JPH03864B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel 1-hydroxy-2-pyridones represented by the following formula, their use for suppressing infections mainly caused by fungi and yeast, and pharmaceuticals containing these compounds. Regarding.
It also relates to certain intermediates produced in the production of novel 1-hydroxy-2-pyridones. West German Patent No. 2234009 specifies the formula Compounds are disclosed in which R ¹ represents, inter alia, aryloxyalkyl or arylmercaptoalkyl having alkyl of 1 to 4 carbon atoms. The only specific illustrations of these groups are phenyloxymethyl or phenylmercaptomethyl. West German patent no.
According to specification 2234009, in addition to aryloxyalkyl or arylmercaptoalkyl,
R ¹ can also include various other groups such as aryl, 1
aralkyl with alkyl of ~4 carbon atoms, arylalkenyl with alkenyl of 2 to 4 carbon atoms, benzhydryl and 1 to 4
phenylsulfonylalkyl having alkyl of 5 carbon atoms can also be represented. Where the patents give specific examples of these groups, they always - with the exception of the aryl group itself (which is also mentioned as naphthyl) - optionally contain 1 to 4 carbon atoms. Only alkyl groups having atoms, alkoxy groups having 1 to 4 carbon atoms, nitro groups, cyano groups or phenyl groups substituted by halogens. In contrast, the present invention provides a substituent at the 6-position (R ¹ in the formula)
1-hydroxy-2-pyridone derivatives having an aromatic system containing at least two separate and optionally substituted aromatic rings and linked to the pyridone residue via an oxymethyl or thiomethyl group and its derivatives are represented by the general formula. That is, the present invention is based on the general formula [Wherein R ¹ , R ² and R ³ are the same or different and represent hydrogen or lower alkyl having 1 to 4 carbon atoms, R ¹ and R ³ are preferably hydrogen , R ² is preferably methyl, X represents S or preferably O, Y represents hydrogen or up to two halogen atoms, namely chlorine and/or bromine, and Z represents a single bond or a divalent Group O, S, -CR ₂ -
(R=H or _C1 - _C4 -alkyl) or 2-
represents 10 carbons and optionally other divalent radicals with oxygen and/or sulfur atoms linked to form a chain, in which case the radical contains two or more oxygen and/or sulfur atoms; When containing sulfur atoms, these atoms contain at least 2
two adjacent carbon atoms can also be connected by a double bond, in which case the free valences of the carbon atoms are H and/or or C ₁ ~ C ₄ −
Ar is attached to an alkyl group, wherein Ar has up to two rings and is selected from the group consisting of fluorine, chlorine, bromine, methoxy, _C1 - _C4 -alkyl, trifluoromethyl and trifluoromethoxy. represents an aromatic ring system which can be substituted by up to 1-hydroxy-2-pyridone. The carbon chain in the Z group is preferably a CH ₂ group. Applicable
If _{the CH2} group is substituted by a _C1 - _C4 -alkyl group, preferred substituents are _CH3 and _C2H5 . Examples of the Z group include the following. -O-, -S-, _-CH2- , -( _CH2 )m-(m=
2-10), -C( _CH3 ) _2- , _-CH2O- , _OCH2- , -
CH ₂ S−, −SCH ₂ −, −SCH(C ₂ H ₅ )−, −CH=
CH−CH ₂ O−, −O−CH ₂ −CH=CH−CH ₂ O
−, OCH ₂ CH ₂ O−, −OCH ₂ CH ₂ CH ₂ O−, −
SCH ₂ CH ₂ CH ₂ S−, −SCH ₂ CH ₂ CH ₂ CH ₂ O−, −
SCH ₂ CH ₂ OCH ₂ CH ₂ O−, −
SCH ₂ CH ₂ OCH ₂ CH ₂ O−CH ₂ CH ₂ S−, -S−CH ₂
-C( _CH3 ) ₂ - _CH2 -S-, etc. The term "aromatic ring system" includes phenyl systems as well as fused systems such as naphthyl, tetrahydronaphthyl and indenyl, as well as non-fused systems such as biphenyl, diphenyl alkanes. , diphenyl ethers and diphenyl thioethers. Important representative examples of compounds defined by the formula include: 6-[4-(4-chlorophenoxy)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, melting point 167℃(1), 6-[4-(2,4-dichlorophenoxy)phenoxymethyl] ]-1-hydroxy-4-methyl-
2-pyridone, melting point 162°C(2), 6-(biphenylyl-4-oxymethyl)-1-
Hydroxy-4-methyl-2-pyridone, melting point
184℃(3), 6-(4-Benzylphenoxymethyl)-1-hydroxy-4-methyl-2-pyridone, melting point 149
°C(4), 6-[4-(2,4-dichlorobenzyloxy)
Phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, melting point 172°C (5), 6-[4-(4-chlorophenoxy)phenoxymethyl]-1-hydroxy-3,4-dimethyl-
2-pyridone, melting point 155°C (6), 6-[4-(2,4-dichlorobenzyl)phenoxymethyl]-1-hydroxy-3,4-dimethyl-2-pyridone, melting point 169°C (7), 6- [4-(cinnamyloxy)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, melting point 179°C (8), 1-hydroxy-4-methyl-6-[4-(4-
trifluoromethylphenoxy) phenoxymethyl]-2-pyridone, melting point 149°C (9), 1-hydroxy-4-methyl-6-[4-(1-
naphthylmethoxy)phenoxymethyl]-2-pyridone, melting point 179°C (10), 6-[4-(4-chlorophenoxy)phenoxymethyl]-1-hydroxy-4,5-dimethyl-
2-pyridone (11), 6-[4-(4-(4-chlorophenoxy)phenoxymethyl)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, melting point 158°C
