fractions 7-10, eluted each time with 400 ml of chloroform, are combined and evaporated to dryness under reduced pressure. N-[α-(3-pyridyl)-phenacyl]-dimethyl-malonic acid mono-ethyl ester mono-amide, oil.

Analogously: N-[α-(3-pyridyl)-phenacyl]-methylmalonic acid-mono-ethyl ester-mono-amide (oil), starting from α-amino-benzyl-(3-pyridyl)-ketone and methyl -malonic acid mono-ethyl ester chloride.

N-[α-(3-pyridyl)-phenacyl]-malonic acid mono-ethyl ester mono-amide, starting from α-amino-benzyl-(3-pyridyl)-ketone and malonic acid mono-ethyl ester chloride.

Example 13

A solution of 2.1 g of N-[a-(3-pyridyl)-phenacyl]-dimethyl-malonic acid-mono-ethyl ester-mono-amide in 40 ml of phosphorus oxychloride is heated for 4 hours under reflux. The mixture is cooled and poured over ice. - The secreted oil is extracted with 100

ml of ethyl acetate. The ethyl acetate solution is extracted twice with each time 20 ml of water, twice with each time 20 IN sodium carbonate solution and again with 20 ml of water, dried over sodium sulfate and evaporated under reduced pressure. The residue is chromatographed on 70 g of silica gel. Fractions 1-5 eluted with each time 80 ml of chloroform are discarded. The factions

6-8, eluted with each time 80 ml of chloroform are combined and evaporated to dryness under reduced pressure. The residue is expelled with petroleum ether, as it crystallizes 2-[4-phenyl]-5-(3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid ethyl ester. Melting point 70-71°C.

Prepared analogously: 2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl]-propionic acid ethyl ester (oil), starting from N-[a-(3-pyridyl)-phenacylj-methyl-malonic acid- mono-ethyl ester-mono-amide. 2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl]-acetic acid ethyl ester (oil), starting from N-[a-(3-pyridyl)-phenacyl-malonic acid mono-ethyl ester monoamide. α-Amino-benzyl-(3-pyridyl)-ketone can be prepared in the following way: 10.8 g of benzyl-(3-pyridyl)-ketone are stirred together with 40 ml of pyridine and a solution of 8 g of hydroxylamine hydrochloride in 15 ml of pyridine in 6 hours at 100°C. The reaction mixture is poured onto ice/water and stirred for 15 minutes. The precipitated crystals are suctioned off, washed with water and dried in a high vacuum. Benzyl (3-pyridyl) ketone oxime of melting point 122-126°C is obtained.

To a solution of 8.5 g of benzyl-(3-pyridyl)-ketone oxime in 20 ml of pyridine, stirred at -10°C, a solution of 7.7 g of p-toluenesulfochloride in 15 ml of pyridine is dripped over the course of 5 minutes. The reaction mixture is stored for 24 hours in an icebox and then poured onto ice/water. After some stirring and extraction, the precipitated oil solidifies into crystals. These are suctioned off and washed with water and dried in a high vacuum. Benzyl-(3-pyridyl)-ketone-oxime-p-toluenesulfonic acid ester is obtained, which is used in the next step without further purification.

11.6 g of crude benzyl-(3-pyridyl)-ketone-oxime-p-toluenesulfoester are suspended in 90 ml of absolute ethanol. The solution of 3.7 g of potassium tert-

butylate in 30 ml of absolute ethanol. The reaction mixture is stirred for 2 hours at 0°C. The suspension is suctioned off and the filtrate containing the desired α-amino-benzyl-(3-pyridyl)-ketone is evaporated under reduced pressure to dryness.

Example 14

An ointment containing 5% 2-[4-phenyl-5-(1-oxido-3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid ethyl ester can be prepared as follows:

Composition:

The fats and the emulsifier merge. The preservative is dissolved in water and the solution is emulsified in the fat melt at an elevated temperature. After cooling, a suspension of the active substance is incorporated into part of the fat melt in the emulsion.

Example 15

A cream containing 10% 2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid ethyl ester can be prepared as follows:

Composition:

The acrylic acid polymer is suspended in a mixture of demineralized water and 1,2-propylene glycol. While stirring, triethanolamine is then added, whereby a slime is obtained. A mixture of isopropyl palmitate, cetyl palmitate, silicone oil, sorbitan monostearate and polysorbate is heated to approx. 75°C and incorporated while stirring in it as well until approx. 75°C heated mucus. The cream base, cooled to room temperature, is then used to produce a concentrate with the active substance. The concentrate is homogenised using a continuous homogeniser and then added in portions to the base.

