JPS62249974A - 1-hydroxy-2-pyridones - 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 The present invention provides novel 1-hydroxy-
Concerning 2-pyridones, their use primarily for inhibiting fungal and yeast infections and medicaments containing these compounds, and also regarding certain compounds produced in the production of novel 1-hydroxy-2-pyridones. Regarding intermediates.

In West German Patent No. 2,234,009, the formula ■-17
Compounds of the formula = (f-) in which R1 represents, inter alia, aryloxyalkyl or arylmercaptoalkyl having alkyl of 1 to 4 carbon atoms are disclosed. The only specific illustrations of these groups are phenyloxymethyl or phenylmercaptomethyl. According to DE 2,234,009, in addition to aryloxyalkyl or arylmercaptoalkyl, R1 can also contain various other groups, such as aryl, 1-
aralkyl having alkyl of 4 carbon atoms, 2-
Arylalkenyl with alkenyl of 4 carbon atoms, benzhydryl and phenylsulfonylalkyl with alkyl of 1 to 4 carbon atoms can also be used. Where specific examples are given for these groups in said patents, they always include groups of 1 to 4 carbon atoms, with the exception of the -aryl group itself (and also mentioned as naphthyl). 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 method in which the substituent at the 6-position (R1 in formula n) contains at least two separate and optionally substituted aromatic rings and is linked via an oxymethyl group or a thiomethyl group. It concerns 1-hydroxy-2-pyridone derivatives having an aromatic system attached to the pyridone residue, which derivatives are represented by the general formula I.

That is, 1 the present invention is based on the general formula I [During the ceremony.

R1, R2 and R5 are the same 5 or different and represent hydrogen or lower alkyl having 1 to 4 carbon atoms, R1 and R2 are preferably hydrogen and R2 is preferably methyl.

X represents S or preferably 0; Y represents hydrogen or up to two halogen atoms, ie chlorine and/or bromine.

2 is a single bond or a divalent group O, S, -CR2-(R
=H or 01-c4-alkyl) or other divalent radicals having 2 to 10 carbons and optionally oxygen and (!) sulfur atoms attached to form the candy; When said number contains two or more oxygen and/or sulfur atoms, these atoms must be separated by at least two carbon atoms and two adjacent carbon atoms must also be separated. bonded by a double bond and one free atom of said carbon atom can be saturated by H and/or 01-c4-alkyl groups, having up to two rings and fluorine, Chlorine, bromine, methoxy, 01-C4-alkyl,
1-hydroxy-2- represents an aromatic ring system which can be substituted by up to 6 groups selected from the group consisting of trifluoromethyl and trifluoromethoxy
Regarding pyridone.

The carbon chain in the two groups is preferably an OH2 group. When the CH2 group is substituted by an 01-C4-alkyl group,
Preferred substituents are OH3 and 02H5. Two examples are listed below.

-O-, -8-, -0H2-, -(CH2)m- (m=
2-10), -c(aHg)2-+-CH20-, 0C
H2-, -0H2S-, -8OH2-, -8OH(02
H5)-.

2l- -oH-c+n-on2o-, -0-OH2-OH=O
H-OH20-1-ocH2aa2o-.

-0OH20H20H20-, -5aH2cu2cn2
s-, -5an2cu2aH2ca2o-.

-8OH20H200H20H20-, -8OH20H
200H20H20-OH20H2S-.

The term "aromatic ring system" such as -8-OH2-0(OH5)2-OH2-8-1 refers to phenyl systems as well as fused systems such as naphthyl, tetrahydronaphthyl and indenyl, and isolated systems such as biphenyl, diphenylalkanes. , diphenyl ethers and diphenylthioethers.

Important representative examples of compounds defined by formula (1) include the following:

6-C4-(4-''lolophenoxy)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, melting point 167°C (1).

6-[4-(2,4-Dichlorophenoquine)phenoxymethyl]-1-hydroxy-4-noble 2-pyridone, melting point 162°C (2).

6-<biphenylyl-4-oxymethyl)-1-hydroxy-4-methyl-2-pyridone.

Melting point 184°C (3), 6-(4-benzylphenoxymethyl)-1-hydroxy-4-methyl-2-L' IJton, melting point 149°C (
4).

6-C4-(2,4-dichlorobandyloxy)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, melting point 172°C (5).

6-C4-C4-chlorophenoxy)phenoxymethyl]-1-hydroxy-3,4-dimethyl-2-pyridone, melting point 155°C (6).

6-C4-(2,4-dichlorobenzyl)phenoxymethyl]-1-hydroxy-6,4-dimethyl-2-pyridone, melting point 169°C (c, 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, mp 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-C4-<4-<4-chlorophenoxy)phenoxymethyl)phenoxymethyl,]-]1-hydroxy-4
-Methyl-2-pyridone, melting point 158°C (12), 6-(2,6-:)chloro-4-(2-naphthylthiomethyl)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, H. Point 168”C (13).

6-(2,6-dichloro-4-(4-phenylphenoxymethyl)phenoxymethyl:)-1-hydroxy-
4-Methyl-2-pyridone, melting point 190°C (14).

6-C4-C4-chlorobenzyloxy)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone,
Melting point 173°C (15).

1-Hydroxy-4-methyl-6-(4-(4-trifluoromethoxyxndyloxy)phenoxymethyl-2-pyridone, melting point 143°C (16), 6-C4-<4-tert-butylbenzyloxy)phenoxy Methyl]-1-hydroxy-4-methyl-2-pyridone, melting point 181°C (17) & 6-[2-(4-chlorobenzyloxy)phenoxymethyl]-1-hydroxy-
4-Methyl-2-pyridone, melting point 161°C (18).