(12), 6-[2,6-dichloro-4-(2-naphthylthiomethyl)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, melting point 138°C (13), 6-[2,6 -dichloro-4-(4-phenylphenoxymethyl)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, melting point 190°C
(14), 6-[4-(4-chlorobenzyloxy)phenoxymethyl]-1-hydroxy-4-methyl-2
-pyridone, melting point 173°C (15), 1-hydroxy-4-methyl-6-[4-(4-
Trifluoromethoxybenzyloxy)phenoxymethyl]-2-pyridone, melting point 143°C (16), 6-[4-(4-tert-butylbenzyloxy)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, melting point 181℃(17), 6-[2-(4-chlorobenzyloxy)phenoxymethyl]-1-hydroxy-4-methyl-2
-Pyridone, melting point 161°C (18), 1-hydroxy-4-methyl-6-[2-(naphth-1-yl-methoxy)phenoxymethyl]-
2-pyridone, melting point 150°C (19), 1-hydroxy-4-methyl-6-[3-(1-
naphthylmethoxy)phenoxymethyl]-2-pyridone, melting point 155°C (20), 6-[3-(4-chlorobenzyloxy)phenoxymethyl]-1-hydroxy-4-methyl-2
-Pyridone, melting point 149°C (21), 6-[4-(4-chlorophenoxy)phenoxymethyl]-1-hydroxy-2-pyridone, melting point
180℃(22), 6-[2,6-dichloro-4-(4-chlorophenoxy)phenoxymethyl]-1-hydroxy-
4-Methyl-2-pyridone, melting point 150°C (23), 6-(4-benzyloxy-2,6-dichlorophenoxymethyl)-1-hydroxy-4-methyl-2-pyridone, melting point 161°C ( 24), 6-(2,6-dichloro-4-phenylphenoxymethyl)-1-hydroxy-4-methyl-2
-Pyridone, melting point 195°C (25), 6-[4-(4-bromo-2-chlorophenoxy)phenoxymethyl]-1-hydroxy-4-
Methyl-2-pyridone, melting point 174°C (26), 1-hydroxy-4-methyl-6-[4-(3,
4,5-Trimethoxybenzyloxy)phenoxymethyl]-2-pyridone, melting point 154°C (27), 6-[4-(2,4-dichlorobenzyl)phenoxymethyl]-1-hydroxy-4-methyl-2
-Pyridone, melting point 173°C (28), 6-[2,6-dibromo-4-(4-chlorophenoxy)phenoxymethyl]-1-hydroxy-
4-Methyl-2-pyridone (29), 6-(2,6-dibromo-4-phenylphenoxymethyl)-1-hydroxy-4-methyl-2
-pyridone (30), 6-(2-bromo-4-phenylphenoxymethyl)-1-hydroxy-4-methyl-2-pyridone, melting point 245°C (31), 6-(2-bromo-6 -chloro-4-phenylphenoxymethyl)-1-hydroxy-4-methyl-2-pyridone (32), 6-[4-(4-fluorophenoxy)phenoxymethyl]-1-hydroxy-4- Methyl-2-
Pyridone, melting point 151°C (33), 6-[3-(4-chlorophenylthio)phenoxymethyl]-1-hydroxy-4-methyl-2-
Pyridone (34), 1-hydroxy-4-methyl-6-[3-(1-
naphthylmethylthio)phenoxymethyl]-2-
Pyridone, melting point 144°C (35), 1-hydroxy-4-methyl-6-[3-(1-
naphthylmethoxy)phenylthiomethyl]-2-
Pyridone, melting point 163°C (36), 1-hydroxy-4-methyl-6-(2-phenylphenoxymethyl)-2-pyridone, melting point 179
°C (37), 6-(2-benzylphenoxymethyl)-1-hydroxy-4-methyl-2-pyridone, melting point 155
°C (38), 1-hydroxy-3,4-dimethyl-6-[3
-(1-naphthylmethylthio)phenoxymethyl]
-2-pyridone, melting point 143°C (39), 6-(2,4-dibromo-6-phenylphenoxymethyl)-1-hydroxy-4-methyl-2
-Pyridone, melting point 130°C (40), 6-[4-(4-(4-chlorophenoxy)phenoxy)phenoxymethyl]-1-hydroxy-
4-Methyl-2-pyridone, melting point 100°C (41), 6-[3-(4-chlorobenzyloxy)phenylthiomethyl]-1-hydroxy-4-methyl-
2-pyridone, melting point 94°C (42), 6-[4-(4-chlorophenylthio)phenoxymethyl]-1-hydroxy-4-methyl-2-
Pyridone, melting point 158°C (43), 1-hydroxy-6-[4-(4-methoxyphenylthio)phenoxymethyl]-4-methyl-2
-pyridone, melting point 162°C (44), 1-hydroxy-4-methyl-6-[3-(2-
phenoxyethoxy) phenoxymethyl]-2-
Pyridone, melting point 148℃ (45), 6-[4-(4-chlorophenoxypropoxy)
phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, melting point 162°C (46), 6-[3-(4-chlorophenylthiopropylthio)phenoxymethyl]-1-hydroxy-4-
Methyl-2-pyridone, melting point 102°C (47), 6-[3-(4-chlorophenylthiobutoxy)
Phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, melting point 104°C (48), 6-[3-(4-chlorophenylthioethoxyethoxy)phenoxymethyl]-1-hydroxy-
4-Methyl-2-pyridone, melting point 98°C (49), 6-[4-(α,α-dimethyl-4-methoxybenzyl)phenoxymethyl]-1-hydroxy-
4-Methyl-2-pyridone, melting point 156°C (50), 6-〈3-[1-(4-chlorophenylthio)-
2,2-dimethylprop-3-ylthio]phenoxymethyl>-1-hydroxy-4-methyl-2
-Pyridone, melting point 134°C (51), 6-〈4-[1-[4-chlorophenyl)buto-
2-en-4-yloxy phenoxymethyl
-1-hydroxy-4-methyl-2-pyridone,
Melting point 167°C (52), 6-[3-(4-chlorophenylthioethoxyethoxyethylthio)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, melting point 95
(53), 6-〈4-[1-(4-chlorophenyl)-5-pentyl]phenoxymethyl〉-1-hydroxy-
4-Methyl-2-pyridone, melting point 159°C (54). The compounds of the present invention can be produced by various methods known per se, for example by formula (wherein R ¹ , R ² and R ³ have the above definitions,
Hal represents a halogen atom, particularly a chlorine or bromine atom), optionally substituted with 6-halogenomethyl-2-pyrone. (wherein X, Y, Z and Ar have the above definitions) with a phenol or thiophenol, resulting in the formula It can be produced by converting aryloxymethylpyrone or arylthiomethylpyrone into hydroxypyridone by the action of hydroxylamine. The alkylation is conveniently carried out in protic or aprotic solvents such as methanol, ethanol, isopropanol, acetone, acetonitrile, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, dimethyl formamide or dimethyl sulfoxide, with aprotic solvents being preferred. .
