EP0865277A1

EP0865277A1 - Use of fungicidal agents for selective decontamination of teeth and dental prostheses

Info

Publication number: EP0865277A1
Application number: EP96939874A
Authority: EP
Inventors: Rainer Pooth
Original assignee: Hoechst AG
Current assignee: Hoechst AG
Priority date: 1995-12-04
Filing date: 1996-11-21
Publication date: 1998-09-23
Also published as: KR19990071885A; DE19545139C1; WO1997020559A1; ZA9610133B; JP2000505782A; CA2239409A1; ZA9610134B; AU7695096A

Abstract

The compound of the formula (I) is suitable for the destruction of fungi or yeasts on teeth and dental prostheses, in particular for decontamination outside the buccal region.

Description

description

Use of fungicidal agents for the selective decontamination of teeth and dentures

Fungal diseases of the mucous membranes in the mouth, throat and esophagus are among the infectious diseases that have not yet been treated satisfactorily; they are subject to frequent recurrences. The topical application of antifungal agents such as nystatin, miconazole, fluconazole or amphoteπcin B in the mouth area for oral inflammation has not led to long-term therapeutic success (J Can Dent (1 995) _ßJ_i3>, pages 1 99 - 205). It has been found that dentures or prostheses such as bridges or dentures that are temporarily removed from the mouth or implants are colonized by fungi. This denture can become a source of infection, from which the adhering fungi easily re-infect the mouth and throat area. In particular, fungal prostheses are a significant risk factor for predisposed patients, even if there are no clinical signs of a disease in the mouth preferred to an infection by fungi, because the infection defense is weakened at these places. In particular, diabetics, asthmatics, smokers, AIDS sufferers, transplant patients or people who are treated with antibiotics or immunosuppressive drugs represent risk groups for recurrent mycoses

The documents EP 0 241 91 8 and EP 0 226 984 describe the anti-mycotic properties of some 1-hydroxy-2-pyridone derivatives. Other antifungal 1-hydroxy-2-pyridone derivatives are described in US Pat. No. 3,968,111 8 known The object of the present invention is to provide fungicidal agents which enable adequate and permanent growth inhibition and / or killing of fungi on teeth and dentures, in particular outside the mouth area.

It has now been found that a compound of Formet I is excellently suitable for inhibiting the growth and / or killing of fungi on teeth or dentures, because this compound has good adsorption on the smooth surface of the teeth or dentures and therefore not only adequate mortality the fungus causes, but also a renewed colonization of the surface difficult. Furthermore, the compound of the formula I shows a strong inhibitory action against fluconazole-resistant strains of the human pathogenic Candida species.

The invention therefore relates to the use of the compound of the formula I.

wherein R ¹ , R ² and R ³ , which are identical or different, denote hydrogen atom or alkyl having 1 to 4 carbon atoms, and

R ^{4 is} a saturated hydrocarbon radical having 6 to 9 carbon atoms or a radical of the formula II

Ar-Z

-> A (πx

X-CH.

in which XS or O means

Y hydrogen atom or up to 2 halogen atoms such as chlorine and / or

Bromine means

Z is a single bond or the divalent radicals O, S, -CR -

(R = H or C ₁ -C ₄ alkyl) or other divalent radicals with 2-10 chain-linked C and optionally O and / or S atoms, where - if the radicals 2 or more 0- and / or S - Contain atoms - the latter must be separated from one another by at least 2 C atoms and where 2 adjacent C atoms can also be linked to one another by a double bond and the free valences of the C atoms by H and / or C -, - C ₄ - Alkyl groups are saturated means

Ar is an aromatic ring system with up to two rings, which can be substituted by up to three radicals from the group fluorine, chlorine, bromine, methoxy, C, -C ₄ -alkyl, trifluoromethyl and trifluoromethoxy, for decontamination of teeth or dentures .

The invention further relates to the use of the compound of formula I for the decontamination of dentures outside the mouth.

