OA11028A - Use of 1-hydroxy-2-pyridones for the treatment of seborrheic dermatitis - Google Patents

Abstract

Compounds of the formula (I) are suitable for the production of pharmaceuticals to treat seborrheic dermatitis.

Description

011028 - 1 -

Use of 1-hydroxy-2-pyridones for the treatment of seborrheic dermatitis

Seborrheic dermatitis is a disorder of the scalp which distinguishes itself from simple dandruff by the presence of erythema as a sign of inflammation, by the more pronounced degree of desquamation with occasional itching and burning sensations, as well as by the appearance of eczematous alterations of other parts of the body. It may appear as stains, but more frequently also attacks the entire scalp and often involves, beyond it, the forehead, around the neck and ears. In serious cases, the scalp may be the site of secondary infections, and the alterations may then show a spongy consistency, form blisters and scabs, and ooze.

Seborrheic dermatitis frequently occurs in infants and usually disappears spontaneously at 8-12 months of age. Denture alterations, consisting of erythema, desquamation and sometimes formation of blisters and crusts, in infants may spontaneously resolve within a few weeks, recur intermittently, or persist throughout childhood. They are frequently associated with a similar process around the eyelids, nose and ears. Later, the disease appears habitually after puberty and may persist during all life or even increase. About 1-3% of the population is affected by this disease.

It is known that 1-hydroxy-2-pyridones and their salts exhibit activity against ordinary films, which are characterized by clinically non-inflammatory desquamation of the scalp - occurring almost in all individuals (DE-22 34,009).

The most promising type of treatment for seborrheic dermatitis has so far been the local application of corticosteroid-based compositions, but more recently local therapy with antimycotic-active substances has gained importance.

While corticosteroid-based compositionsdeploy their activity exclusively by acting on the inflammatory process, antimycotic substances, such as ketoconazole, are exclusively active on yeasts belonging to the genus Pityrosporum, considered as the causative agent of seborrheic dermatitis. However, the 1-hydroxy-2-pyridones according to the invention combine the properties of the two classes of substances into one and exhibit both an anti-inflammatory activity and an antimycotic activity against Pityrosporum layers.

The substances according to the invention rapidly accumulate, in comparison with ketoconazole - even after only a course of local contact time - in the skin layers affected by the growth of fungi and thus contribute to a rapid cure.

While ketoconazole is inactive in vitrocontaining Gram positive bacteria [Kinsman et al., J.Med. Microbiol. (1983) 16, No. 2, IV], the hydroxypyridones according to the invention show an activity against aerobic and anaerobic bacteria with Gram-positive and Gram-negative [Dittmar et al, Arzneim. Forschung (1981) 31 (II), No. 8a, p. 1317-1322], Considering the treatment of cases with secondary infections, this represents a discovery of extreme importance.

Compared with ketoconazole, the compounds used according to the invention also offer very strong advantages as regards their possibilities of in-corporation in pharmaceutical compositions. Due to their solubility in water, alcohols and aqueous alcoholic solutions, the preparation of capillary lotions and compositions in the form of transparent gels is possible without difficulty.

The compositions according to the invention can also be used for the treatment of pityriasis ver-sicolor, a non-inflammatory superficial dermatomycosis of the trunk.

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

in which 12 3 ... R, R and R, which are identical or different, represent a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, and4

R represents a saturated hydrocarbon radical having from 6 to 9 carbon atoms, or a radical of formula II

in which X is S or O, (II). Y represents a hydrogen atom or up to 2 halogen atoms, such as chlorine and / or bromine atoms, Z represents a single bond or O, S, -CR - (R) divalent radicals = H or (C1-C4) alkyl) or other divalent radicals having from 2 to 10 carbon atoms and optionally oxygen and / or sulfur connected in a chain - when the radials contain two or more atoms of oxy-gene and / or sulfur, the latter to be separated from each other by at least two carbon atoms - and two contiguous carbon atoms may also be connected to each other by a doublelaison, and the free valences of the carbon atoms being saturated with H and / or C 1 -C 4 alkyl groups

Ar represents an aromatic ring system having up to two rings, which can carry up to three substituents selected from fluorine atoms, from. chlorine, bromine and methoxy, C1-C4alkyl, trifluoromethyl and trifluoromethoxy groups, in free form or in salt form, for the manufacture of a medicament for the treatment of dermatitisereborrheic.