To bind free hydrogen halides, inorganic or organic bases such as sodium or potassium hydroxide, sodium carbonate, potassium carbonate or calcium carbonate, triethylamine, tributylamine, pyridine, 4-dimethylaminopyridine, diazabicyclo Nonane, N-methylpiperidine is especially used in at least an equivalent amount. The reaction temperature is generally between room temperature and about 80°C, but in special cases obviously higher or lower temperatures such as 110°C or 0°C are possible.
can be advantageous. To convert 2-pyrone to 1-hydroxy-2-pyridone, hydroxylamine is generally added in the form of a salt with an inorganic or organic acid, preferably hydrochloric acid, sulfuric acid or acetic acid, to the hydroxylammonium salt at least about 1. The reaction is carried out in the presence of an equivalent amount of base. The amount of hydroxylamine salt is at least about 1 mole based on the pyrone used, but
However, in order to increase the reaction rate and yield, it is preferable to use an excess amount, e.g. 2 to 10 mol to 1 mol, and it is even more preferable to add this amount in several portions during the reaction time. . Suitable bases for this reaction are both organic and inorganic bases. Preferred organic bases are aminopyridine (derivatives) as well as imidazoles (derivatives) such as 2-aminopyridine, 2-aminopicoline, 2
-methylaminopyridine, imidazole and 2
- methylimidazole, and preferred inorganic bases are alkali metal carbonates and/or bicarbonates (Li ₂ CO ₃ , Na ₂ CO ₃ , K ₂ CO ₃ , NaHCO ₃ ,
KHCO ₂ , Rb ₂ CO ₃ , CsHCO ₃ etc.). Among the inorganic bases mentioned above, sodium and potassium carbonates and bicarbonates, especially Na ₂ CO ₃ are most suitable. The organic bases are generally used in an amount of about 1 to 20 moles, preferably about 3 to 10 moles per mole of pyrone used, and they can simultaneously act as a solvent, which is also usually the case for the hydroxylammonium used. The condition is satisfied that there is at least about 1 equivalent of base relative to the salt. Of course, mixtures of these bases can also be used to reduce the melting range of the system, for example if the operation can be carried out at low temperatures. Generally, the reaction temperature for this is about 20°C to 150°C, preferably about
The temperature is between 50°C and 100°C. If an inorganic base is used, it is advantageous to add an amount at least approximately equal to the amount of hydroxylammonium salt used, as with organic bases. For example, at least 1/2 mole per mole of hydroxylammonium chloride.
Na ₂ CO ₃ or 1 mol NaHCO ₃ should be used. Furthermore, the inorganic bases can be used both alone and in any desired mixtures. A variant of the process using an inorganic base involves mixing and forming 2-pyrone with a hydroxylammonium salt, in this case preferably hydroxylammonium sulfate, and an alkali metal carbonate and/or bicarbonate. It is advantageous to heat the crystalline product until as much of the pyrone as possible is converted, and the 2-pyridone formed after removal of the inorganic salt can be isolated directly or more preferably isolated as a salt of an organic base, e.g. the ethanolamine salt. Can be separated. The temperature when carrying out this variant should never exceed about 120°C. It is conveniently above about 50°C, preferably about 60-105°C. Furthermore, it is also possible to add inert solvents or diluents in both the variants with organic and inorganic bases. Although this is generally not necessary, it can have advantages in individual cases. If a solvent or diluent is added, this is generally done only in small amounts, typically up to about 50% by weight of the total reaction mixture. A preferred amount is about 3-15% by weight. The solvent or diluent may be polar or non-polar and miscible or immiscible with water. Examples of substances that can be used are: water, low molecular weight alcohols such as methanol, ethanol, isopropanol, ethylene glycol, ethylene glycol monomethyl ether and propylene glycol, amides such as dimethylformamide and diethylformamide, ethers such as diisopropyl ether,
Mention may be made of chlorinated hydrocarbons such as chlorobenzene, nitriles such as acetonitrile or aliphatic, cycloaliphatic or aromatic hydrocarbons. 6-halogenomethyl-2-pyrones, especially their chlorine compounds, are available for example from "Chemische Berichte"
100 (1967), p. 658. Another possibility for synthesizing hydroxypyridones is to carry out side chain halogenation of 2-halogeno-6-picoline to form the formula 2-halogeno-6-halogenomethylpyridine having the formula (wherein R ¹ , R ² , R ³ and Hal have the above definitions) is obtained, and the halogenomethyl group thereof is reacted with an optionally appropriately substituted phenol. the resulting compound is oxidized to give the N-oxide and the halogen on its nucleus is hydrolyzed by direct or indirect means. The reaction between the halogenomethyl group and phenol is preferably carried out under the same conditions as described above for the reaction between halogenomethylpyrone and phenol. The oxidizing agents used to convert the pyridines to their N-oxides can be inorganic or organic, such as hydrogen peroxide,
performic acid, peracetic acid, perbenzoic acid, 3-chloroperbenzoic acid and tertiary-butyl hydroperoxide, the conversion of which, if appropriate, may include e.g. sulfuric acid, perchloric acid, toluenesulfonic acid, trifluoroacetic acid and trifluoromethanesulfonic acid. using catalysis with a strong acid such as
Conducted at °C. The hydrolysis of the supranuclear halogens can be carried out directly, for example by reaction with a base such as sodium hydroxide, potassium hydroxide or barium hydroxide, or can be easily removed again in the next turn. It can also be carried out indirectly by etherification with alcohols such as tert-butanol or 2-methoxyethanol. A typical method for preparing compounds of the general formula according to the present invention is illustrated by the following examples. If one of the above methods produces an intermediate that still contains reactive substituents in the Ar or pyrone ring, R ¹
It is possible to introduce further groups corresponding to the substituents pointed out in the definition of ~R ³ and Ar. For example, it is possible to subsequently etherify a free hydroxyl or mercapto group, or to convert a hydroxymethyl group generated, for example by reduction of an aldehyde group, into a halogenomethyl group and then convert the halogen into a phenol or thiophenol. A nucleophilic transformation is possible again. Similarly, if the pyridine derivative obtained from the reaction of the dihalogenopicoline with a phenol or the N-oxide obtained from its oxidation still contains reactive substituents, they can be replaced by other types of substitution. It is also possible to convert it into products. The present invention also provides suitable intermediates of the formula (wherein R ¹ , R ² , R ³ , X, Y and Ar have the above definitions). According to the invention, the compounds of the formula are used against pathogenic fungi such as dermatophytes (filamentous fungi) and fungi that act both on the skin or on the mucous membranes, such as yeasts (e.g. Candida sp.) and molds (e.g. Aspergillus niger). It has excellent topical antifungal properties with a broad spectrum of action. They are therefore useful in veterinary medicine of domestic livestock, such as dogs, cats and birds, as well as commercial livestock, such as ruminants, horses and pigs, and in human medicine, to prevent the infections caused by these pathogens. Can be used to suppress The hydroxypyridones can be used in free form in conventional preparations for fungal control, such as solutions, suspensions, creams, ointments, powders or suppositories (vaginal tablets) or with inorganic or organic bases such as NaOH,
KOH, Ca(OH) ₂ , NH ₃ , H ₂ NCH ₂ CH ₂ OH, etc.)
