FR2552431A1 - NOVEL AZOLIC COMPOUNDS, THEIR PREPARATION AND THEIR USE AS ANTIFUNGAL AND FUNGICIDES - Google Patents

Abstract

THE SUBJECT OF THE INVENTION IS A COMPOUND OF FORMULA I (CF DRAWING IN BOPI) IN WHICH R AND R REPRESENT HYDROGEN, A HALOGEN, A NITRO GROUP, A LOWER ALKYL GROUP, LOWER ALKYL, LOWER ALCYNYL, LOWER ALCYNYL, LOWER ALCYNYL, LOWER ALCYNYL OR LOWER ALCYNYL. NON-SUBSTITUTED OR MONO OR POLYHALOGENOUS OR A PHENYL OR PHENOXY GROUP NOT SUBSTITUTED OR SUBSTITUTED, R REPRESENTS HYDROGEN OR A LOWER ALKYL GROUP, R AND R REPRESENT EACH, INDEPENDENT OF ONE HDALGENE, OR ONE HIDALGENE, OR HIS Y REPRESENTS CH OR N, A REPRESENTS A C2-C7 ALKYLENE GROUP AND N MEANS 0 OR 1. THESE COMPOUNDS CAN BE USED THERAPEUTICALLY AS ANTIFUNGAL AND IN AGRICULTURE AS FUNGICIDES.

Description

The present invention relates to novel azole compounds, their

  preparation and their use as fungicides for controlling phytopathogenic fungi and for treating

  fungal infections in humans.

  The present invention relates in particular to azole compounds of formula I f 4 N

Y 'O H (A)

CH 2 C (C) 1H; <(

R 1 R 2

  wherein R 1 and R 2 each independently of one another is hydrogen, halogen, nitro, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy or lower unsubstituted alkylthio or mono or poly halogenated or unsubstituted or substituted phenyl or phenoxy, R 3 is hydrogen or lower alkyl, R 4 and R 5 are each, independently of one another, hydrogen or halogen Y represents CH or N. A represents a C 2 -C 7 alkylene group and n represents O or 1, in free base form or in the form of an acid addition salt or a physiologically hydrolysable derivative. and acceptable. The term "physiologically hydrolysable and acceptable" means, for example, an ester of a compound according to the invention wherein the hydroxy group is esterified and which is hydrolyzable under physiological conditions to give, in the case of an ester, a acid which is itself physiologically

  acceptable, for example non-toxic at the desired doses.

  The groups and the lower alkyl residues present preferably contain from 1 to 5 carbon atoms, especially from 1 to 3 carbon atoms; the alkenyl and lower alkynyl groups preferably contain from 2 to 5 carbon atoms, especially 2 or 3 carbon atoms. Halogen refers to fluorine, chlorine, bromine or iodine. Examples of halogenated groups represented by R 1 and R 2 there may be mentioned monodi or trisubstituted groups such as CF 3, CH 2 Cl, C 2 H 5 Cl, C Br = CH 2, OCHF 2, SCF 3, CEC Br, Cl C 6 H 4 and C 12 C 6H 30 Examples of suitable unsubstituted groups represented by R 1 and R 2 include

  hydrogen, halogens and CH 3, C 2 H 5, CH = CH 2, C-CH, OCH 3, SCH 3, C 6 H 5, C 6 H 50 and N O 2.

  The compounds of formula I, their acid addition salts and their physiologically hydrolysable and acceptable derivatives can be prepared according to the invention by reacting a compound of formula II ## STR2 ## (II)

R 1 R 2

with a compound of formula I II

N (III)

M

  in which R 1 to R 5, Y, m and N are as defined above and M represents hydrogen, a metal or a trialkylsilyl group,

  and isolating the compound thus obtained as a free base or as an acid addition salt or a physiologically hydrolyzable and acceptable derivative.

  The reaction can be carried out according to the usual methods, for example by treating a compound of formula III in which M represents hydrogen, in solution in a solvent inert under the reaction conditions, for example dimethylsulfoxide, with sodium hydride. and then adding the oxirane

  of formula II preferably dissolved in the same solvent and stirring the mixture at room temperature.

  Examples of metals represented by M include alkali metals such as sodium; as a group example

  trialkylsilyl include for example the trimethylsilyl group.

  The desired end product can be isolated and purified by the usual methods and recovered in free form or as an acid addition salt or a physiologically derived derivative.

hydrolyzable and acceptable.

