JPS59500054A - Tri-substituted oxaza compounds - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Tri-substituted oxaza compounds The present invention relates to novel trisubstituted oxaza compounds, particularly those having the following general formula: (Herein, one of the groups R, , R, means heteroaryl, and the other is carbocyclic aryl. means lyl or heteroaryl, A means a divalent hydrocarbon group, and R8 means a carbon group. carboxy, esterified carboxy or amidated carboxy) compound compounds, their isomers and their salts, their production methods, and pharmaceutical preparations containing these compounds. as a product and as a pharmaceutical active substance or for preparing a pharmaceutical preparation; Concerning the use of compounds according to formula (1), their isomers and their salts.

Carbocyclic aryl is, for example, phenyl optionally with a cy substituent. A carbocyclic aryl having a single ring, such as:

Heteroaryl includes, by way of example, a monocyclic, especially 5- or 6-membered heteroaryl. υ, at least one ring member of which is a heteroatom such as a nitrogen atom, an oxygen atom or a sulfur atom The nitrogen atom may be present in oxidized form if necessary. These five members An example of a ring group is a pyrrolyl group such as 2-pyrrolyl.

Examples of 6-membered heteroaryls include pyridyl such as 2=, 3- or 4-pyridyl. , 1-oxidepyridyl such as 1-oxide-3-pyridyl or 1-oxide- 4-pyridyl and pyrimidyl, such as 2-pyrimidyl.

Carbocyclic aryl such as phenyl, or heteroaryl such as pyridyl or Substituents on 1-oxide-pyridyl include, for example, halogen, lower alkyl, and hydrochloride. xy, lower alkoxy and/or acyloxy. For example, acyloxy It is derived from organic carboxyl alcohols, such as lower alkanoyloxy. Taste.

The hydrocarbon group A is, for example, a divalent aliphatic, alicyclic or alicyclic-aliphatic group. It is a hydrocarbon group.

Examples of divalent aliphatic hydrocarbon groups are lower alkylene, lower alkylidene, and lower aliphatic hydrocarbon groups. Lukenylene or lower alkenylidene. Divalent alicyclic hydrocarbons include, for example, , monocyclic 3- to 8-membered cycloalkylene or cycloalkylidene. alicyclic Examples of group-aliphatic hydrocarbon groups include monocyclic 3- to 8-membered alicyclic groups. It has an alicyclic group and has a lower alkylidene as the aliphatic group, for example, cycloa Lukyl-lower alkylidene.

Examples of esterified carboxy are optionally substituted aliphatic, cycloaliphatic or aromatic Carboquine is diesterified with alcohol. Examples of aliphatic alcohols are , lower alkanols such as methanol, ethanol, propanoyl, isopropanol tools, n-butanol, 5ee- or tert-butanol, alicyclic aliphatic Examples of alcohols include 3- to 8-membered cycloalkanols such as cyclopentanol. and cyclohexanol or cycloheptatool. These lower arcano Examples of substituents for cycloalkanols include hydroxy, mercapto, and If necessary, substituted phenyl, lower alkoxy, if necessary phenyl moiety is substituted. phenyl lower alkoxy, lower alkylthio, phenyl moiety substituted if necessary phenyl lower alkylthio, hydroxy lower alkoxy, lower alkoxy lower alkoxy, phenyl lower alkoxy substituted on the phenyl moiety if necessary lower alkoxy, hydroxy-hydroxy lower alkoxy lower alkoxy, lower alkoxy alkoxy lower alkoxy lower alkoxy, optionally substituted on the phenyl moiety phenyl lower alkoxy lower alkoxy lower alkoxy, carboxy lower alkoxy 7-carbonyl-lower alkoxy, optionally substituted phenyl Lower alkoxycarbonyl lower alkoxy or lower alkanoyl containing It's Kishi. Examples of aromatic alcohols are phenols or heterocyclic alcohols. , these may include lower alkyl, lower alkoxy, halogen and/or torsion if necessary. Phenols or heterocyclic alcohols which can be disubstituted by fluoromethyl, especially Hydroxypyridine, for example 2-13- or 4-hydroxypyridine.

Examples of amidated carboxy are carbamyl (carbamoyl), as well as hydroxy , an amine or optionally substituted phenyl, or a lower atom 4- to 7-membered alkylene substituted with Simonot or Di by alkylene or 3-aza-13-lower alkylaza-, 3-oxo- or 3-thia Carbamyl (carbamoyl) di-substituted by lekylene, as an example. , carbamyl, N-mono- or N,N-di-lower alkylcarbamyl, e.g. thyl-1N-ethyl-1N, N-dimethyl-1N, N-diethyl, or N,N -dibrobylcarbamoyl, pyrrolidino- or piperidino-carbonyl, mole Holino-, piperidino- or 4-methylpiperazino- and thiomorpholino-ca carbonyl, anilinocarbonyl or lower alkyl, lower alkoxy and (or ) Anilinocarbonyl di-substituted with halogen is 6.

In this specification, "lower" organic groups and compounds refer to particularly 7 or less groups, especially 4 or less groups. It means a carbon atom (C atom) containing .

Some terms used in this specification are uniquely defined as follows.

Halogens include halogens having an atomic number of 35 or less, such as fluorine, chlorine or bromine; , meaning iodine.

Examples of lower alkyl include methyl, ethyl, n-propyl, isopropyl, and n-butyl. tyl, isobutyl, 5ea-butyl, tert-7'fl, pentyl, hexyl Also, each group of haheptyl.

Lower alkoxy is, for example, methoxy, ethoxy, n-propionyl, isopropyl. oxy, n-butyloxy, isobutyloxy, 8CC-butyloxy or ta It is rt-butylbutythi.

Lower alkylthio is, for example, methyl-, ethyl-1n-propyl-, isopropyl -1n-butyl-, isobutyl-1see-butyl- or tert-butylthio It is.

Phenyl lower alkoxy is, for example, phenylmethoxy, phenylethoxy or phenyl It is nilpropyl moxibustion.

Phenyl lower alkylthio is, for example, phenyl-, phenylethyl- or phenyl- It is nylpropylthio.

Hydroxy lower alkoxy is, for example, hydroxyethoxy, hydroxypropyl or 1,2-dihydroxypropyloxy.

Lower alkoxylower alkoxy is, for example, methoxyethoxy7, ethoxyethoxy, Methoxypropyloxy or methoxybutyloxy.

Phenyl lower alkoxy to lower alkoxy tllJ, 1f2-benzyloxyeth xy or 2-(2-phenylethoxy)-ethoxy.

Lower alkanoyloxy is, for example, acetyl-, propionyl-, butyryl-, Filter with so-1sec- or tert-butyryloxy.

Lower alkyl 7, methylene, ethylene, 1,3-propylene or 1,4-butylene Even if it is linear like tyrene, 1,2-propylene, 1,2- or 1. ．． 3-(2 -Methyl)-propylene or 1,2-butylene.

Lower alkylidene has a tertiary C atom, especially a quaternary C atom, such as ethylidene or is 1,1- or 2,2-propylidene, and further 1,1- or 2,2-butylidene. or 1,1- or 3,3-pentylidene.

Lower alkenylene is, for example, ethenylene, 1,2- or 1,3-propenylene or is 1,2-11,3- or 1,4-buten-2-ylene.

Lower alkaline earths include ethenylidene, 1,1-propen-1-ylidene, 1 , 1-propen-2-ylidene, furthermore propylidene e.g. 1,1-butene-3-ylidene It's Iriden.

Cycloalkylene is, for example, cyclopropylene, 1,2- or 1,3-cyclobutylene. tylene, 1,2-11,3- or 1,4-cyclobutylene, and also cyclohexylene Lential.

Cycloalkylidene is, for example, cyclopropylidene, cyclobutylidene, cyclope cyclohexylidene or cyclohexylidene.

Cycloalkyl-lower alkylidene is, for example, cyclopropyl-, cyclobutyl- , cyclopentyl- or hacyclohexyl-methylene, -ethylidene or -pro- Pylidene and also cyclohexyl-butylidene.

Carboxy lower alkoxy is, for example, carboxymethoxy, 2-carboxyethoxy 2-13-carboxypropyloxy, 1-carboxy-2-propyloxy C-12-13- or 4-carboxy-n-butyloxy, 1-carboxy-2 -methyl-propyl-3-oxy or 1-carboxy-2-methyl-propyl- It is 2-oxy.

Each lower alkoxy part of lower alkoxycarbonyl-lower alkoxy is , independently of each other, have the meaning given above for lower alkoxy.

The salts of the compounds of the present invention are particularly pharmaceutically usable salts, e.g. possible acid addition salts and/or internal salts or salts with bases (where R1 is a carboxylic acid). (if you mean Kishi). Suitable acid addition salts include - by way of example, inorganic acids such as mineral acids, rufamic acid e.g. cyclohexylsulfamic acid, organic carboxylic acid e.g. lower Alkane carboxylic acids, optionally unsaturated carboxylic acids, hydroxy and (or ) salts of carboxylic or sulfonic acids substituted by oxo, e.g. Hydrologenates such as hydrobromide or hydrochloride, oxalate, malonate , fumarate or maleate, tartrate, pyruvate or quenchate , sulfonates such as methane-, benzene- or P-)luenesulfonates. be.

Suitable salts with bases include, for example, alkali or alkaline earth metal salts, For example, sodium salts, potassium salts or magnesium salts, which can be used pharmacologically. Examples of salts of transition metals include zinc salts or copper salts, or salts with ammonia, or substituted Salts of organic amines such as cyclic amines such as morpholine, thiomorpholine, pipette Lysine, pyrrolidine such as mono-, di- or tri-lower alkylamine or mono-, di- or trihydroxy lower alkyl amines such as mono-, di- or trihydroxy lower alkyl amines; It is a salt of triethanolamine. Mono-lower alkylamines include, for example, ethyl or 1d tert-butylamine. Di-lower alkylamine is, for example, diethyl tri- or diisopropylamine, tri-lower alkylamine is It is thylamine.

The novel compounds according to formula I and their pharmaceutically acceptable salts have useful pharmacological properties. It has excellent anti-inflammatory properties, especially when used topically. Ru.

These characteristics are summarized in G. Tone IJ, L. Thibault, Endocrinology, 77.625 (19 65'), normal rats were treated with croton oil. The edema of the raised ear is 1 to 100 ■/m! It can be suppressed by a dose range of It has been confirmed. In the experiments described above, for example, the compound 2-[4-phenyl -3-(3-pyridyl)-imidazol-2-yl]-acetic acid ethyl ester It has been confirmed that the EDBo value is approximately 17q/d.

Therefore, the compounds of the invention of formula I can be used as pharmaceuticals, especially in cases of inflammatory skin diseases of various origins. For example, medicines for minor skin irritations, skin diseases caused by contact, rashes, burns, etc., especially for external use ( Topically) Used as a skin anti-inflammatory agent and for treating mucous membrane wounds such as the eyes, nose, lips, genitals, and anus. It is particularly suitable as a mucosal anti-inflammatory agent. Also, the compound according to the formula ■ Also used as a means of protection against wires.

The present invention provides for - by way of example, one of the groups RI, R2 containing nitrogen as a petro atom. 5-negative ring or 6-membered heteroaryl (even if unsubstituted, halogen, low alkyl, hydroxy, lower alkoxy and/or lower alkanoyloxy (may be substituted by), and the other is unsubstituted or rogens, lower alkyl, hydroxy, lower alkoxy and/or lower alkali Phenyl disubstituted by noyl, or 5 or 6 containing nitrogen as the petero atom Negative heteroaryl group (even if unsubstituted, halogen, lower alkyl, hydrogen even if di-substituted by roxy, lower alkoxy and/or lower alkanyl A means lower alkylene, lower alkyritene, lower alkenylene, lower alkenylidene, cycloalkylene, cycloalkyritene or cycloalkylene - means lower alkylidene, R3 is carboxy or lower alkanol, 3-membered to 8-negative ring cycloalkanol, phenol, hydroxypyridine, Carboxyl diesterified with substituted phenol or oxypyridine carbamoyl, hydroxy, amine, phenyl or substituted phenyl mono-substituted by nyl or mono- or di-substituted by lower alkyl or 4- to 7-membered alkylene or 3-aza-13-lower alkyl Disubstituted by ruaza-, 3-oxa- or 3-thiaalkylene means carbamoyl, in which the lower alkanol is unsubstituted or Roxy, mercapto, optionally substituted phenyl, lower alkoxy, optionally substituted Phenyl lower alkoxy, lower alkylthio substituted in the phenyl moiety , phenyl lower alkylthio, hydro substituted in the phenyl moiety if necessary xy-lower alkoxy, lower alkoxy-lower alkoxy, if necessary on the phenyl moiety phenyl lower alkoxy lower alkoxy, hydroxy lower alkoxy substituted in koxy lower alkoxy, lower alkoxy lower alkoxy lower alkoxy, required phenyl lower alkoxy lower alkoxy substituted in the phenyl moiety Alkoxy, carboxy lower alkoxy, lower alkoxy carbonyl - lower alkoxy koxy, lower alkoxycarbonyl containing optionally substituted phenyl - lower may be di-substituted by alkoxy or lower alkanoyloxy; phenyl, phenol or hydroxypyridine are lower alkyl, Can be di-substituted by lower alkoxy, halogen and/or trifluoromethyl compounds according to formula I, their isomers and salts, especially pharmaceutically usable salts. I'm being kicked.