In the "Z" radicals, the carbon chain members are preferably CH 2 groups. When the CH 2 groups are substituted by C 1 -C 4 alkyl groups, the CH 3 and C 2 H 5 groups are the preferred substituents. Examples of radicals "Z" include : -O-, -S-, -CH2-, "(CH2) m- (rn = 2-10), -C (CH3) 2-, -CH2 <> -, - OCH2-, -CH2S-, - SCH2-, -SCH (C2H5) -, -CH = CH-CH2O-, -O-CH2-CH = CH-CH2O-, -OCH2-CH2O-, -OCH2-CH2CH2O-, - SCH2CH2CH2S-, -SCH2CH2CH2CH2O-, -SCH2CH2OCH2CH2O -, - SCH2CH2OCH2CH2O-CH2CH2S- or -S-CH2-C (CH3) 2-CH2-S-. 011028

The symbol "S" signifies the sulfur atom, the symbol "O" signifies the oxygen atom. The term "Ar" represents phenyl or fused systems, such as naphthyl, tetrahydronaphthyl and indenyl, as well as isolated systems such as those derived from biphenyl, diphenylalkanes, diphenyl ethers or diphenylthioethers. 4

In formula I, the hydrocarbon radical R is an alkyl or cyclohexyl radical, which may also be linked to the pyridone ring by a methylene or ethylene group, or may contain an endomethyl group. R may also be an aromatic ring which is, however, preferably linked to the pyridone ring by at least one aliphatic carbon atom. Important representatives of the class of compounds characterized by the formula I are the following: 6 - [4- (4-chlorophenoxy) phenoxymethyl] -1-hydroxy-4-methyl-2-pyridone, 6- [4- (2, 4-dichlorophenoxy) phenoxymethyl] -1-hydroxy-4-methyl-2-pyridone, 6- (biphenylyl-4-oxymethyl) -1-hydroxy-4-methyl-2-pyridone, 6- (4-benzylphenoxymethyl) -1 4-hydroxy-4-methyl-2-pyridone, 6- [4- (2,4-dichlorobenzyloxy) -phenoxymethyl] -1-hydroxy-4-methyl-2-pyridone, 6- [4- (4-chlorophenoxy) phenoxymethyl] -hydroxy-4-methyl-2-pyridone 1-hydroxy-3,4-dimethyl-2-pyridone, 6- [4- (2,4-dichlorobenzyl) 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-trifluoromethylphenoxy) phenoxymethyl] -2-pyridone, 1-hydroxy- 4-méthy1-6-cyclohexy1-2-pyridone, l-hydroxy-4-methyl-6- (2,4,4-trimethylpentyl) -2-pyridone, l-hydroxy-4-methyl-6-n-hexyl- , -6-isohexyl-, -6-n-heptyl-or -6-isoheptyl-2-pyridone, 1-hydroxy-4-methyl-6-octyl-o-6-isoo cetyl-2-pyridone, in particular 1-hydroxy-4-methyl-6-cyclohexylmethyl- or -6-cyclohexylethyl-2-pyridone, the cyclohexyl moiety may in each case also carry a methyl group, 1-hydroxy-4-methyl (2-Bicyclo [2.2.1] -heptyl) -2-pyridone, 1-hydroxy-3,4-dimethyl-6-benzyl- or -6-dimethylbenzyl-2-pyridone or 1-hydroxy-4 -methyl-6- (β-phenylethyl) -2-pyridone.

In this case, the term "saturated" refers to those radicals which do not contain aliphatic multiple bonds, i.e., no ethylenic or acetylenic bonds.