may be used in the form of their physiologically acceptable salts. The new formulations are particularly characterized by their high fungicidal activity and long retention time at the site of infection and are superior in this respect to standard commercial formulations, as shown in the comparative tests below. Furthermore, these compounds have antibacterial activity and also have antiviral activity, for example against herpesviruses. The compounds of the invention are contained in the formulation in a concentration of 0.02 to 2% by weight, preferably 0.1 to 1% by weight. Example 1: 6-[4-(2,4-dichlorobenzyl)phenoxymethyl]-1-hydroxy-3,4-dimethyl-2-pyridone (compound 7) 19.85 g of 6-chloromethyl-3,4-dimethyl -2-pyrone (compound A) and 25.3 g of 4-
(2,4-dichlorobenzyl)phenol 70ml
of dimethylformamide, 20 g of pulverized potassium carbonate were added and the mixture was stirred at room temperature for 48 hours. 200 ml of methylene chloride and 500 ml of water were then added, the layers were separated and the organic phase was washed twice with 100 ml of water each time, dried and evaporated under a water pump vacuum. 42.7g
The residue, which was almost pure by thin layer chromatography, was heated with 200 g of 2-aminopyridine at 75°C for 56 hours, with a total of 41.7 g of hydroxylamine hydrochloride added during the first 41 hours. It was added in 5 portions. Next, 250ml of methylene chloride was added, and the organic phase was diluted with diluted hydrochloric acid.
The solution was washed twice with water and the solvent was removed by vacuum distillation. 39.7 g of the residue was recrystallized from ethylene glycol monomethyl ether to yield 32.5 g of pure hydroxypyridone. Melting point: 169℃. 2-19: In the same manner as in Example 1, starting from 4-(4-chlorophenoxy)phenol and A to obtain compound 6, and from 3-(1-naphthylmethylthio)phenol and A to obtain compound 39, Compound 1 was obtained from 4-(4-chlorophenoxy)phenol and 6-chloromethyl-4-methyl-2-pyrone (compound B), and 4-(2,4-dichlorophenoxy)
Compound 2 was obtained from phenol and B, and 4-(4
-trifluoromethylphenoxy)phenol and B to obtain compound 9, 2,6-dichloro-4
-(4-chlorophenoxy)phenol and B
Compound 23 was obtained from 2,6-dichloro-4-phenylphenol and compound 25 was obtained from B, 4-
(4-fluorophenoxy)phenol and B
Compound 33 was obtained from 3-(4-chlorophenylthio)phenol and compound 34 was obtained from B, 3-
(1-naphthylmethylthio)phenol and B
Compound 35 was obtained from 2,4-dibromo-6-phenylphenol and compound 40 was obtained from B, 4-
Compound 41 was obtained from [4-(4-chlorophenoxy)phenoxy]phenol and B, compound 43 was obtained from 4-(4-chlorophenylthio)phenol and B, and compound 4 was obtained from 4-benzylphenol and B. , 2-benzylphenol and B
Compound 38 was obtained from 4-phenylphenol and B, compound 3 was obtained from 4-(4-bromo-2-
Compound 26 was obtained from chlorophenoxy)phenol and B and 4-[1-(4-chlorophenyl)
-5-pentyl]phenol and compound from B
Got 54. 20:1-hydroxy-4-methyl-6-[4-(1
-naphthylmethoxy)phenoxymethyl]-2
-pyridone (compound 10) 100 g of 6-chloromethyl-4-methyl-2-
A mixture of pyrone, 210 g of hydroquinone, 132 g of potassium carbonate and 400 ml of dimethylformamide was stirred at room temperature for 72 hours, water was added, the mixture was neutralized with hydrochloric acid and the precipitate was suctioned off, washed with water and dried. . 68g treated with methylene chloride followed by recrystallization from acetonitrile
Substantially pure 6-(4-hydroxyphenoxymethyl)-4-methyl-2-pyrone was obtained. Melting point: 179℃. 4.8 g of this compound are stirred with 4 g of 1-chloromethylnaphthalene, 20 ml of dimethylformamide and 8 g of potassium carbonate at room temperature for 72 hours, dilute sodium hydroxide solution is added, the mixture is shaken with methylene chloride and the organic phase is separated. After washing with water and drying, the solvent was removed by distillation. 7.0 g of the residue was chromatographed in methylene chloride on a column containing silica gel and 4.6 g of pure 4-methyl-6-
[4-(1-naphthylmethoxy)phenoxymethyl]-2-pyrone was obtained. Melting point: 132℃. This product was heated at 75° C. with 15 g of 2-aminopyridine and 7 g of hydroxylamine hydrochloride was added in 4 portions during 32 hours of stirring. After a total of 42 hours of reaction, the residue was taken up in methylene chloride, the solution was washed with dilute hydrochloric acid and water and dried, the solvent was removed by distillation and the residue was recrystallized from acetonitrile. 1.9g of pure compound 10 was isolated. Melting point: 179℃. 21-30: Compounds 5, 8, 15,
16, 17, 27, 46 and 52 are intermediates 6-(4-hydroxylphenoxymethyl)-4-methyl-2-
Pyrone with chlorides, i.e. 2,4-dichlorobenzyl chloride, cinnamyl chloride, 4
-chlorobenzyl chloride, 4-trifluoromethoxybenzyl chloride, 4-tert-butylbenzyl chloride, 3,4,5-trimethoxybenzyl chloride, 1-chloro-3-(4-chlorophenoxy)propane and 1-chloro -4-
It was obtained by alkylating with (4-chlorophenoxy)-2-butene and converting the obtained pyrone into hydroxypyridone. Using catechol in place of hydroxylone and alkylation with 1-naphthylmethyl chloride gave compound 19, and resorcinol and 4-chlorobenzyl chloride gave compound 21. 31:6-[2,6-dichloro-4-(2-naphthylthiomethyl)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone (compound 13) 4.8 g sodium and 42 g 3,5-dichloro -4-Hydroxybenzaldehyde was dissolved in 250 ml of methanol, the solvent was removed by vacuum distillation,
The residue was taken up in 200 ml of dimethylformamide and 32 g of 6-chloromethyl-4-methyl-2
- Pyrone was added and the mixture was left to react at room temperature for 3 days. The dimethylformamide was then substantially removed by vacuum distillation, methanol was added and a total of 44 g of 6-(2,6-dichloro-4
-formylphenoxymethyl)-4-methyl-2
- The pyrone was isolated in several fractions by cooling and concentrating the mother liquor. 34.5 g of this compound is reduced with 1.5 g of sodium borohydride in a mixture of 250 ml of tetrahydrofuran and 100 ml of methanol at room temperature, the mixture is then heated to 50°C and 10 ml of concentrated sulfuric acid is added, and the solvent water A portion was removed by distillation, the residue was shaken with water and the solid was suctioned off, washed with water and dried. This product (33.1 g, melting point 154° C.) was suspended in 200 ml of methylene chloride, 0.1 ml of dimethylformamide was added and then 11 ml of thionyl chloride was added in portions at room temperature. After 24 hours the solvent was removed by distillation, the residue was boiled with 200 ml of methanol, the mixture was cooled to 0° C. and the product was suctioned off, washed and dried.
