BG64365B1 - The application of 1-hydroxy-2-pyridons for the treatment of seborrheic dermatitis - Google Patents

Abstract

The invention relates to compounds suitable for the preparation of pharmaceutical preparations for the treatment of seborrheic dermatitis. They have the formula where their substituents have the meanings listed in the description.

Description

Technical field

The invention relates to the use of 1-hydroxy-2-pyridones for the treatment of seborrheic dermatitis.

BACKGROUND OF THE INVENTION

Seborrheic dermatitis refers to a disease of the scalp that differs from ordinary dandruff with erythema as a sign of inflammation, dandruff with occasional itching and burning, as well as having eczema changes elsewhere in the body. It can manifest as spots, but more often it covers the entire skin of the scalp and often extends from the base of the hair out to the forehead, around the neck and ears. In severe cases, the scalp may be re-infected and the changes may then show a spongy consistency, the formation of scabs and scabs and moisturizing.

Seborrheic dermatitis occurs as early as infant age and recurs spontaneously, usually at the age of 8 to 12 months. Changes in the scalp that occur in young children with erythema, dandruff, and sometimes blisters and scabs, can spontaneously re-emerge within a few weeks, with recurrence and persist throughout childhood. They are often combined with a similar process on the eyelids, nose and ears. Later, pubertal suffering usually occurs and may persist throughout life. And also to strengthen. About 1 to 3% of the population are affected by the disease.

1-Hydroxy-2-pyridones and their salts are known to exhibit activity against common dandruff, which is clinically characterized by the non-inflammatory skin scaling that occurs in all humans (DE 2234009).

The most promising way of treating seborrheic dermatitis so far is the topical administration of corticosteroid preparations, but before that topical therapy with antifungal agents becomes important.

While corticosteroid preparations exert their effect exclusively on influencing the inflammatory process, antifungal agents such as ketoconazole act exclusively against the yeast fungus from the Pityrosporum strain, which is the cause of seborrheic dermatitis. In contrast, the 1-hydroxy-2-pyridones of the invention combine the properties of the two groups of substances into one substance and exhibit both anti-inflammatory and antifungal activity against Pityrosporum strains.

The compounds of the invention accumulate rapidly in comparison with ketoconazole itself after a short time of topical contact in the growth layers of the fungus and thus contribute to rapid healing.

While in vitro ketoconazole is inactive against gram-positive bacteria (Kinsman et al., J.Med. Microbiol (1983) 16, No. 2, IV) the hydroxypyridones of the invention show activity against gram-positive and gram-negative aerobic and anaerobic bacteria ( Dittmar et al., Arzneim.-Forschung, (1981) 31 (II), No. 8a, S. 1317-1322). This treatment of secondarily infected cases is an extremely important finding.

Compounds according to the invention, in contrast to ketoconazole, also have very decisive advantages in terms of their ability to be processed into pharmaceutical forms. Based on their solubility in water, alcohols and water-alcohol solutions, it is possible to obtain hair water and clear gel forms without problems.

The formulations according to the invention can be used to treat Pityriasis versicolor, which is a superficial non-inflammatory fungal skin disease.

SUMMARY OF THE INVENTION

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

R2 | Rk ζ and I * 0 I 0n in which R ¹ , R ² and R ³ , which are the same

or different, denote hydrogen or alkyl of 1-4 carbon atoms and R ⁴ means a saturated hydrocarbon residue of 6 to 9 carbon atoms or a residue of formula

in which X is S or O,

Y means hydrogen or up to 2 halogen atoms such as chloro and / or bromo,

Z means a simple bond or a divalent moiety O, S, -CR ² - (R - H or (C ₍ -C ₄ ) alkyl)) or another divalent moiety having 2-10 ring 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 bonded to at least 2 C-atoms, and wherein 2 adjacent carbon atoms may also be bonded via double bond and the free valences of the C atoms are saturated with H and / or (C 1 -C ₄ ) alkyl group,

Ar means a ring aromatic system with up to two rings which can be substituted with up to three residues from the group fluoro, chloro, bromo, methoxy, (C 1 -C ₄ ) alkyl, trifluoromethyl and trifluoromethoxy, in free form or as a salt, for preparation of drugs for the topical treatment of skin infections caused by fungi and bacteria.

