MXPA99002865A - Use of 1-hydroxy-2-pyridones for the treatment of skin diseases - Google Patents

Abstract

Compounds of the formula (I) are suitable for producing pharmaceuticals for topical treatment of skin diseases caused by fungi or bacteria.

Description

USE OF l-HIDROXI-2-PYRIDONS FOR THE TREATMENT OF SKIN INFECTIONS Skin infections are caused to a large extent by bacteria or pathogenic fungi of the skin. Its treatment, depending on the specific pathogen, is carried out using antibacterial or antifungal agents. Staphylococci and esptreptococci are a cause of bacterial skin infections in approximately 70% of all cases. Other important pathogens of bacterial skin infections that may be mentioned are Proteus sp. Other bacteria that grow under aerobic and anaerobic conditions, such as enterococci, Escherichia coli, Pseudomonas aeruginosa and Klebsiella, are less frequent pathogens of skin infections. Yeasts, on the other hand, have recently gained importance as pathogens of skin infections, particularly in immunosuppressed patients, in whom the mucocutaneous and systemic spread of yeast may be a therapeutic problem. Since bacteria, as a rule, do not have observable keratinase activity, which is necessary for the onset of an infection, the icotic infections are often a starting point for the occurrence of secondary bacterial infections.

The present invention, therefore, relates to substances that are suitable for the topical treatment of fungal infections and bacterial infections of the skin. The broad-spectrum topical anti-infectives, according to the present invention, up to now have not been available as on-repairs for the treatment of skin infections. In the choice of agents for antibacterial therapy, among others, the development of resistance must be particularly taken into consideration. Especially in the case of * longer treatment, the spectrum of the pathogen must be determined by outbreaks of wounds and their verified behavior with respect to the compositions that are used. In addition, sensitivity to contact and reactions of intolerance should be observed. Especially in the case of neomycin and gentamicin, which have been used for many years in the treatment of skin infections, the danger of sensitization is high. For staphylococcal infections of the skin, which are the most frequent, erythromycin and clindamycin are often also used in addition to gentamicin. These are used locally, mainly in acne therapy, and also systemically.

However, due to systemic administration, which has been carried out for many years, bacterial strains resistant to therapy have been developed against gentamicin and against erythromycin and clindamycin to a large extent, even against modern gyrase inhibitors, as they can be, for example ofloxacin. In a retrospective study, Th. Forss ann et al (H + G volume 69, Part 12, 1994, pp. 828-832) analyzed the antibiotic resistance of Propionibacterium acnes and Staphylococcus epider idis in patients with acne who were pretreated with antibiotics. . Research shows that, with respect to Propionibacteria, resistances were found to erythromycin in 36% and to clindamycin in 11% of cases. With Staphylococcus epidermidis resistances to erythromycin were found in 90% and to clindamycin in 40% of cases. The increasing number of resistance to enterococci to gentamicin (up to 50% in isolates from several centers) gives the reason to think particularly that the same strains are also resistant to many other substances, including vancomycin (Martindale 30th ed, 1993, p. 171.2). The same problem exists with strains of Staphylococcus aureus resistant to gentamicin, which, as a rule, are also insensitive to methicillin and ofloxacin (Martindale 30th ed, 1993, pp. 171, 2 own investigations). Furthermore, it is known from the literature that cross-resistance to conventional antibiotics is developing to an increasing degree. Thus, among others, in the case of patients who were only pretreated with erythromycin, resistance to clindamycin was also observed in 20% of the cases. For the reasons mentioned, this is no longer applied as a therapeutic standard at present as well as to use topical antibiotics that are used systemically.

