AP875A

AP875A - Azole compounds with antimycotic activity for human and veterinary use.

Info

Publication number: AP875A
Application number: APAP/P/1997/001100A
Authority: AP
Inventors: Enrico Albini; Giovanna Schioppacassi
Original assignee: Zambon Spa; Isagro Spa
Priority date: 1995-04-07
Filing date: 1996-04-02
Publication date: 2000-09-27
Also published as: EA199700299A1; ES2164882T3; ITMI950707A0; AU5499496A; DE69616531T2; HUP9801596A1; KR100418128B1; CZ289586B6; MX9707672A; JPH11503141A; AP9701100A0; OA10522A; SK135197A3; CA2217695A1; ITMI950707A1; SK282902B6; KR19980703669A; PT819124E; ATE207909T1; HUP9801596A3

Abstract

Compounds of formula (II), wherein RI is chlorine, fluorine or trifluoromcthyl; Rz is hydrogen, chlorine, fluorine or trifluoromethyl; T. is CH or N; Rs, R4 and Rs, the same or different are hydrogen or Ci-C4 alkyl, provided that R4 is different from Rj when Rs is hydrogen; X is O or S; RA is a Ci-Cs polyfluoroalkyl group containing at least two fluorine atoms a internationally other halogen atoms selected among chlorine and bromine; and their salts with pharmaceutically acceptable acids, are described. The compounds of formula (II) are endowed with antimycotic activity for human and veterinary use.

Description

Azole compounds with antimycotic activity for human and veterinary use *****************************

The present invention relates to compounds with antimycotic activity for human and veteri5 nary use and, more particularly, it relates to azole compounds with antimycotic activity useful for the treatment and prophylaxis of infections caused by fungi and yeasts in human and in animals.

Among the antimycotic compounds known in the literature, the so-called azole derivatives among which there are some compounds used in therapy such as Fluconazole (The Merck

Index, XI ed., No. 4054, page 645), Itraconazole (The Merck Index, XI ed., No. 5131, page 825) and Ketoconazole (The Merck Index, XI ed., No. 5181, page 835) represent a relevant portion.

As far as we know, however, none of these compounds is endowed with a significant antimycotic activity against some pathogenic opportunistic fungal strains which induce infections, sometimes fatal, in immunodepressed patients.

Among the azole derivatives known as antimycotic for human or veterinary use, several compounds have been described which are characterized by the presence of a tertiary alcohol function of formula

Az

AP/P/ 9 7/01100 wherein Az is a triazole or imidazole group, X is preferably chlorine, fluorine or trifluoro25 methyl, R is preferably hydrogen, chlorine or fluorine, R' and R, the same or different, are hydrogens or alkyls, Y is S, SO, SO2 or 0 and A is alkyl;

which hereinafter will be indicated with the term azole tertiary alcohols.

Among these azole tertiary alcohols we cite, for example, the compounds described in the European patent applications No. 54974 (Sumitomo Chemical Company Limited), No. 61835 (Imperial Chemical Industries PLC), No. 107392 (Pfizer Limited), No. 140154 (Sumitomo Chemical Company Limited), No. 178533 (Sumitomo Pharmaceutical Company Limited),

APO 0 0 8 7 5

-2No. 435081 (SS Pharmaceutical Co. Ltd.) and No. 473387 (Sankyo Company Limited).

For some of these compounds a remarkable antimycotic activity for topic as well as for systemic use has been reported, sometimes generically. However, as far as we know, the only compound under study is a compound known as Genaconazole, (2R,3R) a-(2,4-difluorophenyl)-a.-[l-(methylsulfonyl)ethyl]-lH-l,2,4-triazol-l-ethanol, described in the European patent application No. 178533.

Very recently, a class of azole tertiary alcohols (I) with antimycotic activity wherein R' and R are fluorine atoms, Y is a simple bond and A is a difluoromethyl group has been described [Japanese patent application No. 07/70087 in the name of Taisho Pharma Co. Ltd. - Chemical

Abstracts, vol. 123, No. 228190 (1995)].

We have know found that a class of azole derivatives of formula

N (Π) *1 wherein

Rj is chlorine, fluorine ortrifluoromethyl;

R2 is hydrogen, chlorine, fluorine or trifluoromethyl;

ZisCHorN;

R3, R4 and R5, the same or different, are hydrogen or C1-C4 alkyl, provided that R4 is dif25 ferent from R5 when R3 is hydrogen;

X is O or S;

R5 is a C1-C5 polyfluoroalkyl group containing at least two fluorine atoms and optionally other halogen atoms selected among chlorine and bromine;

described in the European patent application No. 315946 (Presidenza del Consiglio dei Mini30 stri - UfScio del Ministero per il Coordinamento delle Iniziative per la Ricerca Scientifica e

Tecnologica) as compounds for agriculture use having immunizing activity against fungal pathogenesis and phytogrowth regulating activity towards useful growings, is endowed with a

AP/P/ 9 7/01100

AP OOO875

--3-, potent antimycotic activity against a wide range of pathogenic fungi in human and in animals, in particular also against fungal strains resistant to antimvcotics used in therapy and azainst opportunistic pathogenic fungal strains responsible for infections in immunodepressed pa5 tients, and is active for topical as well as for systemic route.

Therefore, object of the present inventions are compounds of formula

wherein

Rj is chlorine, fluorine or trifluoromethyi;

, R£ is hydrogen, chlorine, fluorine or trifluoromethyi;

Z is CH or N;

R3, R4 and R5, the same or different, are hydrogen or C1-C4 alkyl, provided that R4 is different from R5 when R3 is hydrogen;

X is 0 or S;

R^ is a Cj-Cj polyfluoroalkyl group containing at least two fluorine atoms and optionally other halogen atoms selected among chlorine and bromine; and their salts with pharmaceutically acceptable acids;

the compounds 1-(1H-1,2,4-triazolyi)-2-hydroxy-2-(2,4-dichlorophenyl)-3-methyI-4-(l, 1,2,225 tetrafluoroethoxyjbutane, l-(lH-l,2,4-triazolyl)-2-hydroxy-2-(2,4-dichlorophenyl)-3-methyl4-(1,1,2,2-tetrafluoroethoxy)hexane, 1-( 1H-1,2,4-triazolyl )-2-hydroxy-2-(4-chlorophenyi)3,3-dimethyl-4-( 1,l,2,2-tetrafluoroethoxy)butane and 1 -(1 Η-1,2,4-triazolyl)-2-hydroxy-2-(4chlorophenyl)-3-methyl-4-(l,l,2,2-tetrafluoroethoxy)butane being excluded.

