NO833349L - TRISUBSTITUTED DIAZAD DERIVATIVES - Google Patents

Description

The invention relates to new substituted diaza compounds, especially compounds of the general formula I

in which R₂ and R₂ independently of each other mean carbocyclic aryl and/or heteroaryl, A means a divalent hydrocarbon-

residue and R^ means formyl or acetalized formyl, their isomers and their salts, especially pharmaceutically usable salts, as well as methods for their preparation, pharmaceutical preparations containing such compounds and their use, e.g. as an active drug 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, in that at least one ring member means a hetero atom such as a nitrogen, oxygen or sulfur atom, in that a nitrogen atom can also optionally be present in oxidized form. Such 5-membered residues are e.g. pyrrolyl such as 2-pyrrolyl,

furyl as 2-furyl, thienyl as 2- or 3-thienyl.

As a 6-membered heteroaryl, there is e.g. in speech pyridyl,

as 2-, 3- or 4-pyridyl, 1-oxidopyridyl as 1-oxido-3-pyridyl or 1-oxido-4-pyridyl and pyrimidyl as T^pyrimidyl.

As substituents of carbocyclic aryl such as phenyl resp. heteroaryl such as pyridyl or 1-oxido-pyridyl, for example halogen, lower alkyl, hydroxy, lower alkoxy and/or acyloxy. 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.

Examples of divalent aliphatic hydrocarbon residues include 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 a monocyclic 3- to 8-membered cycloaliphatic residue as a cycloaliphatic residue and as an aliphatic lower alkylidene such as cyclo-.alkyl-lower alkylidene.

By acetalized formyl is meant, for example, an aliphatic alcohol such as a lower alkenol, a lower alkenediol or especially a lower alkanol such as a lower alkanediol, acetalized formyl for example dimethoxy-, methoxy-ethoxy-, diethoxy-formyl or methylenedioxy-, ethylenedioxy-methyl.

By "lower" organic residues and compounds are preferably understood those which contain up to and including 7, above all up to and including 4 carbon atoms (C atoms).

The general definitions used above and below have, within the scope of the invention, primarily the following meanings: Halogen is e.g. halogen up to and including atomic number 35 such 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 a cyclohexylene.

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

The cycloalkyl-lower alkylidene is e.g. a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexylmethylene, -ethylidene or -propylidene, 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 compounds of formula I according to the invention are preferably pharmaceutically acceptable salts as pharmaceutically usable acid addition salts, 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 using hydroxy and/or oxo substituted carboxylic acids or with sulphonic acid, for example sulphates or hydrohalides such as hydrobromide or hydrochlorides, oxalate, malonate, fumarates or maleinates, tartrates, pyruvates or citrates, sulphonates such as methane, benzene or p-toluene sulphonates.

The 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 characteristic can be determined, for example, by the

G. Tonelli, L. Thibault, "Endocrinology", 77, 625 (1965) developed method by means of inhibition of croton oil induced rat ear edema in the normal rat in a dose range of approx. 1 to approx. 100 mg/ml. Thus, for example, for the compound 2-4(5)-phenyl-5(4)-(3-pyridyl)-imidazol-2-yl-acetaldehyde-dimethylacetal in the above-mentioned sample, an EDj-Q value of 18 mg/ml was determined .

The compounds of formula that can be used according to the invention

I is therefore suitable as a medicine, especially external (topical) skin phlogistics for the treatment of inflamed dermatoses of any genesis such as in light skin irritations, contact dermatitis, exanthemas, burns, as well as as mucous skin phlogistics for the treatment of mucosal inflammation, e.g. in eyes, nose, lip, mouth, genital, anal region. Furthermore, the compounds can be used as a sun protection agent.

The invention also relates to the use of the compound according to the invention and their salts for the treatment of inflammation, e.g. of inflammatory diseases of various genesis, as well as for the production of medicines.

The invention relates in particular to compounds of formula I, in which on the one hand R and R 2 independently of each other mean phenyl and/or with halogen, lower alkyl, hydroxy, lower alkoxy and/or lower alkanoyl substituted phenyl or in which on the other hand one of the radicals R ^ and R2 means pyrrolyl, furyl, thienyl, pyridyl, 1-oxidopyridyl or pyrimidyl which is each unsubstituted or may be substituted with halogen, lower alkyl, hydroxyl, lower alkoxy and/or lower alkanoyloxy and the other means phenyl, pyrrolyl, furyl, thienyl, pyridyl, 1-oxidopyridyl or pyrimidyl which can each be unsubstituted or substituted with halogen, lower alkyl, hydroxy, lower alkoxy and/or lower alkanoyloxy and each time A means the lower alkylene, lower alkylidene, lower alkenylene, lower alkenylidene, cycloalkylene, cycloalkylidene or cycloalkyl-lower alkylidene and R-j means formyl or formyl acetalized with an aliphatic alcohol, their isomers as well as their salts, especially pharmaceutically acceptable s altar.

The invention relates in particular to compounds of formula I, in which R 1 and R 2 independently of each other mean phenyl and/or phenyl substituted with halogen, hydroxy, lower alkyl, lower alkoxy and/or lower alkanoyloxy, A means the lower alkylene with up to 4 C atoms such as methylene, lower alkylidene with up to and including 7 C atoms such as 2,2-propylidene, the lower alkenylene with up to and including 4 C atoms such as 1,3-propen-2-ylene, the lower alkenylidene with up to and including 7 C atoms such as 1,1-butene -3-ylidene,

to the 8-membered cycloalkylene such as cyclopropylene, the 3- to 8-membered cycloalkylidene such as cyclopentylidene or the cycloalkyl lower alkylidene with up to and including .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 formyl or with a lower alkanol, lower alkenol, lower alkanediol or lower alkenediol acetalized formyl, their isomers as well as their salts, especially pharmaceutically usable salts.

The invention relates in particular to compounds of formula I, in which one of the radicals R-1 and R2 is pyridyl or 1-oxido-pyridyl, which may be substituted and/or may each 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 time may be substituted with halogen, hydroxy, lower alkyl, lower alkoxy and/or lower alkanoyloxy, A means the lower alkylene with up to 4 C atoms<*>' as methylene, the lower alkylidene of up to and including 7 C atoms, as 2,2-propylidene, the lower alkenylene of up to and including 7 C atoms as 1,3-propen-2-ylene, the lower alkenylidene of up to and including 4 C atoms as The 1,1-buten-3-ylidene, the 3- to 8-membered cycloalkylene such as cyclopropylene, the 3- to 8-membered cycloalkylidene such as cyclopentylidene or the cycloalkyl-lower alkylidene with up to and including 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 with a lower lkanol, lower alkenol, lower alkanediol or lower alkenediol acetalized formyl, their isomers as well as their salts especially pharmaceutically usable salts.