In the search for a new therapeutic standard for active substances such as antibiotics to be used topically, it has now surprisingly been found that substances of the l-hydroxy-2-pyridone class that have hitherto been used exclusively in therapy as antifungals, They are also excellent for the topical treatment of skin infections caused by bacteria. In more recent experiments, it was possible, in particular, to show that l-hydroxy-2-pyridones have an uninterrupted spectrum of action against bacterial species that occur in skin infections, in particular also against strains resistant to antibiotics. In combination with the well-known antifungal properties of l-hydroxy-2-pyridones, this is an extremely important finding for the successful treatment of skin infections, according to the bacterial identification that has been mandatory up to now with subsequent resistance tests in the treatment with substances according to the invention is no longer necessary, which in the end also gives rise, among other things, to a substantial reduction in the costs of the treatment. The invention, therefore, relates to the use of 1-hydroxy-2-pyridones of the formula I wherein R1, R2 and R3, which are identical or different, are a hydrogen or alkyl atom having 1 to 4 carbon atoms, and 4 R is a saturated hydrocarbon radical having from 6 to 9 carbon atoms or a radical of formula II wherein X is S or O, Y is a hydrogen atom or up to 2 halogen atoms such as chlorine and / or bromine, Z is a single bond or the divalent radicals 0, S, CR2- (R = H or C1 alkyl) -C4) or other divalent radicals having from 2 to 10 carbon atoms and optionally O and / or S atoms bonded in the form of a chain, where the radicals contain 2 or more 0 and / or S atoms, these The latter must be separated from each other by at least 2 carbon atoms and where 2 adjacent carbon atoms can be linked together by a double bond and the free valences of the carbon atoms are replaced by H and / or alkyl groups of ( C1-C4), Ar is an aromatic ring system having up to 2 rings which can be substituted by up to three radicals from the group consisting of: fluorine, chlorine, bromine, methoxy, C1-C4 alkyl, trifluoromethyl and trifluoromethoxy in the free form or in salt, for the production of a pharmaceutical product for the topical treatment of skin infections that are caused by fungi and bacteria. In the * Z "radicals, the members of the carbon chain are preferably CH2 groups If the CH2 groups are substituted by C1-C4 alkyl groups, the substituents CH3 and C2H5 are preferred The examples of the radicals * Z" They are: -O-, -S-, -CH2-, - (CH2) m- (m = 2-10), -C (CH3) 2-, -CH2O-, -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-.

The radical * S "defines a sulfur atom, the radical" O "defines an oxygen atom The term" Ar "defines phenyl or condensed systems such as naphthyl, tetrahydronaphthyl and indenyl, and also isolated systems such as those in which they are derived of biphenyl, diphenylalkanes, diphenylethers and diphenyl thioethers In formula I, the hydrocarbon radical R is an alkyl or cycloalkyl radical which may also be attached to the pyridone ring through a methylene or 4 ethylene group or may contain an endomethyl group R may also be an aromatic radical which, however, is preferably linked to the pyridone radical through at least one aliphatic carbon atom. The important representatives of the class of compound characterized by the formula I are: 6- [4- (4-chlorophenoxy) phenoxymethyl] -l-hydroxy-4-methyl-2-pyridone, 6- [4- (2,4-dichlorophenoxy) phenoxymethyl] -l-hydroxy-4-methyl-2- pyridone, 6- (biphenylyl-4-oxymethyl) -l-hydroxy-4-methyl-2-pyridone6- (4-benzylphenoxymethyl) -l-hydroxy-4-methyl-2-pyridone, 6- [4- (2,4-dichlorobenzyloxy) phenoxymethyl] -1-hydroxy-4-methyl-2-pyridone, 6- [4- (4-chlorophenoxy) phenoxymethyl] -l-hydroxy-3,4-dimethyl-2-pyridone, 6- [4- (2,4-dichlorobenzyl) phenoxymethyl] -l-hydroxy-3,4-dimethyl-2 -pyridone, 6- [4- (cinnamyloxy) phenoxymethyl] -l-hydroxy-4-methyl-2-pyridone, l-hydroxy-4-methyl-6- [4- (4-trifluoromethylphenoxy) phenoxymethyl] -2-pyridone , l-hydroxy-4-methyl-6-cyclohexyl-2-pyridone, l-hydroxy-4-methyl-6- (2,4,4-trimethylpentyl) -2-pyridone, l-hydroxy-4-methyl-β -n-hexyl-, 6-isohexyl-, Bn-eptil- or -6-iso-eptil-2-pyridone, 1-hydroxy-4-methyl-6-octyl- or -6-iso-octyl-2-pyridone, in particular l-hydroxy 4-methyl-6-cyclohexylmethyl- or -6-cyclohexylethyl-2-pyridone, where the radical cycloalkyl in each case can also carry a methyl radical, 1-hydroxy-4-methyl-2- (2-bicyclo [2 , 2, 1] eptil) -2-pyridone, 1-hydroxy-3,4-dimethyl-6-benzyl- or -6-dimethylbenzyl-2-pyridone or 1-hydroxy-4-methyl-6- (β-phenylethyl) -2-pyridone.