A further object of the present invention are the compounds l-(lH-l,2,4-triazolyl)-2-hydroxy30 2-(2,4-dichlorophenyl)-3-methyl-4-(l,l,2,2-tetrafluoroethoxy)butane, l-0H-I,2,4-triazolyl}2-hydroxy-2-(2,4-dichlorophenyl)-3-methyl-4-(l,l,2,2-tetrafluoroethoxy)hexane, 1-(1H-1,2,4triazolyl)-2-hydroxy-2-(4-chlorophenyl)-3,3-dimethyl-4-( 1,1,2,2-tetrafluoroethoxy)butane

AP Ο ΰ Ο 8 7 5

-4and l-(lH-l,2,4-triazolyl)-2-hydroxy-2-(4-chlorophenyl>3-methyl-4-(l,l,2,2-tetrafluoroethoxy)butane, specifically exemplified in the European patent application No. 351946, for use as a medicament.

For the sake of simplicity, all the compounds object of the present invention comprised the compounds for use as a medicament only will be indicated hereinafter as compounds of formula Π.

The compounds of formula Π are endowed with a potent wide-range antimycotic activity, in particular against Candida spp and Cryptococcus neoformans strains, which are Fluconazole and Itraconazole-resistant, and against Candida glabrata, Candida krusei, Aspergillus spp and Fusarium spp, which are Itraconazole-resistant and, as the previous ones, pathogenic strains responsible for mycotic infections in immunodepressed patients, and are useful for the treatment and the prophylaxis of infections caused by fungi and yeasts in human and in animals.

The compounds of formula H contain at least a chiral center and then they can be in the form of stereoisomers.

The single stereoisomers of the compounds of formula Π as well as their mixtures fall within the present invention.

With the term C4-C4 alkyl among the meanings of R3, R4 and R5, we intend methyl, ethyl,

n.propyl, isopropyl, n.butyl, isobutyl, sec.butyl andt.butyl groups, methyl and ethyl being preferred.

With the term C1-C5 polyfluoroalkyl group containing at least two fluorine atoms we preferably intend difluoromethyl, trifluoromethyl, l,l,2-trifluoro-2-chloroethyl groups, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, 1,1,2-trifluoroethyl, 1,1,2,3,3,3-hexafluoropropyl, 2,2,3,325 tetrafluoropropyl, 1,1,2,2-tetrafluoroethyl and their isomers; the 1,1,2,2-tetrafluoroethyl group being still more preferred.

The salts of the compounds of formula H are salts with pharmaceutically acceptable organic or inorganic acids such as chloridric, bromidric, iodidric, sulfuric, nitric, fosforic, acetic, oxalic, maleic, benzoic, benzenesulfonic, 4-methylbenzenesulfonic, fumaric, lactic, tartaric, citric and gluconic acid.

Preferred compounds of formula Π are compounds wherein R] is chlorine or fluorine, Rg is

AP/P/97/01 100

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-5hydrogen, chlorine or fluorine, R3 is methyl, R4 and R5, the same or different, are hydrogen, methyl or ethyl, Z is N and R5 is a 1,1,2,2-tetrafluoroethyl group.

Still more preferred compounds of formula Π are compounds wherein Rj is chlorine or fluo5 rine, R£ is hydrogen, chlorine or fluorine, R3 is methyl, R4 and R5, the same or different, are hydrogen, methyl or ethyl, Z is N and R^ is a 1,1,2,2-tetrafluoroethyl group and X is 0. Specific examples of preferred compounds of formula Π are the following:

-(1H-1,2,4-triazolyi>2-hydroxy-2-(2,4-dichIorophenyi)-3-methyl-4-( 1,1,2,2-tetrafluoroethoxy)butane l-(lH-l,2,4-triazolyl)-2-hydroxy-2-(2,4-dichlorophenyl)-3-methyl-4-(l,l,2,2-tetrafluoroethyIthio)butane

-(1H-1,2,4-tnazolyl)-2-hydroxy-2-(2,4-difluorophenyl>3-methyl -4-(1,1,2,2-tetrafluoroethoxy)butane

1-( 1H-1,2,4-triazolyl)-2-hydroxy-2-(2,4-difluorophenyl)-3-methyl-4-( 1,1,2,2-tetrafluoroethyl15 thio)butane

-(1H-1,2,4-triazolyl>2-hydroxy-2-(4-chlorophenyl)-3-methyI-4-( 1,1,2,2-tetrafluoroethoxy> butane l-(lH-l,2,4-triazolyl)-2-hydroxy-2-(4-chlorophenyl)-3-methyl-4-(l,l,2,2-tetrafluoroethylthio)butane

1-(1H- l,2,4-triazolyl)-2-hydroxy-2-(2,4-difluorophenyl)-3,3-dimethyl-4-( 1,1,2,2-tetrafluoroethoxy)butane

-(1H-1,2,4-triazolyl)-2-hydroxy-2-(2,4-difluorophenyl)-3,3-dimethyl-4-( 1,1,2,2-tetrafluoroethylthio)butane l-(!H-l,2,4-triazolyI)-2-hydroxy-2-(4-fluorophenyl)-3-methyl-4-(l,l,2,2-tetrafluoroethoxy}25 butane

1-( 1H-1,2,4-triazoIyl)-2-hydroxy-2-(4-fluorophenyl)-3-methyl-4-( 1,1,2,2-tetrafluoroethylthio)-butane l-(!H-l,2,4-triazolyl)-2-hydroxy-2-(4-chlorophenyI)-3,3-dimethyl-4-(l,l,2,2-tetrafluoroethoxy)butane

1-(1H-1,2,4-triazolyl)-2-hydroxy-2-(4-chlorophenyI)-3,3-dimethyl-4-( 1,1,2,2-tetrafluoroethylthio)butane

AP/P/ 97/01100

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-6l-(lH-l,2,4-triazolyl)-2-hydroxy-2-(4-fluorophenyl)-3,3-dimethyl-4-(l,l,2,2-tetrafluoroethoxy)butane

1-(1H- l,2,4-triazolyl)-2-hydroxy-2-(4-fluoropheny!)-3,3-dimethyl-4-( 1,1,2,2-tetrafluoroethyi5 thio)butane

1-(1H- 1,2,4-triazolyI)-2-hydroxy-2-(2,4-di chlorophenyl )-3-methyl-4-( 1,1,2,2-tetrafiuoroethoxy)hexane l-(lH-l,2,4-triazolyl)-2-hydroxy-2-(2,4-dichlorophenyl)-3-methyl-4-(l,l,2,2-tetrafluoroethylthio)hexane l-(lH-l,2,4-triazolyl)-2-hydroxy-2-(2,4-difluorophenyl>3-methyl-4-(l,l,2,2-tetrafluoroethoxy)hexane

H1H-1,2,4-triazolyl)-2-hydroxy-2-(2,4-difluorophenyl)-3-methyl-4-( 1, 1,2,2-tetrafiuoroethyl* thio)hexane

1-( 1H-1,2,4-triazolyl)-2-hydroxy-2-(2,4-dichlorophenyl)-3,3-dimethyl-4-( 1,1,2,2-tetrafluoro15 ethoxy)butane

1-(1H-1,2,4-triazolyl>2-hydroxy-2-(2,4-di chlorophenyl )-3,3-dimethyl-4-(l,l, 2,2-tetrafluoroethylthio)butane

The preparation of the compounds of formula Π can be carried out according to synthetic processes described in the already cited European patent application No. 315946.