The present invention provides that - by way of example, one of the radicals R,, R, is pyridyl or 1-oxy do-pyridyl (even if unsubstituted, halogen, hydroxy, lower alkyl, Even if disubstituted with lower alkoxy and/or lower alkanoyloxy the other is phenyl, pyridyl or 1-oxide pyridyl (substituted halogen, hydroxy, lower alkyl, lower alkoxy and ( or) may be substituted with lower alkanoyloxy), and A is Lower alkylene containing up to 4 C atoms, e.g. methylene, up to 7 C atoms lower alkylidenes containing up to 4 C atoms, such as 2,2-glopylidene, Lower alnylene containing, for example, 1゜3-propen-2-ylene, containing up to 7 C atoms Lower alkenylidenes containing children, such as 1,1-butene-3-ylidene, 3 to 8 cycloalkylene, e.g. cyclopropylene, cycloalkylene with 3 to 8 negative numbers Chloalkylidene, e.g. Eva, cyclopentylidene, 7 or less in the alkylidene part Cycloalkyl-lower alkyl containing carbon atoms and having 3 to 8 cycloalkyl members rydene, for example 2-cyclohexyl-1,1-ethylidene, RHld , carboxy, or lower alkanol, 3- to 8-membered cycloalkanol, phenol Carboxy or carba diesterized with nor or substituted phenol moyl, N-mono-1N, N-di lower alkylcarbamoyl, pyrrolidino-, piperidino, morpholino, piperazino-14-lower alkyl-piperazino, thiomorpholino-, anilino- or lower alkyl, lower alkoxy and (or ) means anilinocarbonyl di-substituted with halogen, where lower alkali Nor can also be hydroxy, mercapto, phenyl, substituted or unsubstituted. Replaced phenyl, lower alkoxy, phenyl lower alkoxy, phenyl moiety Substituted phenyl lower alkoxy, lower alkylthio, phenyl lower alkyl Kylthio, phenyl lower alkylthio substituted in the phenyl moiety, hydroxy lower alkoxy, lower alkoxy lower alkoxy, phenyl lower alkoxy lower alkoxy, phenyl lower alkoxy lower alkoxy substituted at the phenyl moiety Koxy, hydroxy lower alkoxy lower alkoxy, lower alkoxy lower alkoxy xy lower alkoxy, phenyl lower alkoxy optionally substituted in the phenyl moiety Rukoxy lower alkoxy lower alkoxy, carbonyl lower alkoxy, lower alkoxy lower alkoxy, optionally substituted phenyl Rukoxycarbonyl - substituted with lower alkoxy or lower alkanoyloxy Substituted phenol and phenyl may also be substituted with lower alkyl, lower may be substituted by alkoxy, halogen and trifluoromethyl It is directed - by way of example - to the compounds according to formula (1), its isomers as well as salts.

The present invention provides that one of the groups R, , R, is unsubstituted phenyl or Halogen such as chlorine with atomic number 35 or less, hydroxy, C atoms number is 4 or less lower alkyl, such as methyl and/or lower alkoxy having up to 4 C atoms; means phenyl substituted with methoxy, for example, and pyridyl, for example 3 -pyridyl or 1-oxide-pyridyl, such as 1-oxide-3-pyridyl ( It may be unsubstituted, and secondarily, halogen having an atomic number of 35 or less, e.g. Chlorine, hydroxy and/or lower alkoxy having up to 4 C atoms, e.g. may be di-substituted by Alkylene e.g. methylene, lower alkylidene having up to 7 C atoms e.g. 2, 2-propylidene, lower alkyl((2+) having up to 7 C atoms) f-n, e.g. 1, 1-buten-3-ylidene, or 3- to 8-membered cyclolower alkylidene, e.g. 1 , 1-cyclopentylidene, R8 is carboxy, the number of C atoms is 5 or less Lower alkoxycarbonyl e.g. ethoxycarbonyl (where lower alkoxy Carbonyl is lower alkanoyloxy having up to 5 C atoms such as pivaloy hydroxy-lower alkoxy-lower alkoxy) alkoxycarbonyl e.g. 2-(2-hydroxyethoxy)-ethoxycarbonyl lower alkoxy-lower alkoxy-lower alkoxycarbonyl e.g. -methoxy-ethoxy)-ethoxycarbonyl, hydroxy lower alkoxy lower Alkoxy-lower alkoxy-carbonyl e.g. 2-4:2-(2-hydroxy ethoxy)-ethoxy]-ethoxycarbonyl, lower alkoxy lower alkoxy xy-lower alkoxy-lower alkoxycarbonyl e.g. 2-[2-(2-methoxycarbonyl) ethoxy)-nidoxy]-ethoxycarbonyl (lower alkoxy moiety, respectively) and its isomers and salts, having up to 4 C atoms in related.

The present invention provides that one of the groups RI　N　R1 is unsubstituted phenyl or A halogen whose atomic number is 35 or less, such as chlorine, hydroxy, or a C atom number of 4 means phenyl disubstituted by lower alkoxy, e.g. methoxy; is pyridyl such as 3- or 4-pyridyl or 1-oxidepyridyl such as 1- means oxide-3-pyridyl or 1-oxide-4-pyridyl, A is C radical Lower alkylidene having 4 or less children, such as 2,2-propylidene, R3 is lower alkoxycarbonyl having 5 or less C atoms, such as ethoxycarbonyl. The meaning is primarily directed to the compounds of formula I, their isomers as well as their salts.

The present invention provides that one of the groups R, , R, is unsubstituted phenyl or A halogen with an atomic number of 35 or less, such as chlorine, hydroxy, or a C atom number of 4 or less means phenyl substituted with lower alkoxy such as methoxy, and the other is phenyl. Lysyl e.g. 3- or 4-pyridyl or 1-oxide pyridyl e.g. 1-ox means sido-3-pyridyl or 1-oxide-4-pyridyl, A is quaternary C Lower alkylidene having C atoms of 4 or less, such as 2,2-propylidene This 4th c atom is directly bonded to the imidazole ring, and R8 has 5 C atoms. lower alkoxycarbonyl, such as ethoxycarbonyl, of the formula , its isomers and salts.

The present invention provides that RI means phenyl and bird means 1-oxide pyridyl e.g. means cydo-3-pyridyl, human means 2,2-propylidene, R8 is C radical Lower alkoxycarbonyl having 5 or less children, such as ethoxycarbonyl It is directed primarily to compounds of formula (2), their isomers and salts.

Specifically, the present invention relates to novel compounds and their salt characteristics shown in each of the following Examples. Pharmacologically usable salts of these compounds containing salt-forming groups, as well as It is directed to its manufacturing method shown in the examples.

The manufacturing method for preparing compounds of formula I comprises, in the formula (formula value), groups X, , X, one means imino which may be substituted, the other means oxy or substituted (means a certain imino) cyclize the compound and/or its tautomer (and) or its salt, provided that the above formula ( In II), when the group X1 represents oxy and the group represents oxy, the condensation cyclized and, if desired, the compound having formula (I) obtained according to the method of preparation compound into another compound, or alternatively, the free compound obtained according to the production method. salt, or alternatively convert the salt obtained according to the production method into another salt or salt. separation compounds and, if desired, isomer mixtures obtained according to the method of preparation. consists in separating the into its components.

Tautomers of the compound of formula (It) are those in which the partial enol- or enamine-groups are paired. exists as a tautomeric keto- or ketimine form or vice versa It means that each tautomer is in equilibrium with each other.

Cyclization of the compound of formula (II) and/or tautomers and/or salts thereof can be carried out by conventional methods. by procedures known from the literature, especially for similar reactions, and if necessary, e.g. in the temperature range from 2C to about 250C, under pressure, and if necessary with catalytic properties. in the presence of an acid or acid anhydride. Examples of acids include inorganic acids such as mineral acids, e.g. Sulfuric acid, polyphosphoric acid, hydrohalic acid such as hydrochloric acid or organic acid such as lower alkali Cancarboxylic acids such as acetic acid are preferred. Examples of acid anhydrides include mineral acid anhydrides such as Sulfuryl halides, such as (oxy)halogen, such as phosphorus oxychloride.

In this case, if necessary, an inert solvent, e.g. For example, chloroform, chlorobenzene, hexane, pyridine or toluene, lower Alkanols such as methanol, such as dimethylformamide or formamide or a lower alkane carboxylic acid such as formic acid or acetic acid and/or an inert gas. For example, it is operated in nitrogen.

The starting materials of formula (If), their tautomers and/or salts are known per se. In the method described, most of the particles are formed in situ and isolated under the reaction conditions. The reaction is further carried out to give a compound of formula (1) without further reaction. Cyclization is a condensation performed in the previous step is carried out after.

According to a preferred embodiment of the production method according to the present invention, the formula (in the formula, Y is the necessary Raba means sensually modified hydroxy) A compound having the formula Ra A Y201b) (wherein Y represents at least one functionally modified carboxy or a salt thereof, if necessary in the presence of a condensing agent, or is also a compound of formula αa) and/or a tautomer thereof and/or a salt thereof (provided that Y, l refers to carboxy which may be functionally modified) and, if necessary, condensation. reaction in the presence of an agent. In this case, the corresponding compound of formula (It) or their mutual Mutants can be produced, and this compound or tautomer can be formed under the reaction conditions. Further processed according to the invention.

According to a particularly preferred embodiment of the method described above, the formula (means hydroxy that can be esterified) A compound having the formula R, -A-COOH (Ilc), a salt thereof or Alternatively, a compound of formula (I) can be reacted with a functional derivative thereof and ammonia. a compound of formula αC) obtained by condensation with an optionally functionalized derivative of a compound of formula αC) React something with ammonia.

Salts of the compound of formula (α, αa) include, for example, acid addition salts such as hydrohalides. be. Functionally modified hydroxy η can be an amine or a reactive ester as an example Inorganic mineral acids such as hydrohalic acids or organic sulfonic acids, e.g. esterified with optionally substituted benzenesulfonic acids. It is.

Examples of reactive esterified hydroxy include primarily halogens such as chlorine or is bromine, sulfonyloxy, for example p-)luenesulfonyloxy. sensual Examples of carboxy Y2 modified to include dehydrated carboxy e.g. halogen carbonyl, lower alkanoyloxycarbonyl or lower alkoxycarbonyl -oxycarbonyl, carbamoyl or amidino.

Examples of reactive esterified hydroxy are particularly strong inorganic or organic acids such as mineral acids, e.g. For example, a hydrohalic acid such as hydrobromic acid or hydrochloric acid or an organic sulfonic acid. Examples of optionally substituted benzenesulfonic acids Hydroxy esterified by acid. Sensory modified formula (If Examples of carboxy derivatives in e) include esterification, amidation or dehydration (no hydrated) corresponding carboxy compounds, such as the corresponding lower alkoxycarbonyl Ru-1 optionally substituted carbamoyl or halogen carbamoyl-1 lower Alkanoyloxycarbonyl or lower alkoxycarbonyloxycarbohydrate Bonyl-derivative.

Suitable shrinking agents include strong protic acids such as mineral acids (e.g. sulfuric acid, hydrohalic acid), phosphoric acid, sulfonic acid such as optionally substituted benzenesulfonic acid, or carboxylic acid. mineral acids such as lower alkane carboxylic acids, or mineral acid anhydrides such as phosphoric acid, carbonic acid or sulfuric acid. Corresponding anhydrides of acids such as pentachloride, phosphorus oxychloride, hillside, thionyl chloride or is phosgene.

The reaction is carried out in a conventional manner, if necessary with heating, using an inert solvent such as a halogenated carbonate. Performed in hydrogen.

According to a preferred embodiment of the production method according to the invention, the formula ( (ii) with the acid halide of formula (II 6), especially the corresponding acid halide. By reacting, a compound of formula (1) in which Xl and X each represent oxy can be obtained. Generate. The compound of the formula (■) thus obtained is dissolved in the presence of an acid such as acetic acid. React with ammonia to obtain the corresponding compound 2 (1).

In particular, Y represents a reactive esterified hydroxy, primarily a halogen. A compound of formula (II By reacting with the reaction compound under the above reaction conditions, XI can be A compound of formula (II) is obtained in which is imino.

Compounds of the formula (If&) where KY means amino, salts thereof and/or The tautomer is defined as Y2 being anhydrated carboxy, uniquely halogen carbonyl. The compound of formula (nb) with the meaning of , a compound of formula (It) is obtained, in which the value is imino and the value is oxo.