The invention relates in particular to compounds of formula I, in which R₂ and R₂ independently of each other mean phenyl and/or with halogen with atomic number up to and including 35 such as chlorine, hydroxy, lower alkyl with up to and including 4 C atoms such as methyl and/or lower alkoxy with up to and with 4 C atoms such as methoxy, substituted phenyl, A means the lower alkylene of up to and including 4 C atoms such as methylene, the lower alkylidene of up to and including 7 C atoms, such as 2,2-propylidene, the lower alkenylidene of up to and including 7 C atoms -atoms such as 1,1-buten-3-ylidene or the 3- to 8-membered cyclolower alkylidene such as 1,1-cyclopentylidene, and R^ means formyl or lower alkoxy-methyl each time with up to 4 C atoms in the lower alkoxy part such as dimethoxy -methyl or lower alkenedioxymethyl with addition of 4 C atoms in the lower alkylene part such as 1,3-dioxolan-2-yl, their isomers as well as their salts, especially pharmaceutically usable salts.

The invention relates in particular to compounds of formula I, in which one of the radicals R 1 and R 2 means phenyl or with halogen with atomic number up to and including 3 5 such as chlorine, hydroxy, lower alkyl with up to and including 4 C atoms such as methyl, and/or lower alkoxy with up to and with 4 C atoms as methoxy, substituted phenyl and the other means pyridyl as 3-pyridyl or 1-oxido-pyridyl as 1-oxido-3-pyridyl which can each be unsubstituted or substituted with halogen of atomic number 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^ denotes formyl or dilavereal oxymethyl each time with

up to 4 C atoms in the lower alkyl moiety such as dimethoxymethyl, or lower alkylenedioxymethyl with up to 4 C atoms in the lower alkylene moiety such as 1,3-dioxolan-2-yl, their isomers

as well as their salts, especially pharmaceutically usable salts.

The invention relates in particular to compounds of formula I, in which R, and R2 independently of each other mean phenyl and/or with lower alkoxy with up to and including 4 C atoms such as methoxy substituted phenyl, A means lower alkylene with up to and including 4 C atoms such as methylene or in particular the lower alkylidene with up to 4 C atoms such as 2,2-propylidene and R^ means formyl or dilavereal oxymethyl each time with up to 4 C atoms in the lower alkoxy part, such as diethoxymethyl or lower alkylenedioxymethyl with up to 4 C atoms in the lower alkylene moiety, such as 1,3-dioxolan-2-yl, their isomers as well as their salts, especially pharmaceutically acceptable salts.

The invention primarily relates to compounds of formula I, in which one of the radicals R^ and R^ means phenyl or 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 such as methoxy, substituted phenyl and the other means pyridyl such as 3- or 4-pyridyl or 1-oxidopyridyl such as 1-oxido-3-pyridyl or 1-oxido-4-pyridyl, A means the lower alkylidene with up to 4 C atoms such as 2,2-propylidene and R^ means formyl or dilavereal oxymethyl, each time with up to 4 C atoms in the lower alkoxy part as diethoxymethyl or lower alkylenedioxymethyl with up to 4 C atoms in the lower alkylene part as 1,3-dioxolan-2-yl, their isomers as well as their salts especially pharmaceutically usable salts.

The invention primarily relates to compounds of formula I, in which one of the radicals R-^ and R 2 means phenyl or^-with halogen with atomic number up to and including 3 5 such as chlorine, hydroxy or lower alkoxy with up to and including 4 C atoms such as methoxy substituted phenyl and the other means pyridyl such as 3- or 4-pyridyl or 1-oxidopyridyl' such as 1-oxido-3-pyridyl or 1-oxido-4-pyridyl, A means the lower alkylidene of up to 4 C atoms having a quaternary C atom such as 2,2-propylidene, the quaternary C atom being bound directly to the imidazole ring and R^ means formyl or dilavereal oxymethyl with up to and including 4 C atoms, each time in the lower alkyl part as diethoxymethyl, their isomers as well as their salts, especially pharmaceutically usable salts.

The invention primarily relates to compounds of formula I, in which one of the radicals R 1 and R 2 means phenyl and the other pyridyl such as 3-pyridyl or 1-oxidopyridyl such as 1-oxido-3-pyridyl, A means 2,2-propylidene and R ^ means formyl or dilavereal oxymethyl each time with up to 4 C atoms in lower alkyl such as diethoxymethyl, their isomers as well as their salts, especially pharmaceutically usable 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 topically applicable pharmaceutical preparations listed in the examples.

The invention likewise relates to methods for the preparation of the compounds of formula I and their salts, in particular pharmaceutically usable salts of such compounds with salt-forming groups, as well as the preparation methods listed in the examples.

The compounds of formula I or their salts can be prepared in a manner known per se.

A method variant consists, for example, in that from

a compound with formula

in which one of the residues Y^ and Yg means hydroxy or amino and the other and Y2 means hydrogen and Y^ means together with Y^ and Y^- a group of formula • =N- or in which Y, together with Yg means a bond, Y2 means hdyrogen, Y^means hydroxy or amino and Y^means together with Y^ a group of formula

-NH- or wherein Y, together with Yg means a bond, Y2

together with Y^ means an additional bond and one of the residues Y^

and Yj- means amino and the other amino, hydroxy or reactive esterified hydroxy, especially halogen or sulfonyloxy, or in which Y-^ means hydroxy, Y2 and Y^ means hydrogen, Y^ means hydroxy or amino and Y^ means together with Yg a group with formula =NH or if Y^means amino, means oxo or imino, or a tautomer and/or salt thereof, is cleaved with the introduction of an optional additional bond H-Z and, if desired, the compound obtained according to the method is transferred to another compound of formula I, a free compound obtained according to the method is transferred in a salt or a salt obtained according to the method in the free compound or in another salt and/or if desired, a mixture of isomeric compounds with formula I obtained according to the invention is divided into the individual isomers.

Here Z means hydroxy or amino, Y^resp. Yg, Y^or

Y^resp. Yj- or halogen resp. sulfonyloxy Y^ resp. Y^.

Reactive esterified hydroxy is, for example, with an inorganic mineral acid such as halogen hydrogen acid or with an organic sulfonic acid such as lower alkane or optionally substituted benzenesulfonic acid esterified hydroxy and primarily means halogen, e.g. fluorine or bromine and sulphonyloxy, e.g. methane- or p-toluenesulfonyloxy.

Tautomers of compounds of formula II are, for example, those in which there are partial enol- or enamine grouping with formula in which Y-^ together with Yg means an additional bond and Y^ means hydroxyl or amino in the form of the corresponding tautomeric keto- or ketimine form, in which Y, means hydrogen and Y,- together with Yg means oxo or imino and/or such in which there are partial enol- or enamine grouping of formula

in which Y2 together with Y^means a bond and Y^means hydroxy or amino, in the form of the corresponding tautomeric form, in which Y2 means hydrogen and Y^ together with Y^ means oxo or imino, as the mentioned tautomers are in equilibrium with each other.