30.1 g of pure 6-(2,6-dichloro-4-chloromethylphenoxymethyl)-4-methyl-2-
Got Piron. Melting point 136℃. 7.5 g of the obtained compound were stirred with 4 g of 2-thionaphthol, 30 ml of dimethylformamide and 7 g of potassium carbonate at room temperature for 24 hours, then water was added, the mixture was shaken with methylene chloride and the solution was washed with water. , dried and chromatographed on a column containing silica gel. 8.5 g of 6-[2,6-dichloro-4-(2-
naphthylthiomethyl) phenoxymethyl]-4-
Methyl-2-pyrone was obtained. Melting point: 125℃. This product was heated at 75° C. with 25 g of 2-aminopyridine and a total of 8 g of hydroxylamine hydrochloride was added in 4 portions within 37 hours. After the reaction had continued for 48 hours, the residue was taken up in methylene chloride, the organic phase was washed with dilute hydrochloric acid and water and dried, and the solvent was removed by distillation. The residue was extracted once from acetonitrile and once from ethyl acetate.
After multiple recrystallizations, 2.1 g of pure compound 13 was obtained. Melting point: 138℃. 32 and 33: Analogous to the procedure in Example 31, compound 14 was prepared by converting the intermediate 6-(2,6-dichloro-4-chloromethylphenoxymethyl)-4-methyl-2-pyrone into 4
-obtained by reacting with phenylphenol and converting the resulting pyrone into hydroxypyridone. A similar reduction is performed using 4-hydroxybenzaldehyde instead of 3,5-dichloro-4-hydroxybenzaldehyde, reacting with thionyl chloride, condensing with 4-(4-chlorophenoxy)phenol, and then reacting with hydroxylamine. Compound 12 was obtained. 34:6-[4-(4-chlorophenoxy)phenoxymethyl]-1-hydroxy-2-pyridone (compound 22) 30 g of 2-bromo-6-picoline was reacted with 31.6 g of N-
Bromosuccinimide, along with 0.015g dibenzoyl peroxide and 150ml carbon tetrachloride
After heating at reflux under UV irradiation for 30 hours, the mixture was filtered, the liquid was washed once with aqueous sodium carbonate solution and three times with water, then dried and the solvent was removed by vacuum distillation. The residue (40.1 g) was shaken with 150 ml of hexane and filtered with suction to give 27.3 g of a mixture consisting primarily of the desired monobromomethyl compound, with the addition of a small amount of dibromomethyl compound.
This mixture was combined with 21.4 g of 4-(4-chlorophenoxy)phenol, 20.7 g of potassium carbonate and 50 g of potassium carbonate.
ml of dimethylformamide for 48 hours at room temperature, then 200 ml of methylene chloride was added and the organic solution was washed three times with water, concentrated and chromatographed on silica gel and recrystallized from diisopropyl ether to give 16.3 g. 2-
Bromo-6-[4-(4-chlorophenoxy)phenoxymethyl]pyridine was isolated. 15.8 g of the compound obtained were heated at 50 °C for 30 h with a solution of 8.5 g peracetic acid dissolved in 50 ml glacial acetic acid, the solvent was partially removed by vacuum distillation at 40 °C, and the residue was dissolved in 200 ml each. It was shaken three times with water and once with aqueous sodium bicarbonate solution, each time decanted, and finally treated with 100 ml of diisopropyl ether, the product was sucked off and dried. 10.2 g of almost pure N-oxide were thus obtained. Melting point 100℃. 5g of this N-oxide
was heated at 70° C. with a solution of 1.2 g of sodium hydroxide dissolved in a mixture of 9 ml of water and 20 ml of ethylene glycol monomethyl ether. During this time, N melts at 125℃ due to the reaction with alcohol.