4. In the compound of formula (II) which is imino, Yl may optionally be a reactive ester. Compounds of 20a) which are hydroxy, which is primarily hydroxy, their salts and and (or) the tautomer with a compound of formula (lb) where Y2 is 'amidino'. It is generated by

Starting materials of formulas (Il&), (Ilb), (IIe) are known substances or by methods known per se.

That is, the compound of formula (II &) is an adult -CH, -COOH or R, -C) (, -C0OH esterified acid to -C0OH or -C0OH esterified acid obtained by ester condensation with tellurized acids, especially in the presence of bases. Ru. An example is the product α-methylene-ketone with the formula, where η is bromine. A compound of formula (It&) or a salt thereof, such as a hydrohalogenide.

formula or a salt thereof is reduced to give a compound of formula (I), if desired, the method of preparation The free compound of formula (I) obtained according to the method is treated as another free compound, and the said manufacturing method The free compound obtained according to the law is converted into a salt, or the free compound obtained according to the relevant production method is converted into a salt. The salt obtained as the free compound or another salt, if desired, obtained according to the process in question. Compounds of formula (I) or their Salt can be manufactured.

The reduction is carried out by methods known per se.

That is, the compound of formula (1) or a salt thereof is mixed with hydrogen in the presence of a hydrogenation catalyst, or Onic acid salts (e.g. nithionic acid), IJium or halogen ratios, e.g. make them respond. Hydrogenation catalysts include elements of subgenus II and their derivatives such as platinum and palladium. palladium or palladium chloride (these can be carried on conventional carriers such as activated carbon or palladium if necessary). compounds of alkaline earth metals (e.g. may be supported on barium carbonate) or Raney Use nickel. Systems consisting of suitable base metals and protic acids, e.g. zinc-vinegar Reduction with acid may also be performed.

The reduction may be carried out under cooling or heating if necessary, e.g. in the temperature range from 0° to about 150°C. and an inert solvent such as a halogenated hydrocarbon such as chloroform, carbon tetrachloride or is chlorobenzene or an ether such as dimethoxyethane, diethyl ether, di in the presence of oxane or tetrahydrofuran and/or an inert gas such as nitrogen. Do it below.

The starting material of formula (1) or its salt has the formula A compound of the form, a tautomer thereof or a salt thereof with the formula R, -AC(-　-　-I(α b) the aldehyde and, if desired at elevated temperature, an acid such as a mineral acid such as hydrochloric acid, sulfonic acid. For example, by reacting with p-toluenesulfonic acid or a carboxylic acid such as acetic acid. and obtained in a manner known per se.

Moreover, the compound 1 of formula (1) has the formula (in the formula, R, / represents a group that can be R3), the group ′ is a group R8, and where If desired, the free compound of formula (1) obtained according to the production method is compound, and the free compound obtained according to the production method as a salt, or The salt obtained according to the method of preparation may be the free compound or another salt, if desired. By separating the isomer mixture obtained according to the production method into its components is also manufactured.

These groups R,7 can be optionally esterified, for example by solvolysis or oxidation. or amidated carboxy R3. For solvolysis Groups that can be used as Rs include functionally modified carboxylic groups that are different from R1. There is a kiss. These groups are, for example, primarily cyanide, dehydrated (anhydrous) boxy such as halogencarbonyl, lower alkanoyloxycarbonyl or lower alkoxycarbonyloxycarbonyl, optionally substituted amidino examples For example, lower alkylamidino, optionally esterified thiocarboxylate, e.g. alkylthiocarbonyl, optionally diesterified dithiocarboxy, optionally thiocarbamoyl substituted by e.g. mono- or di-lower alkyl-thiocarboxylate Bamoyl, optionally esterified or dehydrated carboxydiimidoyl e.g. lower Alkoxy or halogeniminocarbonyl, or orthoformic acid: r-sulfur For example, tri-lower alkoxy- or trihalogenmethyl. child These groups can be used for solvolysis, e.g. hydrolysis, alcohololysis, and anhydrolysis (ammonia). The group R3 can be obtained by decomposition or aminolysis.

Examples of solvolytic agents are water, alkali corresponding to the desired esterified carboxy group. Cole, ammonia, or an amine corresponding to the desired amidated carboxy group. It is.

Treatment with the corresponding solvolytic agents, if necessary in the presence of acids or bases, and It is carried out in an inert solvent or diluent, with cooling or heating if necessary. Examples of acids include e.g. organic or inorganic protic acids e.g. mineral acids (e.g. sulfuric acid or hydrohalic acids) , for example sulfonic acids (e.g. lower alkanes or optionally substituted benzenes) Zensulfonic acids or carboxylic acids such as lower alkanecarboxylic acids are suitable. salt For example, hydroxides such as alkali metal hydroxides may be used as radicals.

Here, for example, a cyan group, optionally esterified thiocarboxy, optionally optionally substituted dithiocarboxy, optionally substituted thiocarbamoyl , optionally substituted or dehydrated carboxyimidoyl, or orthoformic acid The derived group R9' can be decarboxylated (by hydrolysis in the presence of geprotonic acid, if necessary). It may also be boxy R8, in which case cyan, optionally S-esterified. Dilute thiocarboxine or dehydrated carboxy R,l with a suitable alcohol. If necessary, esterified carboxy R by alcoholysis in the presence of protonic acid, It may be Toshi. Amidated carboxy R3 can also be treated, for example, by amine decomposition or is treated with a suitable amine from cyanide (this treatment can be done with a Lewis acid, e.g. chloride). in the presence of aluminum) or by treatment with dehydrated carboxylic acid. be obtained.

Examples of other groups that can be carboxy or esterified carboxy R8 are groups that can be converted to carboxy by oxidation, e.g. It is setalized formyl. This formyl is advantageously used in the process of oxidation reactions. α,β-unsaturated or α,β-dihydroxylated aliphatic or alicyclic carbohydrate Formino acids esterified at the acyl group or optionally at the hydroxyl group. or its functional derivatives such as its acetals, acetals, etc. Released from silal or imine. α,β-unsaturated or α,β-dihydroxy Examples of acyl groups of dylated carboxylic acids include α,β-unsaturated aliphatic mono- or dicarboxylic acids. Acrylic acid groups such as acryloyl, crotonyl or functionally modified as necessary The acyl group of fumaric acid or hamaeric acid, the acyl group of α,β-unsaturated aliphatic carboxylic acid sil groups (e.g. optionally substituted nonnamoyl), aliphatic α,β-dioxyl groups; Cydicarboxylic acids such as tartaric acid or its monofunctional carboxy derivatives such as esters or It is an amide acyl group. Esterified hydroxymethyl group is an example of mineral acid For example, a hydrohalic acid such as hydrochloric acid or hydrobromic acid or a carboxylic acid such as Esterification at the hydroxyl group with acetic acid or optionally substituted benzoic acid. This is the group that was created. The acetalized formyl group is, for example, a lower alkanol or a lower Formyl groups diacetalized with alkanediols, e.g. dimethoxy, di- Ethoxy or ethylenedioxymethyl. The acetalized formyl group is an example lower alkanoyloxymethyl group or dihalogenmethyl group such as diacetyloxymethyl group or dihalogenmethyl group Dimethyl or dichloromethyl. Examples of formyl group imines are as follows: N-benzylimine substituted with , the N-(2-benzothiazoyl)-imine , or an imine with 3,4-di-tart-butyl-0-quinone. oxidation Other groups that can be dicarboxyl groups include, for example, the acetalized formyl group 5 2-Furoy containing optionally substituted groups e.g. jetoxymethyl in position There is a ru group. Groups that can be oxidized to esterified carboxy groups include ether hydroxymethyl group or hydroxymethyl group such as lower alkoxymethyl group There is also a lower alkoxymethyl group.

Oxidation of these groups R3' can be carried out in a suitable oxidizing agent, e.g. in an inert solvent, e.g. Lower alkane carboxylic acids such as acetic acid, ketones such as acetone, ethers such as te trahydrofuran, heteroaromatic compounds such as pyridine, water, or In the mixture, if necessary, cool or heat at about 0°C to about 150°C. This is carried out by reacting in a manner known per se. The oxidizing agent is e.g. Transition metal compounds, especially 1st. It is a compound of elements of subgenus Vl, ■, or ■, and it is a silver compound. compounds such as silver nitrate, silver oxide or silver picolinate, chromium compounds such as chromium trioxide or or potassium dichromate, manganese compounds such as potassium ferrate, and permanganate. Trabutylammonium or benzyl(triethyl)ammonium permanganate It is mu. Examples of other oxidizing agents include suitable compounds of group II elements, e.g. Zinc oxide or balogen-oxygen compounds such as sodium iodine or periodine An example of this is Atsutosumu.

Here, for example, di-etherified hydrogen with hydroxymethyl or lower alkanols can be used. Droxymethyl is oxidized to carboxy or lower alkanol diester becomes carboxy R3. This reaction is preferably carried out in acetone or aqueous solution at room temperature. Perform with potassium permanganate in lysine solution. In response to this, The oxidation of dihydrated formyl to carboxy R8 is oxidized by iodine, It is carried out in a methanol solution of potassium hydroxide.

Oxidizing agent for oxidizing acetalized formyl to esterified carboxy R5 In particular, bromo- or N-bromosuccinimide is used.

The starting materials of formula (g) are prepared in a manner known per se. For example, the expression is the starting material, and this is 2R3'-A-η'Φb) or its salt (6' is required in the formula) means functionally modified carboxy) or R,' -A -C0 OH, their functional derivatives or salts, and ammonia in an inert solvent. and heated in situ to react without isolating the intermediate product to form the formula ([V)]. generate a compound.

For example, in the above-mentioned production method for producing the compound 2〇V), ammonia A (l added in excess amount of kanashi; 1., ammonia liberating (releasing) agent) The ammonia may be liberated at high temperature and, if necessary, under pressure. cormorant. As the ammonia release agent, ammonium salts of lower alkane carboxylic acids, especially ammonium acetate, as well as appropriate lower alkanecarboxylic acids) c *Lumamide is present.

Formula R, -A-C(=O)-H(Ib) Nofludehyde is the compound of formula (I) In the production method described above, for example, under the reaction conditions, the formula ? 1・ It is released from the oxazine conductor. The compound of formula αC) is, by way of example, 2- Methyl-2,4-bentanediol and a nitrile of the formula R, -A -CN are dissolved in sulfuric acid. It is produced by reacting in the presence of. The corresponding replacement generated at this time The resulting dihydro-1,3-oxazine was prepared by combining tetrahydro-7rane and ethanol. By acting sodium borohydride in the mixture at -45°C, approx. It is then reduced to form a tetrahydro-1,3-oxazine of formula αC).

The compound obtained according to the present invention can be converted into another compound of formula (1) according to a conventional method. I can do it.

For example, in the compound of formula (1) obtained according to the present invention, a free carboxy group and the esterified carboxy group R3 can be mutually converted.

Free carboxyl groups can be prepared, for example, by conventional methods such as diazo-lower alkanes, di-lower Alkyl-formamide acetal, alkyl halide, or tri-lower alkyl ruoxinium, tri-lower alkylcarboxinium, or di-lower alkyl Carbonium salts such as hexachloroantimonate or hexafluorophosphate or in particular the corresponding alcohol, reactive derivative e.g. Esters of carboxylic acids, g4 acids, sulfuric acids or carbonic acids, such as lower alkanecarboxylic acids ester, tri-lower alkyl phosphite, di-lower alkyl sulfite or is a pyrocarbonic acid ester, or a mineral acid- or sulfonic acid ester, such as a chloride- or is hydrobromic acid, sulfuric acid, benzenesulfonic acid, toluenesulfonic acid or methane Using each ester of sulfonic acid, the corresponding alcohol or its derived alcohol By reacting with lefin, esterification, esterification, carboxyl group R 3.

The reaction with the corresponding alcohol is preferably carried out using an acid catalyst such as a protic acid, e.g. Hydrohydric acid, hydrobromic acid, sulfuric acid, phosphoric acid, boric acid, benzenesulfonic acid and (or ) Toluenesulfonic acid or Lewis acid such as boron trifluoride ether complex compound in an inert solvent, especially an excess of alcohol, if necessary in the presence of a dehydrating agent. the water of reaction is removed by distillation or azeotropy if necessary; For example, the temperature can be increased.