An alternative method for the preparation of the compounds of formula Π wherein X is O and R^ is a trifluoromethyl group consists in treating an alcohol intermediate of formula

AP/P/ 97/01100

wherein Rj, R₂, R3, R4, R5 and Z have the already reported meanings and X is 0, with car30 bon disulphide and methyliodide under basic conditions and in the subsequent fluorination of the resultant methyidithiocarbonate.

The separation of the stereoisomers of formula H can be earned out with conventional techβΡ Ο ο Ο 8 7 5

-Ί niques such as fractionated crystallization and chromatography.

The preparation of the salts of the compounds of formula Π can be carried out according to conventional techniques, for example by mixing in solution equimolar amounts of the compound of formula Π and of the selected acid and by separating the salt by precipitation and filtration or by evaporation of the solvent.

The compounds of formula Π and their salts are antimycotic compounds useful for the Treatment and the prophylaxis of infections caused by fungi and yeasts in human and animals.

In fact, the compounds of formula Π , object of the present invention, are endowed with an10 timycotic activity against yeasts, filamentosous fungi, dermatophyti and dimorphic fungi.

The antimycotic activity has been evaluated in vitro as IC50 and as MIC (Minimum Inhibiting Concentration) against numerous strains such as, for example, Candida albicans, Cryptococcus neoformans, Trichophyton mentagrophytes, Aspergillus jumigatus, Candida parapsilosis, Candida lusitaniae, Candida kefyr, Candida tropicalis, Candida krusei, Candida glabrata, Aspergillus niger and Fusarium spp.

It is worth underlining that the compounds of formula Π, object of the present invention, resulted to be active against all the tested Candida spp. and Cryptococcus neoformans strains, comprised those Fluconazole, Itraconazole and Genaconazole-resistant

A particularly significant antimycotic activity also resulted against Candida glabrata and

Fusarium spp. strains, Itraconazole and Genaconazole-resistant, and againct Candida krusei and Aspergillus fumigants, Fluconazole and Genaconazole-resistant, all pathogenic strains responsible for infections in immunodepressed patients.

The in vivo antimycotic activity has been evaluated, by intraperitoneal and by oral route, in a Candida model experimentally induced in mouse, against Candida albicans strains sensible to

Fluconazole and Itraconazole.

From the in vivo experiments, the protective dose 50% (PD5Q) of the compounds of formula H has been also determined and it resulted to be at least comparable to that of the reference compounds.

The compounds of formula Π, object of the present invention, are therefore active on wide30 range deep mycosis, but in particular against opportunistic pathogens responsible for infections in immunodepressed patients, administrable by topic, oral and parenteral route and enAP/P/ 97/01100

AP Ο Ο Ο 8 7 5

-8dowed with a good therapeutic index.

The compounds of formula H are then useful in human or veterinary therapy for the treatment and prophylaxis of systemic and mucosal infections caused by fungi and yeasts.

The significant pharmacological activity of the compounds of formula Π which, as already underlined, also results against strains resistant to antimycotic used in therapy and against recently isolated strains responsible for infections in immunodepressed patients, is particularly surprising in that such compounds are described in the European patent application No. 315946 as compounds for agriculture use only, having immunizing activity against fungal pathogenesis and phytoregulating activity on useful growings.

The pharmacological activity of the compounds of formula Π is still more surprising if it is considered that such compounds, while having some structural requirements common to the azole tertiary alcohols described in the literature, are characterized by the presence of a chain with two carbon atoms between the carbon atom bearing the hydroxy group and the oxygen or sulphur atom and by the presence of a polyfluorinated alkyl in the ether or thioether function. These structural requirements have never been described in the literature in combination each other, as far as we know, within the field of compounds of the class of azole tertiary alcohols with antifungal activity.

In this connection, the peculiarity of the structural requirements of the compounds of formula

H, object of the present invention, is extremely surprising by considering that compounds having very similar structural requirements, such as the compound identified as Rl and R2 namely l-(lH-l,2,4-triazolyl)-2-hydroxy-2-(2,4-difluorophenyl)-3.3-dimethyl-4-ethoxybutane and l-(lH-l,2,4-triazolyl)-2-hydroxy-2-(2,4-difluorophenyl)-3-(2,2,3,3-tetTafluoropropoxy)butane, are substantially inactive in comparison with the compounds of formula Π.

For the human or veterinary use, the compounds of formula Π can be administered in admixture with a suitable carrier depending on the kind of administration route.

Therefore, the pharmaceutical compositions containing a compound of formula Π in admixture with a pharmaceutically acceptable carrier are a further object of the present invention.

The compounds of formula Π or their salts can be orally administered in the form of tablets, capsules, solutions or suspensions.

For the parenteral administration, for example by intravenous, intramuscular or subcutaneous

AP/P/ 97/01100 flPO 0 0 8 7 5 .9.

route, the compounds of formula H or their salts will be in the form of sterile aqueous solutions.

Alternatively, the compounds of formula Π or their salts can be administered in the form of 5 suppositories or pessaries.

For the topical administration the compounds of formula Π or their salts will be preferably formulated as creams or powders.

For the oral or parenteral administration the daily dose of the compound of formula Π will be generally from 0.1 to 50 mg/kg, preferably from 1 and 20 mg/kg, to be divided in one or more intervalled doses.

In order to better illustrate the present invention the following examples are now given.

