ITMI20090522A1 - 2-ACRYLOYLPHENOLS AND ANTI-MITIC COMPOSITIONS THAT CONTAIN THEM - Google Patents

Description

Description

â € œ2-ACRYLOYLPHENOLS AND ANTIMICOTIC COMPOSITIONS THAT CONTAIN THEMâ €

The present invention relates to 2-acryloylphenols useful as antifungal agents.

State of the art

Fungi represent an increasingly frequent cause of infections that could compromise public health: an epidemiological study recently conducted in the USA showed that the incidence of fungal infections increased threefold from 1979 to 2000. Although in the majority While such infections can be treated with existing antifungal agents, it has been found that severe invasive fungal infections are becoming an increasing danger. Other reasons for the increased incidence of invasive fungal infections are to be found in the use of immunomodulatory agents for the prevention of rejection in organ and bone marrow transplants, in the use of antineoplastic drugs, in long-term therapies based on corticosteroids and even, paradoxically, in the indiscriminate use of antibiotics, which by reducing the bacterial load, can create optimal development conditions for fungi.

The combination of all these factors (the first of them being constituted in chemoresistance) amply justifies the research activity aimed at identifying innovative and more effective antifungal agents.

Among the most common pathogenic fungi, dermatophytes are fungi that cause infections of the skin, hair and nails, ie of structures containing that keratin which is the source of nourishment for these fungi. Dermatophyte infections, known as tinea (eg tinea pedis or "athlete's foot", tinea capitis, tinea ungulum), are caused by several species of the genus Trichophyton, Microsporium and Epidermophyton.

Among the drugs currently in use against fungal infections caused by dermatophytes, tolnaftate and allylamines can be mentioned, including in particular naftifine, terbinafine and butenafine.

2-propionyl-4,5-methylenedioxyphenol (kakuolo) is a natural compound present in some plants of the genus Asarum (Y. Saiki et al. Yakugaku Zasshi, 1967, 87, 1524-1528; T. Kosuge et al. Chem . Pharm. Bull, 1978, 26, 2284-85) and Piper genus (A.M.P. Diaz, Planta Medica 1979, 35, 190-191; L. S. Ramos et al. J. Nat. Prod. 1986, 49, 712-713). It was also isolated in 2005 from the Asarum sieboldii plant (J.Y. Lee et al. Pest Manag. Sci. 2005, 61, 821-25). In this work and in JP 2006199619 the antifungal activity of kakuolo and its O-methylether is described against some plant pathogenic fungi, such as P. infestans, P. ultimum, Cercospora beticola, Cladosporium cucumerinum, Rhizoctonia solani, Colletotrichum orbiculare , Botrytis cynerea, Phytophthora capsici, in an activity range from over 100 µgml <-1> to 10 µgml <-1>.

The antifungal activity against plant pathogenic fungi of a series of kakuolo derivatives was later confirmed (L. Musso, PhD thesis in Chemistry, Biochemistry and Ecology of pesticides, University of Milan, 2006).

Description of the invention

It has now been surprisingly found that some analogues of kakuolo, endowed with an unsaturated acyl chain, in particular 2-acryloyl-4,5-methylenedioxyphenol and its analogues, have a high antifungal activity against dermatophytes, from one to two orders of larger than that of the kakuolo.

The present invention provides compounds of formula (I)

R.

R5

7

OR OR1

R2

R4

OR

R8R6O R3

(THE)

and their stereoisomers, where

R1Ã ̈ hydrogen, C1-18 alkyl, haloalkyl, C1-4 alkoxy C1-6 alkyl, substituted aryl, substituted heteroaryl, where the substituent is selected from halogen, nitro, amino, OH, C1-4 alkoxy;

R2 and R3, the same or different, are hydrogen or C1-6 alkyl, aryl, halogen, C1-4 alkoxy, nitro, amino, C1-C4 alkylamino, C1-4 alkylthio;

R4Ã ̈ hydrogen, C1-18 alkyl, C1-18 alkenyl, C2-18 alkynyl, C4-18-alkadienyl, phenyl substituted with halogen, cyano, C1-4 alkoxy, C1-4 alkylthio, C1-6 alkyl, haloC1-6 alkyl; 2-hold them; or 3-hold them;

R5 and R6, are hydrogen, halogen, C1-4 alkoxy, nitro, amino, cyano; R7 and R8, the same or different from each other, are hydrogen, C1-6 alkyl, aryl; R7 and R8 being able to constitute, taken together, a cycle with 5, 6, 7 atoms, possibly substituted with C1-6 alkyl, C1-4 alkoxy, halogen, amino;

R2 and R4 being in turn able to form a carbocyclic or heterocyclic ring, possibly substituted with C1-6 alkyl, C1-4 alkoxy, halogen, nitro, amino.