The term "saturated" in this case refers to those radicals that do not contain multiple aliphatic bonds, that is, without ethylenic or acetylenic bonds.The term "topical" is understood as the local action on the skin. The term "fungus" means all cells free of chlorophyll with cellulose or chitin in the cell walls, which contains chromosomes in the cell nucleus. The particular deep includes yeasts, mold fungi, skin fungi, hair and buds. The term "bacterium" means microorganisms with heterotrophic or autotrophic metabolisms that do not have a chromosomal nucleus. The bacteria include gram positive and gram negative microorganisms, in particular those that can grow on the surface of the skin of humans or animals, for example bacteria pathogenic to the skin of the genus Staphylococci, streptococci, corynebacteria, propionibacteria and Proteus, and also other bacteria. of aerobic and anaerobic growth 'such as enterococci, Escherichia coli, Pseudomonas and Klebsiella. The term "antibiotic resistance" means the property of the microorganisms to be insensitive to the concentration of the compound in which it is therapeutically active. The aforementioned compounds of the formula I can be used in free form and as salts; the use in the free form is preferred. If organic bases are used, preferably low-volatile bases are used, for example low molecular weight alkanolamines such as ethanolamine, diethanolamine, N-ethylethanolamine, N-methyldiethanolamine, triethanolamine, diethylaminoethanol, 2-amino-2-methyl-n-propanol, dimethylaminopropanol, 2-amino-2-methylpropanediol, triisopropanole ina. Other weakly volatile bases which may be mentioned are, for example, ethylenediamine [sic], hexamethylenediamine, morpholine, piperidine, piperazine, cyclohexylamine, tributylamine, dodecylamine, N, N-dimethyldodecylamine, stearylamine, oleylamine, benzylamine, dibenzylamine, N -ethylbenzylamine, dimethylstearylamine, N-methylmorpholine, N-methylpiperazine, 4-methylcyclohexylamine, N-hydroxyethylmorpholine. The salts of the quaternary ammonium hydroxides such as trimethylbenzylammonium hydroxide, tetramethylammonium hydroxide or tetraethylammonium hydroxide can also be used, and also guanidine and its derivatives. In particular its alkylation products. However, it is also possible to use, for example, low molecular weight alkylamines, such as methylamine, ethylamine or triethylamine or the salt-forming agents. Salts with inorganic cations, for example alkali metal salts, in particular sodium, potassium or ammonium salts, alkaline earth metal salts such as, in particular, magnesium or calcium salts, and salts with di- to tetravalent cations, for example the zinc, aluminum or zirconium salt are also suitable for the compounds to be used according to the invention. The active compounds of the formula I for use in the preparations can be prepared, for example, by the process according to US 2 540 218. For use according to the invention of the mentioned compounds, liquid pharmaceutical preparations are suitable for semi-solid, in particular solutions, creams, ointments and gel preparations, where the latter is preferably used due to its increased release of the active compound. The production of these preparations is carried out in a manner known per se with addition of the active compound used according to the invention. Of the aforementioned l-hydroxy-2-pyridones, the preparations according to the invention may contain a compound or, otherwise, two or more in combination. In the preparations according to the invention, the active compound is incorporated in amounts that are, typically, between about 0.1 and about 5%, preferably between 0.5 and 1%. Using the pharmaceuticals according to the invention, a drastic cure can be achieved in the topical treatment of skin infections. The compositions according to the invention can also be used for the treatment of acne, rosacea - a disease of not yet clarified etiology - and of erythrasma, pseudomycosis of the skin caused by Corynebacterium minutissimum.