The methoxyethyl ether of the -oxide was rapidly formed and the ether was gradually hydrolyzed. After 60 hours, the solvent was removed by vacuum distillation, the residue was shaken with 200 ml of methylene chloride and 50 ml of dilute sulfuric acid, the organic phase was separated, dried and evaporated. The residue was recrystallized from acetonitrile to obtain 2.5 g of pure compound 22. melting point
180℃. 35:1-hydroxy-4-methyl-6-[3-(1
-naphthylmethoxy)phenylthiomethyl]-
2-Pyridone 26g monothioresorcinol and 31.8g 6
-chloromethyl-4-methyl-2-pyrone 100
ml of dimethylformamide and added within 30 minutes with stirring and cooling in ice, 38 g of powdered potassium carbonate and the mixture was stirred for 4 hours at 0°C and 16 hours at room temperature, to which was added 300 ml of methylene chloride. was added, the organic phase was extracted by shaking three times with water, separated and dried, and the solvent was removed by distillation. The residue was recrystallized from methanol to give 44 g of 6-(3-hydroxyphenylthiomethyl)-4-methyl-2-pyrone, compound
I got (C). Melting point: 129℃. 8.9 g of 1-chloromethylnaphthalene were added to a solution of 8 g of sodium iodide dissolved in 200 ml of acetone, the mixture was stirred at room temperature for 16 hours and 12.4 g of compound C was dissolved in this mixture and it was reduced to 0. ℃ and 6.9 g of powdered potassium carbonate were added portionwise within 5 hours. 0
After a total reaction time of 79 hours at °C, the solvent is removed by distillation in a water pump vacuum, the residue is taken up in methylene chloride and the solution is washed with water, separated, dried and concentrated to give the product. was chromatographed on a column containing silica gel using methylene chloride as the mobile phase and the main fraction was recrystallized from methanol. 9g pure 4-methyl-6-[3-
(1-naphthylmethoxy)phenylthiomethyl]-
2-pyrone was obtained. Melting point: 139℃. 8.5 g of this compound were heated at 75° C. with 50 g of 2-aminopyridine and 8.9 g of hydroxylamine hydrochloride were added in portions within 40 hours. After a reaction time of 60 hours, the mixture was cooled to room temperature, methylene chloride was added and the organic phase was washed once with dilute hydrochloric acid and three times with water and dried, and the solvent was removed by distillation. The residue was recrystallized from ethyl acetate to obtain 4 g of hydroxypyridone. melting point
163℃. 36: Reaction of pyrone C (see Example 35) with 4-chlorobenzyl chloride and remaining steps as in Example 35 provided compound 42. 37:1-hydroxy-4-methyl-6-[4-(4
-chlorophenoxy) phenoxymethyl]-2
-Pyridone 171.4 g (0.5 mol) of 4-methyl-6-[4-(4-chlorophenoxy) in 50 ml of toluene
Phenoxymethyl]-2-pyrone was heated to 80°C. Then 59.9 g (0.36 mol) hydroxylammonium sulfate and 38.3 g (0.36 mol) sodium carbonate were added. 10 minutes later yet another
59.9 g (0.36 mol) hydroxylammonium sulfate and 38.3 g (0.36 mol) sodium carbonate were added. After about 4 hours, remove the heat and cook for about 40 minutes.
500ml of methylene chloride was added at °C.
The dissolved reaction products were then removed from the insoluble salts. The liquid was then dried over sodium sulfate and the methylene chloride was evaporated. The residue was stirred with 500 ml of ethyl acetate and the reaction product crystallized. For final purification, 1-hydroxy-4-
Methyl-6-[4-(4-chlorophenoxy)phenoxymethyl]-2-pyridone was recrystallized from dimethylformamide. Yield 80.5g (45%); melting point 168-170°C. 38:1-hydroxy-4-methyl-6-[3-(2
-Phenoxyethoxy)phenoxymethyl]-
2-Pyridone (Compound 45) A mixture of 80 g of 6-chloromethyl-4-methyl-2-pyrone, 220 g of resorcinol, 400 ml of dimethylformamide and 105 g of micronized potassium carbonate was stirred at room temperature for 72 hours and then diluted with methylene chloride. was added, the organic phase was extracted by shaking several times with water and dried, and the solvent was removed by vacuum distillation. The viscous residue (223 g) was triturated with water and recrystallized from methanol and
53g of 6-(3-hydroxyphenoxymethyl)-
4-Methyl-2-pyrone (Compound D) was isolated. Melting point 145℃. 10g of compound D was mixed with 11.2g of 1-iodo-2-phenoxyethane (2-phenoxyethanol).
(produced by reacting with SOCl ₂ and replacing chlorine with iodine using sodium iodide in acetone), 6.9 g potassium carbonate and 50 ml
of dimethylformamide for 35 hours at 50°C, methylene chloride was added, the solution was washed several times with water, dried and chromatographed on silica gel. The main product isolated is
There were 10.4 g of 4-methyl-6-[3-(2-phenoxyethoxy)phenoxymethyl]-2-pyrone. Melting point: 95℃. 10 g of this pyrone are heated with 50 g of 2-aminopyridine at 75°C for 6 hours, during which time 8.5 g of hydroxylamine hydrochloride are added in portions, the residue is taken up in methylene chloride and the solution is dissolved in dilute hydrochloric acid (in the aqueous phase). PH, 3~
4) and drying, the solvent was removed by distillation and the residue was crystallized from acetonitrile. 4.3 g of pure hydroxypyridone was obtained. Melting point: 148℃. 39 and 40: In the same manner as Example 38, compound 48 is obtained starting from intermediate D and 1-(4-chlorophenylthio)-4-iodobutane, and compound 49 is obtained starting from D and 2-(4-chlorophenylthio)-4-iodobutane. Obtained from enylthio)ethyl 2'-iodoethyl ether. 41:6-[3-(4-chlorophenylthiopropylthio)phenoxymethyl]-1-hydroxy-
4-Methyl-2-pyridone (compound 47) 12.6 g monothioresorcinol, 31.3 g 1-
(4-chlorophenylthio)-3-iodopropane (4-chlorothiophenol and 1-bromo-3-
A mixture of 16.6 g of potassium carbonate and 60 ml of acetone was stirred at room temperature for 24 hours and the solvent was distilled off under reduced pressure. 14.5 g of 3-(4-chlorophenylthiopropylthio ) phenol was isolated. This product
9.5 g of 6-chloromethyl-4-methyl-2-pyrone, 10.4 g of potassium carbonate and 60 ml of acetone were stirred at 50° C. for 31 h, the solvent was removed by vacuum distillation and the residue was dissolved in methylene chloride. and the solution was washed several times with water, dried and chromatographed on silica gel. 11.2 g of the main fraction was heated with 50 g of 2-aminopyridine at 75 DEG C. for 65 hours and a total of 12 g of hydroxylamine hydrochloride was added in portions. The residue was then taken up in methylene chloride, the organic phase was extracted by shaking with dilute hydrochloric acid and several times with water, dried and the solvent was removed by distillation. The residue is
It was 9.9g. Treat this with methanol and get 2.7g
of pure hydroxypyridone was obtained. Melting point: 102℃. 42 and 43: Compound 51 was reacted with monothioresorcinol and 1-(4
-chlorophenylthio)-2,2-dimethyl-3
-obtained starting from iodopropane, compound 53
from monothioresorcinol and (4-chlorophenylthio)ethoxyethoxyethyl iodide. Investigation of activity In in vitro investigations of antifungal substances, it is necessary to distinguish between action against proliferating microorganisms (bacteriostatic action) and action against quiescent microorganisms (fungicidal activity). Fungicidal activity tested on non-growing fungi classifies as a relatively reliable model. This involves a dilution series of the product to be tested (31.25-0.25 μg/ml:
8 stages) are required. Each U-shaped well on the plate is inoculated with 10 ⁴ colony forming units (CFU) of the skin fungus Trickophyton mentagrophytes (vehicle: physiological NaCl solution). After 18 h of incubation at 30 °C, the microorganisms were washed with 50% polyethylene glycol 400 and NaCl solution (centrifuged twice) and streaked onto malt agar plates using an automated device to determine the number of microorganisms. do. After 3 days of culture at 30°C, colonies are counted and their CFU/ml is calculated. The % reduction in the number of microorganisms is determined by comparison with an untreated control (control = 0%). The strength of action is
Standard preparations e.g. the following formula clotrimazole, the common name for a compound with As is clear from Table 1 below, the compound of the present invention showed an extremely small number of CFU compared to the standard preparation clotrimazole. The fungicidal or lethal effect of the compounds according to the invention is therefore clearly more pronounced than that of the standard agents. [Table] [Table] Describe. This weighs 450~
500g Morimotu (Pilbright white variety)
Requires 2 or 4 animals, in each case 1.5 × 10 ⁴ conidia/distributed to 6 infection points on each epidermis.