By halogen, we mean fluorine, chlorine, bromine and iodine; C1-18 alkyl must be understood as comprising both linear and branched saturated chains such as, for example, methyl, ethyl, propyl, butyl, isobutyl, pentyl, neopentyl or thin, etc .; haloalkyl defines C1-18 alkyl where at least one hydrogen atom is replaced by a halogen atom, or also all hydrogen atoms are replaced by halogen atoms such as, for example, fluoromethyl, difluoromethyl, trifluoromethyl, nonafluorobutyl.

Aryl is preferably phenyl or naphthyl, more preferably phenyl. Heteroaryl is preferably pyridyl, thienyl, furyl, imidazolyl, thiazolyl, pyrimidinyl, pyrazinyl.

Preferred compounds of formula (I) are those in which:

R1Ã ̈ hydrogen or C1-6 alkyl;

R 2 and R3, the same or different from each other, are hydrogen or C1-6 alkyl;

R4Ã hydrogen or C1-6 alkyl

R5 and R6 are hydrogen.

Among these, the compounds in which R1 is hydrogen are of even more particular interest.

Particularly preferred is the compound in which R1-R6 are hydrogen, while R7 and R8 constitute a methylenedioxy cycle (R7 = R8 = CH2).

The invention also relates to the salts of the compounds of formula I, in particular the pharmaceutically acceptable salts. However, salts of non-pharmaceutically acceptable acids or bases may find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

The salts can conveniently be obtained by treating the base with suitable acids such as inorganic acids, for example halogenhydric acids, sulfuric acid, nitric acid, phosphoric acids; or organic acids, for example acetic, trifluoroacetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1,2,3-propantricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexylsulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like.

Other salts can be obtained by treating the compounds of formula (I) with suitable inorganic bases, for example hydroxides or carbonates of sodium, potassium, calcium or magnesium, or with organic bases, such as hydroxides of trialkylammonium, diazabicyclononene, trimethylamine, diisopropylethylamine and the like. .

The term salts also includes any hydrated or solvated forms of the compounds of formula (I), for example hydrates, alcoholates and the like. The term â € œstereoisomersâ € as used above defines all the possible stereoisomeric forms of the compounds of formula (I), whether they are enantiomers, enantiomeric mixtures or diastereoisomeric mixtures. Unless otherwise indicated, the chemical name of the compounds indicates the mixture of all possible stereoisomeric forms, therefore both of diastereomers and enantiomers.

The compounds of the present invention can be prepared as exemplified in the reaction scheme, by reacting a suitable salt, typically the magnesium salt of a 3,4-alkylenedioxyphenol with a suitable acyl chloride in a solvent such as toluene or other non-polar solvent, to room temperature, to give a mixture of the phenolic ester (2) and the product of formula (1), which can be separated by crystallization or chromatography, as indicated by L. Musso in the aforementioned thesis.

Scheme

O OHOOH O O R

O O R O O

OR

(1) (2)

The compounds of formula (I), their salts and their stereoisomers have proved to be effective agents for fighting fungi in vitro and in vivo. In vitro experiments, aimed at verifying the sensitivity of fungi towards these compounds, as described in the following examples, demonstrate or? indicate that they possess a marked inhibitory activity towards the growth of a wide range of fungi, such as for example Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Aspergillus spp., eg. Aspergillus fumigatus, Aspergillus niger, Mucor mucedo, Penicillium sp., Epidermophyton floccosum; Microsporum canis; Trichophyton spp., E.g. Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton quinckeanum, as well as dematiaceous hypomycetes.

The results achieved demonstrate the effectiveness of the compounds of the invention for the treatment of fungal infections.

The invention therefore also relates to the use of a compound of formula (I) in the preparation of a medicament for the treatment of fungal infections and pharmaceutical compositions for oral, rectal, topical, percutaneous, transungual administration, or for parenteral injection, comprising a therapeutically effective amount of a compound of formula (I) and pharmaceutically acceptable excipients. Their preparation can take place with conventional procedures.

For example, for the preparation of compositions for oral administration, any of the usual pharmaceutical excipients, e.g. water, glycols, oils, alcohols and the like in the case of liquid preparations such as suspensions, syrups, emulsions, elixirs and solutions; or solid excipients such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets.