Reactions with reactive derivatives of the corresponding alcohols include carbonic acid, phosphoric acid, sulfuric acid, or carbonic acid. Starting from stell, the presence of an acid catalyst, e.g. one of the catalysts mentioned above. in an inert solvent such as an aromatic hydrocarbon such as benzene or toluene or or in the excess amount of the alcohol derivative or corresponding alcohol used. Therefore, it can be done. Starting material is mineral acid ester or sulfonic acid ester and the acid to be esterified is preferably a salt such as a sodium salt or a potassium salt. If necessary, a basic condensing agent such as an inorganic base (e.g. hydroxide) Potassium hydroxide or calcium hydroxide, carbonate) IJum, potassium carbonate or is calcium carbonate, a base containing tertiary nitrogen such as triethylamine or pyridine. and if necessary an inert solvent such as one of the above tertiary nitrogen-containing bases. or in the presence of a polar solvent such as dimethylformamide, if necessary at high temperature. Perform the operation at a higher level.

Dilower alkyl-formamide acetals such as dimethylformamide aceter The reaction with alkyl halides is carried out under heating if necessary, and the reaction with alkyl halides is carried out with bases. For example, in the presence of an amine such as triethylamine.

For example, the reaction with an olefin can be carried out using an acid catalyst such as a Lewis acid such as boron trifluoride, sulfonic acids such as P-1 luenesulfonic acid, or especially basic catalysts such as sodium hydroxide. in the presence of potassium hydroxide or potassium hydroxide, preferably an inert solvent such as ether ( For example, it can be carried out in diethyl ether or tetrahydrofuran).

The above conversion from free carboxyl group to esterified carboxyl group R5 is , you can do it as follows. That is, a compound of formula (I) in which Rs is carboxyl For example, halides of phosphorus or sulfur, such as phosphoric trichloride, phosphoric acid pentachloride, etc. or acid halide via thionyl chloride, or react with the corresponding alcohol. reactive esters, i.e. esters with an electron-withdrawing structure, such as phenol and thiophene. As an ester with alcohol, P-nitrophenol or cyan methyl alcohol , the obtained reactive derivative is processed according to a conventional method, for example, esterified carboxyl MR The corresponding alcohol A desired group may also be formed by reacting with a compound.

The esterified carboxyl group can be treated by conventional methods, for example, by hydrolysis or by catalysis. For example, a radical or acidic agent such as a strong base such as sodium hydroxide or hydroxide By carrying out hydrolysis in the presence of potassium or mineral acids such as hydrochloric acid or phosphoric acid. , a free carboxyl radical.

The esterified carboxyl group can be prepared in a conventional manner using a catalyst such as a strong base such as hydroxyl. IJum or potassium hydroxide or strong acids such as mineral acids such as hydrochloric acid, sulfuric acid or Example: Phosphoric acid or organic sulfonic acid (Bp-) Luenesulfonic acid or Lewis acid For example, in the presence of a boron trifluoride ether complex, the corresponding alcohol itself or its is esterified by reacting with a metal salt such as sodium salt or potassium salt, and then It can be an esterified carboxyl group R8.

In addition, free carboxy or reactive functional carboxy derivatives include ammonia or is a primary amine or a secondary amine (hydroxylamine or hydrazine). by solvolysis using a condensing agent, if necessary in the presence of a condensing agent. The desired amide form can be obtained by dehydration. As a condensing agent, a base, e.g. , inorganic bases such as alkali metal hydroxides such as sodium hydroxide or hydroxide Potassium, organic nitrogen-containing bases (amines) such as tertiary amines such as pyridine, For example, tributylamine or N-dimethylaniline or tetranologensilane For example, tetrachlorosilane is preferred. Similarly, bird means amidated carboxy In the compound of the present invention of formula (1), the υ amide bond can be formed by a method known per se. The carbamoyl can also be cleaved to form the free carboxy.

This operation can be carried out using catalysts such as bases such as alkali metals or alkaline earth metals. hydroxides or carbonates such as sodium hydroxide, potassium hydroxide, calcium hydroxide carbonate, sodium carbonate, potassium carbonate, or calcium carbonate or acids such as minerals. It is carried out in the presence of an acid (eg hydrochloric acid, sulfuric acid or phosphoric acid).

At least one of the substituents R,, Rt, and Ra contains a hydroxyl group as another substituent If so, this is etherified in a manner known per se. Arco alcohol components such as lower alkanols such as ethanol and acids such as mineral acids such as sulfuric acid or When reacted with a dehydrating agent such as dicyclohexylcarbodiimide, lower alkyl xy is generated. Phenol or its salts can be used, for example, with bases, such as alkali metals. hydroxide or carbonate (e.g. hydroxide) in the presence of IJium or potassium carbonate di-lower alkyl sulfate, diazo-lower alkane, or is an aryl halide, the corresponding lower alkyl phenyl ether or aryl It can be a phenyl ether. Conversely, ether can be decomposed to produce alcohol. It can also be a rule. Acids such as mineral acids such as hydrogen chlorides such as water bromide base acids or Lewis acids, such as Group 1 halides such as boron tribromide or Decomposition of the ether is carried out via a base such as a lower primary alkyl amine such as methylamine. Aromatic alcohols are produced from alkoxyaryl compounds by .

Additionally, a desired lower alkane carboxylic acid (e.g. acetic acid) or a reactive derivative thereof , for example acids such as protic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or benign acid). or in the presence of a Lewis acid (e.g. boron trifluoride ether complexation) compound) or in the presence of a hydrophilic agent (dehydrating agent), Hydroxy is changed to lower alkanoyloxy. On the contrary, esterified hydro For example, oxy can be solvolyzed to hydroxy by base-catalyzed reaction. .

The obtained compound according to formula (1) can be converted into a salt in a manner known per se. I can do it. Hydroxy-containing groups such as R, , R, and carboxy R8 can be If the above-mentioned salts are combined with a base such as an alkali metal hydroxide, the above-mentioned Acid addition salt formation can be performed by treatment with an acid to form an acid addition salt.

The obtained salt can be treated with e.g. acidic reagents (e.g. mineral acids) or bases (e.g. alkali hydroxide). ) to form the free compound in a manner known per se. Can be done. Due to the close relationship between the free and salt forms of the compound, the above theory is In the description and the following explanation, the concept of free compound or its salt may be used as appropriate. Therefore, the corresponding salts or free compounds are also purposely included.

The compounds may exist in possible isomeric forms or mixtures thereof, depending on the choice of starting materials and mode of operation. It can exist in the form of compounds.

Compounds containing salts may be obtained in the form of their hydrates and used for crystallization. It may also contain other solvents.

The compounds may exist in possible isomeric forms or mixtures thereof, depending on the choice of starting materials and mode of operation. In the form of compounds, for example, according to the number of asymmetric carbon atoms, pure optical isomers analogy to enantiomers or as isomer mixtures such as racemates, diastereomer mixtures or may exist as racemic mixtures or tautomers.

The diastereomeric mixtures and racemic mixtures obtained are on the basis of chemical differences, e.g. by chromatography and/or fractional crystallization. , separate into pure isomers, diastereomers or racemates as known be able to. In addition, the obtained racemic compound was converted into an optically active solvent by microorganisms. Let crystallize (36) or the acidic end product to form a salt with the racemate. The salt thus obtained is reacted with an optically active base, e.g. Separate into diastereomers based on according to known methods, by liberating the body by the action of suitable agents. , split into optical enantiomers. Isolating the more useful enantiomer is desirable.

The present invention relates to compounds obtained as intermediate products in appropriate steps of the production method. starting from a substance, carrying out the missing step, or using the starting material in the form of a salt, or also relates to an embodiment of the above-mentioned production process, which consists in forming it under particular reaction conditions. It is something to do.

Starting materials of formula 1, IU, IV, specially developed for the preparation of compounds according to the invention The quality, the method of production and the use thereof also form the subject of the invention.

Contains at least one class of active substances (active ingredients) or pharmacologically usable salts thereof , topical use in warm-blooded animals is problematic for the pharmaceutical preparation according to the invention. , in which case the pharmacologically active substance may be present alone or together with a pharmacologically usable carrier substance. Both are included. The daily dosage of the active substance depends on age, individual condition and dosage form. Depends on the situation. For example, creams, ointments or may apply the corresponding agent in the form of a solution, for example 2 to 3 times daily.

Pharmaceutical preparations that can be used topically include mainly creams, ointments, pasta, foams, and tinctures. Water or solutions come into question, these containing about 0.1 to 10% of active substance.

Creams are oil-in-water emulsions containing more than 50 grams of water. For oily bases , Primarily, aliphatic alcohol examples, t halauryl alcohol, ceti lual kohl or stearyl alcohol, fatty acids such as palmitic acid or stearyl alcohol acid, fluid to solid waxes such as isopropyl myristate, wool Wax or beeswax and/or hydrocarbons such as petrolatum (petrolatum) or has paraffin oil. Emulsifiers mainly include hydrophilic surfactants, e.g. Ionic emulsifiers (e.g. fatty acid esters of polyhydric alcohols or their ethylene oxide adducts) esters, such as polyglycerol fatty acid esters or polyoxyethylene sorbitol. Tween fatty acid ester (Tween), and polyoxyethylene aliphatic Alcohol ether or polyoxyethylene fatty acid ester, or corresponding ion emulsifiers such as alkali metal salts of fatty alcohol sulfates [e.g. Sodium cetyl sulfate or sodium stearyl sulfate (These are usually aliphatic alcohols such as cetyl alcohol or stearyl alcohol) (Used in the presence of alcohol) Additives to the aqueous phase dry the cream Inhibitors such as polyhydric alcohols (e.g. glycerin, sorbitol, propylene glycerin) alcohol and/or polyethylene glycol), as well as preservatives, fragrances, etc. Ru.

The ointment may contain up to 70% water or water-in-oil containing an aqueous phase, especially about 20-50%. It's Muljon. The oil phase primarily contains hydroxyl, which is particularly suitable for improving the hydrophilic capacity. compounds such as aliphatic alcohols or their esters such as cetyl alcohol or or wool wax alcohol or a hydrocarbon containing wool wax, such as petrolatum or paraffin. linseed oil and/or solid paraffin. Emulsifiers are the corresponding lipophilic substances e.g. Sorbitan fatty acid ester (SubaySpan) such as fat sorbitan and/or ) Sorbitan isostearate. Additives to the aqueous phase include especially moisture retention agents. Examples include polyhydric alcohols, preservatives, fragrances, and others.

Oily ointments are water-free and contain especially hydrocarbons as a base, such as paraffin, petrolatum, etc. liquid paraffin and/or natural or semi-synthetic oils such as coconut oil. fatty triglycerides, or especially hydrogenated oils such as hydrogenated peanut oil or peanut oil; dog oil, fatty acid partial esters of glycerin, such as mono- and distearic acid glycerol; Serine, as well as fatty alcohols and emulsifiers that increase the water absorption capacity mentioned above for ointments. Contains agents and/or additives.

Pasta contains secretion-absorbing powder ingredients such as metal oxides such as titanium oxide or Zinc, as well as talc and/or aluminum silicate, may are creams and ointments containing powder ingredients with the ability to bind secretions.

Foaming agents are liquid oil-in-water emulsions in the form of aerosols, for example, delivered from pressure vessels. halogenated hydrocarbons such as chlorofluoro lower alkanes (e.g. chlorodifluoromethane and dichlorotetrafluoroethane) are used as propellants. I can stay. The oil phase may in particular include hydrocarbons such as evaporated paraffin oil, fatty alcohols e.g. Cetyl alcohol, fatty acid esters such as isopropyl myristate and (or ) Other waxes may be used. Emulsifiers include mainly hydrophilic emulsifiers, e.g. Ethylene sorbitan fatty acid ester (Tween) and mainly lipophilic emulsifiers For example, sorbitan fatty acid ester (Span) is used. For this purpose ordinary additives For example, preservatives are used.

Tinctures and solutions often have an aqueous-ethanol base, which includes especially polyvalent amines. Alcohols such as glycerin, glycols and/or polyethylene glycols As a water retaining agent to reduce evaporation, or as an agent to return to an oily state, such as low-grade polyethylene. carried away from the skin by glycol-containing fatty acid esters, i.e., ethanol. oleaginous substances soluble in the aqueous mixture to compensate for the added fat content and, if necessary, other auxiliary agents or additives are added.

Pharmaceutical preparations which can be used topically can be used in a manner known per se, e.g. Manufactured by dissolving or suspending the substance in the carrier or, if necessary, in a part thereof. be done. When the active substance is prepared as a solution, it is usually separated into two phase layers before emulsification. It is dissolved into one of the two. When prepared as a suspension, the active substance is added to the base after emulsification. part of the preparation and then added to the remainder of the preparation.

The following examples illustrate, but do not limit, the invention as described above. . Temperatures are given in degrees Celsius.

Example 1 1-phenyl-2-(3-pyridyl)-glyoki dissolved in 500 d of methanol Sal (freshly distilled) 39,9 water for 5 hours with stirring of Or with C It was made to react with 2.52 kg of sodium borohydride. After the addition is complete, keep the mixture at 0° for 2 hours. Stir for a while, leave at o0 for 15 hours, and add 200rn1. reacted with . The suspension is dried under reduced pressure and the residue is reacted with ice and carbonated) A constant solution was added to make it alkaline. The aqueous suspension was extracted with 200 portions of ethyl acetate. I put it out. The combined ethyl acetate solution was washed with 5° of water and poured onto magnesium sulfate. Dry and evaporate under reduced pressure at 40°. The residue, which is a brown oil, is washed with 50% silica gel. 02 was used for chromatographic separation.