Residues "Z" are C-chain residues, preferably CH ₂ groups. When the CH ₂ groups are substituted by a C 1 -C ₄ alkyl group, CH ₃ and C ₂ H ₃ are preferred substituents. Examples of the remainder “Z” are:

-O-, - S-, -CH, -, - (CH ₂ ) _m , (m = 2-10), - C (CH ₃ ) '-CH, O-,

-OCH ₂ -, -CH ₂ S-, -SCH ₂ -, -SCHtCjH,) -, -CH-CH-CH ₂ O-, -O-CH, -CH-CH-CH, O-, -OCH, -CH, O-, -OCH, -01, -01,0-, -SCHjCHjCHjS-,

-SCH ₂ CH ₂ CH ₂ CH ₂ O-, -SCH ₂ CH ₂ OCH ₂ CH ₂ O-, -SCH ₂ CH ₂ OCH ₂ CH ₂ OCH ₂ CH ₂ S-, or -S-CH, C (CH ₃ ) ₂ -CH ₂ -S-.

The residue “S” means sulfur, the residue “O” means oxygen. The residue Ar represents a phenyl or fused system such as naphthyl, tetrahydronaphthyl and indenyl as well as an isolated system such as biphenyl, diphenylalkanes, diphenylethers and diphenylthioethers.

In formula (I), the hydrocarbon moiety R ⁴ means an alkyl or cyclohexyl moiety which is also bonded to a methylene or ethylene group with a pyridone ring or an endomethylene group. R ⁴ may also denote an aromatic moiety which is preferably attached to the pyridone ring through at least one carbon atom.

Important representatives of the compounds of formula (I) are:

6- [4- (4-chlorophenoxy) phenoxymethyl] -1 hydroxy-4-methyl-2-pyridone, 6- [4- (2,4-dichlorophenoxy) phenoxymethyl] -1-hydroxy-4-methyl2-pyridone, 6 - (biphenylyl-4-oxymethyl) -1-hydroxy-4-methyl-2-pyridone, 6- (4-benzylphenoxymethyl) -1-hydroxy-4-methyl-2-pyridone, 6- [4- (2, 4 -dichlorobenzyloxy) -phenoxymethyl] -1-hydroxy-4-methyl-2-pyridone, 6- [4- (4-chlorophenoxy) phenoxymethyl] -1-hydroxy-3,4-dimethyl-2-pyridone, 6- [4 - (2,4-dichlorobenzyl) phenoxymethyl] -1hydroxy-3,4-dimethyl-2-pyridone, 6- [4- (4-cinnamyloxy) phenoxymethyl] -1-hydroxy-4-methyl-2pyridone, 1-hydroxy- 4-methyl-6- [4- (trifluoromethyl-phenoxy) phenoxy methyl] -2-pyridone, 1-hydroxy-4-methyl-6-cyclohexyl-2-pyridone, 1-hydroxy-4-methyl-6- (2,4,4-trimethyl-phenyl) -2-pyridone, 1 -hydroxy-4-methyl-6-nor-hexyl-6-isohexyl-, -6-nor-heptyl- or -6-isoheptyl-2-pyridone, 1-hydroxy-4-methyl-6-octyl- or -6 -isooctyl-2-pyridone, in particular 1-hydroxy-4-methyl-6-cyclohexylmethyl- or -6-cyclohexylethyl-2-pyridone, wherein the cyclohexyl moiety may also carry a methyl moiety, 1-hydroxy-4- methyl- (2-bicyclo [2.2.1] heptyl) 2-pyridone, 1-hydroxy-3,4-dimethyl-6-benzylyl-6-dimethylbenzyl-2-pyridone or 1-hydroxy-4-methyl-6- ( β-phenylethyl) -2-pyri on.

The term "saturated" means here a residue which does not contain any aliphatic complex bonds, nor any ethylene or acetylene bonds.

The above compounds of formula (I) may exist in both free form and salt form, the use of the free form being preferred.

When organic bases are used, predominantly volatile bases are used, for example, low molecular weight alkanolamine such as ethanolamine, diethanolamine, N-ethylethanolamine, N-methyldiethanolamine, triethanolamine, diethylaminoethanol, 2-amino-2-methyl-n-propanol-propanol, -2-methylpropanediol, triisopropanolamine. Other volatile bases include, for example, ethylenediamine, hexamethylenediamine, morpholine, piperidine, piperazine, cyclohexylamine, tributylamine, dodecylamine, N, N-dimethyldodecylamine, stearylamine, oleylamine, benzylamine, dibenzylmethylamine, N-dimethylamine, N-dimethylamine, N-dimethylamine, N-dimethylamine methylpiperazine, 4-methylcyclohexylamine, N-hydroxy-ethylmorpholine. Quaternary ammonium hydroxide salts such as trimethylbenzylammonium hydroxide, tetramethylammonium hydroxide or tetraethylammonium hydroxide, in addition guanidine and its derivatives, in particular its alkylated products, may also be used. It is also possible to use, for example, a low molecular weight alkylamine such as methylamine, ethylamine or triethylamine as forming salts. For the compounds of the invention, salts with inorganic cations, for example alkali salts, in particular sodium, potassium or ammonium salts, alkaline earth salts, in particular magnesium or calcium salts, and salts of di-tetravalent cations, eg zinc, aluminum or aluminum, are also contemplated. zirconium salt.