In the "Z" radicals, the C chain links are preferably CH ₂ groups. If the CH ₂ groups are substituted by C ₁ -C ₄ alkyl groups, CH ₃ and C ₂ H _{5 are} preferred substituents. Exemplary residues "Z" are

-O-, -S-, -CH ₂ -, - (CH ₂ } _m - (m - 2 - 10), -C (CH ₃ ) ₂ -, -CH ₂ 0-, -OCH ₂ -, -CH ₂ S-, -SCH ₂ -, -SCH (C ₂ H ₅ ) -, -CH = CH-CH ₂ 0-, -0-CH ₂ -CH = CH-CH ₂ 0-, -OCH ₂ -CH ₂ O-, -OCH ₂ -CH ₂ CH ₂ 0-, -SCH ₂ CH ₂ CH ₂ S-, -SCH ₂ CH ₂ CH ₂ CH ₂ 0-, -SCH ₂ CH ₂ OCH ₂ CH ₂ 0-, -SCH ₂ CH ₂ OCH ₂ CH ₂ 0-CH ₂ CH ₂ S- or -S-CH ₂ -C (CH Q) ₂ -CH ₂ -S- The remainder "S" means sulfur atom, the remainder "O" means oxygen atom. The term "Ar" means phenyl and condensed systems such as naphthyl, tetrahydronaphthyl and indenyl, as well as isolated systems such as those derived from biphenyl, diphenylalkanes, diphenyl ethers and diphenyl thioethers.

Important representatives of the connection boxes characterized by Formula I are:

6- [4- {4-chlorophenoxy) phenoxymethyl] -1-hydroxy-4-methyl-2-pyridone,

6- [4- '2,4-Dichlorophenoxy) phenoxymethyl] - 1-hydroxy-4-methyl-2-pyridone;

6- (Bιphenylyl-4-oxy-methyl) -1-hydroxy-4-methyl-2-pyrιdon;

6- (4-benzyl-phenoxymethyl) -1-hydroxy-4-methyl-2-pyridone;

6- [4- (2,4-Dιchlorobenzyloxy) phenoxy-methyl] -1-hydroxy-4-methyl-2-pyridone;

6- [4- (4-chlorophenoxy) phenoxymethyl] -1-hydroxy-3,4-dimethyl-2-pyridone;

6- [4- (2,4-Dichlorobenzyl) phenoxymethyl] - 1-hydroxy-3,4-dimethyl-2-pyridone;

6- [4- (Cιnnamyloxy) phenoxymethyl] -1-hydroxy-4-methyl-2-pyrιdon;

1-hydroxy-4-methyl-6- [4- (4-trifluoromethylphenoxy) phenoxymethyl] -2-pyridone;

1-Hydroxy-4-methyl-6-cyclohexyl-2-pyrιdon or

1-Hydroxy-4-methyl-6- (2,4,4-trιmethylpentyl) -2-pyrιdon.

The term dentures is understood to mean means for correcting or replacing the dentition or denture parts, such as dental bridges, braces, dental splints, crowns or implants, as well as artificial dentures or denture parts. Denture materials are, for example, plastics, porcelain or metal parts, preferably porcelain.

The fungi which can be treated according to the invention are all types of fungi which occur in the mouth and throat area, in particular Candida albicans, Candida glabrata, Candida tropicahs, azole-resistant fungi or azole-resistant yeasts The term “azole-resistant fungi” is understood to mean all types of fungus or yeast which have become resistant to antifungals, for example to antifungals which contain azole residues in the molecule, such as fluconazole.

"Decontamination" means the inhibition of growth or killing of fungi or yeast. The "mouth area" encloses the lips, teeth, palate, tongue, oral mucous membranes and throat.

Immunosuppressed denture carriers are preferably treated, such as diabetics, asthmatics, smokers, AIDS sufferers, patients before and after transplants, cancer patients, patients who are treated for a long time with antibiotics, cytostatics or corticosteroids, patients with antifungal fungi, in particular patients with fluconazole -resistant mushrooms or the elderly

The invention further relates to dentures containing a compound of formula I. The compound of formula I can lie on the surface of the denture, be impregnated with it, or the compound of formula I can coat the denture with or without auxiliary substances

The preparation of the dental prosthesis according to the invention and the use of the compound of the formula I for the decontamination of dental prostheses outside the mouth area are carried out by incubation with the compound of the formula I, for example by spraying, application, immersion or incubation with a solution, gel containing a compound of the formula I, varnish, effervescent tablet or suspension. The application on the teeth or dentures in the mouth area is carried out by spraying, gargling or application with a solution, gel, lozenge or suspension containing a compound of the formula I. The compound of formula I is expediently used by means of preparations customary in cosmetics and dermatology, for. B. soaps, syndet soaps, washing solutions, washing cream, toothpaste, water / alcoholic solutions, suspensions, gels or film-forming preparations. Aqueous / alcoholic solutions or dispersion concentrates are preferred.