Compositions suitable for topical administration include creams, gels, emulsions, shampoos, tinctures, pastes, ointments, ointments, powders, transdermal patches, spot-ons, ointments and the like. In compositions suitable for dermal administration, the excipient may comprise an agent which facilitates penetration and / or a suitable wetting agent, optionally combined with suitable additives in smaller proportions.

Compositions for nail use are in the form of a solution and the excipient may include an agent that facilitates penetration into and through the keratinized layer of the nail. Solvents include water mixed with a cosolvent such as a 1-6 carbon alcohol, e.g. ethanol.

For parenteral compositions, the excipient mostly comprises sterile water, a saline solution, glucose or a mixture thereof. The injectable suspensions can be prepared with suitable liquid excipients, suspending agents and the like. For parenteral compositions, other ingredients may be added to facilitate solubility, e.g. cyclodextrins. Other compositions suitable for oral or rectal administration include particles consisting of a solid dispersion of a compound of formula (I) and one or more pharmaceutically acceptable water-soluble polymers.

The aforementioned pharmaceutical forms may also contain another compound effective as an antifungal, such as cell wall active compounds. The term cell wall active compound as used herein means any compound that interferes with the cell wall of fungi. Examples of antifungal compounds suitable for use in combination with the compounds of formula (I) include known azoles such as fluconazole, voriconazole, itraconazole, ketoconazole, miconazole, eberconazole, ER 30346, SCH 56592, ZD-0870, UK-292663; squalene epoxidase inhibitors such as terbinafine and butenafine; polyenes such as amphotericin B, nystatin, nucleotide inhibitors such as flucytosine; polyoxins and nikkomycins, or other chitin inhibitors.

From the results of the tests reported here an expert in the treatment of warm-blooded animals suffering from fungal infections can easily derive the therapeutically effective daily dose. In general, an effective daily dose is believed to be between 0.05 mg / kg and 20 mg / kg body weight.

Determination of antifungal activity

For the study of the antifungal activity in vitro fresh solutions in dimethyl sulfoxide of the samples to be tested were prepared every day, on the basis of the weight / volume ratio, without corrections for the variation in volume due to the compounds.

The fungal strains were obtained from mycotecas such as ATCC (American Type Culture Collection) or NCPF (National Collection of Pathogenic fungi member of UKNCC - United Kingdom National Culture Collection) or from the collection of the Higher Institute of Health, or from hospitals, and university institutes.

The following were used as culture media:

RPMI 1640 (2% glucose) with L-glutamine and without sodium bicarbonate, to the extent of the sensitivity of the fungi to the test;

Sabouraud broth (SB): peptone / dextrose, as a growth medium in the preparation of inocula, both prepared according to the suppliers' instructions and sterilized in an autoclave.

Preparation of the inocula

a) for yeasts: mushroom cultures in SB overnight were diluted 1:10 in the same sterile medium. Fungal suspensions were adjusted to 1x10 <5> cells / mL using a 0.5 McFarland turbidity standard using RPMI 1640 medium;

b) for filamentous fungi: 3-4 day cultures on Saboraud agar were taken with a suitable instrument using Sabouraud broth as medium to which Tween 80 (0.5%) was added. The suspension of the conidia was counted in a BÃ1⁄4rker chamber and standardized at 1x10 <5> cells / ml in RPMI 1640;

c) for dermatophytes: 6-7-day cultures in Sabouraud agar were collected with a suitable rubber instrument using Sabouraud broth as medium to which Tween 80 (0.5%) was added. The suspension of the conidia was counted in a BÃ1⁄4rker chamber and standardized at 2x10 <5> cells / ml in RPMI 1640.

Preparation of the plates

For each sample to be tested, 0.1 ml of each prepared solution of suitable concentration were introduced (two for each concentration) into the wells of a microtiter. Then 0.1 ml of the fungal suspensions were added to each well. In this way a 1: 2 dilution was obtained for both the samples and the mushrooms.

Final concentrations

Yeast and filamentous fungi: 5x10 <4> cells / ml

Dermatophytes: 1x10 <5> cells / ml

Samples: range from 128 mcg / mL to 0.25 mcg / mL in a final volume of 0.2 mL

Vehicle: range from 12.8% to 0.025%

Incubation: the microtitulators thus prepared were incubated at 35 ° C for 48 hours (for yeasts and filamentous fungi) or at 28 ° C for 7 days (for dermatophytes).