Fractions 1 and 2 (eluted with toluene-ethyl acetate (1:1) 10007! ) contains the starting material 1-phenyl-2-(3-pyridyl)-glyoxal. Ta. Fractions 3 and 4 (toluene-ethyl acetate (1:1) 1000rn/! (eluted at ) was washed and evaporated to dryness under reduced pressure. The residue is ether-petroleum The ether was crystallized. α-Hydroxybenzyl-(3-dolysyl)-ke The M point of ton was 109-111°. Fractions 5 and 6 (toluene-vinegar Ethyl acid (1:1) eluted at 1000 d) was discarded. Fraction 7-1 4 (toluene-ethyl acetate (40:60) eluted at 1000 rn1.) is 1 The mixture was dried and evaporated under reduced pressure. Is the leftover pickle ether-petroleum ether? crystallized. α-Hydroxyphenyl [(3-pyridyl)-methyl sieke The melting point of Tong was 93-95°.

Example 2 Triethylamine 1- and α-hydride dissolved in 80 mJ of water-free benzene Roxyphenyl-[(3-pyridyl)-methylcoketone 6, a mixture with Ov, Distillate dissolved in water-free benzene under stirring and introduction of nitrogen 1 for 20 minutes with a solution of 6.09 tyl-malonic acid-mono-ethyl ester-chloride. React at 0°, stir at room temperature for 3 hours, and react with ethyl acetate 30- and water 90- The mixture was stirred for an additional hour at room temperature. Separate the aqueous phase and mix it with 20-20% acetic acid. Washed twice with chill. The combined organic phases were mixed with saturated saline solution 30- and potassium bicarbonate. Wash in sequence with 30 μm of 2-normal solution, then again with 30 μm of saturated saline solution, and wash with sulfuric acid. Dry over magnesium and concentrate under reduced pressure. 200m of silica gel to remove oil from leftover pickles It was separated by chromatography using 1. Fractions 1 and 2 (chloro (eluted with 200 ml of form) was discarded. Fractions 3 to 9 (chloroform- (eluted with methanol (99:1)) was combined and evaporated under reduced pressure to dryness. . The residual dimethyl-malonic acid-monoethyl ester-[α-pensoyl- (3-Pyridylmethyl)ester was obtained as an oil.

Similarly, α-hydroxy-phenyl-((3-pyridyl)-methyl sequence ton and methylmalonic acid-mono-ethyl ester-chloride as starting materials, Methyl-malonic acid-mono-ethyl ester-[α-pensoyl-(3-pyridyl) -methyl) ester 0 is obtained, mata α-hydroxy-phenyl-[(3-methyl) ester 0 is obtained; lysyl)-methylthiketone and malonic acid-monoethyl ester-chloride. As a starting material, malonic acid mono-ethyl ester-[α-benzoyl-(3-p- lysyl-methyl)-ester (the older sister was obtained).

Example 3 Dimethylmalonic acid-mono-ethyl ester-[α-benzoyl-(3-biridyl -methyl)-ester 3.11F.

A mixture of 2.42 ammonium acetate and wood vinegar H24rnt was heated at a bath temperature of 40°C. Stirred for an hour. The reaction mixture was cooled, poured into 100 m of ice water, and poured into concentrated aqueous ammonia. It was adjusted to -8.0 with a solution. Extract 3 times with 70 d of ethyl acetate, The extract was extracted twice with 20 portions of water. The combined organic phase is magnesium sulfate. and evaporated to dryness under reduced pressure. For leftover pickles, use silica gel 10o2 It was separated by chromatography. Fractions 1 to 7 (100d each) (eluted by roform) was discarded. Fraction 8.9 (100tnt each (eluted with chloroform) were combined and evaporated to dryness under reduced pressure.

The residual oil was rubbed with petroleum ether. The precipitated crystals are filtered and poured into cold oil. Washed with ether. 2-[4-phenyl-5-(3-pyridyl)-oxaso The melting point of 2-methyl-2-yl]-2-methyl-propionic acid ethyl ester is 70-71 It was °.

1if1m, methyl-malonic acid-mono-ethyl ester-[α-benzoi 2-(:4-phenylmethyl)-(3-pyridylmethyl)-ester as a starting material. Ethyl-5-(3-pyridyl)-oxazol-2-ylcoupropionate Stell (f■ 3″ 1′ NMR (CDC4): 8,85 (s, br, H-2'); 8,56 (d , br, H-6') Near, 87 (dt, H-4'): 7.64 (m, H -2', 6""l: 7,35-7.45 (residual value obtained.

Mata, malonic acid mono-ethyl ester [α-benzoyl-(3-pyridylmethyl) 2-[4-phenyl-5-(3-pyridyl) )-oxazol-2-yl]-acetic acid ethyl ester (NMR (CDC4): 8,85 (s, br, H-2'): 8,56 (d, br, H-6') Ni A, 87 (dt, H-4'): 7, 64 (m, H-2", 6"): 7, 3 5-7.45 (residual aromatic H'I: 7,18 ('dd, H-5'): 3.92 (a, C Takumi CO).

was obtained.

Example 4 2-[4-phenyl-5-(3-pyridyl)- dissolved in methylene chloride 20- Oxazol-2-yl]-2-methyl-propionic acid ethyl ester 1.62 A solution of 1. m-chloro-perbenzoic acid dissolved in 20 d of methylene chloride was added. Ov's The mixture was added dropwise to react with the solution while stirring at θ°. Stir the mixture for 2 hours. The sample was further reacted with 0.1 t of m-chloro-perbenzoic acid and stirred at θ° for 30 minutes. Ta. The mixture was washed twice with 10 ml of 2N potassium bicarbonate solution and soaked in magnesium sulfate. It was dried over nitrogen and evaporated to dryness under reduced pressure. The oil left over from pickles is silica gel 4 It was separated by chromatography using 01. Fractions 1-3 (chloro Holm 507! (eluted separately) were discarded. Fractions 4-11 (50m/! (eluted with chloroform) were combined and evaporated to dryness under reduced pressure.

The residue i.e. 2-[4-phenyl-5-(1-oxide-3-pyridyl)-oxa Sol-2-yl]-2-methyl-propionic acid ethyl ester was obtained as an oil. It was done.

NMR (CDCLs): 8,39 (t, H-2'): 8,03 (di, H- 6'): 7,10 (dd, H-5'): 7,2-7.6 (m, residual aroma Group H): 1,65 (s.

gem, CH,).

Similarly, 2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl ]-Flopionic acid ethyl ester as a starting material, 2-[4-phenyl-5- (1-oxide-3-pyridyl)-oxazol-2-yl]ethyl propionate ester (Nao) was obtained.

Also, 2-[4-phenyl-5-(3-pyridyl)-oxazol-2-ylz - Acetic acid-ethyl ester is released M material N,! : 2-1:4-phenyl-5- (1-oxide-3-pyridyl)-oxazol-2-ylkuacetic acid ethyl ester Obtained tell (2).

Example 5 2-[4-phenyl-5-(1-oxide-3- pyridyl)-oxazol-2-yl)-2-71 ethyl propionate A solution of 2.1 t of Stell was stirred and reacted with 1N solution of caustic soda 7.2- . The solution was stirred for 5 hours at room temperature and evaporated to dryness under reduced pressure. Add the residue to 50% water. The mixture was dissolved and an aqueous solution was extracted with 20-methylene chloride. Then separate the aqueous phase and add hydrochloric acid The pH was accurately adjusted to 4.0 using a 2N solution. The suspension was stirred for 5 minutes at C and filtered. . 2-[4-phenyl-5-(1-oxide-3-pyridyl)-oxazole- The melting point of 2-yl]-2-methyl-propionic acid was 136-137°.

Similarly, 2-[4-phenyl-5-(1-oxide-3-pyridyl)-oxy From sazol-2-yl]-propionic acid ethyl ester, 2C4-phenyl -5-(1-oxide-3-pyridyl)-oxazol-2-yl2propio phosphoric acid was obtained.

Also, 2-[4-phenyl-5-(nioxide-3-pyridyl)-oxazole -2-yl]acetic acid ethyl ester as a starting material, 2-(4-phenyl-5- (]-]oxido-3-pyridyl-oxazol-2-yltuacetic acid was obtained. Ta.

Also, 2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl]- ethyl 2-methylpropionate (recrystallized) was obtained.

Example 6 α-oximobenzyl(3-pyridyl)-keto suspended in 300 g of glacial acetic acid 11.3 F and 2-(2,2-dimethyl-carboethoxymethyl)-4, 4,6-)dimethyl-2,3,5,5-tetrahydro-1,3-oxime 12. Hydrochloric acid gas was introduced into 2f without cooling and stirring well. Here is the temperature During this time the temperature was increased to 45° and a clear solution was obtained. In this solution, 30 Hydrochloric acid gas was introduced for a minute, then the solution was heated at 115° for 15 hours, cooled and under reduced pressure. Evaporate to dryness at 30°. The residue was dissolved in 300ml of water. This aqueous solution is Make alkaline with a concentrated aqueous solution of Monia, and convert the precipitated crystals into ethyl acetate-chloride. It was dissolved in 300 g of methylene (1:1). The organic phase was washed with 50 ml of water and diluted with sulfuric acid. Dry over magnesium and evaporate to dryness under reduced pressure. Remove leftover pickles from methanol and ethanol. - crystallized from tel. 2-[4-phenyl-5-(3-pyridyl)-(3-o Oxide-oxazole)-2-ylk-2-methyl-propionate ethyl ester The FA point of the sample was 195° to 210°.

Similarly, α-oxymobenzyl-(3-pyridyl)-ketone and 2-(2 -methyl-carbo-ethoxymethyl)-4,4,6-)dimethyl-2,3,5 ,6-titrahydro-1,3-oxazine as a starting material, 2-[4-phenyl -5-(3-pyrido)-(3-oxide-oxazole)-2-ylkuacetic acid Ethyl ester was obtained.

Furthermore, α-oxymobenzyl-(3-pyridyl)-ketone and 2-(carboxylate) ethoxy-methyl)-4,4,6-)dimethyl-2,3,5,6-titrahydride Using rho-1,3-oxazine as a starting material, 2-[4-phenyl-5-(3-pyl) Lido)-(3-oxide-oxazol)-2-yl]acetic acid ethyl ester is Obtained.

Example 7 2-[4-phenyl-5-(3-pyrido)-(3- ethyl oxide-oxazol-2-yl]-2-methyl-propionate Stir a solution of 1.2f of zinc powder at 10' and react little by little with 1.21 of zinc dust. Ta. After the addition was completed, 0.05 ml of concentrated oxalic acid was further added. Cook this mixture for 1 hour at 90'' ', cooled, filtered and washed with 5rnt of glacial acetic acid. Liquid F under reduced pressure , evaporated to dryness at 5 cP. The residue was dissolved in 20ml of water. I'm jealous of this aqueous solution. The mixture was made alkaline with aqueous ammonia solution. The suspension was extracted three times with 30 portions of ethyl acetate. I put it out. The combined organic phases were washed with 10 liters of water and dried over magnesium sulfate. The mixture was concentrated under reduced pressure to obtain a dry product. Chromatize the residue using silica gel 801. It was separated by toography. Fractions 1 to 5 (each 50-chloroform (elution) was discarded. Fractions 6-9 (each eluted with 5°-chloroform) ) were combined and evaporated to dryness under reduced pressure. Rub the remaining pickles with petroleum ether. It was then crystallized. 2-[4-phenyl-5-(3-pyridyl)-oxazole -2-Ilk 2-methyl-propionate ethyl ester has a melting point of 70-7]0 Met.

Example 8 α-prono-benzyl-(3-pyridyl)-ketone 3.68', dimethyl malo phosphoric acid-mono-ethyl ester-mono-amide 1.72 and collidine 1.32. The mixture obtained by mixing in Shiren 100 was heated to 120-130° for 15 hours. The water produced was separated using a water separator. The reaction mixture is then evaporated to dryness under reduced pressure. I set it. The residue was reacted with concentrated aqueous ammonia solution and 30° of water, and 40° each of acetic acid was added. Extracted with ethyl three times. The combined ethyl acetate solution was washed with 20ml of water and diluted with sulfuric acid macerate. Dry over magnesium and evaporate to dryness under reduced pressure. using silica gel sop The residue was separated by chromatography. Fractions 1-3 (10 each (eluted with chloroform) was discarded. Fractions 4-6 (100’m each 2-[4-phenyl-5-(3-pyridyl)- Contains oxazol-2-yl-2-methyl-propionic acid ethyl ester was. These were combined and evaporated to dryness under reduced pressure. The residue is petroleum ether It was poured and the precipitated crystals were collected in a furnace. The melting point was 70-71°.