Example 16

A cream containing 5% 2-[4-phenyl-5-(1-oxido-3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid ethyl ester can be obtained as follows:

Composition

Cetyl alcohol, cetyl palmitate, the triglyceride mixture, stearic acid and glycerine stearate are combined. The microcrystalline cellulose is dispersed in part of the water. In the remaining water part, cetomacrogol and propylene glycol are dissolved and the slime is mixed to this. The fat phase is then added to the water phase under stirring and stirred cold. Finally, the active substance is expelled with part of the base and then the expelled substance is incorporated into the rest of the cream.

Example 17

A transparent hydrogel containing 5% 2-[4-phenyl-5-(1-oxido-3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid ethyl ester is prepared as follows:

Composition:

The hydroxypropyl methyl cellulose swells in water. The active substance is dissolved in a mixture of isopropanol and propylene glycol. The active substance solution is then mixed with a swollen cellulose derivative and, if desired, mixed with odorants (0.1%).

Example 18

A transparent hydrogel containing 5% 2-[4-phenyl-5-(1-oxido-3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid ethyl ester is prepared as follows:

Composition:

The acrylic acid polymer and water are dispersed and neutralized with triethanolamine. The active substance is dissolved in a mixture of isopropanol and propylene glycol. The active substance solution is then mixed with the gel, whereby, if desired,

fragrance (0.1%) can be added.

Example 19

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

Composition:

Cetyl alcohol, paraffin oil, isopropyl myristate, cetomacrogol and sorbitan esterate are combined. Methyl and propyl paraben dissolve in warm water. The melt and the solution are then mixed. The active substance suspended in propylene glycol is incorporated into the foundation. Chemoderm is then added and supplemented with water to the final weight.

Filling:

20 ml of the mixture is filled into an aluminum block box. The box is equipped with a valve and the propellant gas is filled in under pressure.

Example 20

A mixture of 4.0 g of α-hydroxyphenyl-[(3-pyridyl)-methyl]-ketone and 0.6 ml of triethylamine in 70 ml of anhydrous benzene is mixed with stirring and introduction of nitrogen at 10°C with a solution of 3, 7 g of 2-ethoxymethyl-2-methyl-propionic acid chloride in 20 ml of anhydrous benzene during 20 minutes. The mixture is then stirred for 3 hours at room temperature, mixed with 30 ml of ethyl acetate and 60 ml of water and stirred again

one hour at room temperature. The aqueous phase is separated and washed twice with 20 ml of ethyl acetate each time. The combined organic phases are washed with 20 ml saturated sodium chloride solution, 20 ml 2N potassium bicarbonate solution and again 20

ml saturated sodium chloride solution, dried over magnesium sulphate and evaporated under reduced pressure. The residue (2-ethoxymethyl-2-methyl-propionic acid-[a-benzoyl-(3-pyridy1-methyl)]-ester, (oil), is dissolved in 40 ml of glacial acetic acid, 4.1 g of ammonium acetate is added and the mixture is heated with stirring for 2 hours at a bath temperature of 140° C. The reaction mixture is cooled, poured into 150 ml of ice water and adjusted with concentrated aqueous ammonia solution to pH 8.0. It is extracted three times with 100 ml of ethyl acetate each time and the ethyl acetate extracts are washed twice with each time 20 ml of water. The combined organic phases are dried over magnesium sulfate and evaporated under reduced pressure to dryness. The residue is chromatographed on 150 g of silica gel. Fractions 1-5 eluted with each time 150 ml of chloroform are discarded. Fractions 6-9 eluted with each time 150 ml of chloroform combine and evaporate under reduced pressure to dryness.The residue, 2-[4-(phenyl-5-(3-pyridyl)-oxazol-2-yl]-2-methyl-1-ethoxy-propane, is present as an oil.