Example 1

The following compounds were prepared according to the procedures described in the European patent application No. 315946.

f±)-l-flH-1.2.4-triazolvl)-2-hvdroxv-2-(2,4-dichlorophenvl)-3-methvl-4-fI.1.2.2-tetrafluoroethoxvlbutane (Compound 1) fi)-l-flH-1.2.4-triazolvl)-2-hvdroxv-2-(2,4-dichlorophenvl)-3-methvl-4-('I.I.2.2‘tetrafluoroethoxy)hexane (Compound 2) ί±)-1 -f IH-1.2.4-triazolyl)-2-hvdroxv-2-(' 4-chlorophenvl)-3,3-dimethvl-4-( 1.1.2.2-tetrafluoro20 ethoxv)butane (Compound 3) f±>-1 -f IH- 1.2.4-triazolyl)-2-hvdroxv-2-f4-chlorophenvl)-3-methvl-4-f 1,1,2.2-tetrafluoroethoxvlbutane (Compound 4)

Example 2

Preparation of (±)- 1-f IH-I.2.4-triazolyl)-2-hvdroxv-(2.4-difluoroohenvt)-3.3-dimethvl-425 n.l.2.2-tetrafluoroethoxv)butane (Compound 5)

Potassium hydroxide powder (5.33 mg; 9.50 mmoles) was added to a solution of (±)-3-(2,4difluorophenyl)-2,2-dimethyl-4-(lH-l,2,4-triazolyl)-l,3-butanediol (5 g; 16.8 mmoles) and dimethylsulphoxide (8 ml) in toluene (60 ml), under stirring at -5°C.

The reaction atmosphere was substituted by tetrafluoroethylene and the mixture was kept un30 der stirring at -5°C for 90 minutes.

After addition of water (120 ml), the organic phase was washed with 5% hydrochloric acid

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- 10(80 ml) and treated with anhydrous sodium bicarbonate (6.5 g) under stirring for 30 minutes. The liquid phase was filtered and the solvent was evaporated under reduced pressure to give an oil residue which was purified by flash chromatography (eluent hexane.ethyl acetate=6:4).

Compound 5 (5.7 g; 85% yield) was obtained as a white solid. m.p. 81-82.5°C iH-NMR (CDC1₃): 8.01 (d, 1H, CH-tetr.); 7.69 (s, 1H, CH-cat); 7.63-6.56 (m, 3H, Ar); 5.70 (tt, IH, JHF=53.4 Hz, CHF₂); 5.33 (bs, 1H, OH); 5.29-4.41 (m, 2H, CH₂-triazole), AB system; VA=4.19, VB=3.75, JAB=9.8 Hz, CH₂O; 1.06 (d, 3H, JHF=2.4 Hz, CH₃); 0.98 (s,

3H, CH₃).

By working in a similar way the following compounds were prepared. f±)-l-(lH-1.2.4-triazolvl)-2-hvdroxv-2-(2.4-difluorophenvl)-3-methvl-4-(I.1.2.2-tetrafluoroethoxvlbutane (Compound 6) - 88% yield m.p. 112-114°C ^}H-NMR (CDC1₃); 7.81 and 7.74 (2s, 2H, tetr.); 7.36-6.64 (m, 3H, Ar); 5.73 (tt, 1H, JHF=52.9 Hz, CHF₂); 4.99 (bs, IH, OH); 4.95-4.53 (m, 2H, CH₂-triazole), AB portion of an ABX system: VA=4.46, VB=3.94, JAB=10.2 Hz, JAX=7.3 Hz, JBX=4.9 Hz, CH₂O; 2.632.45 (m, IH, CHCH₃); 0.75 (d, 3H, CH₃CH).

(iH -(IH-1.2.4-triazolvI)-2-hvdroxv-2-(2,4-difluorophenvl)-3-ethvl-4-( 1.1.2.2-tetrafluoroeth20 oxy)butane nitrate (Compound 7) - 80% yield m.p. 144-145°C (acetonitrile - isopropylether) ^}H-NMR (CDC1₃): 9.58 (s, IH, CH-triazole); 8.05 (s, IH, CH-triazole); 7.37-6.67 (m, 3H, Ar); 6.08 (bs, H+); 5.80 (tt, IH, JHF=52.6 Hz, CHF₂), AB system: VA=5.11, VB=4.87, JAB=14.2 Hz, CH₂-triazole; AB portion of an ABX system: VA=4.42, VB=4.21, JAB=11.1

Hz, JAX=7.7 Hz, JBX=2.6 Hz, CH₂O; 2.41-2.30 (m, IH, CHCH₂); 1.32-1.18 (m, 2H, CHCH₂); 0.83 (t, 3H, JHH=7.I Hz, CH₃).

(+)-l-(lH-l, 2.4-triazolyl)-2-hvdroxv-2-(2.4-di chlorophenvl )-3.3-dimethvl -4-(1.1.2.2-tetrafluoroethoxvlbutane (Compound 8) - 67% yield m.p. 102.5-104.5°C (hexane - isopropylether) iH-NMR (CDC1₃): 8.23 and 7.71 (2s, 2H, tnazole); 7.86-7.12 (m, 3H, Ar); 5.57 (tt, IH, JHF=53 Hz, CHF₂); 5.86 (s, IH, OH); AB system: VA=5.86, VB=4.45, JAB=14.3 Hz,

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AP ο Ο Ο 8 7 5

-11 CH₂-triazole; AB system: VA=4.23, VB=3.8O, JAB=9.8 Hz, CH₂O; 1.13 and 1.02 (2s, 6H, 2CH₃).

(±)-l-(lH-l,2,4-triazolvl>2-hvdroxv-2-(2.4-difluorophenvl)-3.3-dimethvl-4-(l, 1,2,3,3.35 hexafluoro-1 -propyQbutane (Compound 9) - 18% yield by substituting tetrafluoroethylene with 1,1,2,,3,3,3,-hexafluoropropene. m.p. 84-85°C (hexane) ^H-NMR (CDCI3): 8.00 (d, 1H, CH-tetr.); 7.69 (s, 1H, CH-cat.); 7.63-6.56 (m, 3H, Ar); 5.84 (bs, 1H, OH); 5.78-4.38 (m, 2H, CH₂-triazoIe); 5.00-4.60 (m, 1H, CHF); 4.35-3.73 (m,

2H, OCH₂); 1.07-1.00 (m, 6H, 2CH₃).

Example 3

Preparation of 3-(2.4-difluorophenyl)-3.4-epoxv-2.2-dimethvlbutanoic acid ethyl ester

A solution of isobutyric acid ethyl ester (1.88 g; 16 mmoles) in tetrahydrofuran (10 ml) was added dropwise to a solution of lithium diisopropylamide (prepared from n.butyllithium, 6.8 ml, 2.5 M solution in hexane and diisopropylamine, 2.38 ml, 1.72 g, 17 mmoles) in tetrahydrofuran (10 ml) at -78°C.

After 30 minutes, a solution of 1-(2,4-difluorophenyl)-2-bromoethanone (4.0 g; 17 mmoles) in tetrahydrofuran (10 ml) was added dropwise by keeping the temperature below -70°C.

The reaction mixture was kept under stirring for 90 minutes and the temperature was allowed to rise up to -30°C.

A saturated aqueous solution of ammonium chloride was added, the phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 25 ml).