The concentration of the samples that did not cause visible turbidity or, at least, a growth inhibition of> 50% (for yeasts) was considered to be MIC. To consider a compound effective against filamentous fungi or dermatophytes, the absence of turbidity or an inhibition of growth> 80% was considered.

In the following Tables, by compound ° 1a we mean 2-acryloyl-4,5-methylenedioxyphenol, that is the compound of formula (I) where R1-R6 are hydrogen and R7 and R8 constitute a methylenedioxy cycle (R7 = R8 = CH2).

Table 1. Minimum inhibitory concentration (MIC, mcg / ml) of kakuolo, compound 1a and the standard compound miconazole against

yeasts.

Kakuolo 1a yeast Miconazole Candida albicans ISS 1 128.0 0.5 1.0 Candida albicans 562 128.0 8.0 8.0 Candida tropicalis ISS 1 128.0 4.0 4.0 Candida krusei 128.0 0.5 1.0 Candida albicans IDI D 01011 4.0 16.0 Candida albicans 3575 4.0 16.0 Candida albicans SG 2 III 4.0 4.0 Candida albicans 700-94 4.0 16.0 Candida albicans PG 4, 0 8.0 Candida albicans CA2 8.0 16.0 Candida guillermondii ISS 1 8.0 1.0 Candida krusei IDI D 1046 1.0 4.0 Candida tropicalis 5705 8.0 8.0 Saccharomyces cerevisiae ATCC 7752 128.0 <0.25 <0.25

Table 2. Minimum Inhibitory Concentration (MIC, mcg / mL) of

kakuolo, compound 1a and the standard compound miconazole vs.

filamentous fungi

Kakuolo 1a strain Miconazole Fusarium sp. F77> 64 2.0 16.0

Mucor mucedo ATCC 7941> 64 2.0 16.0 Penicillium sp. 1302> 64 8.0 4.0 Aspergillus niger ATCC 16404> 64 8.0 8.0 Aspergillus fumigatus ATCC 28212> 64 8.0 8.0 Sepulariopsis brevicaulis SG 3 II 0.5 8.0 Cephalosprium sp. SG 11 III 4.0 8.0 Aspergillus fumigatus G.S 16.0 4.0

Table 3. Minimum Inhibitory Concentration (MIC, mcg / mL) of

kakuolo, compound 1a and the standard compound miconazole against dermatophytes

Strain Kakuolo 1a Miconazole Trichophyton rubrum IDI D 1155> 32.0 0.5 2.0 Trichophyton mentagrophytes IDI D 1049> 32.0 0.5 2.0 Trichophyton quinckeanum NCPF 309> 32.0 0.5 2.0 Microsporum canis IMM 3864> 32.0 0.5 2.0 Epidermophyton floccosum SG 3 III> 32.0 0.5 0.5 Trichophyton rubrum SG 10 III <0.25 1.0 Trichophyton rubrum SG 9 II <0.25 0, 5 Trichophyton mentagrophytes SG 1 I <0.25 0.5 Trichophyton soudanense SG 10 I 0.5 0.5 Trichophyton album SG IDI D 0250 8.0 8.0 Trichophyton violaceum IDI D 0086I <0.25 1.0 Microsporum canis IDI D 1011 <0.25 1.0 Microsporum gipseum SG 4 I <0.25 2.0 Epidermophyton floccosum IDI D 0011 <0.25 <0.25

The following examples illustrate the invention in greater detail

Example 1 - preparation of compounds (I)

1- (6-Hydroxy-benzo [1,3] dioxol-5-yl) -propenone (1a). To one

suspension of magnesium shavings (395 mg, 16.29 mmoles) in diethyl ether

anhydrous (8 ml) at about 30-35 ° C methyldide (1 ml, 16.29 mmoles) is added and

it is left to react under stirring until the complete dissolution of the magnesium.

A solution of 3,4-methylenedioxyphenol (1.5 g, 10.86

mmoles) in anhydrous ethyl ether (8 ml) and it is left to react for 1 h. After removing

the ethyl ether the phenate is suspended in anhydrous toluene (16 ml) the

suspension at 0 ° C and acryloyl chloride (880 µl, 10.86

mmoles). It is left to react at room temperature 16h. The reaction mixture

it is poured into a saturated solution of NH4Cl and extracted with ethyl acetate.

The solution is dried (Na2SO4) and the solvent removed by evaporation. The crude obtained is purified by flash chromatography with hexane: ethyl acetate 95: 5, 1.37 g of product are obtained. M.p .: 117-118 ° C.