The cleavage of H-Z from a compound of formula II, a tautomer and/or salt thereof takes place in the usual way, in particular 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. Suitable acids are, for example, inorganic acids such as mineral acids, e.g. sulfuric acid, polyphosphoric acid or hydrohalic acid such as hydrochloric acid or organic acids such as lower alkane carboxylic acid e.g. acetic acid. Thereby, if necessary, one works in an inert solvent, for example any halogenated hydrogen such as chloroform, chlorobenzene, hexane or toluene, a lower alkanol such as methanol or ethanol,

a carboxylic acid amide such as a lower alkane carboxylic acid amide e.g. dimethylformamide or formamide or a lower alkanecarboxyl-

acid such as formic or acetic acid and/or under inert

gas such as nitrogen.

The starting substances with formula II, their tautomers and/or salts are formed according to methods known per se for a predominant part in situ and are reacted under the reaction conditions without isolation further to compounds with formula I. Thereby, the cleavage of H-Z during direct cyclization or in connection with to a preceding cyclization.

Thus, in a preferred embodiment of the above-mentioned method, for example, one can react an acylated ct-amino ketone with the formula

or a salt thereof with ammonia. Thereby one works, for example, during heating, e.g. in a temperature range from approx. 50°C to approx. 250°C and under inert conditions. The starting materials with formula (Illa) are known or are prepared according to procedures known per se. For example, one starts from a compound of formula or a salt thereof and reacts this with an acid derivative of formula R^-A-COOH (Ille), for example a corresponding anhydride, such as a halogenocarbonyl compound. In a further, particularly preferred variant of the method described at the outset, a compound of the formula in which Z, optionally represents a reactive esterified hydroxy or a salt thereof, is reacted with a compound of the formula •

in which Z2 denotes an amidino residue or ammonium carboxylate or a salt thereof optionally with ammonia.

The reaction with an amidine of formula (Ille) usually takes place under heating, for example in a temperature range from approx. 50°C to approx. 250°C.

The reaction of the ammonium carboxylate of formula (Ille) with

a compound of formula (Uld) is carried out with at least a 3-molar or, if the compound of formula (Uld) is in salt form, at least a 4-molar excess of the ammonium salt of the compound of formula (Ille), possibly under heating, e.g. in a temperature range from approx. 50°C to approx. 250°C, preferably at 90°C to 120°C, the compound of formula (Ille) can simultaneously serve as a solvent. This variant can, for example, also be modified so that one uses the ammonium salt of formula Ille, in relation to -the reactive ester Z^ in an approximately equimolar amount and in addition ammonia is optionally added in the form of a salt of an acid weaker than R^-COOH, in excess amount, preferably in 3- to 5-fold excess.

A reactive esterified hydroxy group Z-^ is, for example, one preferably with strong inorganic or organic acids such as strong mineral acids, e.g. halohydrogen acids such as hydrochloric or hydrobromic acid or strong organic sulphonic acids such as corresponding lower alkane or aryl sulphonic acids, e.g. methane or an optionally substituted benzenesulfonic acid, esterified hydroxy group and means e.g. halogen such as chlorine or bromine, lower alkylsulfonyloxy, e.g. methyl or ethylsulfonyloxy or arylsulfonyloxy, e.g. p-toluene or benzenesulfonyloxy.

The ammonium salt of formula Ille can also be formed in situ under the reaction conditions, for example by having the free acid of formula Ille in the reaction mixture and mixing with liquid or gaseous ammonia. In this embodiment, the ammonia can also be added in the form of a salt with a weaker acid compared to R^-A-COOH, such as carbonic acid. Suitable solvents include e.g. in terms of optionally halogenated hydrocarbons such as optionally halogenated aliphatic cycloaliphatic or aromatic hydrocarbons such as hexane, cyclohexane, toluene, chloroform or chlorobenzene, alkanols such as propanol, isopropanol, butanols, pentanols or octanols, ethers such as dimethoxyethane, ethylene glycol mono-ethyl ether, dioxane or tetrahydrofuran, lower alkane carboxylic acids such as formic acid or acetic acid - or preferably acids of formula III, amides such as lower alkanecarboxylic acid amides, e.g. formamides or dimethylformamide as well as lactams, e.g. N-methylpyrrolidone, sulfoxides such as dimethyl sulfoxide or water.

A preferred embodiment of this variant for the preparation according to the invention of a compound of formula I over a compound of formula II consists in reacting a compound of formula Uld, in which Z-^ for example means halogen, such as bromine, with an ammonium salt of formula Ille at a reaction temperature of around 100°C. The compound with formula Ille is added in excess, for example in a ratio in relation to the ester with formula Uld of approx. 4:1 to approx. 6:1 and allows it to form in situ, as one e.g. reacts the corresponding acid under the reaction conditions with liquid ammonia.

The starting materials with the formula Wool are known or can be produced according to known methods.

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

.is brominated, for example, and thus transferred in a compound with formula Uld, resp. a salt, e.g. hydrohalide thereof, wherein Z- means bromine. Moreover, in a further preferred embodiment, an oxazole with formula can be reacted

with ammonia over compound of formula II to compound of formula I.

This reaction is possibly carried out under pressure, for example at 185 ato and/or heating e.g. from-approx. 100°C to approx. 250°C.

The compounds of formula Hig, on the other hand, can be prepared according to methods known in and of themselves, for example by reacting compounds of formula in which Z^ denotes optionally reactive esterified hydroxy with a carboxylic acid of formula R^-A-COOH (Ille), a functional derivative or salt thereof as a corresponding anhydride, e.g. a halocarbonyl derivative, optionally above a compound of formula

and with ammonia.

Thereby, a compound of formula II is formed each time which, according to the invention, further reacts especially in situ to a compound of formula I.

In a further preferred embodiment of the above-mentioned method, one can for example react the diketone with formula

with an aldehyde of the formula R^-A-C-(=0)-H (lill) or a salt thereof, and with an excess of ammonia under heating. Thereby, for example, a compound of formula II is formed intermediately, e.g. one such, in which means hydroxy, Y~ and Yg means hydrogen and Y^ together with Y^ and Y^ means a group with the formula =N-, e.g.

or a tautomeric form thereof which reacts further according to the invention under the reaction conditions.

Thereby, each time a compound of formula II is formed which further reacts according to the invention especially in situ to a compound of formula I.

Some of the above-mentioned process variants can be carried out using mild conditions so that the compounds of formula II or their tautomers and/or salts can be isolated.

The compounds of formula I or salts thereof can be further prepared by, for example, reducing a compound of formula

or a salt thereof to a compound of formula I and, if desired, transfers the free compound obtained by the method to a salt or a salt obtained according to the method in the free compound or to another salt.

The reduction takes place according to methods known per se. Thus, compounds of formula IV or their salts are treated with hydrogen in the presence of a hydrogenation catalyst or with dithionite, e.g. sodium dithionite or with a phosphorus halide, e.g. phosphorus trichloride. As hydrogenation catalysts, it is possible, for example, to use elements from subgroup VIII as well as derivatives thereof, such as platinum, ""palladium or palladium chloride which are possibly drawn up on a common support material such as activated carbon or an alkaline earth metal compound, e.g. barium carbonate or Raney nickel.

