NO312492B1 - Use of 1-hydroxy-2-pyridones in the treatment of seborrheic ± dermatitis - Google Patents

Description

Seborrheic dermatitis is understood to be a disease of the scalp, which differs from normal dandruff by the presence of an erythema as a sign of the inflammation, the stronger dandruff formation with occasional itching and a burning effect, as well as by the presence of eczematous changes in other parts of the body. These can appear patchy, but often attack the entire scalp and often extend beyond the hairline, forehead, circularly around the neck and near the ears. In severe cases, the scalp can be identified secondarily, and the changes can then lead to a spongy consistency, formation of small blisters and crusting and wetting.

Seborrheic dermatitis often appears already in infancy and usually remits spontaneously between the ages of 8-12 months. The scalp changes in young children consisting of erythema, dandruff and occasionally blisters and crusts can spontaneously disappear again within a few weeks, appear intermittently or persist throughout childhood. They are often combined with a similar process around the eyelids, nose and ears. Later, the disorder usually occurs after puberty and can last a lifetime or increase in strength. Around 1-3% of the population is affected by this disease.

It is known that l-hydroxy-2-pyridones and their salts show effectiveness against common dandruff, which is characterized as clinically non-inflamed, occurring in almost all people, scaling of the scalp (DE 22 34 009).

The most promising treatment method of seborrheic dermatitis has hitherto been the topical administration of corticosteroid preparations, but in recent times, topical therapy with antifungal active substances has gained in importance.

While corticosteroid preparations exert their effectiveness exclusively over an influence on the inflammatory process, the antifungal substances such as ketoconazole are exclusively effective against the yeasts of the Pityrosporum strain that predispose to seborrheic dermatitis, the l-hydroxy-2-pyridones according to the present invention, on the other hand, combine the properties of both substance groups in a substance and exhibits both anti-inflammatory and antifungal effects against Pityrosporum strains.

The substances according to the present invention concentrate in comparison with ketoconazole, even after only a short topical contact time, quickly in the skin layers relevant for fungal growth and thus cause a faster slope.

While ketoconazole is inactive against gram-positive bacteria (Kinsman et al., J. Med. Microbiol (1983) 16, no. 2, IV), the hydroxypyridones of the present invention show activity against gram-positive and gram-negative aerobic and anaerobic bacteria (Dittmar et al., Arzneim.-Forschung, (1981) 31 (II), no. 8a, pp. 1317-1322). With regard to the treatment of secondary cases of infection, this is an extremely important diagnosis.

The compounds used according to the present invention have, compared to ketoconazole, further decisive advantages with regard to their processing possibilities in pharmaceutical preparations. Due to their solubility in water, alcohols and aqueous alcoholic solutions, the production of hair lotions and transparent gel preparations is possible without problem.

The preparations according to the present invention can also be used to treat pityriasis versicolor, a skin fungal disease of the trunk that is not inflamed on the surface.

The invention therefore relates to the use of 1-hydroxy-2-pyridones of the formula I,

where R 1 , R 2 and R 3 are the same or different, means hydrogen or alkyl of 1 to 4 carbon atoms, and

R 4 means a saturated hydrocarbon residue with 6 to 9 carbon atoms or a residue of the formula II

where

X means S or O,

Y means hydrogen or up to 2 halogen atoms such as chlorine and/or bromine,

Z means a single bond or the divalent residues O, S, -CR -

(R = H or (CrC4)-alkyl) or other divalent residues with 2-10 chain-linked C and optionally O and/or S atoms, where, when the residue contains 2 or more O and/or S atoms , the latter must be separated from each other by

at least 2 C atoms and where 2 neighboring C atoms can also be connected to each other with a double bond and the free valences of the C atoms are saturated

with H and/or (CrC4)-alkyl groups,

Ar means an aromatic ring system with up to two rings, which can be substituted with up to three residues from the group fluorine, chlorine, bromine, methoxy, (C1-C4)-alkyl, trifluoromethyl and trifluoromethoxy, in free form or in salt form,

for the production of a drug for the treatment of seborrheic dermatitis.