<1> H-NMR: Î ́ 13.49 (s, 1H, OH); 7.13 (s, 1H, Ar); 7.13 (dd, 1H, -CH = CH2, J = 10.42, 16.75); 6.52 (dd, 1H, -CH = CHH, J = 1.49, 16.75); 6.48 (s, 1H, Ar); 5.99 (s, 2H, -OCH2O-); 5.90 (dd, 1H, -CH = CHH, J = 1.49, 10.42).

The following compounds were synthesized with a similar procedure:

1- (6-Hydroxy-benzo [1,3] dioxol-5-yl) -2-methyl-propenone. M.p .: 78-79 ° C.

<1> H-NMR: Î ́ 12.87 (s, 1H, -OH); 7.12 (s, 1H, Ar); 6.97 (s, 1H, Ar); 6.30 (s, 1H,> C = CH2); 5.99 (s, 2H, -OCH2O-); 5.75 (s, 1H,> C = CH2); 2.02 (s, 3H, -CH3).

1- (6-Hydroxy-benzo [1,3] dioxol-5-yl) -3-methyl-but-2-en-1-one. M.p .: 104-106 ° C. <1> H-NMR: Î ́ 13.64 (s, 1H, -OH); 7.11 (s, 1H, Ar); 6.56 (m, 1H, -HC = C (CH3) 2); 6.44 (s, 1H, Ar); 5.96 (s, 2H, -OCH2O-); 2.16 (d, 3H, -CH3, J = 1.12); 2.00 (d, 3H, -CH3, J = 1.12).

1- (6-Methoxy-benzo [1,3] dioxol-5-yl) -propenone. To a solution of 1- (6-hydroxy-benzo [1,3] dioxol-5-yl) -propenone (56 mg, 0.29 mmol) in acetone is added potassium carbonate (40 mg, 0.29 mmol) and methylodide (43 µl, 0.69 mmoles) and heated under reflux for 10 hours. The solvent is evaporated and the raw material is taken up with ethyl acetate, the organic phase is washed with water and brine, anhydrified and dried. The crude is purified by flash chromatography with hexane: ethyl acetate 9: 1. 57 mg of product are obtained. <1> H-NMR: Î ́ 7.25 (s, 1H, Ar); 7.15 (dd, 1H, -CH = CH2, J = 10.42, 16.75); 6.57 (s, 1H, Ar) 6.30 (dd, 1H, -CH = CHH, J = 1.49, 16.75); 6.00 (s, 2H, -OCH2O-); 5.70 (dd, 1H, -CH = CHH, J = 1.49, 10.42) 3.92 (s, 3H, CH3O-).

Example 2 - Composition for nail use

0.144 g H3PO49 g NaCl, 0.528 g Na2HPO4.2H2O are added to 800 ml H2O and the mixture is stirred. The pH is adjusted to 7.4 with NaOH and 500 mg NaN3 are added. Ethanol (42 v / v%) is added and the pH is adjusted to 2.3 with HCl. 15 mg of active ingredient is added to 2.25 ml PBS (Phosphate Buffer Saline) / Ethanol (42%; pH 2.3) and the mixture is stirred and sonicated with ultrasound. 0.25 ml PBS / Ethanol (42%; pH 2.3) are added and the mixture is further stirred and sonicated until all the active ingredient is dissolved.

Example 3 - Capsules

A mixture of 20 grams of the active ingredient, 6 grams of sodium lauryl sulfate, 56 grams of starch, 56 grams of lactose, 0.8 grams of colloidal silicon dioxide, and 1.2 grams of magnesium stearate is vigorously stirred. The resulting mixture is introduced in 1000 capsules of suitable hardened gelatin, each capsule containing 20 mg of active ingredient.

Example 4 - Film coated tablets

a) Preparation of the tablet

A mixture of 100 g of active ingredient, 570 grams of lactose and 200 grams of starch are well mixed and moistened with a solution of 5 grams of sodium dodecyl sulfate and 10 grams of polyvinylpyrrolidone in about 200 ml of water. The wet powder is sieved, dried and sieved again. 100 grams of microcrystalline cellulose and 15 grams of hydrogenated vegetable oil are added. The whole is well mixed and compressed into tablets, giving 10000 tablets, each containing 10 mg of active ingredient.

b) Coating

A solution of 5 grams of ethyl cellulose in 150 ml of dichloromethane is added to a solution of 10 grams of methylcellulose in 75 ml of denatured ethyl alcohol. Then 75 ml of dichloromethane and 2.5 ml of 1,2,3-propantriol are added. 10 grams of polyethylene glycol are melted and dissolved in 75 ml of dichloromethane. This solution is added to the first; 2.5 grams of magnesium octadecanoate, 5 grams of polyvinylpyrrolidone and 30 ml of a concentrated suspension of a dye are added and the whole is homogenized. The tablets are coated with this mixture in a suitable coating apparatus.