1-hydroxy-4-methyl-6-(2-(naphtho-1
-yl-methoxy)phenoxymethyl-2-pyridone, melting point 150°C C1q).

1-Hydroxy-4-methyl-6-[ro-C1-naphthylmethoxy)]-2-pyrylene, melting point 155°C (20).

6-[3-(4-chlorobenzyloxy)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone,
Melting point 149°C (21).

6-C4-C4-chlorophenoxy)phenoxymethyl]-1-hydroxy-2-pyridone, melting point 180°C (2
2).

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, m.p. 161°C (24).

6-(2,6-')chloro-4-phenylphenoxymethyl)-1-hydroxy-4-methyl-2-pyridone, m.p. 195°C (25).

6-(4-(4-promo-2-chlorophenoxy)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, mp 174°C (26).

1-hydroxy-4-methyl-6-C4-(3,4,5
-Trimethoxybenzyloxy)phenoxymethyl]-
2-Pyridone, melting point 154°C (27).

6-(4-(2,4-dichlorobenzyl)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, m.p. 173°C (28).

6-(2,6-dibromo4-(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-promo 4-phenylphenoxymethyl)-
1-Hydroxy-4-methyl-2-pyridone, melting point 24
5°C (31), 6-(2-promo-6-chloro-4-phenylphenoxymethyl)-1-hydroxy-4-methyl-2-pyridone (32).

6-C4-<4-Fluorophenoki et al.)butydimethyl]-1-hydroxy-4-mebu-9-2-pyridone, melting point 151°C (33).

6-C3-<4-chlorophenylthio)phenoxymethyl]-1-hydroxy-414-1°-2-pyridone (
34).

1-Hydroxy-4-methyl-6-(3-(1-naphthylmethylthio)phenoxymethyl]-2-pyridone, melting point 144°C<55).

1-Hydroxy-4-methyl-6-(3-(1-naphthylmethoxy)phenylthiomethyl]-2-pyridone, mp 165°C (36).

1-Hydroxy-4-methyl-6-(2-phenylphenoxymethyl>-2-pyridone, melting point 179°C (37
).

6-C2-vanzylphenoxymethyl)-1-hydroxy4-methyl-2-pyridone, melting point 155°C (38)
.

1-hydroxy-5,4-')methyl-6-[3-(1
-naphthylmethylthio)phenoxymethyl]-2-pyridone, melting point 143°C (39).

6-(2,4-)furomor6-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, mp 100"C (41)% 6-[3-(4-chlorobenzyloxy)phenylthiomethyl]-1-hydroxy-4-methyl-2-pyridone, mp 94C (42).

6-C4-(4-chlorophenylthio)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, mp 158°C (43).

1-HyVroxy6-(4-(4-methoxyphenylthio)phenoxymethyl]-4-methyl-2-pyridone,
Melting point 162°C (44), 1-human 10xy-4-methyl-6-(3-(2=phenoxyethoxy)phenoxymethyl)=2-bilin, melting point 148°C (45).

6-C4-<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-C3-(4-chlorophenylthiophthoxy)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, melting point 104°C (48), 6-C3-<4-chlorophenylthioethoxyethoxy)phenoxymethyl] −
1-Hydroxy-4-methyl-2-pyridone, melting point 98
°C (49).

6-(4-(α,α-dimethyl-4-methoxyvanzyl)phenoxymethyl]-1-hydroxy-4-methyl-
2-Pyridone, melting point 156°C (50).

6-(3-[1-(4-chlorophenylthio)-2,2
-dimethylprop-6-ylthio]phenoxymethyl>
-1-hydroxy-4-methyl-2-pyridone, melting point 1
34°C (51).

6-<4-[1-(4-chlorophenyl)boudo-2-en-4-yloxy]phenoxymethyl>-1-hydroxy-4-methyl-2-pyrifone, melting point 167°C (52
).

6-(3-(4-chlorophenylthioethoxyethoxyethylthio)phenoxymethyl]-1-hydroxy4
-Methyl-2-pyridone, melting point 95°C (53).

6-(4-(1-(4-chlorophenyl)-5-ethylphenoxymethyl)-1-hydroxy-4-methyl-2-pyridone, mp 159"C (54).

The compounds of the present invention can be produced by various methods known per se. For example, the compounds of the formula
6-halogenomethyl-2-pyrone of the formula (wherein X, Y, Z and Ar have the above definition The alkylation is conveniently carried out by reacting a phenol or thiophenol with a phenol or thiophenol and converting the resulting formula V aryloxymethylpyrone or arylthiomethylpyrone into a hydroxypyridone by the action of hydroxylamine. Protic solvents such as methanol.

ethanol, impropatul, acetone, acetoni)
The reaction is carried out in IJ, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, dimethyl formamide or dimethyl sulfoxide, but aprotic solvents are preferred. To bind the liberated hydrogen halides, inorganic or organic bases are used, such as sodium or potassium hydroxide, sodium carbonate, potassium carbonate or calcium carbonate, triethylabane, tributylamine, pyridine, 4-dimethylaminopyridine: The 5-azabicyclononane, N-methyl biboridine, is especially used in at least an equivalent amount. The reaction temperature is generally between room temperature and about 80°C, but clearly higher or lower temperatures, such as 110°C or 0°C, may, however, be advantageous in special cases.