If necessary, the reduction can be carried out during cooling or heating, for example in a temperature range from approx. 0°C 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 above-mentioned production method is carried out

primarily with such compounds of formula IV, wherein means acetalized formyl.

The starting substances with formula IV 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 in situ is reacted with an excess of ammonia and an aldehyde of formula R^-A-C(=0)-H (lill) at an elevated temperature. Compounds of formula I can be further prepared by using a compound of formula

wherein R^' means a residue transferable to R^, transfer the residue R-j1 into a residue R^ and, if desired, transfer the free compound obtained according to the method to a salt or^the salt obtained according to the method to the free compound or another salt.

Such groups R^' are, for example, reductive to the residue R^ transferable groups such as optionally functionally modified carboxy. In particular, carboxy, halocarbonyl, lower alkoxycarbonyl or carbamoyl R^' is transferred by reduction to formyl R^.

The reduction of the aforementioned residues R^' takes place on i and for

known manner, for example using a suitable reducing agent in an inert solvent, possibly during cooling or heating. Thus, for example, halocarbonyl is reduced to formyl with the help of hydrogen on noble metal catalysts such as palladium, which is possibly bound to the support material such as barium sulphate, while the reduction of carboxy to formyl is for example reduced with the help of formic acid or possibly complex hydrides such as lithium-aluminum hydride or lithium-tri-tert -butoxy or lithium triethoxy aluminate. Likewise, lower alkoxycarbonyl or carbamoyl is reductively reduced to formyl by means of suitable or complex hydrides.

Further to R^ transferable groups are, for example, oxidatively transferable residues such as optionally esterified or etherified hydroxymethyl.

Esterified hydroxymethyl is, for example, hydroxymethyl esterified with a mineral acid such as halogen hydrogen, such as hydrochloric acid or a carboxylic acid such as lower alkane carboxylic acid, e.g. acetic acid or optionally substituted benzoic acid. Etherated hydroxymethyl is, for example, etherified with a lower alkanol.

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 alkyl 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. from approx. 0° to approx. 150°C.- Oxidizing agents include, for example, oxidizing transition metal compounds, especially those with the elements from subgroup I, VI, VII or VIII.

Examples include: silver compounds such as silver nitrate,

-oxide or picolinate, chromium compounds such as chromium trioxide or potassium dichromate, manganese compounds such as tetrabutyl-

ammonium or benzyl (triethyl) ammonium permanganate, further iron compounds such as potassium ferrate. In particular, selective oxidizing agents such as pyridinium chlorochromate, a suitable ketone such as cyclohexanone are used in the presence of aluminum tert-butylate or when hydroxymethyl is reactively esterified with p-toluenesulfonyl dimethylsulfoxide.

Thus, for example, hydroxymethyl R is oxidized with bis-tetrabutylammonium dichromate, while e.g. hydroxymethyl R^' esterified with hydrochloric acid is oxidized with 4-dimethyl-amino-pyridine-N-oxide to formyl R^.

Furthermore, in R^ transferable groups R^' are functionally modified formyl groups or formyl protected with protective groups. Functionally modified formyl has as functionally modified oxo, for example thioxo, optionally N-substituted imino, such as N-lower alkyl- or N-phenyl-imino, hydroxy-imino, optionally substituted hydrazono, such as N-tosyl- or N,N-dilower alkyl-hydrazono . Such functionally modified formyl is transferred in the usual way hydrolytically if necessary in the presence of protonic acid to formyl R^. Formyl protected with protective groups is, for example, with a mercaptan such as lower alkanediol or lower alkylenediol or with a mercaptan and alcohol such as lower alkanol or lower alkanethiol or mercaptolower alkanol, acetalized formyl. Furthermore, formyl can be present as di- or tetrahydro-1,3-oxazine, as 3,3,5-trimethyl-1,3-oxazin-2-yl, or as imidazolidine as optionally N-mono- or N,N-disubstituted imidazolidin-2-yl, as well as hemiacetal with an alcohol such as lower alkanol or with a mercaptan such as lower alkanethiol. Corresponding protective groups can be removed oxidatively, hydrolytically, if necessary in the presence of a protonic acid. In particular, corresponding thioacetals resp. -hemiacetals oxidatively, for example under the influence of N-bromosuccinimide, chloramine-T, thallium-(III)-nitrite, heavy metal compounds, e.g. mercury(II) oxide, copper(II) oxide bar chloride or is transferred electrochemically to formyl, while from the corresponding oxazine resp. imidazolidine derivatives as well as hemiacetals are released with lower alkanols, the rest formyl hydrolytically in the presence of strong protonic acids such as mineral acids, e.g. sulfuric acid, hydrohalic acid or phosphoric acids, such as sulphonic acids, e.g. p-toluenesulfonic acid or as carboxylic acids, e.g. glacial acetic acid.

The starting materials with formula V are prepared according to methods known per se. For example, you start from a diketone with formula.

and further reacts this with ammonia and an aldehyde of formula<1->A-C(=0)-H in an inert solvent and under heating to the in situ formed compound of formula V without isolation. The aldehyde with the formula R^-A-C(=0)-H (lill) can, for example, also be released under the reaction conditions from an oxazine derivative with the formula

The compounds of formula V 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 action of sodium borohydride to the tetrahydro-1,3-oxazine of formula V.

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

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

An acetal of formula I obtained according to the method

(R^' = acetalized formyl) can be hydrolyzed in the usual way if necessary in the presence of a suitable hydrolysis agent to an aldehyde of formula I (R^' = optionally hydrated formyl). Suitable hydrolysis agents are, for example, protonic acids such as mineral acids, e.g. hydrochloric or hydrobromic acid, sulfuric or phosphoric acid, or organic carboxylic or sulphonic acids such as lower alkanoic acids, e.g. acetic acid or lower alkyl resp. arylsulfonic acid, e.g. p-toluenesulfonic acid. Conversely, one can transfer to acetals (I, R^<1>= acetalized formyl) an aldehyde obtained according to the method (I, R^'

= formyl) in the usual way, e.g. by reaction with the corresponding alcohol in the presence of an acidic condensation agent such as a mineral acid or organic sulphonic acid, preferably under distillative resp. azeotropic-distillative removal of the reaction water or by reaction with an orthocarboxylic acid ester, e.g. an orthoformic acid lower alkyl ester or with an acetal resp. ketal et e.g. with benzaldehyde dilower-alkyl acetal resp.--lower alkylene acetal resp. an acetophenone dilave alkyl ketal resp. -lower alkylene ketal, preferably in the presence of catalytic amounts of a mineral or sulphonic acid, e.g. of chlorohydrogen or p-toluenesulfonic acid.