The active compounds used in the formulations, the compounds of formula I, can be prepared, for example, by methods according to US 2 540 218.

For use in the present invention, known compounds include liquid to semi-solid pharmaceutical forms, in particular hair, shampoos, liquid soaps, as well as creams, ointments and gels.

These are always forms which, according to the actual purpose of application, are applied to the hair and / or scalp for a shorter or longer period of time. By adding the compounds of the present invention, effective treatment of seborrheic dermatitis is induced.

When the formulation according to the invention is shampoos, they may be clear liquids, opaque liquids, creams or also gels. The bases for these shampoos, surfactants can be anionic, cationic, nonionic and amphoteric and can be combinations of these substances.

Preferably, the anionic surfactants are used alone or in combination with other surfactants as major surfactants, optionally with the addition of amphoteric surfactants as co-active surfactants.

Amphoteric surfactants are themselves of no practical importance as detergents, as the foaming properties, the ability to thicken and partly also the tolerance to the skin and eye mucosa are moderate. However, in combination with various anionic surfactants, these properties are improved synergistically. This explains the relative importance of amphoteric surfactants for optimizing anionic shampoo bases.

Also, non-ionic surfactants can be administered as co-active surfactants.

Examples of such anionic detergents are: (C ₁₀ -C ₂₀ ) alkyl and alkylenecarboxylate, alkyl ether carboxylate, fatty alcohol sulfate, fatty alcohol estersulphate, and alkylsulfonylacetylacetyl olefin sulfonate, isothionate acetyl ester, α-sulfomatic acid ester, alkylbenzosulfonate, alkylphenol glycolester sulfonate, sulfosuccinate, semester and diester of sulfoacetic acid, fatty acid ester phosphosate non-protein and fatty acid product, alkyl monoglyceride sulfate and -sulfonate, alkylglyceridetersulfonate, fatty acid methyltaurid, fatty acid sarcosinate or sulforicinoleate. These compounds and mixtures thereof 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 the analogous alkyl-ammonium salt.

Examples of amphoteric surfactants added to shampoos are: N - ((C ₁₂ -C ₁₈ ) alkyl) -β-aminopropionate and N ((C ₁₂ -C ₁₈ ) alkyl) -β-iminodipropionate such as alkali and mono-, di- and trialkylammonium salts; L1-acylamidoalkyl-N, N-dimethylacetobetaine, preferably N - ((C ₈ -C ₁₈ ) acyl) amidopropyl, N-dimethylacetobetaine; (C ₁₂ -C ₁₈ ) alkyl dimethylsulfopropylbetaine; amphoteric surfactants based on imidazoline (trade name Miranol®, Steinapon®), preferably the 1- (β-carboxymethyloxyethyl) -1- (carboxymethyl) -2-laurimimidazoline sodium salt; an amino acid, e.g. (C ₁₂ -C ₁₈ ) alkyldimethylaminoxide or fatty acid amidoalkyldimethylamine oxide.

Non-ionic surfactants that can be used as detergents include, for example: fatty alcohol ethoxylate (alkyl polyethylene glycol); alkylphenol polyethylene glycol; alkylmercaptanpolyethylene glycol; fatty amine ethoxylate (alkylaminopolyethylene glycol); fatty acid ethoxylate (acyl polyethylene glycol), polypropylene glycolethoxylate (Pluronic®); fatty acid alkylamide (fatty amide polyethylene glycol); sugar; alkylpolyglucoside; sorbiter and polyglycoleter.