For the conversion of 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. 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; however, to increase the reaction rate and yield it is preferred to use an excess amount, e.g. 2 to 10 moles to 1 mole; Furthermore, it is 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) and imidazoles (derivatives) such as 2-aminopyridine, 2-aminopicoline, 2-methylaminopyridine, imidazole and 2-methylimidazole, and preferred inorganic bases are alkali metal carbonates. salt and/or bicarbonate (Lt
2co3°Na2005. K2O05, NaHOJ,
KHOJ, Rb2005. CBHOOx.

etc.). Among the above inorganic bases, Na2005 is most suitable for 1% of sodium and potassium carbonates and hydrogen carbonates.

The organic base is generally about 1 mole of pyrone used.
~20 mol Preferably used in amounts of about 3 to 10 mol, which can act at the same time as a solvent, which also usually satisfies the condition that there are at least P11 equivalents of base with respect to the hydroxylammonium salt used. .

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<0>C to 150<0>C, preferably about 50<0>C to 100<0>C.

When using alpha bases, it is advantageous to add at least approximately the same amount to the hydroxylammonium salt used as in the case of organic bases. For example at least 172 mol Na 2003 or 1 mol N per mole of hydroxylammonium chloride
aHCO2 should be used. Furthermore, the inorganic bases can be used both in single glazes and in any desired mixtures.

A variant thereof using an inorganic base is to convert the 2-pyrone into a hydroxylammonium salt, in this case preferably tL<R hydroxylammonium sulf-3 phosphate, as well as an alkali metal carbonate and/or
It is advantageous to mix with the bicarbonate and to heat the resulting crystalline product in a housing in which as much pyrone is converted as possible, and the 2-pyridone formed after removal of the inorganic salt can be isolated directly or more preferably It can be isolated as a salt of an organic base, such as an ethanolamine salt.

The temperature when carrying out this variant should never exceed about 120°C. It is conveniently above about 50°C, preferably about 6D to 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, 1
There may be advantages in individual cases. If a solvent or diluent is added, this is generally done only in small amounts, usually up to about 50% by weight of the total reaction mixture.

Preferred amounts are about 3 to 15 parts by weight.

The solvent or diluent may be astringent or non-polar and water-miscible or immiscible. 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. Mention may be made of ethers, chlorinated hydrogen ash such as chlorobenzene, nitriles such as acetonitrile or aliphatic, cyclic or aromatic hydrocarbons.

6-halogenomethyl-2-pyrones, especially their chlorine compounds, can be used, for example (-0hemische Bericht
e jsu 0 (1967), 658 can be produced by the method described in -.

Another possibility for synthesizing hydroxypyridone is 2
- Halogeno-6-picoline is subjected to side M halogenation to obtain 2-halogeno-6-halogenomethylpyridine having the formula It consists of reacting the group with an optionally suitably substituted phenol, oxidizing the resulting compound to give the N-oxide and hydrolyzing the halogen on the nucleus 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 halogenomethylviron 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, 6-chloroperbenzoic acid and tert-butylhydroxide. , for example sulfuric acid, if the transformation is appropriate
With catalysis by strong acids such as perchloric acid, toluenesulfonic acid, trifluoroacetic acid and trifluoromethanesulfonic acid.

Preferably carried out at room temperature to about 100"C. Hydrolysis of the supranuclear halogens 1 can be carried out directly by reaction with a base such as sodium hydroxide, potassium hydroxide or barium hydroxide. Alternatively, it can also be carried out indirectly by etherification with an alcohol, such as tert-butanol or 2-methoxyethanol, which can be easily removed again in the next turn.

A typical method for preparing compounds of general formula 1 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 pyrone ring, then the definitions of R1-R3 and the It is possible to introduce further groups corresponding to the substituents.

For example, it is possible to subsequently etherify free hydroxyl or mercapto groups.

Alternatively, it is possible, for example, to convert the hydroxymethyl group produced by reduction of an aldehyde group into a halogenomethyl group and then exchange the halogen nucleophilically again with phenol or thiophenol. Similarly,
Pyridine derivatives obtained from the reaction of dihalogenopicoline of formula ■ with phenol or N- obtained by oxidation thereof
If the oxides still contain reactive substituents, it is also possible to convert them into other types of substitution products.

The present invention also includes: Formula V (where RζR2
, R3, X% Y and Ar have the above definitions).

According to the invention, compounds of the formula (III) are used against pathogenic fungi, such as dermatophytes (filamentous fungi) and fungi that act on both the skin and the mucous membranes, such as yeasts (e.g. Candida sp.) and molds (e.g. Asus niger). On the other hand, the broad spectrum has excellent topical antifungal properties with the action of a cuttle. They are therefore useful in veterinary medicine for domestic livestock such as dogs, cats and birds as well as commercial livestock such as livestock animals, horses and pigs, and in human medicine to control infections caused by these pathogens. can be used. The hydroxypyridones are used in conventional formulations for fungal control, such as solutions.

Suspension-tL, as a cream, ointment, powder or suppository (vaginal tablet) in pre-absorbent form or with an inorganic or organic base (e.g. NaOH, KOH, 0a(OH)2.NH5°H2
NOH20H20H 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 antiviral activity, for example against viruses.