The aforementioned compounds of formula I can be used both in free form and in the form of desels; use in free form is preferred.

If organic bases are used, preferably low volatility bases are used, for example, low molecular weight alka-nolamines such as ethanolamine, diethanolamine, N-ethylethanolamine, N-methyldiethanolamine, triethanolamine, and the like. , diethylaminoethanol, 2-amino-2-methyl-n-propanol, dimethylamino-propanol, 2-amino-2-methylpropanediol, tri-isopropanolamine. Other low volatility bases that may be mentioned include, for example, ethylenediamine, hexamethylenediamine, morpholine, piperidine, piperazine, acyclohexylamine, tributylamine, dodecylamine, N, N-dimethyldodecylamine, stearylamine and oleylamine. benzylamine, dibenzylamine, N-ethylbenzylamine, dimethylstearylamine, N-methylmorpholine, N-methylpiperazine, 4-methylcyclohexylamine, N-hydroxyethylmorpholine. It is also possible to use quaternary ammonium hydroxide salts, such as trimethylbenzylammonium hydroxide, tetramethylammonium hydroxide or tetraethylammonium hydroxide, as well as guanidine and its derivatives, in particular its products. alkylation. However, it is also possible to use as salifying agents, for example, lower alkylamines such as methylamine, ethylamine or triethylamine. It is also contemplated for the compounds to be used according to the invention of salts with inorganic cations, for example alkaline alkalis, in particular sodium, potassium or ammonium salts, alkaline earth salts such as especially the calcium or magnesium salt, as well as salts with di- to tetravalent cations, for example the zinc, aluminum or zirconium salt.

The active compounds of the compound of formula I for use in the compositions may be prepared, for example, according to the process of US-A-2 540 218.

For the use according to the invention of said compounds, liquid-to-semi-solid pharmaceutical compositions are considered, in particular capillary lotions, shampoos, liquid soaps, as well as compositions in the form of creams, ointments and creams. gels.

In this case, it is always a question of compositions which, according to their own purpose of use, are applied for a longer or shorter time on the skin and / or on the leatherback. Thanks to the addition of the compounds according to the invention, an effective treatment of dermatitisereborrheic is achieved.

If the compositions according to the invention are in the form of shampoo, they can be liquid and translucent, liquid and opaque, in the form of creams or gels. The surfactants at the base of these shampoos may be of anionic, cationic, nonionic or amphoteric nature and may also be associated with such substances.

However, anionic surfactants are preferably used alone or in admixture with other anionic surfactants as base surfactants, optionally with the addition of amphoteric surfactants as co-surfactants.

The amphoteric surfactants are practically without importance as cleansing substances alone, since they are only average with regard to their foaming behavior, their thickening power and, partly, their tolerance by the skin and the mucous membranes of the eyes. . In combination with various anionic surfactants, however, these properties are, however, improved by a synergistic effect. This explains the relatively high importance of amphoteric surfactants for the optimization of shampoo compositions bases.

Nonionic surfactants can also be used as co-surfactants.

As examples of such anionic washing substances, mention may be made of: alkyl- and alkylene (C 10 -C 20) -carboxylates, alkyl ether carboxylates, sulphates of fatty alcohols, ether-sulphates of fatty alcohols, alkylolamide sulphates and sulphonates, alkylolamide polyglycol ether sulphates of fatty acids, alkanesulphonates and hydroxyalkane sulfonates, olefin sulfonates, iso-thionate acyl esters, α-sulfonated fatty acid esters, alkylbenzenesulfonates, alkylphenolglycolethersulfonates, sulfosuccinates, sulfosuccinic acid half esters and diesters, fatty alcohol ether phosphates , Protein and fatty acid condensation products, alkyl monoglyceride sulphates and sulphonates, alkyl glyceride ether sulphonates, fatty acid methyl taurides, fatty acid sarcosinates or sul-foricinoleates. These compounds and mixtures thereof are used in the form of their salts which are soluble in water or dissolvable in water, for example sodium, potassium, magnesium, ammonium, mono-, di- and triethanolammonium salts. as well as analogous alkylammonium salts.