Example 1 A preparation according to the invention has the following composition: l-hydroxy-4-methyl-6- (2,4-, 4-trimethylpentyl) -2 (1H) pyridone 0.50% Hydroxyethylcellulose 1.50% Glycerylcocoate polyethylene glycol-7 5.00% 1,2-propylene glycol 10.00% Isopropyl alcohol 20.00% Demineralized water 63.00% Example 2 A preparation according to the invention has the following composition: l-hydroxy-4-methyl-6-cyclohexyl-2 (1H) pyridone 1.00% Polyacrylic acid polymer (for example 0.70% Carbomer 934P) 0.20% sodium hydroxide Sodium dioctyl sulfosuccinate 0.05% 2-octyldodecanol 7.50% Isopropyl Alcohol 25.00% Demyelinated water 65.55% Example 3 A preparation according to the invention has the following composition: l-hydroxy-4-methyl-6-cyclohexyl-2 (1H) pyridone 0.50% polyacrylic acid polymer (eg Carbomer 0.50% 940) 0.20% sodium hydroxide Sorbitan monostearate polyoxyethylene (20) 3.50% Isopropyl myristate 10.00% Ethanol 20.00% Demineralized water 65.30% Example 4 A preparation according to the invention has the following composition: l-hydroxy-4-methyl-6- (2,4, 4-trimethylpentyl) -2 (1H) -pyridone 1.00% Hydroxypropylcellulose 1.00% 1,2-propylene glycol 2.50% Ethanol 20.00% Demineralized water 75.50% Example 5 A preparation according to the invention has the following composition: l-hydroxy-4-methyl-6-cyclohexyl-2 (1H) -pyridone 1.00% Isopropyl Alcohol 25.00% Polyethylene glycol 400 5.00% Demineralized water 69.00% Example 6 A preparation according to the invention has the following composition: l-hydroxy-4-methyl-6- (trimethylpentyl) -2 (1H) -pyridone 1.00% 2-octyldocenol 5.00% Liquid paraffin 5.00% Cetyl Alcohol 5.00% Stearyl alcohol 5.00% Myristyl alcohol 5.00% Sorbitan monostearate - polyoxyethylene 20 3.00% Sorbitan monostearate 2.00% Demineralized water 69.00% Example 7 Activity test The determination of the antibacterial activity of 1-hydroxy-4-methyl-6-cyclohexyl-2 (1H) pyridone for aerobic gram-positive and gram-negative bacteria pathogenic to the skin. The minimum inhibitory concentration (MIC) was determined in an agar dilution test on Mueller-Hinton agar. The active compound was first dissolved in dimethyl sulfoxide at 10% concentration and then diluted to twice the amount in each case in equal steps with agar to obtain in the concentrations of the final effect between 128 μg / ml and 1 μg / l. The overnight cultures of the bacterial strains for the test were diluted with liquid medium and used as inoculum. Bacterial suspensions (1 x 10 cfu / ml) were applied to the surface of the agar plates containing the active compound. With the exception of the methicillin-resistant strains of Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE), the MIC values were read after 24 hours at 37 ° C (MRSA and MRSE: 48 hours at 30 ° C). The lowest concentration at which growth was no longer observed was designated as the MIC. Using the known methods, the antibiotic-resistant and investigated bacteria can be isolated from patients or hospitals in which resistance to antibiotics has been found. The other bacterial species mentioned can be easily isolated by a person skilled in the art taking into account their species and generic man or can be acquired from a collection of strains. Results In vitro activity of l-hydroxy-4-methyl-6-cyclohexyl-2 (1H) pyridone against aerobic bacteria. n = number of strains investigated; the number mentioned in brackets provides the strains tested in which the mentioned MIC was determined.