The collected organic phases were washed with an aqueous solution of sodium bicarbonate 5% (25 ml) and with water (25 ml), dried on sodium sulphate and evaporated under reduced pressure to give 3-(2,4-difluorophenyI)-3,4-epoxy-2,2-dimethylbutanoic acid ethyl ester (4.2 g; 96% yield) as a light yellow oil.

^-NMR (CDCI3): 7.41-6.67 (m, 3H, Ar); 4.11 (q, 2H, COOCH₂); 3.26-2.71 (m, 2H, CH₂O); 1.22 (t, 3H, CH₃CH₂); 1.20 (s, 6H, 2CH₃).

Example 4

Preparation of 3-(2,4-difluorophenvl)-3.4-epoxv-2,2-dimethvl-l-butanol

Lithium boron hydride (120 mg; 5.5 mmoles) was added to a solution of 3-(2,4-difluorophenAP/P/ 97/01100

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- 12yl>3,4-epoxy-2,2-dimethylbutanoic acid eihyl ester (lg; 3.7 mmoles), prepared as described in example 3, in ethyl ether (10 ml).

After cooling at +10°C, methanol (0.22 ml; 3.5 mmoles) was added dropwise under stirring and the reaction mixture was kept at +10°C under stirring for 2 hours.

Then, a 5% hydrochloric acid solution (15 ml) was added dropwise, the phases were separated and the aqueous phase was extracted with ethyl acetate (2x15 ml).

The collected organic phases were washed with a 5% aqueous solution of sodium bicarbonate (20 ml) and with brine (20 ml), dried on sodium sulphate and evaporated under reduced pres10 sure to give an oil residue (0.8 g) which was purified by column chromatography on silica gel (eluent hexane: ethyl acetatef=8:2) obtaining 3-(2,4-difluorophenyl>3,4-epoxy-2,2-dimethyl-lbutanol (823 mg; 65% yield) as a light yellow oil.

*

1H-NMR (CDC1₃): 7.47-6.70 (m, 3H, Ar); 3.50-3.29 (m, 2H, CH₂OH); 3.31-2.72 (m, 2H, CH₂O); 1.00 (s, 3H, CH3C); 0.93 (s, 3H, CH3C).

Example 5

Preparation of 3-(2.4-difluorophenvI)-3.4-epoxv-2.2-dimethvl-l-butanol trifluoromethylsulphonyl ester

Trifluoromethanesulphonic anhydride (22 ml; 131 mmoles) was added dropwise to a solution of 3-(2,4-difluorophenyl)-3,4-epoxy-2,2-dimethyl-l-butanol (10 g; 44 mmoles), prepared as described in example 4, and pyridine (20.1 g; 263 mmoles) in methylene chloride (70 ml) at -20°C, while keeping the temperature below -10°C.

The reaction mixture was kept under stirring at 0°C for 30 minutes, then a 10% aqueous solution of citric acid (50 ml) was added.

The phases were separated, the aqueous phase was extracted with methylene chloride (50 ml) and the collected organic phase were washed with water (50 ml), dried on sodium sulphate and evaporated under reduced pressure at 15°C.

3-(2,4-difluorophenyl)-3,4-epoxy-2,2-dimethyl-l-butanol trifluoromethylsulphonyi ester (13 g; 81% yield) was obtained as a reddish oil which was used as such in the subsequent steps. iH-NMR (CDCI3): 7.41-6.75 (m, 3H, Ar); 4.25 (s, 2H, CH₂OSO₂); 3.19-2.71 (m, 2H,

CH₂O); 1.07 (s, 6H, 2CH₃C).

AP/P/ 9 7/01180

Example 6

ΑΡ ύ Ο ΰ 8 7 5

- 13Preparation of 2-f2,4-difIuorophenyl)-2-r2-(2.2,3,3-tetrafluoropropoxv)-l.l-dimethvlethyloxirane

2,2,3,3,-Tetrafluoropropanol (2.25 ml; 25 mmoles) was added dropwise to a suspension of 5 sodium hydride (625 mg, 80%, 21 mmoles) in dimethyiformamide (5 ml) at 0°C.

The mixture was kept under stirring at room temperature for 1 hour.

After cooling at -8°C, a solution of 3-(2,4-difluorophenyl)-3,4-epoxy-2,2-dimethyl-l-butanol trifluoromethylsulphonyl ester (3 g; 8.3 mmoles), prepared as described in example 5, in dimethyiformaxnide (5 ml) was added.

The reaction mixture was kept under stirring for 6 hours at 0°C, then poured into water (200 ml) and extracted with ethyl ether (4 x 25ml).

The organic phases were dried on sodium sulphate, evaporated under reduced pressure to give an oil residue (1.58 g) which was purified by column chromatography on silica gel (eluent hexane:ethyl acetate=99:l) obtaining 2-(2,4-difluorophenyl)-2-[2-(2,2,3,3-tetrafluoroprop15 oxy)-l,l-dimethylethyl]oxirane (1.2 g; 42% yield) as a colourless oil.

^H-NMR (CDC1₃): 7.42-6.70 (m, 3H, Ar); 5.88 (m, 2H, OCHF); 3-72 (m, 2H, OCH₂CF₂); 3.32-3.20 (m, 2H, CH₂OCH₂CF₂); 3.12-2.64 (m, 2H, CH₂O); 0.98 and 0.97 (2s, 6H, 2CH3C).

By working in a similar way, the following compound was prepared:

2-(2,4-difluorophenvl)-2T2-(^,2,2,2-trifluoroethoxv)-l, 1 -dimethylethvlloxirane as a colourless oil

44% yield ^-NMR (CDCI3): 7.42-6.70 (m, 3H, Ar); 3.82-3.69 (m, 2H, OCH₂CF₃), 3.41-3.25 (m, 2H, CH₂OCH₂CF₃); 3.19-2.64 (m, 2H, CH₂O); 0.98 and 0.97 (2s, 6H, 2CH₃C).

Example 7

Preparation of (±)-I-(lH-l,2,4-tnazolvl)-2-hvdroxv-2-(2,4-difiuorophenvl)-3.3-dimethvl-4(2.2,3,3-tetrafluoropropoxv)butane (Compound 10)

A mixture of 2-(2,4-difiuorophenyl )-2-[2-(2,2,3,3-tetrafluoropropoxy)-1,1 -dimethyl ethyl]oxirane (1.2 g; 3.5 mmoles), 1,2,4-triazole (480 mg; 7 mmoles) and potassium carbonate (970 mg; 7 mmoles) in dimethylformamide (12 ml) was kept under stirring at 105°C for 8 hours.

AP/P/ 9 7 /01400

AP ο Ο Ο 8 7 5

-14The mixture was cooled, the precipitate was filtered and the solution was concentrate under reduced pressure.