Example 21

A solution of 2.0 g of (2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl]-2-methyl-1-ethoxy-propane in 40 ml of acetone and 12 ml of water is mixed at room temperature with vigorous stirring in portions with potassium permanganate, until no more discoloration is observed. The mixture is then stirred for 10 hours at room temperature and then filtered off. The filtrate is evaporated below 11 torr at 50°C to dryness. The residue is mixed with 150 ml of ice water and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue is chromatographed on 70 g of silica gel. Fractions 1-3 eluted with each time 50 ml of chloroform are discarded. Fractions 4-8 eluted with each time 50 ml of chloroform are combined and evaporated to dryness under reduced pressure. The residue is extracted with cold petroleum ether. After standing overnight, the separated crystals are filtered off. 2-[ 4-phenyl-5-(3-pyridyl)-oxazol-2-yl]-2 -methyl-propionic acid ethyl ester melts at 70-71°C.

Example 22

A mixture of 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 in 30 ml of methylene chloride is mixed at room temperature with good stirring and introduction of nitrogen with 0.7 g of dicyclohexylcarbodiimide. Stir for 48 hours at room temperature, add 40 ml of toluene and filter off. The filtrate is evaporated under reduced pressure to dryness. The residue is dissolved in 20 ml of methylene chloride. The methylene chloride solution is washed with 5 ml of 0.1N sodium carbonate solution and 5 ml of water, dried over magnesium sulphate and evaporated under reduced pressure to dryness. The residue 2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid-2-[2-(2-methoxyethoxy)-ethoxy]-ethyl ester is present as an oil.

NMR (CDCl 3 ): 8.85 (s, br, H-2'), 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'), 1.75 (s, according to CH3) .

Analogously obtained: 2-[4-phenyl-5-(1-oxido-3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid-2-[2-(2-methoxyethoxy)-ethoxy]-ethyl ester folje), NMR (CDCl 3 ): 8.39 (t, H-2'), 8.03 (dt, H-6'), 7.10 (dd, H-5<1>), 7.2- 7.6 (m, other aromatic H), 1.65 (s, according to CH3), and

2-[4-Phenyl-5-(1-oxido-3-pyridyl)-oxazol-2-yl]-2-methyl-propionic 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<1>), 7.2-7.6 (m, other aromatic H), 1.65 (s, according to CH3),

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

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

NMR (CDCl 3 ): 8.85 (s, br, H-2'), 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'), 1.75 (s, according to CH3),

starting from 2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid and triethylene glycol.

Example 23

A solution of 1.43 g of diethylene glycol monochlorohydrin in 6 ml of hexamethylphosphoric triamide is mixed at 50-60°C with stirring with 3.46 g of 2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl]- 2-Methylpropionic acid sodium salt. The mixture is stirred for 4 hours at 100°C, cooled and poured into 50 ml of ice water. The separated oil is extracted with 100 ml of ether. The ether phase is washed with 20 ml of water, 20 ml of 2N potassium bicarbonate solution and again 20 ml of water, dried over magnesium sulphate and evaporated under reduced pressure. The residue is chromatographed on 100 g of silica gel. Fractions 1-3, eluted with each time 80 ml of chloroform are discarded. Fractions 4-6, eluted each time with 80 ml of chloroform, are combined and evaporated under reduced pressure to dryness. The residue 2-[4-phenyl-5-(1-oxido-3-pyridyl)oxazol-2-yl]-2-methyl-propionic acid-[2-(2-hydroxyethoxy)-ethyl]-ester is present as an 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, according to CH3 ) .

Analogously, one obtains: 2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl]-2-methyl-propionic 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, H-4"), 7.64 (m, H-2",6"), 7.35-7.45 (m, other aromatic H), 7.18 (dd, H- 5'), 1.75 (s, according to CH3),

starting from 2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid sodium salt and diethylene glycol mono-chlorohydrin.

Claims (45)