infected the animal. These animals were infected with
1 day and 4 days before treatment by applying a solution of the product at a concentration of 0.3% on 3 infection sites on the right side of the back in each case. The left side of the back, with three infection sites in each case, was treated in the same way with vehicle without any product (vehicle control). Besides the animals treated with the substance according to the invention, two animals were treated with the reference substance clotrimazole and two infected animals were left untreated (infection controls). As is clear from Table 2, the compounds according to the invention showed a clearly greater difference in the diameter (mm) of mycosis than the standard preparation clotrimazole. The antifungal effect of the compounds according to the invention was thus undoubtedly superior to that of clotrimazole. [Table] X￣=Average value
(S)=Standard deviation value Examples of the acute toxicity of the compounds of the present invention and drug preparation are shown below. Acute toxicity: Single-dose oral toxicity study in rats.
-(4-chlorophenoxy)phenoxymethyl]-
1-Hydroxy-4-methyl-2-pyridone, i.e. the following formula: Compound (1) of the present invention having the following formula was administered to 3 male and 3 female rats at a maximum single oral dose of 10,000 mg/kg body weight. Upon administration of the compound, only one rat had slightly decreased motility and continued narrowing of the eyelid gap until the following night. On days 1 to 3 after administration, the faces of all rats were slightly red due to the large amount of compound administered. Weight gain for all these animals was regular during the 3 week follow-up period. Macroscopic examination of the dissected bodies of these animals, which were killed at the end of the follow-up period, revealed no morphological changes. Under the conditions of this study, the maximum tolerated oral dose for rats is
It was larger than the maximum dose that can be administered, which is 10,000 mg. Pharmaceutical Preparation: 1. Powder Each powder was obtained by vigorously mixing the following components in the relative amounts shown below. % (by weight) 6-[4-(4
-chlorophenoxy) phenoxymethyl]-1
-Hydroxy-4-methyl-2-pyridone
2 Colloidal Kaolin 20 Talc 35 ANM (Amylum non muciluginosum) 43 (=gelling rice starch) 2 Suspension The micronised active ingredient was dispersed in glycerol at room temperature. Sorbic acid and potassium sorbate were dissolved in water, and then hydroxyethylcellulose was dispersed in this solution at 60°C. Both dispersions were mixed at room temperature. The operation was carried out under slight vacuum to avoid the introduction of air. The nature of the active ingredients and the relative amounts of each used were as follows. % (by weight) Micronized (particle size 100%<10μ) 1-hydroxy-4-methyl-6 which is the compound of the present invention (35)
-[3-(1-naphthylmethylthio)phenoxymethyl)-2-pyridone 0.3 Hydroxyethylcellulose 1.5 Glycerol (85%) 10.0 Sorbic acid 0.1 Potassium sorbate 0.1 Water 88

Claims (1)

[Claims] 1 formula [Wherein R ¹ , R ² and R ³ are the same or different and represent hydrogen or lower alkyl having 1 to 4 carbon atoms, R ¹ and R ³ are preferably hydrogen , R ₂ is preferably methyl, X represents S or preferably O, Y represents hydrogen or up to two halogen atoms, namely chlorine and/or bromine, and Z represents a single bond or a divalent Group O, S, -CR ₂ -
(R=H or _C1 - _C4 -alkyl) or 2-
represents 10 carbons and optionally other divalent radicals with oxygen and/or sulfur atoms linked to form a chain, in which case the radical contains two or more oxygen and/or sulfur atoms; When containing sulfur atoms, these atoms contain at least 2
two adjacent carbon atoms can also be connected by a double bond, in which case the free valences of the carbon atoms are H and / or C ₁ ~
attached to a _C4 -alkyl group, Ar has up to two rings and is selected from the group consisting of fluorine, chlorine, bromine, methoxy, _C1 - _C4 -alkyl, trifluoromethyl and trifluoromethoxy 1-Hydroxy-2-pyridone represents an aromatic ring system which can be substituted by up to three groups. 2. A compound according to claim 1, wherein 2 Ar represents an optionally substituted phenyl ring. 3. Compounds according to claim 1, wherein 3 Ar represents an unfused bicyclic system, preferably derived from biphenyl, diphenyl alkane or diphenyl ether and optionally substituted. 4. The compound according to any one of claims 1 to 3, wherein Z is a single bond. 5. The compound according to any one of claims 1 to 3, wherein Z represents or contains oxygen. 6 6-[4-4-chlorophenoxy)phenoxymethyl]-1-hydroxy-4-methyl-2-
Pyridone, i.e. in the formula R ¹ , R ³ and Y are H, R ² is CH ₃ and X is O;
2. A compound according to claim 1, wherein Z is O in the 4-position with respect to the XCH ₂ group and Ar is [Formula]. 7 6-(4-biphenyloxymethyl)-1-hydroxy-4-methyl-2-pyridone, i.e. in which R ¹ , R ³ and Y are H and R ² is
2. A compound according to claim 1, which is _CH3 , X is O, Z is a single bond and Ar is _C6H5 in the 4- _position relative to the _XCH2 group. 8 1-hydroxy-4-methyl-6-[4-(4
-trifluoromethylphenoxy)phenoxymethyl]-2-pyridone, i.e. in the formula R ¹ ,
R ³ and Y are H, and R ² is 4 to CH ₃ group.