In vitro activity of l-hydroxy-4-methyl-6-cyclohexyl-2 (1H) pyridone against aerobic bacteria (the test was carried out in an agar dilution test using ilkins-Chalgren agar (Oxoid).

Description of MIC bacteria (μg / ml) Propionibacterium acnes strain 6919 32.0 Propionibacterium acnes strain 6922 32.0 Propionibacterium acnes strain 15549 32.0 Propionibacterium acnes strain DSM 20458 32.0 All tested bacterial strains were inhibited in their growth, without exception, in a very narrow concentration range of l-hydroxy-2-pyridones . This also applies to strains that are resistant to antibiotic therapy such as methicillin, ofloxacin and vancomycin.

Claims (9)

1. RE I VIND I CAC I ONE S The use of l-hydroxy-2-pyridones of the formula I wherein R 1, R 2 and R 3, which are identical or different, are a hydrogen or alkyl atom having from 1 to 4 carbon atoms, and 4 R is a saturated hydrocarbon radical having from 6 to 9 carbon atoms or a radical of formula II wherein X is S or 0, Y is a hydrogen atom or up to 2 halogen atoms such as chlorine and / or bromine, Z is a single bond or the divalent radicals 0, S, CR2- (R = H or C1-C4 alkyl) or other divalent radicals having from 2 to 10 carbon atoms and optionally O and / or S atoms bonded in the form of a chain, where the radicals contain 2 or more atoms of 0 and / or S, the latter must be separated from each other by at least 2 carbon atoms and where 2 adjacent carbon atoms can be linked together by a double bond and the free valences of the carbon atoms are substituted by H and / or (C1-C4) alkyl groups, Ar is an aromatic ring system having up to 2 rings which can be substituted by up to three radicals from the group consisting of: fluorine, chlorine, bromine, methoxy, alkyl of C1-C4, trifluoromethyl and trifluoromethoxy, for the production of a pharmaceutical product for the treatment of skin infections which are caused by bacteria resistant to antibiotics.
2. 2. The use as claimed in claim 1, wherein the compound of the formula I is used, wherein Ar is a bicyclic system derived from biphenyl, diphenylalkane or diphenyl ether.
3. 3. The use as recited in claim 1 or 2, wherein the compound of the formula I contains a cyclshexyl radical in the R position.
4. 4. The use as claimed in one or more of claims 1 to 3, wherein the compound of the formula I contains an octyl radical of the formula -CH2-CH (CH3) -CH2-C (CH3) 3 in the R position.
5. 5. The use as claimed in claim 1, wherein l-hydroxy-4-methyl-6- [4- (4-chlorophenoxy) phenoxymethyl] -2- (1H) pyridone, l-hydroxy-4- is used. methyl-6-cyclohexyl-2- (1H) pyridone or l-hydroxy-4-methyl-6- (2,4,4-trimethylpentyl) -2- (1H) pyridone.
6. 6. The use as mentioned in one or more of claims 1 to 5, wherein the treatment is carried out topically.
7. 7. The use as claimed in claim 6, wherein the origin of the antibiotic resistant bacteria is from the group comprising gram positive and / or gram negative microorganisms, in particular those that can grow on the skin surface of humans or animals.
8. The use as mentioned in claim 7, for the topical treatment of skin infections that are caused by bacteria pathogenic to the skin coming from one or more of the genera staphylococci, streptococci, Proteus, corynebacteria and propionibacteria or which are caused by other bacteria that grow in an aerobic or anaerobic form, such as Escherichia coli, enterococci, Pseudomonas or Klebsiella.
9. 9. The use as mentioned in one or more of claims 1 to 8, wherein acne, rosacea or erythrasma are treated.