In the residues "Z", the C chain links are preferably CH2 groups. When the CH 2 groups are substituted with C 1 -C 4 alkyl groups, CH 3 and C 2 H 5 are preferred substituents. Examples of "Z" residues are: -O-, -S-, -CH2-, -C<H>2)m-(m = 2-10), -C(CH3)2-, -<C>H20 -, -OCH2-, -CH2S-, -SCH2-, -SCH(C2H5)-, -CH=CH-CH20-, -0-CH2-CH=CH-CH20-, -OCH2-CH20-, -OCH2- CH2CH20-, -SCH2CH2CH2S-, -SCH2CH2CH2CH20-, -SCH2CH2OCH2CH20-, -SCH2CH2OCH2CH20-CH2CH2S- or

-S-CH2-C(CH3)2-CH2-S-.

The residue "S" means a sulfur atom, the residue "O" means an oxygen atom. The term "Ar" means phenyl or fused systems such as naphthyl, tetrahydronaphthyl and indenyl, as well as isolated systems such as those derived from biphenyl, diphenylalkanes, diphenylethers and diphenylthioethers.

In the formula I, the hydrocarbon residue R<4> is an alkyl or cyclohexyl residue, where a methylene or ethylene group may also be attached to the pyridone ring or may contain an endomethyl group. R<4> can also represent an aromatic residue which, however, is preferably bonded via at least one aliphatic C atom to the pyridone residue.

Important representatives of the class of compounds characterized by the formula I are: 6-[4-(4-chloro-phenoxy)-phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, 6-[4-(2,4-dichloro -phenoxy)-phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, 6-(biphenylyl-4-oxy-methyl)-1-hydroxy-4-methyl-2-pyridone, 6-(4-benzyl- phenoxymethyl)-1 -hydroxy-4-methyl-2-pyridone, 6-[4-(2,4-dichlorobenzyloxy)-phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone, 6-[4-(4 -chloro-phenoxy)-phenoxymethyl]-1-hydroxy-3,4-dimethyl-2-pyridone, 6-[4-(2,4-dichloro-benzyl)-phenoxymethyl]-1-hydroxy-3,4-dimethyl -2-pyridone, 6-[4-(cinnamyloxy)-phenoxymethyl]-1 -hydroxy-4-methyl-2-pyridone, 1 -hydroxy-4-methyl-6-[4-(4-trifluoromethyl-phenoxy)- phenoxymethyl]-2-pyridone, 1-hydroxy-4-methyl-6-cyclohexyl-2-pyridone, 1-hydroxy-4-methyl-6-(2,4,4-trimethylphenyl)-2-pyridone, 1-hydroxy -4-methyl-6-n-hexyl-, -6-iso-hexyl-, -6-n-heptyl- or -6-iso-heptyl-2-pyridone, l-hydroxy-4-methyl-6-octyl - or -6-iso-octyl-2-pyridone, especially 1-hydroxy-4-methyl-6-cyclohexylmethyl- or -6-cyc lohexylethyl-2-pyridone, where the cyclohexyl residue can however also carry a methyl residue, l-hydroxy-4-methyl-6-(2-bicyclo[2,2,1]heptyl)-2-pyridone, l-hydroxy-3,4- dimethyl-6-benzyl- or -6-dimethylbenzyl-2-pyridone or 1-hydroxy-4-methyl-6-(B-phenyl-ethyl)-2-pyridone.

The term "saturated" here denotes such residues, which contain no aliphatic polyvalent bonds, i.e. no ethylene-like or acetylene-like bonds.

The above-mentioned compounds of the formula I can be used both in free form and also as salts, the use in free form being preferred.

If organic bases are used, heavy volatile bases are preferably used, for example low molecular weight alkanolamines such as ethanolamine, diethanolamine, N-ethylethanolamine, N-methyl-diethanolamine, triethanolamine, diethylamino-ethanol, 2-amino-2-methyl-n-propanol, diethylaminopropanol, 2-amino-2-methyl-propanediol, tri-isopropanolamine. As additional heavy volatile bases, for example, ethyleneamine, hexamethylenediamine, morpholine, piperidine, piperazine, cyclohexylamine, tributylamine, dodecylamine, N,N-dimethyldodecylamine, stearylamine, oleylamine, benzylamine, dibenzylamine, N-ethylbenzylamine, dimethylstearylamine, N-methylmorpholine can be mentioned , N-methylpiperazine, 4-methylcyclohexylamine, N-hydroxyethyl morpholine. Also the quaternary ammonium hydroxide salts such as trimethylbenzylammonium hydroxide, tetramethylammonium hydroxide or tetraethylammonium hydroxide can be used, further guanidine and its derivatives, especially its alkylation products. However, it is also possible to use as a salt former, e.g. low molecular weight alkylamines such as methylamine, ethylamine or triethylamine. Also salts with inorganic cations, for example alkali salts, especially sodium, potassium or ammonium salts, alkaline earth salts such as especially the magnesium or calcium salt, as well as salts with divalent to tetravalent cations, e.g. the zinc, aluminum or zirconium salt can be considered as a compound used in the present invention.