The oil residue (1.5 g) was purified by column chromatography on silica gel (eluent 5 hexane:ethyl acetate=8:2) to give compound 10 (1.1 g; 76% yield) as a white solid.

m.p. 84-86°C ^-NMR (CDC1₃): 8.01 (bs, 1H, triazole); 7.69 (s, 1H, triazole); 7.62-7.65 (m, 3H, Ar); 5.87 (tt, 1H, JHF=53.5 Hz, CHF₂); 5.38-4.42 (m, 2H, CH₂-triazole); 5.22 (s, 1H, OH); 3.88-3.75 (m, 2H, CH₂CF₂); AB system: VA=3.63, VB=3.28, JAB=9.3 Hz, CH₂-O; 1.0110 0.96 (m, 6H, CH₃CCH₃).

. By working in a similar way, the following compound was prepared: fi)-l-(lH-1.2.4-triazolvl)-2-hvdroxv-2-(2.4-difluorophenvl)-3.3-dimethvl-4-f2.2.2-trifluoro* ethoxylbutane (Compound 11)- 55% yield m.p. 71-72°C

H-NMR (CDC1₃): 8.01-8.00 (m, 1H, CH-triazoie); 7.68 (s, 1H, CH-triazole); 7.62-6.55 (m, 3H, Ar); 5.39-4.45 (m, 2H, CH₂-triazole); 5.23 (s, 1H, OH); AB system: VA=3.84, VB=3.77, JAB=8.7 Hz, CCH₂O; AB system: VA=3.70, VB=3.30, JAB=8.8 Hz, CH₂CF₃; 1.00-0.96 (m, 6H, CH₃CCH₃).

Example 8

Preparation of 0-r3-(2.4-difluorophenvl)-3-hvdroxv-2,2-dimethvl-4-(lH-l,2.4-triazolvl)l-butyl-S-methvl dithiocarbonate

A 50% aqueous solution of sodium hydroxide (25 ml) and tetrabutylammonium hydrogenosulphate (8 mg) were added to a solution of (±)-3-(2,4-difiuorophenyl)-2,2-dimethyl-4-(lHl,2,4-triazoly)-l,3-butandiol (818 mg; 2.75 mmoles) in carbon disulphide (10 ml) and methyl25 ene chloride (15 ml). Under stirring at 10°C, methyl iodide (430 mg; 3.02 mmoles) was added and the stirring was kept for 1 hour at 10°C.

The phases were separated, the aqueous phase was extracted with methylene chloride (25 ml), the collected organic phases were washed with water (25 mJ), dried on sodium sulphate and evaporated to give a solid yellow residue (1.35 g) which was purified by column <0 chromatography on silica gel (eluent ethyl acetate:hexane=7:3) obtaining 0-(3-(2,4difluorophenyl)-3-hydroxy-2,2-dimethyl-4-(lH-l, 2,4-triazolyl)]butyl-S-methyl di thiocarbonate

AP/P/ 97/01100

APO 0 0 8 7 5

- 15(950 mg; 89% yield) as a light yellow solid. m.p.113-115°C ^-NMR (CDC1₃): 8.01 (d, 1H, CH-tetr.); 7.70 (s, 1H, CH-tetr.); 7.66-6.52 (m, 3H, Ar); 5 5.25-4.41 (m, 2H, CH₂-triazole); 4.71-4.40 (m, 2H, CH₂O); 2.55 (s, 3H, CH3S); 1.11 and

1.09 (2s, 6H, 2CH3C).

Example 9

Preparation of (i)-l-(lH-1.2.4-triazolvl')-2-hvdroxv-2-(2,4-difluorophenvl)-3.3-dimethvl-4trifluoromethoxv-butane (Compound 12)

The complex fluoridric acid - pyridine [(HF)9/pyridine; 2.67 ml; 11.79 mmoles] and, then, O[3-(2,4-difluorophenyl)-3-hydroxy-2,2-dimethyl-4-( 1H-1,2,4-triazolyl)]butyl-S-methyldithiocarbonate (520 mg; 1.34 mmoles), prepared as described in example 8, dissolved in methylene chloride (2 ml) were added dropwise to a solution of l,3-dibromo-5,5-dimethylhydantoin (1.14 g; 4.02 mmoles) in methylene chloride (10 ml) at -70°C.

The temperature was allowed to rise to -20°C and the reaction mixture was kept under stirring for 2 hours.

The mixture was poured into a 5% aqueous solution of sodium bisulphite (25 ml) and the mixture was brought to pH 14 with 33% sodium hydroxide.

The phases were separated, the aqueous phase was extracted with methylene chloride (25 ml) and the organic phases were dried on sodium sulphate, evaporated under reduced pressure and the oil residue (480 mg) was purified by column chromatography on silica gel (eluent ethyl acetate:hexane=6:4) to give compound 12 (120 mg; 25% yield) as a white solid, m.p. 96-98°C ^-NMR (CDCI3): 8.02 (d, 1H, JHH=2.9 Hz, CH-triazole); 7.70 (s, 1H, CH-triazole); 7.6325 7.57 (m, 3H, Ar); 5.37 (s, 1H, OH); AB portion of an ABX system: VA=5.26, VB=4.46,

JAB=13.96 Hz, JAX=3.0 Hz, JBX=2.2 Hz, CH₂-triazole; AB system: VA=4.20, VB=3.71, JAB=9.5 Hz, CH₂OCF₃; 1.09 (d, 3H, JHF=2.4 Hz, CH₃); 0.98 (s, 3H, CH3).

Comparative Example A

Preparation of (±Fl-(lH-I,2,4-triazolvl)-2-hvdroxv-2-(2.4-difluorophenvl)-3.3-dimethvl-430 ethoxv-butane (Compound Rl)

By working in a way similar to that described in example 6 but by using ethanol instead of

AP/P/97/0 1 100

AP O 0 0 8 7 5

- 162.2.3.3- tetrafluoropropanol, the following compound was obtained.

2-(2,4-difluorophenyl)-2-(2-ethoxy-l,l-dimethyl)ethyloxirane (20% yield) as a colourless oil. ^JH-NMR (CDCI3): 7.45-6.70 (m, 3H, Ar); 3.38 (q, 2H, CH₂CH₃); 3.20-2.60 (m, 2H, CH₂ epoxide); 3.17-3.02 (m, 2H, CH₂OCH₂CH₃); 0.98 (s, 3H, CH₃C); 0.97 (s, 3H, CH₃C).

By working in a way similar to that described in example 7, 2-(2,4-difluorophenyl)-2-(2ethoxy-l,l-dimethyl)ethyloxirane was treated with 1,2,4-triazole obtaining compound R1 as a white solid.