Example 9 α-bromo-benzyl-(3-pyridyl)-ketone-hydropromide 3.56 t and dimethyl-malonic acid-mono-ethyl ester-sodium salt 3.66f. The mixture obtained by mixing in a 100% aqueous ethanol solution was heated under reflux while stirring. Ta. After adding 1 d of concentrated sulfuric acid, the solution was kept under reflux for 1 hour and then at 50° for 15 hours. Stirred with. It was then cooled and concentrated to dryness under reduced pressure. Remove the residual oil Kagel 250. Separated by chromatography at r. Fractions 1 to 5 ( each eluted with 300-chloroform) was discarded. Fraction/6~8( (each eluted with 300 tnl of chloroform) were combined and evaporated to dryness under reduced pressure. I set it. The oily residue dimethyl-malonic acid-mono-ethyl ester-[α- Nicotinoyl-benzyl co-ester was obtained.

Similarly, α-bromo-benzyl-(3-pyridyl)-ketone-hydropromycin and methyl-malonic acid-mono-ethyl ester-+) IJum salt Kara, Methyl Tyl-malonic acid-mono-ethyl ester-[α-nicotinoyl-benzyl ester] Stell (Standard was acquired.

Furthermore, α-bromo-benzyl-(3-pyridyl)-ketone hydropromide and castor Malonic acid mono-ethyl ester-1)-) IJum salt Kara, malonic acid mono- -Ethyl ester-[α-nicotinoyl-benzyl co-ester (also obtained) Ta.

Example 10 Dimethyl-malonic acid-mono-ethyl ester-[α-nicotinoyl-benzyl ester] - Ester 6,5 fN vinegar ell ammonium 4.81 and glacial acetic acid 50 g The mixture was stirred for 2 hours at a bath temperature of 1400°C. Cool the reaction mixture and add 400 ml of ice water. The solution was poured into a serving and adjusted to -8.0 with a concentrated aqueous ammonia solution.゛1 each (10t Extracted three times with 30 nt of ethyl acetate, and each ethyl acetate extract was diluted with 30 nt of saturated sodium chloride solution. Washed twice with liquid. The combined organic phases were dried over magnesium sulfate and vacuum Evaporated to dryness under water. The residue was chromatographed using silica gel 30o2. It was separated. Fraction 1 (eluted with 300-chloroform) was discarded. Ta. Fractions 2 to 4 (each eluted with chloroform 3007!) were combined into one. , evaporated to dryness under reduced pressure. The residue was poured in with petroleum ether. precipitated The crystals were removed from the oven and washed with cold petroleum ether. 2-[4-Fue two people-5-(3- pyridyl)-oxazol-2-yl2-methyl-propionate ethyl ester The melting point of tel was 70-71°.

Fractions 5 to 10 (each eluted with 300 ml of chloroform) were discarded. . Fractions 11 to 15 (eluted with 300 mg of chloroform each) are one and evaporated to dryness under reduced pressure. Residue 2-C4-(3-pyridyl)-5-phe Nyl-oxazol-2-yl]-2-)f-propionic acid ethyl ester is , precipitated by rubbing with cold petroleum ether. Melting point 41-42°.

Similarly, methyl-malonic acid-mono-ethyl ester-[α-nicotinoyl- As a starting material for 2-[4-phenyl]-ester, 2-[4-phenyl-5-(3-pyri Zyl)-oxazol-2-ylcypropionic acid ethyl ester (N and 2) -[:4-(3-pyridyl)-5-phenyl-oxazol-2-yl]-furo Pionic acid ethyl ester (?O) was obtained.

Sarani, malonic acid mono-ethyl ester [α-Nico (52) 2-(4-phenyl-5-( 3-Pyridyl)-Othikinsole~2-yl]-acetic acid ethyl ester (and 2- (4-(3-pyridy-5-phenyl-oxazol-2-yl)-ethyl acetate Ester (Tao was obtained.

Sarani, malonic acid-mono-LerL-butyl ester [α~nicotinoylube] 2-[4-phenyl-5-(3-pyridine)]-ester as a starting material. terL-butyl)-oxazol-2-yl-2-methyl-propionic acid Le Esther (Naoto) NMR (CDC4): 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 (residual aromatic H); 7,18 (dd, H-5' G'l, 75 (g, gem, CR2 included and 2-[4-(3-pyridyl)-5-phenyl-oxazol-2-ylku2- Methyl-propionic acid-Lert butyl ester (2) NMR (CDC4): 8.90 (s+, br, H-2'): 8,57 ( d, br+H-6' C8,00 (dL, H-4'); 7,55 (m, H- 2", 6〃): 7,35-7.45 (b, remaining aromatic H); 7132 (d d+H-5'): 1.73 (s, gem, cHl) was obtained.

Example 11 In the same manner as in Example 4, 2-[:4-(3-pyridyl)-5-phenyl-oxy Starting from sasol-2-yl]-2-,t-y-lupropionic acid ethyl ester As a substance, 2-(4-(1-oxide-3-pyridyl)-5-phenyl-oxy Sasol-2-yl]-2-methyl-propionic acid ethyl ester Q■ was obtained. It was. Melting point 85-90° (ether-petroleum ether).

Furthermore, 2-(4-(3-pyridyl)-5-phenyl-oxazol-2-ylz) - Using propionic acid ethyl ester as a starting material, 2-(4-(1-oxide- Ethyl 3-pyridyl)-5-phenyl-oxazol-2-yl-2-propionate luester was obtained.

Furthermore, 2-44-(3-pyridyl)-5-phenyl-oxazol-2-yl] - Using acetic acid ethyl ester as a starting material, 2-[:4-(1-oxide-3- pyridyl)-5-phenyl-oxazol-2-yl)-D acid ethyl ester Obtained.

Furthermore, 2-[4-phenyl-5-(3-pyridyl)-oxazol-2-ylyo -2-methyl-propionic acid-tart butyl ester as a starting material, 2- [4-phenyl-5-(1-oxido-3-pyridyl)-oxazol-2-y ]-2-methylpropionic acid-tertbutyl ester, oil, NMR (CDC4,): 8,39 (t, H-2'); 8,03 (dt, H- 6'); 7,10(dd, H-5'G 7,2-7.6(m, remaining aromatic H): I H65 (81g am.

CH,) was obtained.

Furthermore, 2-[4·-(3-pyridyl)-5-phenyl-oxazole-2-y Luyo 2-methyl-propionic acid-terL-butyl ester as starting material , 2-[4-(1-oxido-3-pyridyl)-oxazol-2-ylyo2 -Methyl-propionic acid-tert-butyl ester, oil, was obtained.

Example 12 α-Aminobenzyl-(3-pyridyl) in 100 rRT of dry tetrahydrofuran ) - A solution containing 6.2f of ketone was stirred and nitrogen gas was introduced under pressure. Methyl-malonic acid-monoethyl ester-chloro IJ)” 8.8 f and HN , N diisopropylethylamine 7.2 times. Mixture for 15 hours Mix and evaporate to dryness under reduced pressure. Chromatograph the residue on silica gel 500f. Separated by fees. Fractions 1 to 6 (400 ylf each) (eluted by) were discarded. Fractions 7-1° (each containing 400 grams of chloroform) (eluted at 100 ml) were combined and evaporated to dryness under reduced pressure. N-[α-(3-pyri dimethyl)-phenacyl]-dimethyl-malonic acid-mono-ethyl ester-mono-a Mido, oil, was obtained.

Similarly, α-amino-benzyl-(3-pyridyl)-ketone and methyl-mer Using rononic acid-7noethyl ester-chloride as a starting material, N-[α-(3- pyridyl)-7enacyl]-methylmalonic acid-mono-ethyl ester-mono-a Mid (γ) was obtained.

Furthermore, α-amino-benzyl-(3-pyridyl)-ke (55) N-[ α-(3-pyridyl)-phenacyl comalonic acid-monoethyl ester-mono - amide was obtained.

Example 13 N-[α-(3-pyridyl)-phenacyl]-dimethyl-malonic acid-mono-ethyl Obtained by dissolving ester-mono-amide 2,1f in phosphoryl chloride 40- The solution was heated under reflux for 4 hours. The mixture was cooled, poured onto ice, and the precipitated oil was dissolved in acetic acid. Extraction was performed using Chill 100wt. The ethyl acetate solution was diluted twice with 20 m of water each. Extract twice with 0-1N sodium carbonate solution and once with 20-1N water, and extract with sulfuric acid mug. Dry over nesium and evaporate to dryness under reduced pressure. The residue is 70 tons of silica gel. It was separated by chromatography using . Fractions 1-5 (80r each nt chloroform elution) was discarded. Fractions 6-8 (each 80- (eluted with chloroform) were combined and evaporated to dryness under reduced pressure. Remove leftover pickles from petroleum 2-[4-phenyl]-5-(3-pyridyl)-oxazo -2-yl]-2-methyl-propionic acid ethyl ester (melting point 70-71 °) was crystallized.

Similarly, N-[α-(3-pyridyl)-7enacyl]-methyl-malonic acid- Starting from monoethyl ester-mono-amide, 2-[:4-phenyl- 5-(3-pyridyl)-oxazol-2-yl]propionic acid ethyl ester (Tao was acquired.

Furthermore, N-[α-(3-pyridyl)-phenacyl]-malonic acid-monoethyl ethyl 2-[4-phenyl-5-(3-pyrynylated) (diyl)-oxazol-2-ylkuacetic acid ethyl ester (Tao) was obtained.

α-Amino-benzyl-(3-pyridyl)-ketone can be produced as follows. I can do it.

Pyridine 40- and hydroxylamine hydrochloride srl pyridine 15- The resulting solution was mixed with benzyl-(3-pyridyl)-ketone 10.8F. , stirred at 100° for 6 hours. Pour the reaction mixture onto ice water and stir for another 15 minutes. mixed. The crystals formed were filtered, washed with water and dried under high vacuum. melting point 12 2-126° benzyl (3-pyridyl)-ketone-oxime was obtained .

Benzyl-(3-pyridyl)-ketone-oxime 8,5v in pyridine 201nt Stir the solution obtained by dissolving in Drop a solution obtained by dissolving 7.72 p-toluenesulfonic acid chloride within 5 minutes. did. The reaction mixture was kept in an icebox for 24 hours and then poured into ice water. Generate The oil solidified into crystals after stirring and rubbing. I tear this crystal with water Washed and dried under high vacuum. Benzyl-(3-pyridyl)-ketone-oxime -p-toluenesulfonic acid ester is obtained, which requires further purification. It was possible to use it in the next step without removing it.

Crude benzyl-(3-pyridyl)-ketone-oxime=p-)luenesulfonic acid ester The mixture was suspended in 90% of ethanol. Then potassium-t ert-butyler) 3.7F in 30 ml of absolute ethanol. It was added dropwise while stirring at °C. The reaction mixture was stirred at O0 for 2 hours. Filter the suspension. F solution containing the target product α-amino-benzyl-(3-pyridyl)-ketone was evaporated to dryness under reduced pressure.

Example 14 2-[4-phenyl-5-(1-oxide-3-pyridyl)-oxazole-2 Production composition of ointment containing 5th-yl]-2-methyl-propion aqueous ethyl ester Active substance (active ingredient) 5.0% Wash line 45.0% Paraffin oil 19.6% Anlu and tan-sesquiolate 5゜O% P-hydroxyben & aromatic acid ester 0. The 2% solids and emulsifier were dissolved together. Are preservatives soluble in water? The solution was then emulsified in molten fat at high temperature. Agents in a portion of the molten fat after cooling The quality suspension was incorporated into an emulsion.

Example 15 2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl2- Manufacturing composition of cream containing 10% methyl-propionate ethyl ester Active substance 10.0% Isopropyl valmitate 8.0% Cetyl palmitate 1.5 t Silicone oil 1000, 5% Sorbitan monostearate 3.0% polysolvatoro 0 3゜5chi 1.2-Propylene glycol: +-L PH20, 0% Acrylic acid polymer 0.5% Triethanolamine 0.7t Acrylic acid is added to a mixture of water and 1,2-propylene glycol from which the antidepressant has been removed. The coalescence was suspended. Add triethanolamine to this mixture while stirring. Tonyoshi, I got a slime. Isopropyl valmitate, cetyl palmitate, Add a mixture of silicone oil, sorbitan monostearate and polysorbate to approx. Heat the slime to 75° and mix it with the slime that has been heated to about 75°. 5 9) I set it. Use the cream-base cooled to room temperature with the active substance for the preparation of concentrates. used. A once-through homogenizer homogenizes the concentrate and adds it to the base one after another. added.