The active substances of the compound of formula I which can be used for the preparation can, for example, is produced from the method according to US patent 2,540,218.

For the administration according to the present invention of the aforementioned compounds, liquid to semi-solid pharmaceutical preparations come into consideration, especially hair lotions, shampoos, liquid soaps, as well as cream, ointment and gel preparations.

This is always about preparations, which are applied to the skin and/or the scalp for a shorter or longer time, depending on their intended purpose. By adding the compound according to the present invention, an effective treatment of seborrheic dermatitis is achieved.

Present preparation according to the present invention as a shampoo, then they can be clear liquid, opaque liquid, creamy or also gel-like. The surfactants that form the basis of these shampoos can be of anionic, cationic, non-ionic and amphoteric nature and can be present in a combination of these substances.

However, the use of anionic surfactants alone or in a mixture with other anionic surfactants as base surfactants, possibly with the addition of amphoteric surfactants as cosurfactants, is preferred.

Amphoteric surfactants are, as the only detergent-active substance, practically insignificant, as their foaming properties, thickening potential and partly also skin and eye mucus acceptability are limited. In combination with various anionic surfactants, precisely these properties are synergistically improved. This explains the relatively large importance of amphoteric surfactants for the optimization of anionic shampoo base substances.

Optionally, non-ionic surfactants can be used as co-surfactants.

Examples of such anionic detergent active substances can be mentioned:

(C10-C2o)-alkyl and alkylene carboxylates, alkyl ether carboxylates, fatty alcohol sulfates, fatty alcohol ether sulfates, alkylolamide sulfates and sulfonates, fatty acid alkylamide polyglycol ether sulfates, alkane sulfonates and hydroxyalkanesulfonates, olefin sulfonates, acyl esters of isothionates, α-sulfo fatty acid esters, alkyl benzosulfonates, alkylphenyl glycol ether sulfonates, sulfosuccinates, sulfoacetic acid half esters and -diesters, fatty alcohol ether phosphates, egg white fatty acid condensation products, alkyl monoglyceride sulphates and -sulphonates, alkyl glyceride ether sulphonates, fatty acid methyl taurides, fatty acid sarcosinates or sulphoricinoleates. These compounds and their mixtures are used in the form of their water-soluble or water-dispersible salts, for example sodium, potassium, magnesium, ammonium, mono-, di- and triethanolammonium as well as analogous alkylolammonium salts.

Examples of the amphoteric surfactants that can be added to the shampoos are: N-((Ci2-C18-alkyl)-B-aminopropionate and N-((C12-C18-alkyl)-B-iminodipropionate as alkali and mono-, di- and trialkylolammonium salts) , N-acylamidoalkyl-N,N-dimethyl-acetobetaine, preferably N-((C8-C! 8-acyl)-amidopropyl-N,N-dimethyl-acetobetaine; (C j 2-C x 8-)-alkyldimethyl- sulfopropyl betaine, amphoteric surfactants based on imidazoline (trade names: "Miranol", "Steinapon"), preferably the sodium salt of l-(6-carboxymethyloxyethyl)-l-(carboxymethyl)-2-lauryl-imidazolinium, amine oxide, for example ( C12-C18-)-alkyldimethylamine oxide or fatty acid amidoalkyldimethylamine oxide.