Scheme I NC-CH r (A) Br A -R

NC: -C U

- \ R 5

Diagram III o C Diagram II I

HOOC C CH

R 3 I S 2 Cl I C 1 Oc C 7-CH

R 3 5

  R 1. Ln (A R 2 + {(C 2115)} 3 o 3 + BF 4 NaOH I + Free bases and other forms such as salts and for example esters may be converted into

  the other according to the usual methods.

  The starting materials of formula II are novel and can be prepared, for example, according to Reaction Schemes 1, 2 and 3 wherein R 1 to R 5, A and N are as defined above, unless otherwise indicated, and DABCO means the These reactions can be carried out according to the usual methods, for example as described in the examples. The products can be isolated and purified according to the methods described in US Pat.

  or be submitted directly to the subsequent reaction.

  The other intermediates are known or can be prepared analogously to known processes

  and / or those described in the examples below.

  The compounds of formula I possess interesting chemotherapeutic properties, in particular antimycotic properties by local application and orally, and can therefore be used therapeutically to combat infections and diseases caused by fungi. This anti-mycotic activity has been carried out evidence in in vitro assays on families and various types of fungi, eg Trichophyton, Aspergillus, Microsporium, Sporothrix and Candida in serial dilution tests at concentrations between 1.5 and pg / ml and in the test. Germination inhibition (C albicans) at a concentration of 0.05 Mg / ml The antimycotic activity has also been demonstrated in vivo, for example after administration of the compounds orally at doses of between about 3 and 25 mg / kg in mice and in

  in whom vaginal infection has been caused.

  Thanks to these properties, the compounds of the invention

  can be used as drugs, especially as antifungals.

  For their therapeutic use as antifungal agents, the compounds of the invention will be administered at a daily dose of between approximately 20 and 1500 mg, advantageously in divided doses 2 to 4 times per day in the form of unitary doses each containing from approximately 5 to 750 mg of substance

  active, or in delayed release form.

  The compounds may be used in free base form or in the form of a chemotherapeutically acceptable acid addition salt, for example in the form of hydrochloride, hydrogen fumarate or naphthalene 1,5-disulphonate, or in the form of a a physiologically hydrolyzable and acceptable derivative

  have the same order of activity as free bases.

  The invention therefore also relates to the compounds of formula I, in free base form or in the form of a chemotherapeutically acceptable acid addition salt or a physiologically hydrolysable and acceptable derivative, for use as medicaments, in particular The invention also comprises a medicament containing, as active substance, a compound of formula I in free base form or in the form of a chemotherapeutically acceptable acid addition salt or a

  physiologically hydrolyzable and acceptable derivative.

  As medicaments, the compounds of the invention may be used in the form of pharmaceutical compositions containing the active substance in combination with chemotherapeutically acceptable diluents or carriers and, optionally, with other excipients. Such compositions, which are also of the invention may be, for example, in the form of tablets, capsules, creams, tinctures or injectable preparations, intended to be administered orally,

  topical, intravenous or parenteral.

  The compounds of the invention in free base form or salt form or metal complex acceptable in agriculture, are also suitable for combating phytopathogenic fungi This fungicidal activity has been demonstrated, inter alia, in in vivo tests against Uromyces appendiculatus (bean rust) on row beans, against other rust fungi (such as Hemileia, Puccinia) on coffee, wheat, flax and ornamentals (eg geranium and gules). de-wolf), and against Erysiphe cichoracearum on cucumber and other oidiums (eg E graminis f sp tritici, E gram f sp hordei, Podosphaera leucotricha, Uncinula necator)

  on wheat, barley, apples and vine.

  The preferred meanings of the substituents are as follows: R 1 and R 2 are each, independently of one another, a) hydrogen, b) halogen, especially chlorine, or c) R 1 or R 2 represents hydrogen and the other represents halogen, especially F or Cl, R 3 = a) hydrogen, b) alkyl, R 4 and R 5, each independently of one another, a) hydrogen, b) halogen, especially F or Cl or c) R 4 or R 5 is hydrogen and the other is halogen, especially F or Cl, Y = a) N, b) CH, A = a) a C 2-, C 4 or C 6 alkylene group, b) an ethylene or butylene group, n = a) 0, b) 1. Combinations of such meanings are especially preferred Free bases and salts addition

of acids are preferred.

  A particularly preferred group of compounds is that comprising the compounds of formula I wherein R 1 and R 2 each independently represent hydrogen, halogen, nitro, lower alkyl, alkenyl lower, lower alkynyl, lower alkoxy or optionally halogenated lower alkylthio or phenyl or optionally substituted phenoxy, R 3 is hydrogen or alkyl, R 4 is hydrogen or halogen, R 5 is halogen, Y is CH or N. A represents a C 2 -C 7 alkylene group and N represents 0 or 1,

  in free base form or in the form of an acid addition salt.