Such preparations can also contain other additives in addition to the customary auxiliaries known from the literature, for. B. antimicrobial substances, disinfectants, anti-inflammatory agents, healing agents, for example enzyme-activating or enzyme-inhibiting substances, penetration-promoting substances, eg. B. surfactants, fatty acid alkylolamides, hydro-regulating substances, oxidizing agents such as perborates, fluorine compounds, polar solvents, eg. B. dimethyl sulfoxide, 2-pyrrole and / or N-alkyl-2-pyrrole, thickeners such as cellulose derivatives, natural gums, plant extracts, protein derivatives, for. B gelatin, collagen hydrolyzates, ohgo and polypeptides on a natural and synthetic basis, film formers, e.g. Example, poly-N-vinylpyrrolidone and alkyl-substituted poly-N-vinylpyrrolidones, polyvinyl acetate and partially saponified polyvinyl acetate, polyvinyl alcohol, copolymers of vinyl acetate and N-vinylpyrrodone, reaction products of copolymers of vinyl acetate and acrylic acid and crotonic acid, mixed vinyl acetate with organic bases, mixed vinyl acetate with organic bases Maleic acid half-as well as film formers on a semi-synthetic basis, e.g. B cellulose derivatives or on a natural basis, for example alginic acid salts.

The preparations are prepared in a manner known per se by combining the individual components and, if necessary, further processing adapted to the respective preparation type (EP 0 288 945, EP 0 649 660). Some of these diverse possible preparation forms are described in the exemplary embodiments The compound of formula I or its salts are used in amounts between about 0.1% and about 5% against fungi or yeast. Within this range, the concentrations of the special preparations depend on their intended use.

Preparations that only remain on the denture for a short time after application and are rinsed off again, e.g. B. soaps, washing solutions, toothpastes or washing creams, contain the compound of formula I in concentrations of about 1% to about 5%, preferably from 0.5% to 2%. In preparations which are intended to remain on the dentures, such as suspensions or gels, lower concentrations of approximately 0.1% to 1% are appropriate.

The invention further relates to the use of dentures containing the compound of formula I for the prophylaxis and treatment of fungal infections in the mouth

The invention further relates to the use of the compound of formula I for the manufacture of a medicament for the treatment of diseases which are caused by azole-resistant fungi or azole-resistant yeasts.

Another application is to use the compound of formula I in combination with disinfectants such as sodium perborate or surface-active quaternary ammonium compounds such as alkyl-benzyl-dimethylammonium chloride. Example 1 6- [4 (4-chlorophenoxy) phenoxymethyl] -1-hydroxy-4-methyl-2-pyridone

20 g of 6-chloromethyl-4-methyl-2-pyrone and 25 g of 4- (4-chlorophenoxy) phenol are dissolved in 70 ml of dimethylformamide, 20 g of finely ground potassium carbonate are added and the mixture is stirred for 48 hours at room temperature. Then 200 ml of methylene chloride and 500 ml of water are added, the layers are separated, the organic phase is washed twice with 100 ml of water each, dried and evaporated in a vacuum from the water jet pump. The almost uniformly thin layer chromatography residue of 42.7 g is heated with 200 g of 2-aminopyridine at 75 ° C. for 56 hours and a total of 41.7 g of hydroxylamine hydrochloride are added in 5 portions during the first 41 hours. Then 250 ml of methylene chloride are added, washed once with dilute hydrochloric acid and twice with water, the organic phase is dried and the solvent is distilled off under reduced pressure and the title compound is obtained; Melting point 167 ° C.

Example 2 Dispersion concentrate

The compound according to Example 1 (1.0 g), Lipoid S 75 (1.8, 75 g), Cremophor RH 40 (6.25 g) and Glycofurol (74.0 g) are mixed and mixed with water to a final concentration of 0 , 1% of the compound diluted according to Example 1.