Examples of amphoteric surfactants which can be added for shampoos are N- [C12-C18) alkyl-β-aminopropionates and N- [(C₁₂-C₁ g)) alkyl] -3-iminodipropionates in the form of alkaline salts and mono-, di- and trialkylolammonium; N-acyl-amidoalkyl-N, N-dimethylacetobetaine, preferably N-acyl (CQ-C₁)) amidopropyl-N, N-dimethylacetobetaine; a (C12-C18) alkyl dimethylsulfopropylbetaine; amphoteric surfactants based on imidazoline (trade name: Miranol, Stemapon), preferably the sodium salt of 1- (β-carboxymethyloxyethyl) -1- (carboxymethyl) -2-laurylimidazolinium; aminoxides, for example an alkyl- (C 12 -C 18) dimethyl amine oxide or a fatty acid amidoalkyldimethyl aminoxide.

Nonionic surfactants which may be used as washing substances are, for example,: oxyethylation products of fatty alcohols (alkylpolyethylene glycols); alkyl phenol polyethylene glycols; alkylmercaptanpolyethylene glycols; oxyethylation products of fatty amines (alkylaminopolyethylene glycols); fatty acid oxyethylation products (acyl polyethylene glycols), polypropylene glycol oxyethylation products (Pluronic®); fatty acid alkylolamides (polyethylene glycols of amidesgras); sucrose esters; alkylpolyglucosides, sorbitol esters and polyglycol ethers.

Suitable cationic surfactants are, for example, quaternary ammonium salts such as di (C 1 -C 4) alkyl dimethyl ammonium chloride or bromide, preferably a di [C 12 -C 18 alkyl] dimethyl ammonium chloride or bromide; (C1-C24) -dimethylethylammonium chloride or bromide; an alkyl- (C1-C24) trimethylammonium chloride or bromide, preferably cetyltrimethylammonium chloride or bromide, and a (C2-C22) trimethylammonium chloride or bromide; a (C 10 -C 24) alkyl dimethyl benzyl ammonium chloride or bromide, preferably a (C 12 -C 18) alkyl dimethyl benzyl ammonium chloride, or a N-alkyl (C 1 -C 4) pyridinium chloride or bromide, preferably a chloride or bromide; N-alkyl (CL-C4) pyridinium; N-alkyl (C1Q-C18) isoquinolinium chloride, bromide or monoalkylsulphate; N- [alkyl- (C12-C18)) colaminoformylmethyl] pyridinium chloride; N-alkyl (C12-C18) -N-methyl-morpholiniura chloride, bromide or monoalkylsulphate, N-alkyl (C12-C18) -N-ethylmorpholinium chloride, bromide or monoalkylsulphate; an alkyl- (C16-C18) pentaoxethylammonium chloride; diisobutyl-phenoxyethoxyethyldimethylbenzylammonium chloride; salts of Ν, Ν-diethylaminoethylstearylamide and -oleylamide with hydrochloric acid, acetic acid, lactic acid, citric acid, phosphoric acid: N-acylamidoethyl-N-chloride, bromide or monoalkylsulphate, N-diethyl-N-methylammonium and an N-acylamidoethyl-N, N-diethyl-N-benzylammonium chloride, bromide or monoalkyl sulphate, the acyl radical preferably representing the stearyl or oleyl radical.

The compositions according to the invention may contain, in addition to other additives, for example perfumes, dyes, opacity agents and pearlescent agents, for example esters of fatty acids and of polyols, magnesium and zinc salts of acids. copolymers, thickeners such as sodium chloride, potassium chloride, ammonium chloride, desodium sulfate, fatty acid alkylolamides, cellulose derivatives, natural gums, hydrolysates of col- lagene, as well as fats, oils, fatty alcohols, silicones, substances with keratolytic or keratoplastic effects, for example sulfur, salicylic acid or enzymes.