Example 1: 6-C4-(2,4-dichlorobenzyl)phenoxymethyl]-1-hydroxy-3,4-dimethyl-
2-pyridone (compound 19.85jl of 6-chloromethyl-3,4-dimethyl-2-pyrone (compound A) and 25.39g of 4-(2,4-dichlorobenzyl)phenol dissolved in 701rlQ of dimethylformamide 209 ml of finely ground potassium carbonate was added and the mixture was stirred at room temperature for 48 hours. Then 2QQmQ of methylene chloride and 5DDmQ of water were added, the layers were separated and the organic phase was washed twice with 1oome of water each, Dry and evaporate under water pump vacuum.42.
The residue of 79 was nearly pure by thin layer chromatography and was heated with 200F 2-aminopyridine at 75°C for 56 hours, during the first 41 hours the hydroxyl of K VB tt 4 t 79 Amine hydrochloride was added in 5 portions. Then 250 μm of methylene chloride was added and the organic phase was washed once with dilute hydrochloric acid and twice with water, and the solvent was removed by wave pressure distillation. 39.
The residue of 79 was recrystallized from ethylene glycol monomethyl ether to give 32.5F pure hydroxypyridone. Melting point: 169°C.

2-19: In the same manner as Example 1, starting from 4-(4-chlorophenoxy)phenol and A, compound 6
Compound 39 was obtained from 3-(1-naphthylmethylthio)phenol and A, 4-(4-10lophenoxy)phenol and 6-chloromethyl-4-methyl-2
Compound 1 is obtained from -pyrone (compound B), and 4-(2,
Compound 2 was obtained from 4-dichlorophenoxy)phenol and B, and 4-(4-trifluoromethylphenoxy)
Compound 9 was obtained from phenol and B, 2,6-dichloro-4-(4-chlorophenoxy)phenol and B
From compound 2346-14L 2.6-:) chloro-4-phenylphenol and from B, compound 25 was obtained, from 4-(4-fluorophenoxy)phenol and from B, compound 36 was obtained, and!
Compound 34 was obtained from +-(4-chlorophenylthio)phenol and B, compound 35 was obtained from 3-(1-naphthylmethylthio)phenol and B, and compound 40 was obtained from 2,4-dibromo-6-phenylphenol and B. obtained, 4-C4-(4-chlorophenoxy)phenoxy]
Compound 41 was obtained from phenol and B, and compound 43 was obtained from 4-C4-chlorophenylthio)phenol and B.
Compound 4 was obtained from 4-benzylphenol and B, and compound 38 was obtained from 2-benzylphenol and B.

Compound 3 was obtained from 4-phenylphenol and B, and 4
-(4-7' lomo-2-chlorophenoxy)phenol and B gave compound 26 and 4-[1-(4-chlorophenyl)-5-ethyl]phenol and B gave compound 54.

20: 1-hydroxy-4-methyl-6-'4-(1
-naphthylmethoxy)phenoxymethyl]-2-pyridone (compound 10) 100P of 6-chloromethyl-4-methyl-2-pyrone, 210jl of hydroquinone,
A mixture of 132 jl of potassium carbonate and 400 mQ of dimethylformamide was stirred at room temperature for 72 hours and water was added.

The mixture was neutralized with hydrochloric acid and the precipitate was removed with suction, washed with water and dried. treated with methylene chloride,
Subsequent recrystallization from acetonitrile yielded 689, substantially pure 6-(4-hydroxyphenoxymethyl)-4.
-Methyl-2-pyrone was obtained. Melting point: 179°C. This compound 489 1-chloromethylnaphthalene of 49.

Stirred with 20 mQ of dimethylformamide and 89 m of potassium carbonate at room temperature for 7214 h and diluted with hydroxide), the IJ solution was added, the mixture was shaken with methylene chloride, the organic phase was washed with water and dried,
The solvent was removed by distillation. The residue of 7.09 was chromatographed in methylene chloride on a column containing silica gel to yield 4.69 of pure 4-methyl-6-[4-(1-naphthylmethoxy)phenoxymethyl]-2-pyrone. . Melting point: 132°C. This product was heated at 75°C with 159 2-aminopyridine,
During stirring for 32 hours, 7F hydroxylamine hydrochloride was added in four portions. After continuing the reaction for a total of 42 hours,
The residue was taken up in methylene chloride and 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. Compound 10 in the K11l frame of 1.99
was isolated. Melting point: 179°C.

21-30: Compounds 5, 8 in the same manner as Example 20
．． 15,16.17.27.46 and 52 are intermediate 6
-(4-hydroxyphenoxymethyl)-4-methyl-
2-pyrone chlorides, i.e. 2,4-dichloronzyl chloride, cinnamyl chloride, 4-chlorobenzyl chloride, 4-trifluoromethoxybenzyl chloride.

4-Tertiary butylbenzyl chloride, 3,4.5-
Trimethoxybenzyl chloride, 1-chloro-3-(
4-chlorophenoxy)furopane and 1-chloro-4
It was obtained by alkylating with -(4-10)-2-butene and converting the obtained h7-11-ene into hydroxypyridone. Using catechol in place of hydroquinone and alkylation with 1-nasothylmethyl chloride gave compound 19, and resorcinol and 4-chlorobenzyl chloride gave compound 21.