1. Trisubstituted oxaza compounds of the general formula, in which one of the residues R- and R2 means heteroaryl and the other carbocyclic aryl or heteroaryl and A means a divalent hydrocarbon residue and R^ means carboxy, esterified or amidated carboxy as well as their isomers and their salts. 2. Compound with formula (I) according to claim 1, with the precaution that R^ resp. R 2 is different from unsubstituted thienyl and from unsubstituted furyl. 3. Compound with formula (I) according to claim 1, in which one of the radicals R 1 and R 2 means a 5- or 6-membered heteroatom nitrogen-containing heteroaryl radical, which can each be unsubstituted or substituted with halogen, lower alkyl, hydroxy, lower alkoxy, and/or lower alkanoyloxy and the other means unsubstituted or with halogen, lower alkyl, hydroxy, lower alkoxy and/or lower alkanoyl substituted phenyl or a 5- or 6-membered, as heteroatom nitrogen-containing heteroaryl residue, which may be unsubstituted or substituted with halogen, lower alkyl, hydroxy . . hydroxypyridine esterified carboxy, carbamoyl or with hydroxy, amino, phenyl or substituted phenyl monosubstituted, with lower alkyl mono- or disubstituted or with 4- to 7-membered alkylene resp. 3-aza-, 3-lower alkylaza-, 3-oxa- or 3-thiaalkylene disubstituted carbamoyl, wherein a lower alkanol can be unsubstituted or can be substituted with hydroxy, mercapto, optionally substituted phenyl, lower alkoxy, optionally in the phenyl part substituted phenyl lower alkyloxy, lower alkylthio , eventuelt i fenyldelen substituert fenyllaverealkyltio, hydroksylaverealkoksy, laverealkoksylaverealkoksy, eventuelt i fenyldelen substituert fenyllaverealkoksylaverealkoksy, hydroksylaverealkoksylaverealkoksy, laverealkoksylaverealkoksylaverealkoksy, eventuelt i fenyldelen substituert fenyllaverealkoksylaverealkoksylaverealkoksy, karboksylaverealkoksy, laverealkoksykarbonyl-laverealkoksy, eventuelt substituert fenylholdig laverealkoksy-karbonyl-laverealkoksy eller laverealkanoyloksy og substituert fenyl, fenol resp. hydroxypyridine can each be substituted with lower alkyl, lower alkoxy, halogen and/or trifluoromethyl as well as their isomers as well as their salts. 4. Compound of formula (I) according to claim 1, in which one of the residues and R2 means pyridyl or 1-oxido-pyridyl which can be unsubstituted and/or each time can be substituted with halogen, hydroxy, lower alkyl, lower alkoxy and/or lower alkanoyloxy and the other means phenyl, pyridyl or 1-oxidopyridyl which may be unsubstituted and/or each substituted by halogen, hydroxy, lower alkyl, lower alkoxy and/or lower alkanoyloxy, A means the lower alkylene with up to 4 C atoms such as methylene, the lower alkylidene with up to and including 7 C atoms such as 2,2-propylidene, lower alkylidene with up to and including 4 C atoms as well as 1,3-propen-2-ylene, lower alkenylidene with up to and including 7 C atoms, such as 1,1-butene -3-ylidene, 3- to 8-membered cycloalkylene such as cyclopropylene, 3- to 8-membered cycloalkylidene as well as cyclopentylidene or cycloalkyl-lower alkylene with up to 7 C atoms in the alkylidene moiety and with a 3- to 8-membered cycloalkyl moiety such as 2 -cyclohexyl-1,1-ethylidene, and R^ means carboxy with a lower alkanol, a 3- il 8-membered cycloalkanol, phenol or a substituted phenol esterified carboxy, carbamoyl, N-mono-, N,N-diloweralkylcarbamoyl, pyrrolidino-, piperidino-, morpholino-, piperazino-, 4-loweralkyl-piperazino-, thiomorpholino-, anilino - or with lower alkyl, lower alkoxy and/or halogen substituted anilino carbonyl, the lower alkanol can be unsubstituted or substituted with hydroxy, mercapto, phenyl, substituted phenyl, lower alkoxy, phenyl lower alkyl, in the phenyl part substituted phenyl lower alkyl, lower alkyl thio, phenyl lower alkyl thio, i fenyldelen substituert fenyllaverealkyltio, hdyroksylavere-alkoksy, laverealkoksylaverealkoksy, fenyllaverealkoksylaverealkoksy, i fenyldelen substituert fenyllaverealkoksylaverealkoksy, hydroksylaverealkoksylaverealkoksy, laverealkoksylaverealkoksylaverealkoksy, eventuelt i fenyldelen substituert fenyllaverealkoksylaverealkoksy, karboksylaverealkoksy, laverealkoksykarbonyl-laverealkoksy, eventuelt substituert fenylholdig laverealkoksykarbonyl-laverealkoksy eller laverealkanoyloksy og substituert fenol resp. phenyl can each be substituted with lower alkyl, lower alkoxy, halogen and/or trifluoromethyl as well as their isomers and salts. 