Example 5 - 2% cream

Stearyl alcohol (75 mg), cetyl alcohol (20 mg), sorbitan monostearate (20 mg) and isopropyl myristate (10 mg) are placed in a double-jacketed vessel and the mixture is heated until completely melted. This mixture is added to a separately prepared mixture of pure water, propylene glycol (200 mg) and polysorbate 60 (15 mg) at a temperature of 70-75 ° C, using a liquid homogenizer. The resulting mixture is left to cool below 25 ° C, always under stirring. A solution of the active ingredient (20 mg), polysorbate 80 (1 mg) and pure water as required for 1 g and a solution of anhydrous sodium sulphite (2 mg) in pure water is then added to the emulsion, always stirring. The cream is homogenized and introduced into the appropriate tubes.

Example 6 - 2% cream

A mixture of the active ingredient (2 g), phosphatidylcholine (20 g), cholesterol (5 g) and ethyl alcohol (10 g) is heated under stirring at 55-60 ° C until completely dissolved and added to a solution of methyl paraben (0.2 g), propyl paraben (0.02 g), edetate disodium (0.15 g) and sodium chloride (0.3 g) in pure water (at 100 g) in a homogenizer. Hydroxypropylmethylcellulose (1.5g) in pure water is added and the mixture stirred until the swelling process is complete.

Claims (10)

CLAIMS 1. Compounds of formula (I) R. R5 7 OR O1 R2 R4 OR R8R6O R3 (THE) and their stereoisomers, where R1Ã ̈ hydrogen, C1-18 alkyl, haloalkyl, C1-4 alkoxy C1-6 alkyl, substituted aryl, substituted heteroaryl, where the substituent is selected from halogen, nitro, amino, OH, C1-4 alkoxy; R2 and R3, the same or different, are hydrogen or C1-6 alkyl, aryl, halogen, C1-4 alkoxy, nitro, amino, C1-4 alkylamino, C1-4 alkylthio; R4Ã ̈ hydrogen, C1-18 alkyl, C1-18 alkenyl, C2-18 alkynyl, C4-18-alkadienyl, phenyl substituted with halogen, cyano, C1-4 alkoxy, C1-4 alkylthio, C1-6 alkyl, haloC1-6 alkyl; 2-hold them; or 3-hold them; R5 and R6, are hydrogen, halogen, C1-4 alkoxy, nitro, amino, cyano; R7 and R8, the same or different from each other, are hydrogen, C1-6 alkyl, aryl; R7 and R8 being able to constitute, taken together, a cycle with 5, 6, 7 atoms, possibly substituted with C1-6 alkyl, C1-4 alkoxy, halogen, amino; R2 and R4 being able in turn to form a carbocyclic or heterocyclic ring, possibly substituted with C1-6 alkyl, C1-4 alkoxy, halogen, nitro, amino. 2. Compounds according to claim 1 wherein: R1Ã ̈ hydrogen or C1-6 alkyl; R 2 and R3, the same or different from each other, are hydrogen or C1-6 alkyl; R4Ã ̈ hydrogen or C1-6 alkyl; R5 and R6 are hydrogen. 3. Compounds according to claim 2 wherein R1 is hydrogen. 4. Compound according to claim 3 wherein R1-R6 are hydrogen, while R7 and R8 constitute a methylenedioxy cycle (R7 = R8 = CH2). 5. Use of the compounds of claims 1-4 for the preparation of anti-fungal medicaments. Use according to claim 5 wherein the medicaments are useful for the treatment of dermatophyte infections. 7. Pharmaceutical compositions comprising a compound of claims 1-4 in admixture with suitable excipients. 8. Pharmaceutical compositions according to claim 7 further containing one or more compounds active on the cell walls of the fungi. 9. Compositions according to claim 8 wherein the cell wall active compounds are selected from the group consisting of fluconazole, voriconazole, itraconazole, ketoconazole, miconazole, eberconazole, ER 30346, SCH 56592, ZD-0870, UK-292663; terbinafine and butenafine; amphotericin B, nystatin, flucytosine; polyoxins and nikkomycins. 10. Compositions according to one or more of claims 7 to 9 for oral, rectal, topical, percutaneous, transungual or parenteral administration.