51: 6-(2,S-dichloro-4-(2-naphthylthiomethyl)noenoxytatyl]-1-hydroxy-
4-Methyl-2-pyridone (compound 13) 250 mff1 of 4.82 sodium and 429 3.5-:)chloro-4-hydroxybenzaldehyde
of methanol, the solvent was removed by vacuum distillation, and the residue was taken up in 200 mQ of dimethylformamide.
62F 6-chloromethyl-4-methyl-2-pyrone was added to the mixture and the mixture was left to react indoors for 3 days. The dimethylformamide was then substantially removed by vacuum distillation, methanol was added and a total of 4451 6
- (2,6-dichloro-4-formylphenoxymethyl)-4-methyl-2-pyrone was isolated in several fractions by cooling and concentrating the mother liquor. This compound 64.
59 for 250m1! of nato2hydrofuran and 100
mff1 was reduced with sodium borohydride in a mixture of methanol at room temperature, the mixture was then heated to 50°C and 10 mQ of concentrated sulfuric acid was added, most of the solvent was removed by distillation and the residue was It was shaken with water and the solids were suctioned off, washed with water and dried. This product (33.1jl, melting point 154°C) was heated to 200
The moth was suspended in methylene chloride, 01 mQ of dimethylformamide was added, and 11 mQ of thionyl chloride was added portionwise at room temperature. After 24 hours the solvent was removed by distillation, the residue was boiled with 200 methanol, the mixture was cooled to 0° C. and the product was suctioned off.
Washed and dried. 3[Lljl pure 6-
(2,6-dichloro-4-chloromethylphenoxymethyl)=4-methyl-2-pyrone was obtained. Melting point 136℃0
The resulting compound of 7,59 was stirred with 2-thionaphthol of 42, dimethylformamide of 30me and potassium carbonate of 7P for 24 hours at room temperature, then water was added,
Shake the mixture with methylene chloride and wash the solution with water.

It was dried and chromatographed on a column containing silica gel. a5P 6-1” 2,6-dichloro-4-(2-naphthylthiomethyl)phenoxymethyl]
-4-methyl-2-pyrone was obtained. Melting point: 125°C. This product was heated at 75° C. with 259 portions of 2-aminopyridine and a total of 89 portions of hydroxylamine hydrochloride were added in four 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 recrystallized once from acetonitrile and once from ethyl acetate to give 2.19 of pure compound 13. Melting point: 138°C.

32 and 33: Same procedure as in Example 31.

Compound 14 can be obtained by subjecting the intermediate 6-(2,6-dichloro-4-chloromethylphenoxymethyl)-4-methyl-2-pyrone to 4-phenylphenol reaction and converting the resulting pyrone to hydroxypyridone. Obtained. Similar reduction was carried out using 4-hydroxybenzaldehyde instead of 3,5-dichloro-4-hydroxybenzaldehyde, and reaction with thionylchloride resulted in 4-hydroxybenzaldehyde.
Condensation with (4-chlorophenoxy)phenol followed by reaction with hydroxylamine gave compound 12.

34: 6-C4-<4-chlorophenoquine)phenoxymethyl]-1-hydroxy-2-pyridone (compound 22) UV with benzoyl peroxide and 150me carbon tetrachloride
After heating at reflux under irradiation for 50 hours, the mixture was filtered, the P solution was washed once with aqueous sodium carbonate and three times with water, then dried and the solvent was removed by vacuum distillation. Residue (40
,19) 150m+! Shaking with 100 ml of hexane followed by suction filtration yielded 27.39 of a mixture consisting primarily of the desired monobromomethyl compound, but with a small amount of dibromomethyl compound. Add this mixture to 21.42 4-
(4-chlorophenoxy)phenol.

Stir at room temperature for 48 hours with 2α7P potassium carbonate and 50 μm dimethylformamide, then 200 mf
Methylene chloride of f1 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 2-bromo 6-C4-C4-chlorophenoxy)phenoxymethyl of 16.3j1. Copyridine was isolated.

The resulting compound is,ap was incubated with a solution of 5 (F3,59 peracetic acid dissolved in 1 mlj of glacial acetic acid at 50 °C for 30 min.
After heating for an hour, the solvent was partially removed by vacuum distillation at 40° C., the residue was shaken three times with 200 ml of water and once with aqueous sodium bicarbonate solution, decanted each time, and finally dissolved in vcl. Process it with.

The product was removed with suction and dried. Thus 1α2
Almost pure N-oxide of 9 was obtained. Melting point: 100°C. This N-oxide 5P is 9m? of water (j 2[1m
7 with a solution of sodium hydroxide of 1,29 dissolved in a mixture of ethylene glycol monomethyl ether of Q.
Heated at 0°C. During this time, 12
The methoxyethyl ether of the N-oxide, which melts at 5°C, was rapidly formed and the ether was slowly hydrolyzed. After 60 hours, the solvent was removed by vacuum distillation and the residue was diluted with 200 g 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 yield 2.59 pure compound 22. Melting point 180℃
.

35: 1-hydroxy-4-methyl-6-[3-(1
-naphthylmethoxy)phenylthiomethyl]-2-pyridone 269 monothioresorcinol and 31.89 6
-10lomethyl-4-methyl-2-pyrone 100II
Dissolve IQ in dimethylformamide.

38p of powdered potassium carbonate was added within 30 minutes while stirring and cooling in water and the mixture was stirred for 4 hours at 0°C and 16 hours at room temperature, to which 500g of methylene chloride was added and the 2M organic phase was dissolved in water. It was extracted by shaking three times, separated for one minute and then dried, and the solvent was removed by distillation.

The residue was recrystallized from methanol to give 449 6-(3
-hydroxyphenylthiomethyl)-4-methyl-2-
Pyrone, compound (C) was obtained. Melting point: 129°C. 200+
F! to a solution of 89 sodium iodide dissolved in ++ft acetone! , 99 of 1-chloromethylnaphthalene was added, the mixture was stirred at room temperature for 16 hours and 12.49 of compound C was dissolved in this mixture, it was cooled to 0° C. and 6.99 of powdered potassium carbonate was added. was added little by little within 5 hours. After a total reaction time of 79 hours at 0° C., the solvent was removed by distillation in a water pump vacuum, the residue was taken up in methylene chloride and the solution was washed with water, separated and dried. After concentration, the product was chromatographed on a column containing silica gel using methylene chloride F as the mobile phase and the main fraction was recrystallized from methanol. 9F pure 4-methyl-6-(3-(1-naphthylmethoxy)phenylthiomethyl]-2-pyrone was obtained. Melting point 139°C.