Suitable cationic surfactants are, for example, a quaternary ammonium salt such as di - ((C ₁₀ -C ₂₄ ) alkyl) -dimethylammonium chloride or bromide, preferably di - ((C ₁₂ -C ₁₈ ) alkyl) dimethylammonium chloride or bromide; (C ₁₀ -C ₂₄₎ alkyl- dimetiletilamoniev chloride or bromide, (C ₁₀ -C _m) alkyltrimethylammonium chloride or bromide, preferably cetyltrimethylammonium chloride or bromide, and (C ₂₂₎ alkyltrimethylammonium chloride or bromide; (C ₁₀ -C ₂₄ ) alkyl dimethylbenzylammonium chloride or bromide, preferably (C ₁₂ -C ₁₈ ) alkyl dimethylbenzyl ammonium chloride or bromide; N ((C ₁₀ -C ₁₈ ) alkyl) pyridine chloride or bromide, preferably b (- ((C ₁₂ -C ₁₆ ) alkyl) pyridinium chloride or bromide; M - ((C ₁₀ -C ₁₈ ) alkyl) isoquinoline chloride, bromide or monoalkyl sulphate; N- ((C ₁₂ -C ₁₈ ) -alkylaminoformyl-methyl) pyridinium chloride; N - ((C ₁₂ -C ₁₈ ) alkyl) -N-Methyl-morpholinium chloride, bromide or monoalkyl sulfate, N- ((C ₁₂ -C ₁₈ ) alkyl) -N-ethylmorpholinium chloride, bromide or monoalkylsulfate; (C ₁₆ -C ₁₈ alkylpentanoacetylammonium chloride; diisobutylphenylphenoxyethoxyldimethylmethylbenzylammonium chloride; lina, acetic acid, lactic acid, citric acid, phosphoric acid; N-acylamidoethyl-N, N-diethyl-N-methylammonium chloride bromide or monoalkylsulfate and N-acylamidoethyl-N, N-diethyl-1 N -benzylammonyl chloride wherein acyl is preferably stearyl or oleyl.

The formulations according to the invention may also contain other additives, for example aromatic substances, dyes, matting and pearl gloss agents, for example fatty acid ester and polyols, fatty acid magnesium and zirconium salts, dispersions based on mixed polymers, thickeners such as sodium, potassium, ammonium chloride, sodium sulfate, fatty acid alkylamide, cellulose derivatives of natural resins, collagen hydrolyzate, fats, oils, fatty alcohols, silicone, substances with catalytic and keratoplastic activity, or instance sulfur, salicylic acid or an enzyme.

The production of shampoo is carried out in a known manner by mixing the individual components and, as necessary, appropriate subsequent processing of the form. Some of these numerous possible forms are described in the following examples.

The formulations according to the invention may be aqueous and water-alcoholic water for the hair, also in gel and aerosol form as spray or foam. Ethanol and isopropyl alcohol are preferably used as alcohol.

Other forms in which 1-hydroxy-2-pyridone according to the invention may be used may, for example, include creams, ointments, products that may first be used for the treatment of hairless portions and portions of hair. the body.

The preparation of all these forms is carried out, as indicated in the shampoos, in a known manner by the addition of the active substance of the invention. The formulations of the invention may contain one of the above compounds 1-hydroxy-2-pyridones or more in combination.

The pH of the forms is within the physiological range of the skin from about 5 pH 4.5 to 6.5. When administering the compounds as salts, the pH of the organic acid region must be adjusted, and this measure is not necessary when administering the free compounds.

In the formulations according to the invention, the amount of active substance is typically between about 0.05 and about 10%. Within this range, concentrations of specific forms are targeted according to their purpose of application. Certain forms such as concentrates, which must be diluted prior to administration, may show significantly higher concentrations.

In the case of forms which remain on the skin or on the scalp, for example gel forms, ointments, creams or hair waters, then lower concentrations are used, for example from about 0.05% to about 1%. Preferably from 0.1 to 0.5%. In higher concentrations, they are appropriately applied when it comes to forms which, if diluted, only act briefly on the scalp, such as shampoos or liquid soaps, after dilution. For example, concentrations of about 0.2 to about 10%, preferably about 0.5% to about 2%, may be appropriate in these cases. The following figures are by weight, unless otherwise noted.

Examples of carrying out the invention

Example 1

Formulation according to the invention with the following composition in%:

Shampoo (based on anionic detergents)

-Hydroxy-4-methyl-6-cyclohexyl-2 (1H) pyridone Sodium lauryldiglycoletersulphate (27% solution) Disodium laurylpolyglycoletersulphosuccinate (33% solution)

Sodium chloride

Water

1.00 40.00 10.00

2.50

46,50.

Example 2. Formulation according to the invention with the following composition in%.

Shampoo (based on anionic detergents with amphoteric surfactant as a co-active surfactant)

-Hydroxy-4-methyl-6-cyclohexyl-2 (1H) pyridone Sodium lauryldiglycolethersulfate (27% solution) Cocamidopropylbetaine (33% solution)

Sodium chloride

Water

1.00 36.00 6.00

3.30

53.70

Example 3.