Example 3

Efficacy against azole-resistant strains of Candida albicans

Azole-resistant strains of Candida albicans are isolated in patients who, for example, are treated with fluconazole (Diflucan ^® ) for more than one year. For this purpose, samples are taken from the patient in the mouth area and undiluted or diluted 1: 1 00 on an RPMI 1 640 agar (Gibco / BRL, Life Technologies GmbH, 76339 Eggenstein, Germany) applied, which contains about 1.0 μg / ml fluconazole. Resistant Candida albicans strains are isolated, further purified on agar and kept isolated in peptone dextrose agar tubes. The Candida albicans strains 94/3 and 94/57 are isolated.

The activity of the compound according to Example 1 is determined using the microtiter dilution technique in RPMI 1 640 medium. The growth medium RPMI 1 640, buffered with 0.165 M morphohnpropanesulfonic acid pH 7.0, is filled into 96-well microtiter plates. The compound according to Example 1 is serially diluted by a factor of 2, so that final concentrations of 256 to 0.002 // g / ml of compound 1 and fluconazole are obtained. The microtiter plates prepared in this way are inoculated with the fungi Candida albicans ATCC 90028 and Candida albicans ATCC 90029 (both not resistant to fluconazole) and with the isolates Candida albicans 94/3 and 94/57 (both resistant to fluconazole). The initial cell count is 1 - 5 * 1 0 ³ colony-forming units per ml of growth medium. The microtiter plates are incubated at 35 ° C for 48 hours. The minimum inhibitory concentration is determined photometrically at 510 nm. Table 1 shows the results: Table 1

Table 1 shows that the compound according to Example 1 prevents both fluconazole-resistant and non-resistant C. albicans strains from growing Example 4

Adsorptive properties of the compound according to Example 1

Candida albicans cells are incubated in glass tubes with the compound according to Example 1 (1.0 mg / g) for 10 or 20 minutes. The samples are then sterile filtered and the concentration of the compound according to Example 1 is determined in the cell-free supernatants. Table 2 shows the results:

Table 2

The compound according to Example 1 strongly adsorbed on the Candida albicans cells and on the sample vessel walls.

Claims

Claims:

1. Use of the compound of formula I.

wherein

R ¹ , R ² and R ³ , which are the same or different, are hydrogen atoms or

Are alkyl with 1-4 carbon atoms, and

R ^{4 is} a saturated hydrocarbon residue with 6 to 9

Carbon atoms or a radical of formula II means

in which

X means S or O,

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

Z is a single bond or the divalent radicals O, S, -CR ₂ -

(R = H or C -C ^ alkyl) or other divalent radicals with 2 to 10 chain-linked C and optionally O and / or S atoms, where - if the radicals 2 or more O and / or S atoms contain - the latter by at least 2 carbon atoms must be separated from one another and where 2 adjacent C atoms can also be linked to one another by a double bond and the free valences of the C atoms are saturated by H and / or C 1 -C ₄ -alkyl groups,

2. Use according to claim 1, characterized in that one uses a compound of formula I, in which Ar represents Phenylπng and R ¹ and R ^{3 are} hydrogen and R ^{2 is} methyl.

3. Use according to claim 1, characterized in that a compound of formula I is used, in which Ar is a bicyclic system which is derived from biphenyl, diphenylalkane or diphenyl ether.

4. Use according to one or more of claims 1 to 3, characterized in that one uses a compound of formula I, wherein Z is a single bond or Z represents oxygen

5. Use according to claim 1, characterized in that 6- [4- (4-chlorophenoxy) phenoxymethyl] - 1-hydroxy-4-methyl-2-pyridone, 1 - hydroxy-4-methyl-6- cyclohexyl-2-pyrιdon or 1-hydroxy-4-methyl-6- (2,4,4-trιmethylpentyl) -2-pyrιdon used.

6. Use according to one or more of claims 1 to 5, characterized in that the decontamination of dentures takes place outside the mouth area.

7. Use according to one or more of claims 1 to 6, characterized in that a disinfectant such as sodium perborate or surface-active quaternary ammonium compounds such as alkyl-benzyl-dimethyl-ammonium chloride is additionally used.

8. dentures containing the compound of formula I according to claims 1 to 5.

9. A method for producing the denture according to claim 8, characterized in that the compound of formula I according to claims 1 to 5 is incubated with dentures.

10. The use of dentures, according to claim 8, for the prophylaxis and treatment of fungal or yeast infections in the mouth area.