The preparation of the shampoos performs in a manner known per se, by bringing together the individual components and - if necessary - a suitable transformation autype respective composition. Some of these multiple possible compositions are described by way of examples in the exemplary embodiments.

The compositions according to the invention may also be in the form of aqueous or aqueous-alcoholic hair lotions, also those in the form of gel and in aerosol form, as foam or aerosol composition. As alcohol, ethanol and isopropyl alcohol are preferably used.

Other compositions in which the 1-hydroxy-2-pyridones can be used according to the invention include, for example, compositions in the form of creams and ointments, which products are used primarily for the treatment of parts without body hair and head.

The preparation of all these compositions is also carried out - as already mentioned for shampooing - in a manner known per se, with the addition of the active ingredient used according to the invention. The compositions according to the invention may contain one of the 1-hydroxy-2-pyridones mentioned above or several thereof in combination.

The pH of the compositions is in the physiological range of the skin of about pH 4.5 to 6.5. While in the case of the use of the compounds in the form of desels, the adjustment of said pH interval must be carried out with organic acids, this provision is not necessary when using the free compounds.

In the compositions according to the invention, the active substance is incorporated in proportions which are usually between 0.05 and about 10%. In this range, the concentrations of the particular compositions depend on their purpose of use. Certain forms of compositions, such as concentrates, which may be diluted prior to use, may have much higher concentrations. In the case of compositions which remain on the skin and on the scalp, for example compositions in the form of gels, ointments, creams or ciliary lotions, lower concentrations of, for example, about 0.05 are used. % to about 1%, preferably 0.1 to 0.5%. They are suitably used at higher concentrations when it comes to compositions which, possibly after dilution, act only briefly on the scalp, for example shampoos or liquid soaps. In these cases, for example, con-centrations of from about 0.2 to about 10%, preferably from about 0.5 to about 2%, are suitable.

The quantitative data below are for weight unless otherwise indicated.

Example 1

A preparation according to the invention has the following composition:

Shampoo (based on anionic washing substances) 1-hydroxy-4-methyl-6-cyclohexyl-2 (1H) pyridone 1.00%

Sodium lauryl diglycol ether sulphate (27% solution) 40.00%

Disodium Laurylpolyglycolethersulfosuccinate (33% solution) 10.00%

Sodium chloride 2.50%

Water 46.50%

Example 2

A preparation according to the invention has the following composition:

Shampoo (based on anionic washing substance with an amphoteric surfactant as co-surfactant) 1-hydroxy-4-methyl-6-cyclohex-1-yl (1H) pyridone 1.00%

Sodium lauryldiglycolethersulfate (27% solution) 36.00%

Cocosamidopropylbetaine (30% solution) 6,00%

Sodium chloride 3.30%

Water 53.70% 011028 - 13

Example 3

A preparation according to the invention has the following composition:

Shampoo (based on anionic washing substance with a nonionic surfactant as co-surfactant) 1-hydroxy-4-methyl-6-cyclohexyl-2 (1H) pyridone 1.50%

Sodium lauryldiglycolethersulfate (27% solution) 30.00%

Polyglucoside of lauryl alcohol 8.00%

Sodium Chloride 2.00%

Water 58.50%

Example 4

A preparation according to the invention has the following composition:

Liquid soap 1-hydroxy-4-methyl-6-cyclohexyl-2 (1H) pyridone 1.00%

Sodium lauryldiglycolethersulfate (27% solution) 35.00%

Cocosamidopolyglycol magnesium ether sulfate (30% solution) 8.00%

Cocosamidopropylbetaine (30% solution) 10.00%

Glycolic Ethanol of Lauryl Alcohol 2.00%

Sodium Chloride 2.00%

Water 42.00%

Example 5

A preparation according to the invention has the following composition:

Hair lotion 1-hydroxy-4-methyl-6- [4- (4-chlorophenoxy) phenoxymethyl] -2- (1H) pyridone 0.05% 2- propanol 60.00%

Water 39.95% 14 011028

Example 6

A preparation according to the invention has the following composition:

Composition in the form of 1-hydroxy-4-methyl-cyclohexyl-2 (1H) pyridone gel 0.75% 2-propanol 15.00% 2-octyldodecanol 7.50%

Carbomer 4,000,000 0.50%

Polysorbate 60 1.50%

Sodium hydroxide 0.18%

Water 74.57%

Example 7

A preparation according to the invention has the following composition:

Composition in the form of cream 1-hydroxy-4-methyl-6-cyclohexyl-2 (1H) pyridone, aminoethanol salt 1: 1 1.00% 2-octyldodecanol 7.50% Paraffin oil 7.50% Stearyl alcohol 7.50% Cetyl alcohol 7.50% Polysorbate 60 3.00% Sorbitan monostearate 2.00% Lactic acid 90% 0.51% Water 63.49% Example 8

In a clinical study with 180 patients in total, it was shown that symptoms of seborrheal dermatitis of the scalp (severe desquamation, inflammation, pruritus) could be effectively treated within 4 weeks. by treatment 1-2 times a week with a 1% deciclopirox shampoo composition. 011028 15

Example 9

In a clinical study, a total of 180 patients with seborrheic dermatitis of the scalp, face and upper body were successfully treated within 4 weeks by application of a preparation. in the form of 0.77% ciclopirox gel.

Claims (9)

011028 - 16 - CLAIMS 1. Use of a 1-hydroxy-2-pyridone Formula I, Wherein R 3, R 3 and R 4, which are the same or different, represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R 4 represents a saturated hydrocarbon radical having 6 to 9 carbon atoms, or a radical of formula II Ιζχ, χΛ. (Π) · X-CFL, wherein X is S or O, Y is hydrogen or up to 2 halogen atoms, such as chlorine and / or bromine atoms, Z is a single bond or the divalent radicals O, S, -CR - (R "H or a C 1 -C 4 alkyl group) or other divalent radicals having from 2 to 10 carbon atoms and optionally oxygen and / or sulfur connected in a chain - when the radicals contain two or more oxygenic and / or sulfur atoms, the latter to be separated from each other by at least two carbon atoms - and two carbon atoms contiguous with 30 011028 -1? - Also be connected to each other by a doublelaison, and the free valences of the carbon atoms being saturated with H and / or by C ^ -C ^ alkyl groups, Ar represents an aromatic ring system withjusqu ' with two rings, which can carry up to three substituents selected from fluorine, chlorine, bromine and methoxy, C 1 -C 4 -alkyl, trifluoromethyl and trifluoromethoxy, for the manufacture of a medical shampoo containing at least one anionic surfactant cationic, nonionic or amphoteric, or a mixture of surfactants, and which has a pH in the physiological range of the skin, for the treatment of seborrheic dermatitis. 2. The use as claimed in claim 1, wherein the compound of formula I in which Ar represents a bicyclic system which is derived from biphenyl, diphenylalkane or diphenyl ether is used. 3. Use according to claim 1 or 2, characterized in that the compound of formula I contains in R4 a cyclohexyl radical. 4. Use according to one or more of revendi-cations 1 to 3, characterized in that the Formula compound I contains in position R4 an octyl radical of-mule -ch2-ch (ch3) -ch2-c (ch3 ) 3. 5. Use according to claim 1, character-ized in that 1-hydroxy-4-methyl-6- [4- (4-chlorophenoxy) phenoxymethyl] -2- (1H) pyridone, 1-hydroxy is used. 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 6, character-ized in that one uses as surfactant at least one anionic surfactant alone or in admixture with other anionic anionic surfactants and / or amphoteric surfactants. 7. Use according to claim 1, character-ized in that 1-hydroxy-2-pyridone of formula I &amp; a concentration of 0.2 to 10%. 8. Use according to claim 7, character-ized in that 1-hydroxy-2-pyridone of formula I is used at a concentration of 0.5 to 2%. 9. Use according to claim 1, characterized in that the medical shampoo has a pH of 4.5 to 6.5.