As non-ionic surfactants that can be used as detergent active substances, for example: fatty alcohol ethoxylates (alkyl polyethylene glycols), alkylphenol polyethylene glycols, alkyl mercaptan polyethylene glycols, fatty amine ethoxylates (alkylamine polyethylene glycols), fatty acid ethoxylates (acyl polyethylene glycols), polypropylene glycol ethoxylates ("Pluronic"), fatty acid alkyl amides ( fatty acid amide polyethylene glycols), sucrose esters, alkyl polyglucosides, sorbite esters and the polyglycol ether.

Suitable cationic surfactants are e.g. quaternary ammonium salts such as Di-((C10-C24)-alkyl)-dimethylammonium chloride or bromide, preferably Di-((C12-C18)-alkyl)-dimethylammonium chloride or bromide, (C10-C24 )-alkyldimethylethylammonium chloride or bromide, (C10-C24)-alkyltrimethylammonium chloride or bromide, preferably cetyltrimethylammonium chloride or bromide and (C20-C22)-alkyltrimethylammonium chloride or bromide, (C10-C24)-alkyldimethylbenzylammonium -chloride or -bromide, preferably (C:2-C18)-alkyldimethylbenzylammonium chloride, N-((C x0-C x 8)-alkyl)-pyridinium chloride or -bromide, preferably N-((C12-C16) -alkyl)pyridinium chloride eOr -bromide, N-((C10-C18)-alkyl)isoquinolinium chloride, -bromide or - monoalkyl sulfate, N-((C 12-Ci8)-alkylcolaminoformylmethyl)pyridinium chloride, N-( (C x2-C18)-alkyl)-N-methylformfolinium chloride, -bromide or -monoalkyl sulfate, N-((C12-C18)-alkyl)-N-ethylmorpholinium chloride, -bromide or -monoalkyl sulfate, (C16-C18 )-alkyl-pentaoxyethylammonium chloride, Di-isobutylphenoxyethoxyethyldimethylbenzy l-ammonium chloride, salts of N,N-diethylaminoethylstearyl-amides and -oleylamides with hydrochloric acid, acetic acid, lactic acid, citric acid, phosphoric acid, N-acyl-amidoethyl-N,N-diethyl-N-methyl-ammonium chloride, -bromide or - monoalkyl sulfate and N-acylamido-ethyl-N,N-diethyl-N-benzyl ammonium chloride, bromide or monoalkyl sulfate, where acyl preferably stands for stearyl or oleyl.

The preparation according to the present invention may also contain further additives, such as e.g. fragrances, dyes, turbidity agents and pearl gloss agents, for example esters of fatty acids and polyols, magnesium and zinc salts of fatty acids, dispersions of base mix polymers, thickeners such as sodium, potassium, ammonium chloride, sodium sulfate, fatty acid alkylolamide, cellulose derivatives, natural gums, collagen hydrolysates, further fats , oils, fatty alcohols, silicones, substances with keratolytic and keratoplastic effects, e.g. sulphur, salicylic acid or enzymes.

The production of the shampoos takes place in a generally known manner by combining the individual components and, when necessary, further processing adapted to the respective type of preparation. Some of these many possible preparations are, for example, described in the export examples.

The preparations according to the present invention can also be available in the form of aqueous or aqueous-alcoholic hair lotions, and such in gel form and in aerosol form such as spray or foam. Ethanol and isopropyl alcohol are preferably used as alcohol.

Further preparations in which the l-hydroxy-2-pyridones according to the present invention can be used can be mentioned, for example, cream and ointment preparations, products which are primarily used for the treatment of hairless head and body parts.

The production of all these preparations also takes place, as already mentioned with the shampoo, in an already known manner, with the addition of the active ingredient used according to the present invention. The preparations according to the present invention may contain one compound or several in combination of the above-mentioned 1-hydroxy-2-pyridones.

The pH value of the preparation is in the physiological skin range of around pH 4.5 to 6.5. While the setting of the mentioned pH range when using the compounds in salt form must be carried out with organic acids, this measure is not necessary when using free compounds.

In the preparations according to the present invention, the active ingredient will be incorporated in quantities usually between about 0.05 and about 10%. Within this range, the concentration depends on the particular preparation and its intended use. Certain preparation forms such as concentrates, which must be diluted before their use, can exhibit significantly higher concentrations.