Formulation according to the invention with the following composition: Shampoo (based on anionic detergents with a non-ionic surfactant as a co-active surfactant)

-Hydroxy-4-methyl-6-cyclohexyl-2 (1H) pyridone 1.50

Sodium lauryldiglycolethersulfate (27% solution) 30.00

Lauryl alcohol polyglucoside 8,00

Sodium chloride 2.00

Water58.50

Example 4

Formulation according to the invention with the following composition in%: Liquid soap 1-Hydroxy-4-methyl-6-cyclohexyl-2 (1H) pyridone

Sodium lauryl diglycolethersulfate (27% solution)

Cocamidopolyglycolsulfate magnesium salt (30% solution)

Cocamidopropylbetaine (33% solution)

Laurylalcoholglycol ether

Sodium chloride

Water

1.00 35.00 8.00

10,00

2.00

2,00 42,00.

Example 5

Formulation according to the invention with the following composition in%:

Hair water

-Hydroxy-4-methyl-6- [4- (4-chlorophenoxy) -phenoxymethyl] -2 (1H) pyridone 2-Propanol

Water

0.05 60.00 39.95.

Example 6

Formulation according to the invention with the following composition in%: Gel 1-Hydroxy-4-methyl-6-cyclohexyl-2 (1H) pyridone 2-Propanol

2-Octyldodecanol

Carbomer 4,000,000

Polysorbate 60

Sodium hydroxide

Water

0.75 15.00

7.50

0.50

1.50

0.18

74.57.

Example 7

Formulation according to the invention with the following composition in%: Cream

-Hydroxy-4-methyl-6-cyclohexyl-2 (1H) pyridone aminoetonyl salt 1: 1

2-Octyldodecanol

Vaseline oil

Stearyl alcohol

Cetyl alcohol

Polysorbate 60

Sorbitan monostearate

Lactic acid 90%

Water

1.00

7.50

7.50

7.50

7.50

3.00

2.00

0.51

63.49

Example 8.

In a clinical study involving a total of 180 patients, it was shown that the symptoms of seborrheic dermatitis of the scalp (severe scaling, inflammation, itching) can be completely cured by 1 to 2 weekly treatment with shampoo containing 1% cyclopirox for 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 were treated successfully by administering a 0.77% cyclopirox gel form over a 4-week period.

Claims (9)

Claims Use of 1-hydroxy-2-pyridone of formula I in which R ¹ , R ² and R ³ , which are the same or different, denote hydrogen or alkyl of 1-4 carbon atoms and R ⁴ represents a saturated hydrocarbon moiety of 6 to 9 carbon atoms or a moiety of formula wherein X is S or O, Y means hydrogen or up to 2 halogen atoms such as chloro and / or bromo, Z represents a simple bond or a divalent moiety O, S, -CR ² -, where R is H or (C 1 -C ₄ ) alkyl or another divalent moiety having 2-10 ring-linked C- and optionally O- and / or S atoms, where, when the residue contains 2 or more 0 and / or S atoms, the latter must be linked to at least 2 C atoms, and wherein 2 adjacent carbon atoms may also be bonded by double bond and the free valences of the C atoms are saturated with H and / or (C 1 -C ₄ ) alkyl, Ar means a ring aromatic system with up to two rings which can be substituted with up to three residues from the group fluoro, chloro, bromo, methoxy, (C 1 -C ₄ ) alkyl, three 25 fluoromethyl and trifluoromethoxy for the preparation of medical shampoo containing at least one anionic, cationic, non-ionic or amphoteric surfactant or mixture of surfactants and having a pH value in the field of skin physiology for the treatment of seborrheic dermatitis. The use of claim 1, wherein the compound of formula (I) wherein Ar is a bicyclic system of biphenyl, diphenylalkane or diphenyl ether. Use according to claim 1 or 2, wherein the compound of formula (1) wherein R ⁴ is a cyclohexyl moiety. Use according to one or more of claims 1 to 3, wherein the compound is of formula (I), wherein R ⁴ is an octyl moiety of formula -CH ^ CHiCH ^ -CHj-CiCH,), The use according to claim 1, wherein the compound is 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-trimethylphenyl) -2- (1H) pyridone. The use according to claim 1, wherein the surfactant is at least one anionic surfactant alone or in combination with other anionic surfactants and / or amphoteric surfactants. The use according to claim 1, wherein the 1-hydroxy-2-pyridone of formula (I) is at a concentration of 0.2 to 10%. The use according to claim 7, wherein the 1-hydroxy-2-pyridone of formula (I) is at a concentration of 0.5 to 2%. The use according to claim 1, wherein the medical shampoo has a pH value of from about 4.5 to 6.5. Expert: R. Jovovich Publication of the Patent Office of the Republic of Bulgaria 1113 Sofia, 52-B Dr. GM Dimitrov Blvd. Editor: R. Georgieva Cf. № 42531 Circulation: 40 CS