  Another group of compounds is that comprising compounds of formula I wherein R 1 and R 2 are hydrogen or halogen, R 3 is hydrogen, R 4 and R 5 are hydrogen or halogen and Y is A and N are such that

defined above.

  In this group, halogen preferably means F or Cl

  and one of R 1 and R 2 and one of R 4 and R 5 is hydrogen.

  In this case, the halogen is preferably located in the para position. A preferred compound is 1- [1- (4-chlorophenyl) -1-hydroxy-2- (1H, 1,2,4-triazol-1-yl) ethyl] -1- (4-fluorophenyl) cyclopropane, base form. free or in the form of an acid addition salt or a physiologically hydrolyzable and acceptable derivative.

  The following examples illustrate the present invention without in any way limiting its scope.

  temperatures are given in degrees Celsius.

  EXAMPLE 1 1- (4-Chlorophenyl) -1-hydroxy-2- (1H-1,2,4-triazol-1-yl) ethyl-1- (4-chlorophenyl) cyclopropane While stirring and cooling with To the ice, a solution of 1.81 g of 1,2,4-triazole in 20 ml of anhydrous dimethylsulfoxide was mixed under an argon atmosphere with 0.63 g of sodium hydride (a dispersion of about 50% in the mineral oil) and the mixture is then allowed to warm to room temperature within one hour. A solution of 0.8 g of 2- (1- (4-chlorophenyl) 1 -cyclopropyl is then added to this mixture. -2- (4-chlorophenyl) oxirane in 5 ml of anhydrous dimethylsulfoxide and stirred for 24 hours at room temperature. For the subsequent treatment, the reaction mixture is poured into a saturated solution of sodium chloride, extracted with ethyl acetate, the organic phase is dried over sodium sulfate and evaporated. The product is dissolved. crude in a little dichloromethane and diluted with ether to give

colorless crystals; F = 103-106.

  The following compounds may be prepared analogously to those described in Example I or as indicated by Ex R 1 R 2 R) R 4 RN Characteristics 1 2 3 4 5 m Ph Xsico-chemioues2 4-CI HH 4-CI CH 2 OF 194-1980 3 4-C HH 4-CIN 4 OF 127 _ 1350

4 4-CI H H 4-CI CH 4 O F 155-1600

4-CI H H H 4-CIN 2 1 F 140-1500

  6 4-CI H H H 4-CI CH 2 1 F 183-185

7 4-Cl HH H 4 Cl Cl 4 1 F 169-1720

8 4-C H H 2 -F N 2 O F 1200

9 4-E H H 4 -E N 2 O F 103-105

4-CIH H 4 -F N 2 O F 1250

11 H H H H N 2 O F 185-1870

-F 18-1 87

  The starting materials can be prepared as follows: A) 2- (1- (4-chlorophenyl) cyclopropyl) -2- (4-chlorophenyl) oxirane (for Examples 1 and 2) a) 1- (4-chlorophenyl) cyclopropane carbonitrile 30 g of 4-chlorobenzyl cyanide are dissolved in 300 ml of a mixture of anhydrous tetrahydrofuran and dimethylsulfoxide (1/1) cooled to 100 and the mixture is stirred with 79 g of sodium hydroxide spray and Anhydrous (in a ball mill) 37.1 g of 1,2-dibromoethane are added dropwise to this mixture while stirring thoroughly so that the temperature does not exceed 150. The mixture is then stirred for 45 minutes at room temperature. room temperature, poured into a saturated solution of sodium chloride and extracted with ethyl acetate The ethyl acetate phases are washed with NaCl solution, dried over sodium sulfate sodium and concentrated in vacuo The residue is distilled under vacuum; E = 92-94 '/ 1.33 pascal The product starts with

  crystallize in the refrigerant; F = 42-45 '.

  b) 1- (4-Chlorobenzoyl) -1- (4-chlorophenyl) cyclopropane A Grignard solution is prepared according to the usual methods from 54.9 g of 4-bromochlorobenzene and 7.5 g of magnesium chips in anhydrous ether 17 g of 1- (4chlorophenyl) cyclopropanecarbonitrile are added dropwise to this mixture and the mixture is heated under reflux for 2 hours. The reaction mixture is carefully mixed under cooling with half of its volume in H Cl 6 N and heated at reflux for 3 hours to hydrolyze the ketimine which was formed. For further treatment, the mixture is diluted in NaCl solution and extracted with ethyl acetate. It is evaporated and chromatographed on silica gel 60 (petroleum ether / ether:

  (1) A colorless oil is obtained which is homogeneous according to thin layer chromatography and the NMR spectrum.