If it concerns preparations, which remain on the skin and on the scalp, e.g. gel preparations, ointments, creams or hair lotions, then lower concentrations will be used, for example from about 0.05% to about 1%, preferably from 0.1 to 0.5%. In higher concentrations, they are usefully used when it comes to preparations which, if necessary, after dilution, only have a short-term effect on the scalp, for example shampoos or liquid soaps. In these cases, e.g. concentrations from about 0.2 to about 10%, preferably from 0.5%" to about 2% be expedient.

The subsequent quantities relate to the weight, as long as nothing else is noted.

Example 1

A preparation according to the present invention exhibits the following composition:

Shampoo

(on the basis of anionic detergent active substances)

Example 2

A preparation according to the present invention exhibits the following composition:

Shampoo

(on the basis of anionic detergent active substances with amphoteric surfactants as cosurfactants)

Example 3

A preparation according to the present invention exhibits the following composition:

Shampoo

(on the basis of anionic detergent active substances with non-ionic surfactant as co-surfactant)

Example 4

A preparation according to the present invention exhibits the following composition:

Liquid soap

Example 5

A preparation according to the present invention exhibits the following composition:

Hair water

Example 6

A preparation according to the present invention exhibits the following composition:

Gel preparation

Example 7

A preparation according to the present invention exhibits the following composition:

Cream preparation

Example 8

In a clinical study with a total of 180 patients, it could be shown that the symptoms of seborrheic dermatitis on the scalp (severe dandruff, inflammation, itching) could be effectively treated with 1 - 2 x weekly treatments with a 1% ciclopirox shampoo preparation over a period of 4 weeks.

Example 9

In a clinical study, a total of 180 patients with seborrheic dermatitis of the scalp, face and upper body could be successfully treated by administering a 0.77% ciclopirox gel preparation over a period of 4 weeks.

Claims (9)

1. The use of 1-hydroxy-2-pyridones of formula I, where R 1 , R 2 and R 3 are the same or different, means hydrogen or alkyl of 1 to 4 carbon atoms, and R<4>means a saturated hydrocarbon residue with 6 to 9 carbon atoms or a residue of the formula II where X means S or O, Y means hydrogen or up to 2 halogen atoms such as chlorine and/or bromine, Z means a single bond or the divalent residues O, S, -CR2-, where (R = H or (C,-C4)-alkyl), or other divalent residues with 2-10 chain-shaped connected C- and optionally O- and /or S atoms, where, when the residue contains 2 or more O and/or S atoms, the latter must be separated from each other by at least 2 C atoms and where 2 neighboring C atoms can also be connected to each other by a double bond and the free valences of the C atoms are saturated with H and/or (C1-C4)-alkyl groups, Ar means an aromatic ring system with up to two rings, which may be substituted with up to three residues from the group fluorine, chlorine, bromine, methoxy, (CrC4)-alkyl, trifluoromethyl and trifluoromethoxy, for the preparation of a medical shampoo, containing at least one anionic, cationic or nonionic or amphoteric surfactant or a mixture of surfactants and which has a pH value in the skin physiological range for the treatment of seborrheic dermatitis. 2. Use according to claim 1, where the compound of formula I is used, in which Ar represents a bicyclic system, which is derived from biphenyl, diphenylalkane or diphenylether. 3. Use according to claim 1 or 2, where the compound of formula I at position R<4> contains a cyclohexyl residue. 4. Use according to one or more of claims 1 to 3, where the compound of formula I at position R<4> contains an octyl residue of the formula -CH2-CH(CH3)-CH2-(C(CH3)3). 5. Use according to claim 1, where one uses 1-hydroxy-4-methyl-6-[4-(4-chlorophenoxy)-phenoxymethyl]-2-(1H)pyridone, 1-hydroxy-4-methyl-6-cyclohexyl -2-(1H)pyridone or 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2-(1H)pyridone. 6. Use according to claim 1, where as surfactant at least an anionic surfactant is used alone or in a mixture with other anionic surfactants and/or amphoteric surfactants. 7. Use according to claim 1, where the 1-hydroxy-2-pyridone of formula I is used in a concentration from 0.2% to 10. 8. Use according to claim 7, where the 1-hydroxy-2-pyridone of formula I is used in a concentration of from 0.5% to 2%. 9. Use according to claim 1, where the medical shampoo exhibits a pH value of about 4.5 to 6.5.