This compound a59 was heated at 75° C. with 2-aminopyridine of 509, and 89F hydroxylamine hydrochloride was added portionwise 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 six times with water and dried, and the solvent was removed by distillation.

The residue was recrystallized from ethyl acetate to give 49 hydroxypyridone. Melting point: 163°C.

56: Reaction of pyrone C (see Example 35) with 4-chlorobenzyl chloride and remaining steps as in Example 65 gave compound 42.

37: 1-hydroxy-4-methyl-6-[4-(
4-chlorophenoxy)phenoxymethyl]-2-pyridone 171.49 (0.5 mol) of 4-methyl-6-C4-<4-chlorophenoxy)phenoxymethyl]-2-pyridone in 50 mQ of toluene to 80 "CK heating. Then 59.9jl ([1,36 mol) of hydroxylammonium sulfate and 3a3jl ([
36 mol) of sodium carbonate was added. After 10 minutes, K separated (7) 59.99 (0.36 mol) of hydroxylammonium sulfate and 3a39 (0.36 mol).
36 mol) of sodium carbonate was added. After about 4 hours, the heat was removed and 500 mff1 of methylene chloride was added at about 40°C. The dissolved reaction product was then removed from the insoluble salts. Next, the P solution was dried with sodium sulfate, and the methylene chloride was evaporated. 5o of residue
otI11! The mixture was stirred with ethyl acetate to crystallize a reaction product. For final purification, 1-hydroxy-4
-Methyl-6-[4-(4-chlorophenoxy)phenoxymethyl]-2-pyridone was recrystallized from dimethylformamide.

Yield 815F (45 inches); Melting point 168-170"C63
8: 1-hydroxy-4-methyl-6-[3-(2-
phenoxyethoxy) phenoxymethyl]-2-pyridone (compound 45) 6-chloromethyl-4-methyl-2-pyrone of 809,
A mixture of 2209 resorcinol, 400 mff1 dimethylformamide and 105j1 micronized potassium carbonate was stirred at room temperature for 72 hours.

Methylene chloride was then 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 C223p) was triturated with water and recrystallized from methanol and 539 6-(3-hydroxyphenoxymethyl)-4-methyl-2-pyrone (compound D) was isolated. Melting point 145℃
.

The compound of 10j+ is 1 t2jl of 1-iodo-2-
Phenoxyethane (SOO 2-phenoxyethanol)
(produced by reacting with β2 and replacing chlorine with iodine using sodium iodide in acetone)
, 6.99 m potassium carbonate and 50 me dimethylformamide at 50°C for 35 h, methylene chloride was added, the solution was washed several times with water, dried and chromatographed on silica gel. The main product isolated was 4-methyl-6-[3-
(2-phenoxyethoxy)phenoxymethyl]-2-
It was Piron. Melting point: 95°C. 50 of this piron 109
2 with the 2-aminopyridine at 75° C. for 63 hours, during which time the hydroxylamine hydrochloride of a5F was added in portions, the residue was taken up in methylene chloride, and the solution was dissolved in dilute hydrochloric acid (in the aqueous phase).

3-4) and drying, the solvent was removed by distillation and the residue was crystallized from acetonitrile. 4.39 of pure hydroxypyridone was obtained. Melting point: 148°C.

39 and 40: Compound 4 in the same manner as Example 38
8 is an intermediate and 1-(4-di-tetraphenylthio)-
obtained starting from 4-iodobutane, compound 49 is D
and 2-(4-chlorophenylthio)ethyl 2'-iodoethyl ether.

41: 6-[3-(4-chlorophenylthiopropylthio)phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone (compound 47) 12.6F monothioresorcinol, 31.3F 1
-(4-10lophenylthio)-3-iodopropane (
prepared by reacting 4-chlorothiophenol with 1-bromo-3-chloropronophenol and replacing chlorine with iodine using sodium iodide in acetone), 16.69 mQ of potassium carbonate and 60 mQ of acetone. The mixture was stirred at room temperature for 24 hours, the solvent was removed by vacuum distillation, and methylene chloride was added.

The solution was washed several times with water, dried and 1.5j of 3-(4-chlorophenylthiopropylthio)phenol was isolated by chromatography on silica gel using methylene chloride as the mobile phase. This product was converted into 959 6-chloromethyl-4-methyl-2-pyrone.

After stirring for 31 hours at 50° C. with 1a42 of potassium carbonate and 60 m(L) of acetone, the solvent was removed by distillation under reduced pressure, the residue was taken up in methylene chloride and the solution was washed several times with water.

It was dried and chromatographed on silica gel. The main fraction of 1t29 was heated with 50g of 2-aminopyridine at 75°C for 65 hours to give a total of 129
of hydroxylamine hydrochloride was added in several 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 remained at 9.9 pm. This was treated with methanol to give 2.79 pure hydroxypyridone. Melting point: 102°C.

42 and 45: In the same reaction sequence and under the same conditions as above, compound 51 was reacted with monothioresorcinol and 1
-(4-chlorophenylthio)-2,2-dimethyl-3
Compound 53 was obtained starting from monothioresorcinol and (4-chlorophenylthio)ethoxyethoxyethyl iodide.