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

extra substituents hydroxy, then this can be preferred

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 by hydrating agents such as dicyclohexylcarbodiimide leads to lower alkoxy. Phenols or their salts can 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 sulphates, diazola alkanes or alkyl resp. aryl halides transfer into corresponding lower alkyl phenyl ethers resp. aryl phenyl ethers. Conversely, ethers can be split into alcohols. It occurs, e.g. of alkoxyaryl compounds aromatic alcohols, carrying out the ether cleavage with the help of acids such as mineral acids, e.g. hydrohalic acid as hydrobromic acid or as Lewis acids, e.g. halides of elements from the 3rd main group such as boron tribromide or with the help of bases e.g. lower alkylamines, 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 proton acid such as e.g. chloric, 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 can be solvolysed, e.g. by means of base catalysis to hydroxy.

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

Formed salts can be converted in a manner known per se to the free compounds, e.g. by treatment with an acidic reagent such as a mineral acid or a base, e.g. alkali hydroxide.

Because of the narrow relationship between the new compounds

in free form and in the form of their salts, in the foregoing and the following, free compounds or their salts also possibly mean the corresponding salts or the free connections.

Compounds of formula I can, depending on the choice of starting materials and working methods, exist in the form of one of the possible isomers or as mixtures thereof.

The compounds of formula I including their salts can also be obtained in the form of their hydrates or contain other solvents used for crystallization.

The compounds with formula I can, depending on the choice of starting materials and methods of working, exist in the form of one of the possible isomers or as mixtures thereof, e.g. depending on the number of asymmetric carbon atoms as pure optical isomers such as antipodes or as isomeric mixtures such as racemates, diastereoisomeric mixtures or racemate mixtures, further as tau isomers.

Formed diastereomer mixtures and racemate mixtures can

due to the physico-chemical differences of the constituent parts in a known manner, they are divided into the pure isomers, diastereomers or racemates, for example by means of chromatography and/or fractional crystallization. Formed racemates can be further divided into the optical antipodes according to known methods, for example by recrystallization from 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 are separated in this way formed salts, e.g. because of their different solubilities in the diastereomers, the antipodes of which can be liberated by the action of suitable agents.

Preferably, the most effective of the two antipodes is isolated.

The invention also relates to the embodiments of the method according to which one starts from a compound obtained as an intermediate in one or other step of the method 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 materials with the formulas II, IV and V which are especially developed for the production of the compounds according to the invention, the method for their production and their use are also covered by the invention.

In the case of pharmaceutical preparations containing the compounds produced according to the invention or pharmaceutically usable salts, these are preferably for topical use on warm-blooded animals, the pharmacologically active substance being contained alone or together with a pharmaceutically usable carrier material. The daily dose of the active substance depends on the age and the individual condition as well as the method of application. Corresponding funds with a concentration range from approx. 1 to approx. 10% G/G e.g. in the form of creams, ointments or solutions can, for example, be applied 2-3 times a day.

As topically applicable pharmaceutical preparations it comes

primarily creams, ointments, pastes, foams, tinctures and solutions containing from approx. 0.1 to"<*>approx.

10% of the active substance.

Creams are oil-in-water emulsions that are more than 50% water. Fatty alcohols are primarily used as an oily base, e.g. lauryl, cetyl or stearyl alcohol, fatty acids 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 sorbitan fatty acid esters (Tweens), further polyoxyethylene fatty alcohol ether 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 reduce the drying out of the creams, e.g. polyalcohols, such as glycerol, sorbitol, propylene glycol and/or polyethylene glycols, further preservatives, fragrances etc. Ointments are water-in-oil emulsions containing up to 70%, preferably however from approx. 20% to approx. 50% water or aqueous phases. The fatty phase primarily refers to 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, e.g. cetyl alcohol or wool wax alcohols or wool wax. Emulsifiers are equivalent lipophilic substances such as sorbitan fatty acid esters (Spans), e.g. sorbitan oleate and/or sorbitan isostearate. Additions to the water phase include humectants such as polyalcohols, e.g. glycerol, propylene glycol, sorbitol and/or polyethylene glycol as well as preservatives, fragrances, etc. Fat ointments are anhydrous and contain as a basis in particular hydrocarbons, such as paraffin, vaseline and/or liquid paraffins, further a natural or partially synthetic fat, 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 ointments 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 available 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. Emulsifiers used include 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). In addition, there are the usual additives such as preservatives etc.

Tinctures and solutions mostly have an aqueous-ethanolic base to which, among other things, polyalcohols have been added, e.g. glycerol, glycols and/or polyethylene glycol as humectants to reduce evaporation and re-greasing substances such as fatty acid esters with lower polyethylene glycols, i.e. soluble in water, lipophilic substances as a replacement for the fatty substances that are removed from the skin with ethanol and, if necessary, other aids and additives.

The preparation of the topically applicable pharmaceutical preparations takes place in a manner known per se, e.g. by means of dissolving or suspending the active substance in the base or in 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, after emulsification it is mixed with part of the base and then the rest is added

to the formulation.

The invention will be explained in more detail with the help of some examples, in which the temperature is indicated in degrees Celsius.

Example 1

A mixture of 30.0 g of α-bromo-benzyl-(3-pyridyl)-ketone hydrobromide and 50.0 g of the ammonium salt of malonaldehyde acid dimethyl acetals in 180 ml of anhydrous dimethylformamide is heated with stirring and introduction of nitrogen gas during of four hours at 100°C. The mixture is then cooled and evaporated at 70°C under 11 torr to dryness. The residue is mixed with 100 ml of water and 400 ml of ethyl acetate. By adding a concentrated aqueous ammonia solution, the pH is set to 8.0. The organic phase is separated, washed with 50 ml of water, dried over magnesium sulphate and evaporated to dryness under 11 torr. The residue is chromatographed on 500 g of silica gel. Fractions 1-4, eluted with each time 600 ml of chloroform are discarded. Fractions 5-16, eluted each time with 600 ml of chloroform-methanol (98:2), are combined and evaporated under reduced pressure to dryness. The residue, N-[α-(3-pyridyl)-phenacyl]-malonaldehyde-acid-dimethylacetal-amide is present as a yellow oil.

Fractions 19-24, eluted each time with 600 ml of chloroform-methanol (97:3), are combined and evaporated under reduced pressure to dryness. The residue is crystallized from ether-petroleum ether.

2-[4-(5)-phenyl-5(4)-(3-pyridyl)-imidazol-2-yl]-acetaldehyde dimethylacetal melts at 142-145°C.

The starting material can be prepared as follows:

A mixture of 10.0 g of N-[a-(3-pyridyl)-phenacyl]-malonaldehyde-acid-dimethylacetal-amide, 30.0 g of ammonium acetate and 100 ml of glacial acetic acid is boiled for two hours under reflux and then poured under strong stirring in a mixture of 200 g of ice and 50 ml of concentrated aqueous ammonia solution. The crystal slurry is extracted twice with 150 ml of ethyl acetate each time and the organic phase is washed neutrally with water, dried with magnesium sulphate and evaporated to dryness below 11 torr at 40°C. The residue is chromatographed on 500 g of silica gel. Fractions 1-4, eluted each time with 500 ml of chloroform-methanol (99:1) are discarded. Fractions 5-15, eluted each time with 500 ml of chloroform-methanol (99:2), are combined and evaporated under reduced pressure to dryness. The residue is crystallized from ether-petroleum ether. 2-[4(5)-phenyl-5(4)-(3-pyridyl)-imidazol-2-yl]-acetaldehyde-dimethylacetal melts at 142-145°C.