Example 16 2-[4-phenyl-5-(l-oxide-3-pyridyl)-oxazole-2 -yl]~2-methyl-propionic acid ethyl ester 5th cream containing Manufacturing composition Active substance 5.0% Cetyl palmitate PH2.0 yen Cetyl alcohol PH2, 0ch intermediate fat saturated fatty acid Triglyceride mixture m 5.0 steamed rice Stearic acid 3.0 t Glyceryl stearate PH4゜0chi Seto macro goal 1000 1.0chi Microcrystalline cellulose 0.5 inch 1.2-Propylene Grinyl (distilled, dest) 20, 0% dehydrated until the total water reaches 100.0% Cetyl alcohol, cetyl palmitate, triglyceride mixture, stearic acid and glyceryl stearate were melted together. Microcrystalline cellulose is Dispersed in a portion of water. Dissolve the cetomacrogol in the remaining water and add the propylene This was mixed with glycol and slime. Add fat phase to water phase with stirring and stirred at room temperature. Next, mix the active ingredient with some of the base. It was combined into the rest of Ream.

Example 17 2-[4-phenyl-5-(1-oxide-3-pyridyl)-oxazole-2 -Clear hydrocarbon containing 5% 2-methyl-propionate ethyl ester Manufacture of gel composition Active substance 5% Propylene glycol 10-20% Water total 100 chi Hydroxypropyl-methylcellulose was swollen in water. Inject the active substance It was dissolved in a mixture of propatool and propylene glycol. then the agent The solution is mixed with the swollen cellulose derivative and flavoring (0.1%) is added if desired. Added.

Example 18 2-[4-phenyl-5-(1-oxide-3-pyridyl)-oxazole-2 -yl]-2-methyl-propionic acid ethyl ester 5-containing transparent hydrogen Manufacture of logel Active substance 5ch Propylene glycol 20ch Itsuprobanol 20ch Acrylic acid polymer 2ch Doliethanolamine 3ch Water total 100 chi The acrylic acid polymer and water were dispersed and neutralized with triethanolamine. agent The substance was dissolved in a mixture of isopronoquinol and propylene glycol. Next The solution of active substance was mixed with the gel and, if desired, perfume' (0.1%) was added.

Example 19 2-[4-phenyl-5-(1-oxide-3-pyridyl)-oxazole-2 -yl]-2-methyl-propionic acid monochloride composition Product quality 1.00% Cetyl alcohol PH1.70% Paraffin oil (viscous liquid) 1, O0% isopropyl myristate 2.0 0 Tisetomacrogol 1000 2, 40% Sorbitan Monostearate 1 ．． 50% 1.2-Propylene Glyco-/I/PH5,00% Methylparaben 0 ．． 18chi Bropylparaben 0.02t Kemodem 314 0.10chi Cetyl alcohol, paraffin oil, isopropyl myristate, cetomacrogor sorbitan stearate and sorbitan stearate were melted together. methylparaben and pro Pilparaben was dissolved in hot water. The melt and solution were then mixed. Propi The active substance suspended in lene glycol was suspended in the base and incorporated into the base. . Then apply Chemodem ((hsmode rm) and add water to final weight. Mixture 20- was filled into an aluminum block dose. The dose has a valve and Advance gas was injected under pressure.

Example 20 α-Hydroxyphenyl-[(3-pyridyl) dissolved in dry benzene 7Osd )-methyl]-ketone 4. A mixture of Of and triethylamine (096ml) was dried. 2-Ethoxymethyl-2-methyl-propionic acid dissolved in 2° dry benzene solution of chloride 3.72 and incubate for 20 minutes under stirring and a 10' nitrogen supply. I responded. The mixture was then stirred for 3 hours at room temperature, mixed with 30 tnt of ethyl acetate and 6 tnt of water. The mixture was reacted with Ogo and further stirred at room temperature for 1 hour. Then the aqueous phase was removed and each 20 m Washed twice with ethyl acetate. The combined organic phase was added with 20 fnt of saturated sodium chloride solution. and 20% of 2N potassium bicarbonate solution, then washed again with 20% of saturated saline solution. 0 mg, dried over magnesium sulfate and concentrated under reduced pressure. Residue Residue (2-ethoxymethyl-2-methyl-propionic acid-[α-benzoyl-( 3-pyridyl-methyl)]-ester (2) was dissolved in glacial acetic acid 40- Add Monium 4.12 and heat the mixture with stirring at a bath temperature of 140° for 2 hours. Ta. The reaction mixture was cooled and poured with 150 tons of ice water! Pour over concentrated ammonia water The solution was adjusted to -8.0. Extracted 3 times with 100% ethyl acetate each and vinegar The ethyl acid extracts were each washed twice with 20-mL water. Pour the combined organic phase into a sulfuric acid mug. Dry over nesium and evaporate to dryness under reduced pressure. Using 150t of silica gel The residue was separated by chromatography.

7 lactations 1-5 (each dissolved in chloroform at 150 Wtt) were discarded.

Fractions 6 to 9 (each eluted with 150 rnt of chloroform) were combined. , evaporated to dryness under reduced pressure. Oily residue 2-[:4-(phenyl-5-(3 -pyridyl)-oxazol-2-yl2-methyl-1-epoxy-propyl was obtained.

Example 21 (2-[4-phenyl-5-(3 -pyridyl)-oxazol-2-yl]-2-meth-1-ethoxy-propyl Potassium permanganate was added to the solution of 2.02 until no decolorization was observed. was added little by little at room temperature with vigorous stirring. The mixture was then heated at room temperature for 10 hours. After stirring, the mixture was filtered. Concentrate the p solution to dryness at 50° under 11 Torr. I let it happen. The remaining pickles were poured with 15 ml of ice water and extracted with ethyl acetate. The organic phase is chlorinated Washed with sodium saturated bath solution, dried over sodium sulfate and evaporated under reduced pressure. Allowed to dry.

Eight pickles were separated by chromatography using silica gel 702. frac Sections 1-3 (each eluted with 50-chloroform) were discarded. fraction 4 to 8 (each eluted with 50-chloroform) were combined and evaporated to dryness under reduced pressure. I set it. The residue was poured into cold petroleum ether. - fK was deposited after being left for day and night. I counted the crystals. 2-[4-phenyl-5-(3-pyridyl)-oxazole- The melting point of 2-yl]-2-methyl-propionic acid ethyl ester is 70-71°. there were.

Example 22 2-[4-phenyl-5-(3-pyridyl)-oxazol-2-ylcu-2- Methylpropionic acid i, or.

Triethylene glycol-monoethyl ether 0.6f and 4-dimethylamino Dicyclohexyl React with carbodiimide 0.72 at room temperature while stirring vigorously and supplying nitrogen. Ta. Stir at room temperature for 48 hours, add 4° of toluene, and filter. The filtrate is under reduced pressure Evaporated to dryness under water.

The remaining pickles were dissolved in 20% of methylene chloride. Methylene chloride solution is sodium carbonate Wash with 01 normal solution 5 and water, dry over magnesium sulfate, and reduce pressure Evaporated to dryness under water. Oily residue 2-[4-phenyl-5-(3-pyridyl) -oxazol-2-yl]-2-methyl-propionic acid-2-[:2-(2- methoxyethoxy)-ethoxycouethyl ester was obtained.

NMR (CDCts): 8,85 (s, br, H-2'G 8,56 (d , br, H-6') near, 87 (dt, H-4''); 7,64 (m, H-2 ”, 6”): 7.35-7.45 (residual aromatic H); 7,18 (dd, H-5' G 1,75 (s, gem, CH,') Similarly, 2-[4-frame phenyl-5-(1-oxide-3-pyridylco-2-methylpropionic acid and Liethylene glycol - monoethyl ether or triethylene glycol As starting material, 2-(4-phenyl-5-(1-oxide-3-pyridyl)- Oxazol-2-ylk-2-methyl-propion-2-[2-(2-meth) xyethoxy)-ethoxyethyl ester (also NMR (CDC4): 8,39 (t, H-2'); 8,03 (di,) I-6”): 7,10 (dd, H-5’): 7,2-7.6 (m, residual aroma aromatic family H); 1,65 (s, gem.

CF(,) and 2-[4-phenyl-5-(1-oxide-3-pyridylnooxazole-2 -Irk-2-methyl-propion-2-(2-(2-hydroxyethoxy) -ethoxycouethyl ester (also NMR (CDC4): 8.39 (t, H-2”l; 8,03 (dt, H-6 ’); 7,10 (dd, H-5’): 7,2-7.6 (m, remaining aromatic H): 1,65 (s, gem.

CH,) was obtained.

Similarly, 2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl ]-2-methyl-propionic acid and hydryethylene glycol as starting materials, 2-[4-phenyl-s-(3,-hy+)sil)-oxal-l-2-yl ]-2-methyl-propionic acid-2(2-(2-hydroxyethoxy)-ethoxy) Thikuethyl ester (2) NMR (CDC15) 28.85 (s, br, H-2'): 8 + 56 (d, br, H-6'); 7.87 (dt, H-4"): 716 4 (m, H-2″, 6″G 7.35-7.45 (residual aromatic H): 7,1 8 (dd+H-5'); 1,75 (s, gem, CH,') was obtained .

Example 23 Diethylene glycol monochloro dissolved in hexamethylphosphoric triamide 6- A solution of 1.439 hydrin was added to 2-[4-phenyl-5-(3-pyridyl)-ol Xazol-2-yl]-2-methylpropionic acid-sodium salt 3.46F was added with stirring at 50-60°. Stir the mixture at 100° for 4 hours. , cooled and poured into 50 g of ice water. The precipitated oil was extracted with ether 100g.

The ether phase was sequentially washed with 20 d of water and 20 d of 2N potassium hydrogen carbonate solution, Then washed again with 20 kg of water, dried over magnesium sulfate, and evaporated under reduced pressure. I let it happen.

1) The remaining pickles were separated by chromatography using Kagel 100F. centre Reactions 1-3 (each eluted with 100 m chloroform) were discarded. frac Sections 4 to 6 (each eluted with 80-chloroform) were combined and evaporated under reduced pressure. It was dried and solidified. The oily residue 2-[4-phenyl-5-(1-oxide-3-p- lysyl)-oxazol-2-yl]-2-methyl-propionic acid-[2-(2 -Hydroxyethoxy)-ethyl two ester NMR (CDC4): 8,39 (Also, H-2' G 8,03 (dt, f (-6'): 7,10 (dd.

H-5'): 7,2-7.6(m, remaining aromatic H): 1,65(lllg em, cH3) were obtained.

Similarly, 2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl ]-2-Methyl-propionic acid-sodium salt and diethylene glycol-mono Starting from chlorohydrin, 2-[:4-phenyl-5-(3-pyridyl) )-oxazol-2-yl]-2-methyl-propionic acid-2-(2-hydro xyethoxy)-ethyl ester (■ NMR (CDC43): 8,85 (s, br, H-2'); 8,56 (d , br, H-6') Near, 87 (dt, H-4' G 7.64 (m, H-2 ″, 6″): 7.35-7,45(m+remaining aromatic HG 7,18(dd, H-5'): 1,75 (s, gem, CH,) was obtained.

international search report

Claims (1)