5. Compound of formula (I) according to claim 1, in which one of the radicals R-^ and R2 means unsubstituted or primarily halogen with atomic number up to and including 35 such as chlorine, hydroxy, lower alkyl with up to and including 4 C atoms which methyl and/or lower alkoxy with up to 4 C atoms such as methoxy, substituted phenyl and the other means pyridyl such as 3-pyridyl or 1-oxido-pyridyl such as 1-oxido-3-pyridyl, which is each time unsubstituted or in other series substituted with halogen with atomic number up to and including 35, such as chlorine, hydroxy and/or lower alkoxy with up to and including 4 C atoms such as methoxy, A means the lower alkylene with up to and including 4 C atoms such as methylene, the lower alkylidene with up to and including 7 C atoms such as 2,2-propylidene, lower alkenylidene with up to 7 C atoms such as 1,1-buten-3-ylidene or 3- to 8-membered cyclolower alkylidene such as -1,1-cyclopentylidene and R^ means carboxy, lower alkoxycarbonyl with up to and including 5 C atoms such as ethoxycarbonyl, the lower alkoxycarbonyl may be substituted with lower alkanoyloxy with t 1 and with 5 C atoms, such as pivaloyloxy, hydroxyl-lower-real-oxy-lower-real-oxycarbonyl as 2-(2-hydroxyethoxy)-ethoxycarbonyl, lower-alkyl-lower-real-oxy-lower-real-oxycarbonyl as 2-(2-methoxy-ethoxy)-ethoxycarbonyl, hydroxyl-lower-real-alkyl-lower-real-oxy-lower-real-oxycarbonyl as 2-[ 2- (2-Hydroxyethoxy)-ethoxy ]-ethoxycarbonyl or lower alkoxy-1-averealoxy-lower-alkoxy-lower-alkoxycarbonyl as 2-[2-(2-methoxyethoxy)-ethoxy-ethoxycarbonyl, each time with up to 4 C atoms in the lower alkoxy part as well as their isomers and salts. 6. Compound of formula (I) according to claim 1, in which one of the radicals R-^ and R^ means unsubstituted or in another series with halogen with atomic number up to and including 35 such as chlorine, hydroxy or lower alkoxy with up to and including 4 C atoms as methoxy, substituted phenyl and the other means pyridyl as 3- or 4-pyridyl or 1-oxidopyridyl as 1-oxido-3-pyridyl or 1-oxido-4-pyridyl, A means the lower alkylidene with up to 4 C atoms which 2,2-propylidene, and R 1 means lower alkoxycarbonyl with up to 5 carbon atoms such as ethoxycarbonyl as well as their isomers as well as their salts. 7. Compound of formula (I) according to claim 1, wherein phenyl means, R₁ means 1-oxidopyridyl such as 1-oxido-3-pyridyl, A means 2,2-propylidene and R₁ means lower alkoxycarbonyl with up to 5 C- atoms such as ethoxycarbonyl as well as their isomers and salts. 8. 2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid ethyl ester or a salt thereof. 9. 2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl]-propionic acid ethyl ester or a salt thereof. 10. 2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl]-acetic acid ethyl ester or a salt thereof. 11. 2-[4-phenyl-5-(1-oxido-3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid ethyl ester. 12 . 2-[4-(4-phenyl-5-(1-oxidol-.3-pyridyl)-oxazol-2-yl]-propionic acid ethyl ester. 13. 2-[4-phenyl-5-(1-oxido-3-pyridyl)-oxazol-2-yl]-acetic acid ethyl ester. 14. 2-[4-phenyl-5-(1-oxido-3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid or a salt thereof. 15. 2-[4-phenyl-5-(1-oxido-3-pyridyl)-oxazol-2-yl]-propionic acid or a salt thereof. 16. 2-[4-phenyl-5-(1-oxido-3-pyridyl)-oxazol-2-yl]-acetic acid or a salt thereof. 17. 2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid. 18. 2-[4-(3-pyridyl)-5-phenyl-oxazol-2-yl]-2-methyl-propionic acid ethyl ester. 19. 2-[4-(3-pyridyl)-5-phenyl-oxazol-2-yl]-propionic acid ethyl ester. 20. 2-[4-(3-pyridyl)-5-phenyl-oxazol-2-yl]-acetic acid ethyl ester. 21. 2-[4-(1-oxido-3-pyridyl)-5-phenyl-oxazol-2-yl]-2-methyl-propionic acid ethyl ester. 22. 2-[4-(1-oxido-3-pyridyl)-5-phenyl-oxazol-2-yl]-propionic acid ethyl ester. 23. 2-[4-(1-oxido-3-pyridyl)-5-phenyl-oxazol-2-yl]-acetic acid ethyl ester-. 24. 2-[4-phenyl-5(4)-(3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid tert-butyl ester or a salt thereof. 25. 2-[4-(3-pyridyl)-5-phenyl-oxazol-2-yl]-2-methyl-propionic acid tert-butyl ester or a salt thereof. 26. 2-[4-Phenyl-5-(1-oxido-3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid^tert-butyl ester. 27. 