The starting material is prepared as follows: 19.7 g of malonaldehyde acid dimethyl acetal (V.V. Shikina et al. "J. Gen. Chem." U.S.S.R. 25, 723-725 (1955)) is dissolved in 300 ml of anhydrous ether.

Ammonia gas is introduced into the solution at 0°C over the course of one hour. The mixture is then evaporated under reduced pressure to dryness. The ammonium salt of the malonaldehyde acid dimethyl acetal is present as an oil.

Example 2

A solution of 5.9 g of 2-[4(5)-phenyl-5(4)-(3-pyridyl)-imidazol-2-yl]-acetaldehyde-dimethylacetal in 120 ml of methylene chloride is cooled to 0-5°C and mixed with 3.5 g of m-chloroperbenzoic acid. The mixture is stirred for 24 hours at room temperature. It

yellow solution is then washed twice with each time 20 ml of 2N potassium bicarbonate solution and with 30 ml of water, dried over magnesium sulfate and evaporated at 40°C

under reduced pressure. The residue is dissolved in a little methanol.

After the addition of water, 2-[4(5)-phenyl-5(4)-(1-oxido-3-pyridyl)-imidazol-2-yl]-acetaldehyde dimethylacetal crystallizes. ■*••-

Example 3

A suspension of 3.29 g of 2-[4(5)-phenyl-5(4)-(3-pyridyl)-imidazol-2-yl]-2-methyl-propionic acid sodium salt in 70 ml of anhydrous benzene is added dropwise with stirring during 10 minutes at 5°C 3.2 ml of oxalyl chloride. The mixture is stirred for one hour at 5°C and 15 hours at room temperature, cooled and evaporated to dryness under reduced pressure. The residue is mixed with 70 ml of anhydrous benzene and evaporated again under reduced pressure to dryness. 2-[4(5)-phenyl-4(5)-(3-pyridyl)-imidazol-2-yl]-2-methyl-propionic acid chloride is present as an oil. The acid chloride is unstable and reacts immediately.

3.4 g of freshly prepared 2-[4(5)-phenyl-8(4)-(3-pyridyl)-imidazol-2-yl]-2-methyl-propionic acid chloride are dissolved in 60 ml of diethylene glycol dimethyl ester. The solution is cooled to -75°C and mixed with stirring and introduction of nitrogen gas during 30 minutes with a suspension of 2.54 g of lithium-tri-tert-butoxy-aluminum hydride. The suspension is stirred after the end of dripping, for a further 30 minutes at -70°C and one hour without cooling, as the internal temperature increases to 0°C. The mixture is poured into 500 ml of ice water and filtered through a layer of Hyflo Super Cd. The filtrate is adjusted with concentrated aqueous ammonia solution to pH 8.0. The mixture is shaken with 100 ml of methylene chloride. The water-methylene chloride mixture is filtered through a layer of Hyflo Super Cd. The filtrate is extracted three times with 40 ml of methylene chloride each time. The organic extracts are combined, washed with 50

ml of water and evaporated under reduced pressure to dryness. Then freed at 50°C below 0.1 mm of diethylene glycol dimethyl ether. The residue is chromatographed on a lobar ready-made column (size C, Merck) for low pressure liquid chromatography. Fractions 1-14, eluted with each time 10 ml of chloroform-isopropanol (95:5) are discarded. Fractions 15-29, eluted each time with 10 ml of chloroform-isopropanol (85:15), are combined and evaporated under reduced pressure to dryness. The residue, 2-[4(5)-phenyl-5(4)-(3-pyridyl)-imidazol-2-yl]-2-methyl-propionaldehyde is present as an oil.

NMR (CDCl 3 ): 9.70 (s,CHO), 8.68 (br, H-2' ), 8.34 (dbr, H-6'), 7.85 (dm, H-4<1> ), 7.1-7.5 (m, other aromatic H), 1.60 (s, CH3).

Example 4

In an analogous way as in examples 1-3 as well as corresponding to the way demonstrated in the description, it is possible to obtain: 2-[4(5)-phenyl-5(4)-(3-pyridyl)-imidazol-2-yl]-propanol- dimethyl acetal, oil, NMR (CDC13): 8.72 (br. H-2'),

8.45 (dbr, H-6'), 7.84 (dm, H-4'), 7.1-7.5 (m, other aromatic H), 4.61 (d, CH-O), 3.4 (OCH3), 3.51 (dq, CH-CH3), 1.63 (d, C-CH3),

2-[4(5)-phenyl-5(4)-(3-pyridyl)-imidazol-2-yl]-2-methyl-propanol-dimethyl acetal, oil, NMR (CDCl 3 ): 8.73 (br, H -2<1>), 8.41 (dbr, H-6'), 7.85 (dm, H-4"), 7.1-7.5 (m, other aromatic H), 4.60 ( s, CH), 3.47 (s, OCH3), 1.65 (CCH3); 2-[4(5)-phenyl-5(4)-(1-oxido-3-pyridyl)-imidazole-2- yl]-2-methyl-propanol-dimethylacetol, oil,

2-[4(5)-phenyl-5(4)-(1-oxido-3-pyridyl)-imidazol-2-yl]-2-methyl-propanol-dimethylacetol, oil;

2-[4(5)-phenyl-5(4)-(3-pyridyl)-imidazol-2-yl]-2-methyl-T,1-methylenedioxypropane, oil;

2-[4(5)-phenyl-5(4)-(3-pyridyl)-imidazol-2-yl]-2-methyl-1,1-ethylenedioxypropane, oil;

2-[4(5)-phenyl-5(4)-(3-pyridyl)-imidazol-2-yl]-butyraldehyde, oil;

2-[4(5)-phenyl-5(4)-(3-pyridyl)-imidazol-2-yl]-acetaldehyde, oil;

NMR (CDCl 3 ): 9.70 (s, CHO), 8.71 (br, H-2'), 8.35 (dbr, H-6'), 7.84 (dm, H-4'), 7.1-7.5 (m, other atomic H), 4.03 (s, CH2);

2-[4(5)-phenyl-5(4)-(3-pyridyl)-imidazol-2-yl]-propionaldehyde, oil, NMR (CDCl 3 ): 9.72 (s, CHO), 8, 73 (br, H-2'), 8.40 (br, H-6'), 7.85 (dbr, H-4'), 7.1-7.5 (m, other aromatic H), 3 .97 (q, CHCH 3 ), 1.65 (d, CH 3 ); 2-[4(5)-phenyl-5(4)-(1-oxido-3-pyridyl)-imidazol-2-yl]-acetaldehyde, oil,

2-[4(5)-phenyl-5(4)-(1-oxido-3-pyridyl)-imidazol-2-yl]-propionaldehyde, oil;

2-[4(5)-phenyl-5(4)-(1-oxido-3-pyridyl)-imidazol-2-yl]-2-methyl-propionaldehyde, oil;

2-[4(5)-phenyl-5(4)-(1-oxido-3-pyridyl)-imidazol-2-yl]-butyraldehyde, oil, starting from the corresponding sodium salt of the possible acid above any acid chloride.