[Claims] 1. General formula (in the formula, one of the groups R11- means heteroaryl, and the other represents carbocyclic aryl) or heteroaryl, A means a divalent hydrocarbon group, and Rj represents a carboxyl group. (meaning esterified or amidated carboxy), isomers and salts thereof. 2.R,,R, are different from unsubstituted chenyl and unsubstituted furyl, respectively. A compound having the formula (1) according to claim 1. 3. One of the groups R1 is a 5-membered ring or a 6-membered ring, and has nitrogen as a heteroatom. refers to a heteroaryl group, even if unsubstituted, containing halogen, low alkyl, hydroxy, lower alkoxy and/or lower alkanoyloxy phenyl, which may be unsubstituted or di-substituted by lower alkyl, hydroxy, lower alkoxy, and/or lower alkanoyl, or 5-membered Nitrogen as a heteroatom in a ring or a 6-membered ring means a heteroaryl group containing an element, which heteroaryl group is unsubstituted (69) < even if disubstituted by temo, halogen, lower alkyl, hydroxy, lower alkoxy and/or lower alkanoyloxy Often, A is lower alkylene, lower cycloalkylidene, lower alkenylene, lower alkenylidene, cycloalkylene, cycloalkylidene, or cycloalkyl-lower alkylidene; hydroxypyridine, substituted phenol or carboxy or carbamoyl diesterified with hydroxypyridine, or hydroxy, amine phenyl or substituted phenyl, or lower alkyl mono-substituted or di-substituted, or 4- to 7-membered ring alkylene or 3-aza-13-lower alkylaza, 3-oxa- or 3-thiaalkylene. means di-substituted carbamoyl, where lower alkanol includes hydroxy, mercapto, optionally substituted phenyl, lower alkanol, even if unsubstituted. phenyl moiety substituted if necessary, lower alkoxy, lower alkoxy, Kylthio, phenyl lower alkylthio substituted on the phenyl moiety if necessary, hydro Roxy lower alkoxy, lower alkoxy lower alkoxy, phenyl lower alkoxy lower alkoxy substituted on the phenyl moiety if necessary, hydroxy lower alkoxy lower alkoxy, lower alkoxy, lower alkoxy, lower alkoxy, if necessary, phenyl-substituted phenyl lower alkoxy, lower alkoxy, lower alkoxy, carboxy lower alkoxy, lower alkoxycarbonyl-lower alkoxy, necessarily Lower alkoxy-carbonyl-lower alkoxy containing optionally substituted phenyl may be di-substituted by di- or lower alkanoyloxy, substituted phenyloxy 2. Compounds of formula CI), isomers or salts thereof, according to claim 1, wherein phenol, phenol or hydroxypyridine can be disubstituted by lower alkyl, lower alkoxy, halogen and/or trifluoromethyl. 4. -10,000 of the group R,, R, means pyridyl or 1-oxide-pyridyl, and this are halogen, hydroxy, lower alkyl, lower alkyl, even if unsubstituted. may be disubstituted by Lower alkoxy and (or is optionally substituted by lower alkanoyloxy, A is lower alkylene containing up to 4 carbon atoms, such as methylene, lower alkylene containing up to 7 carbon atoms, Kylidene e.g. 2,2-propylidene, lower alkenyl containing up to 4 carbon atoms For example, 1,3-propen-2-ylene, lower alkylidene having up to 7 members, e.g. 1,1-buten-3-ylidene, cycloalkylene having 3 to 8 members, e.g. Lopropylene, a 3- to 8-membered cycloalkylidene, such as cyclopentylidene, or a cycloalkyl-lower alkylidene, in which the alkylidene moiety contains up to 7 carbon atoms and the cycloalkyl moiety is a 3- to 8-membered ring, such as 2-cyclohexyl. -1,1-ethylidene, R8 is carboxy, lower alkanol, 3- to 8-membered cycloalkanol, carboxy or carbamoyl diesterified with phenol or substituted phenol, or N-mono-1N , N-di-lower al Kylcarbamoyl, pyrrolidino-, piperidino-, morpholino-, piperazino-14-lower alkyl-piperazino-, thiomorpholino-, anilino-1 or lower aniline di-substituted with lower alkyl, lower alkoxy, and/or halogen; means no-carbonyl; lower alkanol is hydroxyl even if unsubstituted. mercapto, phenyl, substituted phenyl, lower alkoxy, phenyl lower alkoxy, phenyl lower alkoxy substituted with phenyl moiety, lower alkyl Thio, phenyl lower alkylthio, phenyl lower alkyl substituted on the phenyl moiety ruthio, hydroxy lower alkoxy, lower alkoxy lower alkoxy, phenyl lower alkoxy lower alkoxy, phenyl lower alkoxy substituted with phenyl hydroxy lower alkoxy, hydroxy lower alkoxy lower alkoxy, lower alkoxy lower alkoxy lower alkoxy, phenyl lower substituted on the phenyl moiety if necessary alkoxy lower alkoxy, carboxy lower alkoxy, lower alkoxy Bonyl lower alkoxy, optionally substituted phenyl lower alkoxy carbonyl-lower alkoxy, or may be di-substituted by lower alkanoyloxy. Substituted phenol or phenyl is lower alkyl, lower alkoxy, or A compound having the formula (I) according to claim 1, which may be disubstituted by rogene and trifluoromethyl, isomers or salts thereof. 5. One of the groups RI%R1 is not substituted or secondarily has an atomic number Halogens up to No. 35 such as chlorine, hydroxy, lower alkyl containing up to 4 carbon atoms, such as methyl, and/or lower alkyl containing up to 4 carbon atoms means phenyl substituted, for example by methoxy, and the other is unsubstituted or secondarily halogen with atomic number up to 35, such as chlorine, hydroxy and (or) lower alkoxy containing up to 4 carbon atoms. For example, methoxy, optionally substituted pyridyl, such as 3-pyridyl or 1-oxide-pyridyl. bal-oxide-3-pyridyl, and A is a lower atom containing up to 4 carbon atoms. alkylidene containing up to 7 carbon atoms, such as 2,2-propylidene, lower alkylidene containing up to 7 carbon atoms, such as 1,1-buten-3-ylidene, or Cyclo-lower alkylidene, for example 1,1-cyclopentylidene, R3 means carboxy, lower alkanoyloxy containing up to 5 carbon atoms, di-substituteable for example pivaloyloxy, Lower alkoxycarbonyl containing the following carbon atoms (e.g. t haethoxycarbonyl), hydroxy lower alkoxy-lower alkoxycarbonyl e.g. 1j2-(2-hydroxyethoxy)-ethoxycarbonyl, lower alkoxy lower alkoxy-carbonyl e.g. methoxy-epoxy)-ethoxycarbonyl,hydro Roxy lower alkoxy-lower alkoxy-lower alkoxycarbonyl, e.g. z-[2-(2-hi)"o*jetoxy)-ethoxycuethoxycarbonyl, or c lower alkoxy lower alkoxy lower alkoxy-lower alkoxy-carbonyl example 2-(2-(2-methoxyethoxy)-ethoxycouethoxycarbonyl), each lower alkoxy moiety containing up to 4 carbon atoms, a compound having formula (I) according to claim 1, Isomers and salts thereof. 6. One of the radicals R2, avian, is unsubstituted or secondarily substituted by halogen with atomic number up to 35, such as chlorine, hydroxy or lower alkoxy having up to 4 carbon atoms, such as methoxy. If the other is pyridyl, it means 3-pyridyl or 4-pyridyl or 1-oxide biridyl, such as 1-oxide-3-pyridyl or 1-oxide-4-pyridyl, and A is 4. Lower alkylidene containing the following carbon atoms, e.g. 2,2-propylidene, and R8 means lower alkoxycarbonyl containing up to 5 carbon atoms, e.g. ethoxycarbonyl. A compound having the formula (I) according to claim 1, an isomer or a salt thereof, which tastes good. 7. R, means phenyl, R3 is 1-oxide pyridyl, e.g. 1-oxy means do-3-pyridyl, A means 2,2-propylidene, and R8 is 5 or more. Compounds, isomers and salts thereof having the formula (1) according to claim 1, meaning lower alkoxycarbonyl containing lower carbon atoms, such as ethoxycarbonyl. 8.2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl2-methyl-propionic acid ethyl ester or salt thereof. 9.2-[4-,phenyl-5-(3-pyridyl)-oxazol-2-ylz -Flopionic acid ethyl ester or its salt. 10.2-[4-phenyl-5-(3-pyridyl)-oxazol-2-ylz -Ethyl acetate or its salt. 11, z -C4-phenyl-5-(1-oxide-3-pyridyl)-oxa Sol-2-yl-2-methyl-propionic acid ethyl ester. 1, 2-(4-(4-phenyl-5-(1-oxide-3-pyridyl)-oxy) sazol-2-yl)]-propionic acid ethyl ester. 13,2-(4-phenyl-5-(1-oxide-3-pyridyl)-oxazo ethyl-2-yltoacetic acid ethyl ester. 14.2-[4-phenyl-5-(1-oxide-3-pyridyl)-oxazo 2-yl-2-methyl-propionic acid or a salt thereof. 15,2-(4-phenyl-5-(1-oxide-3-pyridyl)-oxazo [R-2-yl]-propionic acid or a salt thereof. 16,2-[4-phenyl-5-(1-oxide-3-pyridyl)-oxazo 2-yltoacetic acid or a salt thereof. 17, 2-(4-phenyl-5-(3-pyridyl)-oxazol-2-yl Two-2-methyl-propionic acid. 18.2-(4-(3-pyridyl)-5-phenyl-oxazol-2-ylz) -2-Methyl-propionic acid ethyl ester. 19.2-(4-(3-pyridyl)-5-phenyl-oxasol-2-ilz) -Flopionic acid ethyl ester. 20.2-(4-(3-pyridyl)-5-phenyl-oxazol-2-yl)-acetic acid [ethyl ester. 21.2-(4-(1-oxide-3-pyridyl)-5-phenyl-oxazo L-2-yl-2-methyl-propionic acid ethyl ester. 22.2-(4-(1-oxide-3-pyridyl)-5-phenyl-oxazo 2-yl2-propionic acid ethyl ester. 23.2-(4-(1-oxide-3-pyridyl)-5-phenyl-oxaso (2-yl)-acetic acid-m-thyl ester. 24, 2-[4-phenyl-5(4)-(3-pyridyl)-oxazol-2-yl2-methyl-propionic acid-1art-butyl ester or salt thereof. 25.2-(4-(3-pyridyl)-5-phenyl-oxazol-2-ylz) -2-methyl-propion e-1ert-butyl ester or a salt thereof. 26, 2-(4-phenyl-5-(1-oxide-3-pyridyl)-oxazo 2-(4-(1-oxide-3-pyridyl)-5-phenyl-oxazole) L-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 its salt. 29, 2-(4-phenyl-5-(1-oxide-3-pyridyl)-oxazo -2-yl-2-methyl-propionic acid-2-[:2-(2-methoxyester) toxy)-ethoxy]-ethyl ester. 30, 2-(4-722-5-(3-pyridyl)-oxazol-2-y Rutu 2-methyl-propionic acid-2-(2-hydroxyethoxy)-ethyl ether Stell or its salt. 31, 2-[: 4-phenyl-5-(1-oxide-3-pyridyl)-oxy sazol-2-yl)-2-methyl-propionic acid-z-(z-hydroxyeth xy)-ethyl ester. 32, 2-(4-phenyl-5-(3-pyridyl)-oxazol-2-yl 2-2-methyl-propionic acid-2-(2-5(2-hydroxyethoxyl)-ethoxy)-ethyl ester or a salt thereof. 33, 2-(4-phenyl-5-(1-oxide-3-pyridyl)-oxazo 2-yl-2-methyl-propion ff-2-[2-(2-hydroxy ethoxy)-ethoxy]-ethyl ester. 34. Claims 1 to 33 have an effect as an external therapeutic agent for skin diseases. Compounds listed. 35. Pharmaceutical preparations containing at least one compound according to claims 1 to 34 in addition to the customary auxiliaries and carriers. (In the formula, one of the groups Cyclization of the mutant and/or salt thereof, provided that in the above formula, when the group XI represents oxy and the group X represents oxo, they are converted under condensation, or the compound having the formula or its salt is reduced. to give a compound having the formula (1), or in a compound having the formula (in the formula R, / means a group which can be changed to R5), changing the group R, l to a group R3, if desired, the preparation The free compound with formula (1) obtained according to the method can be converted into another free compound or alternatively according to the method of preparation. converting the free compound obtained by As claimed in claim 1, the isomer mixture obtained is separated into its components. A method for producing a compound having the formula (1) shown below. 37. A compound obtained in any intermediate step of the production method is used as a starting material. be used as The compounds or enantiomers can be used as starting materials or produced under reaction conditions. The manufacturing method according to claim 36, characterized in that: (in the formula Yl means functionally modified hydroxy if necessary) and/or its tautomers and/or salts thereof are defined as having the formula Ra - A Yt (lb) (in the formula Y is functionally modified to contain at least one nitrogen atom and means 9 carboxylic acid, or a salt thereof, optionally in the presence of a condensing agent, or alternatively a compound of the formula and (or) its tautomers and (or) its salts (wherein Y means amino) or its salts (wherein Y means carboxy which may be functionally modified). ), optionally in the presence of a condensing agent, or alternatively, a compound having the formula (in which Y stands for hydroxy which may be reactably esterified) is reacted with a compound of the formula R, -A-cooH(me) carboxylic acid, its salt or its A compound of the formula (1!c) obtained by condensing the compound of the formula (1!c) with a functional derivative of the formula (1! 38. The manufacturing method according to claims 36 and 37, characterized in that the product is reacted with ammonia. 39, when a compound of formula α) or a salt thereof is used as a starting material, and R8/ in the formula represents a group that can be changed to R8 by solvolysis, Rv is changed to R8 by solvolysis, and in the formula 38. The manufacturing method according to claims 36 and 37, characterized in that when R1' represents a group that can be changed into R8 by oxidation, R, / is changed into R8 by oxidation. 40, if necessary, at least one compound described in claims 1 to 34- A process for the production of pharmaceutical preparations, characterized in that they are brought into suitable application forms using customary auxiliaries and carrier substances. 41. The compound according to claims 1 to 34 for use in treating humans or animals. 42. The compound according to claims 1 to 34 in the method for treating inflammatory skin diseases. Use of compounds. 43, Examples 1-] Novel compounds shown in 3 and 20-27. 44, a novel compound obtained by the production method of Examples 1 to 27 and No. 9. 45, novel starting materials and novel starting materials used in the production method according to claims 36 to 39- and/or intermediate products.