The compound according to claim 1, wherein O is in the - position and Ar is [Formula]. 9 formula [Wherein R ¹ , R ² and R ³ are the same or different and represent hydrogen or lower alkyl having 1 to 4 carbon atoms, R ¹ and R ³ are preferably hydrogen , R ² is preferably methyl, X represents S or preferably O, Y represents hydrogen or up to two halogen atoms, namely chlorine and/or bromine, and Z represents a single bond or a divalent Group O, S, -CR ₂ -
(R=H or _C1 - _C4 -alkyl) or 2-
represents other divalent radicals with 10 carbons and optionally oxygen and/or sulfur atoms linked to form a chain, in which case the radical contains two or more oxygen and/or sulfur atoms; If it contains atoms, these atoms must be separated by at least two carbon atoms;
And two adjacent carbon atoms can also be connected by a double bond, the free valence of the carbon atoms being H and/or C ₁ -C ₄ -
3 bonded to an alkyl group, Ar has up to two rings and is selected from the group consisting of fluorine, chlorine, bromine, methoxy, _C1 - _C4 -alkyl, trifluoromethyl and trifluoromethoxy; represents an aromatic ring system which can be substituted by up to groups of the formula (wherein R ¹ , R ² and R ³ have the above definitions,
Hal represents a halogen atom, especially chlorine or bromine)
6-halogenomethyl-2-pyrone of formula (wherein X, Y, Z and Ar have the above definitions) with a phenol or thiophenol, resulting in the formula or aryloxymethylpyrone or arylthiomethylpyrone of formula into a hydroxypyridone of the formula by the action of a hydroxyamine, or other substituents according to the definitions of the substituents of the groups R ¹ , R ² , R ³ and Ar of the above formula, consisting of introducing into the compound obtained by the above action or into an intermediate still containing a reactive group in the Ar or pyridone ring by substitution of said reactive group. Method of manufacturing compounds. 10 The conversion of an aryloxymethylpyrone or an arylthiomethylpyrone having the formula to a hydroxypyrodone having the formula 1
10. The process of claim 9, carried out by reaction in the presence of at least about 1 mole per mole of hydroxylammonium salt and at least about 1 equivalent of at least one organic or inorganic base relative to the salt. 11. Process according to claim 10, wherein the base used is a carbonate and/or bicarbonate of an alkali metal, preferably sodium and/or potassium, in particular Na ₂ CO ₃ . 12 The hydroxylammonium salt used is
12. The method of claim 11, wherein the hydroxylammonium sulfate is hydroxylammonium sulfate. 13 formula [Wherein R ¹ , R ² and R ³ are the same or different and represent hydrogen or lower alkyl having 1 to 4 carbon atoms, R ¹ and R ³ are preferably hydrogen , R ² is preferably methyl, X represents S or preferably O, Y represents hydrogen or up to two halogen atoms, namely chlorine and/or bromine, and Z represents a single bond or a divalent Group O, S, -CR ₂ -
(R=H or _C1 - _C4 -alkyl) or 2-
represents 10 carbons and optionally other divalent radicals with oxygen and/or sulfur atoms linked to form a chain, in which case the radical contains two or more oxygen and/or sulfur atoms; When containing sulfur atoms, these atoms contain at least 2
two adjacent carbon atoms can also be connected by a double bond, in which case the free valences of the carbon atoms are H and / or C ₁ ~
attached to a _C4 -alkyl group, Ar has up to two rings and is selected from the group consisting of fluorine, chlorine, bromine, methoxy, _C1 - _C4 -alkyl, trifluoromethyl and trifluoromethoxy represents an aromatic ring system which can be substituted by up to three groups of the formula (wherein R ¹ , R ² , R ³ and Hal have the above definitions) is reacted with a phenol of the formula and the resulting compound is oxidized to N-
oxide and then converting that compound into a compound of formula by hydrolysis of the halogen on its nucleus, or other substituents according to the definitions of the substituents of the groups R ¹ , R ² , R ³ and Ar. into the compound obtained by the above operation or into an intermediate still containing a reactive group in the Ar or pyridone ring by substitution of said reactive group. Method of manufacturing compounds. 14 At least one formula [Wherein R ¹ , R ² and R ³ are the same or different and represent hydrogen or lower alkyl having 1 to 4 carbon atoms, R ¹ and R ³ are preferably hydrogen , R ² is preferably methyl, X represents S or preferably O, Y represents hydrogen or up to two halogen atoms, namely chlorine and/or bromine, and Z represents a single bond or a divalent Group O, S, -CR ₂ -
(R=H or _C1 - _C4 -alkyl) or 2-
represents 10 carbons and optionally other divalent radicals with oxygen and/or sulfur atoms linked to form a chain, in which case the radical contains two or more oxygen and/or sulfur atoms; When containing sulfur atoms, these atoms contain at least 2
two adjacent carbon atoms can also be connected by a double bond, in which case the free valences of the carbon atoms are H and / or C ₁ ~
attached to a _C4 -alkyl group, Ar has up to two rings and is selected from the group consisting of fluorine, chlorine, bromine, methoxy, _C1 - _C4 -alkyl, trifluoromethyl and trifluoromethoxy 1-hydroxy-2-pyridone and/or an inorganic or organic base representing an aromatic ring system which can be substituted by up to 3 groups. An antifungal medicament containing an effective amount of an acceptable salt in addition to a physiologically acceptable vehicle and if appropriate further additives and/or auxiliaries. 15. The medicament according to claim 14 for use against pathogenic skin fungi and mucosal fungi.