Investigation of activity In in vitro investigations of antifungal substances, it is necessary to distinguish between action on proliferating microorganisms (bacteriostatic action) and action on stationary microorganisms (fungicidal activity).

Fungicidal activity tested on non-growing fungi classifies as a relatively reliable model.

This includes a dilution series of the product to be tested prepared in microtiter plates (31, 25-D, 251t9/
mQ; 8 stages) is required. Each U-shaped well on the plate contains 104 colony forming units (OFU) of the skin mana, Trichophyton mentagrophytes (Trick).
(vehicle: physiological NaOβ solution). After incubation for 18 hours at 30"C, the microorganisms were washed with 50% polyethylene glycol 400 and NaCA solution, centrifuged twice) and streaked onto malt agar plates using an automated device to determine the number of microorganisms. After 3 days of incubation at 60°C, colonies are counted and their OFU/mff1 is calculated. The reduction factor in the number of microorganisms is determined by comparison with the untreated control (control - 0%). The formulation is measured by IJ Mazole, which is a common name for a compound having the following formula:

As is clear from Figure 1 below, the compound of the present invention showed a significantly lower number of OFU than the standard preparation clotrimazole. Thus, the fungicidal or lethal effect of the compounds according to the invention is significantly greater than that of the standard agents.

Table 1 15 1 99.32 17 15 98.98 Clotrimazole 63,6 57
Untreated control 147.9 0 n - Number of measurements i - Mean value 68 - As an example of the high in vivo activity of topical compounds according to the invention, laboratory animals experimentally infected with Trichophyton mentagrophytes were Detail the results of the treatment. This requires 2 or 4 guinea pigs (Pilbride White breed) each weighing 450-5009 kg, in each case.

1,5 x 104 cells distributed to 6 infection points on each epidermis.
Individualispores/animals were infected. The animals were treated 3 and 4 days before the infection by applying a solution of the product at a concentration of αδ on the three 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 = 69- (infected control).

As is clear from Table 2, the compound according to the invention has a significantly larger mycosis diameter (
(days). The antifungal effect of the compounds according to the invention was thus undoubtedly superior to that of Clo) IJ mazole.

Claims (1)