Example 5

An ointment, containing 5% 2-[4(5)-phenyl-5(4)-(1-oxido-3-pyridyl)-imidazol-2-yl]-2-methylpropanol-dimethyl acetal, can be prepared as follows:

Composition:

The fats and emulsifiers merge. The preservative is dissolved in water and the solution is absorbed into 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 6

A cream containing 10% 2-[4(5)-phenyl-5(4)-(3-pyridyl)-imidazol-2-yl]-acetaldehyde-dimethylacetal 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 the same 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 homogenized using a through-flow homogenizer and then added in portions to the base.

Example 7 -^-r-

A cream containing 5% 2-[4(5)-phenyl-5(4)-(1-oxido-3-pyridyl)-imidazole T2-yl1-2-methylpropanol-dimethylacetal can be obtained as follows:

Composition:

Cetyl alcohol, cetyl palmitate, the triglyceride mixture, the stearic acid and the glycerine stearate are combined. The microcrystalline cellulose is dispersed in part of the water. In the remaining water part, cetomacrogol is dissolved and propylene glycol and mucus are mixed in. 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 incorporated expelled into the rest of the cream.

Example 8

A transparent hydrogel, containing 5% 2-[4(5)-phenyl-5(4)-((4.-pyridyl)-imidazol-2-yl]-acetaldehyde-dimethyl acetal 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

des with odorants (0.1%).

Example 9

A transparent hydrogel containing 5% 2-[4(5)-phenyl-5(4)-(1-oxido-3-pyridyl)-imidazol-2-yl]-2-methylpropanal-dimethylacetal is prepared as follows:

Composition:

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, and if desired, odorant (0.1%) can be added.

Example 10

A foam spray containing 1% 2-[4(5)-phenyl-5(4)-(1-oxido-3-pyridyl)-imidazol-2-yl]-2-methylpropanal-dimethylacetal can be prepared as follows:

Composition:

Cetyl alcohol, paraffin oil, isopropyl myristate, cetomacrogol and sorbitan stearate 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.

Claims (34)