35% yield

m.p. 57-58°C ^-NMR (CDC1₃): 8.07 (bs, IH, CH-triazole); 7.68 (s, IH, CH-triazole); 7.60-6.57 (m, 3H, Ar); 5.47 (bs, IH, OH); 5.32-4.48 (m, 2H, CH₂-triazole); 3.45 (q, 2H, JHH=6.9 Hz, CH₂CH₃); AB system: VA=3.30, VB=3.22, JAB=9.5 Hz, CH₂OCH₂CH₃); 1.21 (t, 3H, CH₃CH₂); 1.02 (d, 3H, >2.3 Hz, CH₃C); 0.94 (d, 3H, >1.5 Hz, CH₃C).

Comparative Example B

Preparation of (±V-l-flH-l,2.4-triazolyl)-2-hvdroxv-2-i2.4-difluorophenvl)-3-(2,2.3.3tetrafluoropropoxvlbutane (Compound R2)

2.2.3.3- Tetrafluoropropanol (2.25 ml; 25 mmoles) was added dropwise to a suspension of sodium hydride (625 mg; 80%; 21 mmoles) in dimethylformamide (5 ml) at 0°C.

The mixture was kept under stirring at room temperature for 1 hour, then 3-(2,4-difluoro phenyl)-4-(lH-l,2,4-triazolyl)-2,3-epoxy-butane (1.25 g; 5 mmoles), prepared as described in Bull. Chem. Soc. Jap., 67 (1994), 1427-1433, dissolved in dimethylformamide (1 ml) was added and the reaction mixture was kept at 105°C for 3 hours. The mixture was poured into water (50 ml) and extracted with ethyl ether (4 x 15 ml).

The organic phases were dried on sodium sulphate, evaporated under reduced pressure to give an oil residue (1.40 g) which was purified by column chromatography on silica gel (eluent ethyl acetate:hexane=6:4) obtaining compound R2 (385 mg; 20% yield) as a white solid, m.p. 77.0-78.5°C

NMR (CDCI3): 7.85 and 7.72 (2s, 2H, 2CH-triazole); 7.48-6.66 (m, 3H, Ar); 5.91 (tt,

IH, JHF=54.0 Hz, CHF₂); 4.93-4.63 (m, 2H, CH₂-triazole); 4.31 (bs, IH, OH); 4.17-3.75 (m, 3H, CHOCH₂); 1.05 (d, 3H, JHH=8.2 Hz, CH₃CH).

AP/PJ 9 7/01108

AP Ο Ο Ο 8 7 5

- 17Example 10

In vitro antimycotic activity

The determination of the activity inhibiting the growth of mycetes was evaluated by the ma5 cromethod of scalar brothdilutions in geometrical progression (M.R. McGinnis and M.G. Rinaldi, Antifungal drugs; mechanisms of action, drug resistance, susceptibility testing and assay of activity in biological fluids, in Antibiotic in Laboratory Medicine, Ed. V. Lorian, Baltimora 1991).

As culture media Yeast Nitrogen Base broth (YNB) and Sabouraud Dextrose broth (SDB) were used for yeasts and moulds, respectively.

The results obtained in SDB (after incubation at 28°C for 7 days) were expressed as minimum inhibiting concentrations (MIC) the growth of mycetes, while those obtained in YNB (after incubation at 35°C for 48 hours) were expressed as concentrations able to inhibit at 50% (IC50) the growth of the yeast.

As reference compounds Fluconazole, Itraconazole and Genaconazole were used.

In the following tables the in vitro antimycotic activity data against various strains of Candida spp., Aspergillus spp., Fusarium spp., Cryptococcus ne of ormans and Trychophyton mentagrophytes of the some representative compounds of formula Π are reported.

& ft U 0 / I 8 /d/dV

AP Ο Ο Ο 8 7 5

- 18Table 1

In vitro antimycotic activity of compounds 1-10, 12 and of the reference compound Fluconazole against C. albicans, C. neoformans, T. mentagrophytes and A. fumigatus.

Compound	IC50 (MS/nd)	MIC (pg/ml)
C. albicans 1040	C. neoformans	T. mentagrophyte.	r \ A. fumigatus
1	0.0156	0.004	0.125	8
2	0.0312	0.125	2	4
3	0.0625	0.0625	1	>128
4	0.0312	0.5	4	>128
5	0.0156	0.0156	0.25	8
6	0.0312	0.0625	' 0.5	16
7	0.0312	0.125	0.5	16
8	0.0312	0.0156	0.25	>4
9	0.0156	0.125	2	>128
10	0.0156	0.0625	0.5	8
12	0.0156	0.0156	0.125	4
Fluconazole	0.5	2	16	>128

APIPI 9 7 / 0 1 1« 0

AP Ο Ο Ο 8 7 5

- 19Table 2

In vitro antimycotic activity of compounds 1, 3, 5 and of the reference compounds Fluconazole, Itraconazole and Genaconazole against Candida spp., Cryptococcus neoformans and other recently isolated strains (Tnchasporon sp., B. capitatus, Fusarium sp.).

STRAINS (No.)	Compound 1 MICgg MICgg	Compound 3 MICgg MICgg	Compound 5 MlC₅₀ MICgg	Fluconazole MICgg MICgg	Itraconazole MICgg MICgg	Genaconazole MICgg MICgg
C. albicans	(7)	50.03 0.06	50.03 2	50.03 0.5	4 32	0.06 0.12	2	32
C. spp *	(5)	<0.03 50.03	50.03 50.03	50.03 <0.03	1 2	50.03 0.06	0.5	1
.tropicaBs	(2)	0.12	0.5	0.12	4-16	0.1	>64
C. krusei	(2)	50.03-0.12	50.03-0.5	50.03 0.12	16->64	<0.03-0.12	16-32
C. glabrata	(2)	0.12	0.5-2	0.12	32->64	2->16	32->64
C. neoformans	(4)	50.03 50.03	50.03 0.5	50.03 50.03	1 32	50.03 0.1	8	16
Trichosporon sp. (1)	50.03	0.12	50.03	32	—	32
B. capitatus	0)	50.03	0.06	0.06	4	—	16
Fusarium sp.	(1)	0,25	16-64	0.25	—	—	64

* C. parapsilosis, lusitaniae, kefyr

Note to the table: MIC expressed as gg/ml

Within brackets the number of tested strains

Table 3

In vitro antimycotic activity of compound 1 and of the reference compounds Itraconazole and Genaconazole against recently isolated Aspergillus niger and Fusarium spp.

Species	Strain	Compound 1	Itraconazole	Genaconazole
A. niger	94-6222	<0.03	<0.03	32
Fusarium sp	81-256	0.25	2	64
Fusarium sp	86-3369	0.5	2-16	—
Fusarium sp	88-2116	0.5	2-8	—
Fusarium sp	946301	0.5	2-16	—

ΑΡ ΰ Ο Ο 8 7 5

-20From the data reported in the table, it results that the compounds object of the present invention have a wide-range in vitro activity. In particular, the compounds of formula Π are endowed with a significant activity also against Fluconazole and Itraconazole-resistant strains (Candida spp. and Cryptococcus neoformans) and against the other pathogenic strains re5 sponsible for infections in immunodepressed patients (C. glabrata, C. krusei, Aspergillus spp. and Fusarium spp.).