2-[4-(1-oxido-3-pyridyl)-5-phenyl-oxazol-2-yl]-2-methyl-propionic acid tert-butyl ester. 28. 2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid-2-[2-(2-methoxyethoxy)-ethoxy]-ethyl ester or a salt thereof. 29. 2-[4-Phenyl-5-(1-oxido-3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid 2-[2-(2-methoxyethoxy)-ethoxy]-ethyl ester. 30. 2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid-2-(2-hydroxyethoxy)-ethyl ester or a salt thereof. 31. 2-[4-Phenyl-5-(1-oxido-3-pyridyl)-oxazol-2-yl)-2-methyl-propionic acid 2-(2-hydroxyethoxy)-ethyl ester. 32. 2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid-2-[2-(2-hydroxyethoxy)-ethoxy]-ethyl ester or a salt thereof. 33. 2-[4-Phenyl-5-(1-oxido-3-pyridyl)-oxazol-2-yl]-2-methyl-propionic acid 2-[2-(2-hydroxyethoxy)-ethoxy]-ethyl ester. 34. Compound according to one of the claims 1 to 33 with an effect as an external skin phlogistic. 35. Pharmaceutical preparations containing at least one compound according to one of claims 1 to 34 in addition to usual excipients and carriers. 36. Method for producing a compound of formula (I) according to claim 1, characterized in that a compound of formula a tautomer and/or salt thereof, of which one of the residues X-, and X^ means optionally substituted imino and the other oxy or optionally substituted imino, is cyclized or, in which X-^ means oxy and X2 means oxo is cyclized during condensation or a compound with formula or a salt thereof is reduced to a compound of formula (I) or to a compound of formula where R^ ' means a residue transferable to R^, the residue R^<1> is transferred to a residue R^ and if desired, a free compound of formula (I) formed according to the method is transferred to another free compound, a free compound obtained according to the method is transferred to a salt or a salt obtained according to the method is transferred in another salt or to a free compound and if desired, an isomer mixture obtained according to the method is divided into its components. 37. Method according to claim 36, characterized in that the starting point is a compound obtained as an intermediate step and the missing steps are carried out or a starting substance is used in the form of a salt isomer and/or racemate resp. antipodes or are formed under the reaction conditions. 38. Method according to one of claims 36 and 37, characterized in that a compound of formula a tautomer and/or a salt thereof, in which Y means optionally functionally modified hydroxy is reacted with a compound of formula R.j-A-Y2 (Ilb), in which Y2 at least means a nitrogen-containing functionally modified carboxy or a salt thereof or a compound of formula (Ila), a tautomer and/or a salt thereof, in which Y^ means amino is reacted with a compound of formula (Ilb), in which Y2 means optionally functionally modified carboxy or a salt thereof, optionally in the presence of a condensing agent or compounds of formula in which Y^ means optionally reactive esterified hydroxy is reacted with carboxylic acids of the formula R^ -A-COOH (lic), their salts or their functional derivatives and with ammonia, or compounds of the formula which is obtained by condensation of compounds of formula (Ila) with possibly functional derivatives of compounds of formula (Ic) is reacted with ammonia. 39. Method according to one of claims 36 and 37, characterized in that it starts from compounds of formula (IV) or their salts, in which ' means a solvolytically to R^ transferable residue, R^ 1 is transferred by means of solvolysis to R^ or in which R^' means an oxidative to R^ transferable residue, R^<1> is transferred by oxidation to R-j. 40. Process for the production of pharmaceutical preparations, characterized in that at least one compound according to one of claims 1 to 34 is transferred into a suitable application form, possibly using common excipients and carriers. 41. Method according to one of claims 1 to 35 for therapeutic treatment of humans or animals. 42. Use of compounds according to one of claims 1 to 34 in a method for treating inflamed dermatoses. 43. The new compounds mentioned in Examples 1 to 13 and 20 to 27. 44. The method according to examples 1 to 27 and the new compounds obtained therefrom. 45. The method according to one of claims 36 to 39 used new starting materials and/or intermediate products.