1. Substituted diaza compounds of the general formula wherein and R 2 independently of each other means carbocyclic aryl and/or heteroaryl, A means a divalent hydrocarbon residue and R 2 means formyl or acetalized formyl as well as their isomers and their salts. 2. Compound of formula (I) according to claim 1, in which on the one hand R 1 and R 2 independently of each other mean phenyl and/or with halogen, lower alkyl, hydroxy, lower alkoxy and/or lower alkanoyl substituted phenyl, or in which on the other side one of the residues R 1 and R 2 means pyrrolyl, furyl, thienyl, pyridyl, 1-oxidopyridyl or pyrimidyl each of which may be unsubstituted or substituted with halogen, lower alkyl, hydroxy, lower alkoxy and/or lower alkanoyloxy and the other means phenyl, pyrrolyl, furyl, thienyl, pyridyl, 1-oxidopyridyl or pyrimidyl which each may be unsubstituted or substituted with halogen, lower alkyl, hydroxy, lower alkoxy and/or lower alkanoyloxy and each time A means lower alkylene, lower alkylidene, lower alkenylene, lower alkenylidene, cycloalkylene, cycloalkylidene or cycloalkyl-lower alkylidene and R 1 means formyl or T with an aliphatic alcohol acetalized formyl as well as their isomers as well as their salts. 3. Compound of formula (I) according to claim 1, wherein R-^ and R2 independently of each other mean phenyl and/or phenyl substituted with 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, lower alkylidene with up to 7 C atoms such as 2,2-propylidene, lower alkenylene with up to 4 C atoms such as 1,3-propen-2-ylene, lower alkenylidene with up to 7 C atoms such as 1,1-buteh-3-ylidene, the 3- to 8-membered cycloalkylene such as cyclopropylene, the 3- to 8-membered cycloalkylidene such as cyclopentylidene or the 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 formyl or with a lower alkanol, lower alkenol, lower alkanediol or lower alkenedib acetalized formyl as well as their isomers as well as their salts. 4. Compound with formula (I) according to claim 1, in which one of the radicals R-1 and R2 means pyridyl or 1-oxido-pyridyl, which may be unsubstituted and/or each time substituted with halogen, hydroxy, lower alkyl, lower alkoxy and/or or lower alkanoyloxy and the other means phenyl, pyridyl or 1-oxidopyridyl which may be unsubstituted and/or each time substituted with halogen, hydroxy, lower alkyl, lower alkoxy and/or lower alkanoyloxy, A means the lower alkylene with up to 4 C atoms such as methylene, lower alkylidene with up to and including 7 C atoms such as 2,2-propylidene, the lower alkenylene with up to and including 7 C atoms such as 1,3-propen-2-ylene, the lower alkenylidene with up to and including 4 C atoms such as 1,1-butene -3-ylidene, 3- to 8-membered cycloalkylene such as cyclopropylene, 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 as 2-cyclohexyl-1,1-ethylidene, and R^ means formyl or with a lower alkanol, lower alkeny 1, lower alkanediol or lower alkenediol''acetalized formyl as well as their isomers as well as their salts. 5. Compound with formula (I) according to claim 1, in which R 1 and R 2 independently of each other mean phenyl and/or with halogen with atomic number up to and including 35 such as chlorine, hydroxy, lower alkyl with up to and including 4 C atoms such as methyl, and/or lower alkoxy with up to 4 C atoms such as methoxy, substituted phenyl, A means lower alkylene with up to 4 C atoms such as methylene, lower alkylidene with up to 7 C atoms such as 2,2-propylidene, 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 means formyl or dilavereal oxymethyl each time with up to 4 C atoms in the lower alkoxy part as dimethoxy-methyl, or lower alkenedioxy-methyl with up to 4 C atoms in the lower alkylene part as 1,3-dioxolan-2-yl as well as their isomers as well as their salts. 6. Compound with formula (I) according to claim 1, in which one of the radicals R 1 and R 2 means phenyl or with halogen with atomic number up to and including 35 such as chlorine, hydroxy, lower alkyl with up to and including 4 C atoms such as 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 may each be unsubstituted or substituted with halogen of atomic number to and with 35 as chlorine, hydroxy and/or lower alkoxy of up to 4 C atoms as methoxy, A means the lower alkylene of up to 4 C atoms as methylene, the lower alkylidene of up to 7 C atoms as 2,2- propylidene, 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 1 means formyl or dilavereal oxymethyl, each time with up to 4 C atoms in the lower alkyl moiety such as dimethoxymethyl or lower alkylenedioxymethyl with up to 4 C atoms in the lower alkylene moiety such as 1,3-dioxolan-2-yl as well as their isomers as well as their salts. 7. Compound of formula (I) according to claim 1, in which R 1 and R 2 independently of each other mean phenyl and/or with lower alkoxy with up to and including 4 C atoms such as methoxy, substituted phenyl, A means lower alkylene with up to and including 4 C -atoms, such as methylene or especially the lower alkylidene with up to 4 C atoms such as 2,2-propylidene and R^ means dilavereal oxymethyl each time with up to 4 C atoms in the lower alkoxy part such as diethoxymethyl or lower alkylenedioxymethyl with up to 4 C atoms in the lower alkylene moiety such as 1,3-dioxolan-2-yl as well as their isomers as well as their salts. 8. Compound of formula (I) according to claim 1, in which one of the radicals R-^ and R2 means phenyl or 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 such as methoxy, substituted phenyl and the other means pyridyl such as 3- or 4-pyridyl or 1-oxidopyridyl such as 1-oxido-3-pyridyl or 1-oxido-4-pyridyl, A means the lower alkylidene with up to 4 C atoms such as 2,2- propylidene and R^ means formyl or dilavearyloxymethyl each time with up to 4 C atoms in the lower alkoxy part as diethoxymethyl or lower alkylenedioxymethyl with up to 4 C atoms in the lower alkylene part as 1,3-dioxo-lan-2-yl as well as their isomers as well as their salts. 9. Compound of formula (I) according to claim 1, in which one of the radicals R 1 and R 2 means phenyl or 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 such as methoxy, substituted phenyl and the other means pyridyl such as 3- or 4-pyridyl or 1-oxidopyridyl such as 1-oxido-3-pyridyl or 1-oxido-4-pyridyl, A means a quaternary C-atom-containing lower alkylidene with up to 4 C atoms which 2,2-propylidene, the quaternary C atom being bound directly to the imidazole ring and R-j means formyl or dilavereal oxymethyl with up to 4 C atoms each time in the lower alkyl part such as diethoxymethyl as well as their isomers as well as their salts. 10. Compound of formula (I) according to claim 1, in which one of the radicals R 1 and R 2 means phenyl and the other pyridyl such as 3-pyridyl or 1-oxido-pyridyl such as 1-oxido-3-pyridyl, A means 2,2 -propylidene and R₁ means formyl or dilavearyl oxymethyl each time with up to 4 C atoms in lower alkoxy such as diethoxymethyl as well as their isomers as well as their salts. 11. 2-[4(5)-phenyl-5(4).-(3-pyridyl)-imidazol-2-yl]-acetaldehyde-dimethyl acetal. 12 . 2 - [4-(5)-phenyl-5(4)-(1-oxido-3-pyridyl)-imidazol-2-yl]-acetaldehyde-dimethylacetyl. 13. 2-[4(5)-phenyl-5-(4)-(3-pyridyl)-imidazol-2-yl]-propanedimethyl acetal. 14 . 2-[4-(5)-phenyl-5(4)-(3-pyridyl)-imidazol-2-yl]-methyl-propanol-dimethyl acetal. 15 . 2-[4(51-phenyl-5(4)-(1-oxido-3-pyridyl)-imidazol-2-yl]-propanedimethylacetal. 16 . 2-[4(5)-phenyl-5(4)-(1-oxido-3-pyridyl)-imidazol-2-yl]-2-methyl-propanedimethyl acetal. 17. 2-[4(5)-phenyl-5(4)-(3-pyridyl)-imidazol-2-yl]-2-methyl-1,1-methylenedioxypropane. 18. 2-[4(5)-phenyl-5(4)-(3-pyridyl)-imidazol-2-yl-2-methyl-1,1-ethylenedioxypropane. 19. 2-[4(5)-phenyl-5(4)-(3-pyridyl)-imidazol-2-yl]-2-methyl-propionaldehyde. 20. 2-[4(5)-phenyl-5(4)-(3-pyridyl)-imidazol-2-yl]-2-methyl-butyraldehyde. 21. 2-[4(5)-phenyl-5(4)-(3-pyridyl)-imidazol-2-yl]-propionaldehyde. 22 . 2-[4(5)-phenyl-5(4)-(1-oxido-3-pyridyl)-imidazol-2-yl]-acetaldehyde. 23 . 2-[4(5)-phenyl-5(4)-(1-oxido-3-pyridyl)-imidazol-2-yl]-propionaldehyde, 2-[4(5)-phenyl-5(4)-( 1-oxido-3-pyridyl)-imidazol-2-yl]-2-methyl-propionaldehyde, 2-[4(5)-phenyl-5(4)-(1-oxido-3-pyridyl)-imidazol- 2-yl]-butyraldehyde. 24. A compound according to one of claims 11-23 in the form of an acid addition salt. 25. Compound according to one of claims 1-24 with an effect as an external skin phlogistic. 26. Pharmaceutical preparations containing at least one compound according to one of claims 1-25. 27. Process for the preparation of a compound of formula (I) according to claim 1, characterized in that from a compound of formula in which one of the residues Y-^ and Yg means hydroxy or amino and the other and Y2 means hydrogen and Y^ means together with Y^ and Yc- a group of formula =N- or in which Y^ together with Yg means a bond, Y2 means hydrogen, Y^ means hydroxy or amino and Y^ means together with Y^ a group of formula -NH- or in which Y-^ together with Yg means a bond, Yej~- means together with Y^ an additional bond or reactive esterified hydroxy, especially halogen or sulfonyloxy or in which Y-^ means hydroxy, Y2 and Y^ means hydrogen, Y^ means hydroxy or amino and Y^ means, together with Yg, a group of the formula =NH or, if Y^ is amino, means oxo or imino or a tautomer and/or salt thereof, is cleaved with the introduction of an optional additional bond H-Z as Z means hydroxy or amino, Y-^ resp.Y g, Y^ orY^ resp. Y^ or halogen resp. sulfonyloxy Y^ resp. Y, - or a compound with formula or a salt thereof is reduced to a compound of formula (I), in a compound of formula in which R^' means a residue transferable to R^ or in a salt thereof, R^<1> is transferred to R^ and, if desired, the compound obtained according to the method is transferred in another compound of formula I, a compound obtained according to the method is transferred in a salt or a salt obtained according to the method is transferred in the free compound or to another salt and/or if desired, a mixture of isomeric compounds with formula (I) obtained according to the invention is divided into the individual isomers. 28. Method according to claim 27, character e~'~ r i-sed by starting from one or other step of the method as an intermediate compound obtained and carrying out the missing steps or using a starting substance in the form of a salt, isomer and /or racemate or antipodes or form it under the reaction conditions. 29. Process for the production of pharmaceutical preparations, characterized in that at least one compound according to one of claims 1-25 is mixed with usual pharmaceutical excipients and carriers. 30. Compound according to one of claims 1-25 for therapeutic treatment of the human or animal body. 31. Use of compounds according to one of claims 1-25 in a method for treating inflamed dermatoses: 32. The new compounds mentioned in examples 1-4. 33. Process according to examples 1-10 and the subsequently obtained process products. 34. The new starting materials and intermediates used in the method according to claims 27, 28 and 32.