Example 11

In vivo antimycotic activity

Charles River white mice (CD1 strain) weighing from 23 to 25 g, normo-feeded with standard 10 diet and water ad libitum were used.

A suspension (0.2 ml containing 2.5x10? cells/ml) of Candida albicans 1040 in physiologic *

solution was injected to each animal by venous route. Immediately after the infection and after 4, 24 and 48 hours, the animals received by oral route (in arabic gum at 2%) doses increasing in a geometrical progression of the compound to be tested. The infected group was used as control.

The observation of the mortality of the mice was prolonged up to 14 days. From the number of survived animals for each concentration the average protective dose (DP^q) was calculated by probits analysis (L.Lison - Statistics applicata alia biologia sperimentale. La programmazione dell'esperimento e l'analisi dei risultati - Casa Editrice Ambrosiana, 1961).

Compounds R1 and R2 were used as comparative compounds.

Fluconazole and Itraconazole were used as reference compounds.

The in vivo antimycotic activity data of some representative compounds of formula Π after in vivo administration are reported in the following tables:

OH 0 / 16 /d/dV

AP ο Ο Ο 8 7 5

-21 Table 4

In vivo antimycotic activity of compounds 1-3 and of the reference compound Itraconazole in mice experimentally infected by C. albicans, expressed as percentage of survival.

Compound	dose mg/kg/os	% percentage of survival after day
3	6
1	25	100	100
2	25	100	100
3	25	100	100
Itraconazole	25	100	100
Control	—	50	0

Table 5

Antimycotic efficacy by oral route of compounds 1, 3-7, 9, 12, Rl, R2 and of the reference compounds Fluconazole and Itraconazole, expressed as average protective dose (PD50) after 8 and 14 days from the infection.

Compound	PD50 (mg/kg/os) at 8th day	PD₅₀ (mg/kg/os) at 14th day
1	0.120	0.74
3	0.49	1.3
4	0.31	1.29
5	0.50	1.14
6	0.42	1.10
7	1.5	2.19
9	0.89	1.57
12	1.09	1.39
^R1	>4	>4
^R2	>4	>4
Itraconazole	2.31	>8
Fluconazole	0.125	0.61

AP/P/ 97/0 1100

AP 0 Ο Ο 8 7 5

-22From the reported data it results that the compounds of formula H, object of the present invention, are active by oral administration at an average protective dose lower than that of Itraconazole and at least equivalent to that of Fluconazole.

Furthermore, the data reported in table 5 suggest, particularly for compound 1, characteristics 5 similar to those of Fluconazole.

Claims

Claims

1) A compound of formula

R₂ OH r₃ r₅

R (Π)

10 wherein

Rj is chlorine, fluorine or trifluoromethyl;

R₂ is hydrogen, chlorine, fluorine or trifluoromethyl;

Z is CH or N;

R₃, R4 and R5, the same or different, are hydrogen or C1-C4 alkyl, provided that R4 is dif15 ferent from R5 when R₃ is hydrogen;

X is O or S;

R^ is a C1-C5 polyfiuoroalkyl group containing at least two fluorine atoms and optionally other halogen atoms selected among chlorine and bromine; and their salts with pharmaceutically acceptable acids;

20 the compounds l-(lH-l,2,4-triazoIyI)-2-hydroxy-2-(2,4-dichlorophenyI)-3-methyl-4-(l, 1,2,2tetrafluoroethoxy)butane, l-(lH-l,2,4-triazolyl)-2-hydroxy-2-(2,4-dichIorophenyI)-3-methyl4-(1,1,2,2-tetrafluoroethoxy)hexane, 1 -(1H-1,2,4-triazolyl)-2-hydroxy-2-(4-chlorophenyl)3,3-dimethyl-4-( 1,1,2,2-tetrafluoroethoxy)butane and 1 -(1H-1,2,4-triazolyl)-2-hydroxy-2-(4chlorophenyl)-3-methyl-4-(l,l,2,2-tetrafluoroethoxy)butane being excluded.

25
2) A compound according to claim 1 wherein R₃, R4 and R5, the same or different, are hydrogen, methyl or ethyl.
3) A compound according to claim 1 or 2 wherein R^ is selected among difluoromethyl, trifluoromethyl, l,l,2-trifluoro-2-chloroethyl, 1,1-difIuoroethyl, 2,2,2-trifIuoroethyl, 1,1,2-trifluoroethyi, 1,1,2,3,3,3-hexafluaropropyl, 2,2,3,3-tetrafluoropropyl, 1,1,2,2-tetrafluoroethyl

30 groups and their isomers.
4) A compound according to claim 3 wherein R^ is a 1,1,2,2-tetrafluoroethyl group.

AP ο Ο Ο 8 7 5

-245) A compound according to claim 1 wherein Rj is chlorine or fluorine, R2 is hydrogen, chlorine or fluorine, R3 is methyl, R4 and R5, the same or different, are hydrogen, methyl or ethyl, Z is N and R^ is a 1,1,2,2-tetrafluoroethyl group.
6) A compound according to claim 1 wherein Rj is chlorine or fluorine, R2 is hydrogen, 5 chlorine or fluorine, R3 is methyl, R4 and R5, the same or different, are hydrogen, methyl or ethyl, Z is N and R5 is a 1,1,2,2-tetrafluoroethyl group and X is 0.
7) The compounds l-(lH-l,2,4-triazolyl>-2-hydroxy-2-(2,4-dichlorophenyl)-3-methyl-4(1,1,2,2-tetrafluoroethoxy)butane, 1 -(lH-l,2,4-triazolyl)-2-hydroxy-2-(2,4-dichlorophaiyl)-3methyl-4-(l,l,2,2-tetrafluoroethoxy)hexane, l-(lH-l,2,4-triazolyl>2-hydroxy-2-(4-cIiloroJ 10 phenyl)-3,3-dimethyl-4-(l,l,2,2-tetrafluoroethoxy)butane and l-(lH-l,2,4-triazolyI)-2-hydroxy-2-(4-chlorphenyl)-3-methyl-4-(l,l,2,2,-tetrafluoroethoxy)butane for use as a medicament.
8) A pharmaceutical composition containing a compound according to claim 1 in admixture with a pharmaceutically acceptable carrier.

15 9) A pharmaceutical composition containing a compound according to claim 7 in admixture with a pharmaceutically acceptable carrier.