[Claims] 1) Formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I [In the formula, R^1, R^2 and R^3 are the same or different, and hydrogen or 1 represents lower alkyl having ~4 carbon atoms, R^1 and R^2 are preferably hydrogen, R^2 is preferably methyl, X represents S or preferably O, and Y is represents hydrogen or up to two halogen atoms, i.e. chlorine and/or bromine, Z is a single bond or a divalent group O, S, -CR_2-(R-H or C_1-C_4-alkyl) or 2-10 represents two or more carbon atoms and optionally other divalent radicals with oxygen and/or sulfur atoms bonded to form a chain, in which case the radical represents two or more oxygen and/or sulfur atoms. When containing atoms, these atoms must be separated by at least two carbon atoms and two adjacent carbon atoms are also connected by a double bond and the free valence of the carbon atom is H and/or C_1-C_4-alkyl groups, Ar having up to two rings and containing fluorine, chlorine, bromine, methoxy, C_1-C_4-alkyl, trifluoromethyl and trifluorocarbons. 1-Hydroxy-2-pyridone represents an aromatic ring system which can be substituted by up to three groups selected from the group consisting of fluoromethoxy. 2) The compound according to claim 1, wherein Ar represents an optionally substituted phenyl ring. 3) Compounds according to claim 1, wherein Ar represents an isolated bicyclic system, preferably derived from biphenyl, diphenylalkane or diphenyl ether and optionally substituted. 4) The compound according to one or more of claims 1 to 3, wherein Z is a single bond. 5) Compounds according to one or more 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 formula I, R^1, R^3 and Y are H and R^2 is CH_3, X is O, and Z is XC
O in the 4-position relative to the H_2 group and Ar is ▲
The compound according to claim 1, which has a mathematical formula, a chemical formula, a table, etc. 7) 6-(4-biphenyloxymethyl)-1-hydroxy-4-methyl-2-pyridone, i.e. in formula I, R^1, R^3 and Y are H and R^2 is CH_
3, X is O, Z is a single bond, and Ar
2. A compound according to claim 1, wherein is C_6H_5 in the 4-position relative to the XCH_2 group. 8) 1-hydroxy-4-methyl-6-[4-(4-trifluoromethylphenoxy)phenoxymethyl]-2
- pyridone, i.e., in formula I, R^1, R^3 and Y are H, R^2 is CH_3, X is O, Z is O in the 4-position relative to the XCH_2 group, and The compound according to claim 1, wherein Ar is ▲a mathematical formula, a chemical formula, a table, etc.▼. 9) Formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I [In the formula, R^1, R^2 and R^3 are the same or different, and hydrogen or 1 to 4 carbon atoms R^1 and R^2 are preferably hydrogen, R^2 is preferably methyl, X represents S or preferably O, and Y represents hydrogen or up to 2 represents a halogen atom, i.e. chlorine and/or bromine, Z represents a single bond or a divalent group O, S, -CR_2- (R=H or C_1-C_4-alkyl) or 2 to 10 carbons and stands for other divalent radicals having oxygen and/or sulfur atoms linked to form a chain, in which case the radical contains two or more oxygen and/or sulfur atoms;
or) if it contains sulfur atoms, these atoms must be separated by at least two carbon atoms, and two adjacent carbon atoms are also bound by a double bond and the free The valence is H and/
or C_1-C_4-alkyl groups, Ar having up to two rings and fluorine, chlorine, bromine, methoxy, C_1-C_4-alkyl, trifluoromethyl and trifluoro represents an aromatic ring system which may be substituted by up to three groups selected from the group consisting of methoxy. a) Formula III ▲ Numerical formula, chemical formula, table etc. ▼III (wherein R^1, R^2 and R^3 have the above definitions and Hal represents a halogen atom, especially chlorine or bromine), by the formula IV ▲Mathematical formulas, chemical formulas, tables, etc.▼IV (In the formula, X, Y, Z and Ar have the above definitions)
React with phenol or thiophenol of formula V to obtain formula V ▲Mathematical formulas, chemical formulas, tables, etc.▼Is aryloxymethylpyrone or arylthiomethylpyrone of V converted to hydroxypyridone of formula I by the action of hydroxylamine? or b) Formula IV ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Dihalogenopicoline of formula IV (wherein R^1, R^2, R^3 and Hal have the above definitions) with phenol of formula IV reacting, oxidizing the compound obtained to obtain the N-oxide and converting the compound into a compound of formula I by hydrolysis of the halogen on its nucleus or with the radicals R^1, R^2, R^3 and other substituents according to the definition of substituents for Ar in the compound obtained by operation a) or b), or
or a process for the preparation of compounds of formula I, which comprises introducing the reactive group into an intermediate which still contains the reactive group in the pyridone ring by substitution. 10) As an alternative to a), aryloxymethylpyrones or arylthiomethylpyrones of formula V have the formula I
with at least about 1 mole of hydroxyammonium salt per mole of compound of formula V in the presence of at least about 1 equivalent of at least one organic or inorganic base relative to the salt. The method according to claim 9, which is carried out by. 11) Claim 1, wherein the base used is a carbonate and/or bicarbonate of an alkali metal, preferably sodium and/or potassium, in particular Na_2CO_3
The method described in item 0. 12) The method according to claim 11, wherein the hydroxylammonium salt used is hydroxylammonium sulfate. 13) Compounds according to one or more of claims 1 to 8 or compounds obtained according to one or more of claims 9 to 12 for pharmaceutical use and/or a physiologically acceptable salt of at least one compound of this type with an inorganic or organic base. 14) At least one compound according to one or more of claims 1 to 8 or obtained from one or more of claims 9 to 12 Formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I [In the formula, R^1, R^2 and R^3 are the same or different and have hydrogen or 1 to 4 carbon atoms represents lower alkyl, R^1 and R^2 are preferably hydrogen, R^2 is preferably methyl, X represents S or preferably 0, Y represents hydrogen or up to 2 halogen atoms , i.e. chlorine and/or bromine, Z is a single bond or a divalent group O, S, -CR_2 (R=H or C_1-C_4-alkyl) or 2 to 10 carbons and optionally a chain represents other divalent radicals having oxygen and/or sulfur atoms combined to form, if the radical contains two or more oxygen and/or sulfur atoms; These atoms must be separated by at least two carbon atoms and two adjacent carbon atoms are also connected by a double bond and the free valence of the carbon atom is H and/or C_1-C_4-alkyl. Ar can have up to two rings and be selected from the group consisting of fluorine, chlorine, bromine, methoxy, C_1-C_4-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 A medicament containing an effective amount of a 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 as an antifungal agent, particularly against pathogenic skin rot fungi and mucosal fungi. 16) Compounds according to one or more of claims 1 to 8 or claims 9 to 1
At least one formula obtained by one or more of the following two terms I ▲ May be a mathematical formula, chemical formula, table, etc. ▼ I [In the formula, R^1, R^2 and R^3 are the same or R^1 and R^2, which are different and represent hydrogen or lower alkyl having 1 to 4 carbon atoms, are preferably hydrogen and R^2 is preferably methyl. X represents S or preferably O, Y represents hydrogen or up to two halogen atoms, i.e. chlorine and/or bromine, Z represents a single bond or a divalent group O, S, -OR_2-(R= H or C_1-C_4-alkyl) or other divalent radicals having 2 to 10 carbons and optionally oxygen and/or sulfur atoms bonded to form a chain, in which case the radicals When containing two or more oxygen and/or sulfur atoms, these atoms must be separated by at least two carbon atoms and two adjacent carbon atoms must also be separated by a double bond. bonded and the free valency of the carbon atom can be saturated by H and/or C_1-C_4-alkyl groups, Ar having up to 2 rings and containing fluorine, chlorine, bromine, methoxy , C_1-C_4-alkyl, trifluoromethyl and trifluoromethoxy. converting the physiologically acceptable salts of at least one of the above-mentioned compounds with an inorganic or organic base into a suitable formulation with a physiologically acceptable vehicle and, if appropriate, further additives and/or auxiliaries; A method for producing a medicament according to claim 14 or 15, comprising: 17) Formula V ▲There are mathematical formulas, chemical formulas, tables, etc.▼V (In the formula, R^1, R^2, R^3, X, Y, and Ar have the definitions described in claim 1) A compound represented by 18) Formula III ▲There are mathematical formulas, chemical formulas, tables, etc.▼III (In the formula, R^1, R^2 and R^3 have the definitions in claim 1 and Hal is a halogen atom, especially 6-halogenomethyl-2 (representing chlorine or bromine)
- Reacting pyrone with phenol or thiophenol of formula IV ▲ Numerical formula, chemical formula, table, etc. ▼ IV (wherein X, Y, Z and Ar have the definitions in claim 1) Formula V consisting of ▲There are mathematical formulas, chemical formulas, tables, etc.▼V Method for producing the compound represented by.