  NMR spectrum (CD C 13): 1.25 and 1.68 (each 2H, m, CH 2); 7.18 (4H, m);

7.25 (2H, m); 7.70 (2H, m).

  c) 1- (4-Chlorophenyl) -1-1- (4-chlorophenyl) -1-hydroxy-2-phenylthiolethyl-cyclopropane A solution of 7.46 g of thioanisole and 6 g of thioanisole is cooled to 0 under an argon atmosphere. 74 g of 1,4-diazabicyclo-1,2,2,5-octane ("DABCO") in 40 ml of anhydrous tetrahydrofuran were added and slowly mixed with a solution of 3.85 g of n-butyllithium in n-hexane. The mixture is cooled to room temperature and stirring is continued for 40 minutes. The mixture is further cooled to 0. A solution of 7 g of 1- (4-chlorobenzoyl) -1- (4chlorophenyl) is added dropwise with stirring. cyclopropane in 40 ml of anhydrous tetrahydrofuran and, after removing the refrigerant, stirring is continued for 45 minutes. The subsequent treatment is carried out by pouring the mixture into an ice-cold solution of NaCl, extracted with ice-cold ethyl acetate is evaporated and the residue is chromatographed on silica gel 60 (toluene / methacrylate). petroleum ether: 1/1) A colorless oil is obtained which is homogeneous according to layer chromatography

thin and the NMR spectrum.

  NMR spectrum (CD C 13): 0.63 and 1.30 (each 2 H, m, cyclopropane-CH 2); 3.04 (1H, s, OH); 3.42 and 3.83 (each 1H, AB-q, J = 13, 1 Hz,

  -SCH 2); 6.8-7.4 (13H, m, aromatics).

  d) 2- [1- (4-Chlorophenyl) cyclopropyl] -2- (4-chloro-phenyl) oxirane 8 g of 1- (4-chlorophenyl) -1-1- (4-chlorophenyl) -1-hydroxy are dissolved -2-phenylthiolethyl-cyclopropane in 30 ml of anhydrous dichloromethane and this mixture is reacted with 9.1 g of triethyloxonium fluoroborate with stirring at room temperature for 3 hours. Then an equal volume is added

  0.5 N sodium hydroxide and the mixture is stirred overnight.

  For the subsequent treatment, the phases are separated, the solvent is removed and the residue is chromatographed on silica gel 60 (toluene / petroleum ether: 1/1). A viscous, colorless mass is obtained which is homogeneous according to the chromatography. thin layer

and the NMR spectrum.

  NMR spectrum (CDCl3): 0.7-1.25 (4H, m, cyclopropane); 2.92 and 3.10 (each 1H, AB-q, J = 5.4Hz, -CH 20); 7.0-7.3 (8H, m, aromatics).

  B) 2- [1- (4-fluorophenyl) cyclopropyl] -2- (4-chlorophenyl) oxirane (for example 10) a) 1- (4-chlorobenzoyl) -1- (4-fluorophenyl) cyclopropane A Grignard solution according to the usual methods starting from 45.2 g of 4-bromochlorobenzene and 6 g of magnesium chips in anhydrous ether. After having reacted under reflux for 30 minutes, the mixture is added dropwise and with stirring. 6 g of anhydrous pyridine and then 12.7 g of 1- (4-fluorophenyl) cyclopropanecarbonitrile The mixture is refluxed for 2 hours, carefully mixed under ice-cooling with 250 ml of 6N HCl and The mixture is heated under reflux for 3 hours to hydrolyze the ketimine which has formed. For further treatment, the mixture is diluted with NaCl solution, extracted with ethyl acetate, and extracted with ethyl acetate. evaporated and the residue is chromatographed on silica gel 60 ml 1: 1 mixture of toluene and petroleum ether (E = 60-80). obtains a colorless oil which is homogeneous according to the chromatography

in thin layer and the NMR spectrum.

  NMR spectrum (CDCl3): 1.33 and 1.66 (each 2H, m, cyclopropane); 6, 85-7.35 (6H, m, aromatics); 7.60-7.75 (2H, m, aromatics).

  b) 1- (4-fluorophenyl) -1-1- (4-chlorophenyl) -1-hydroxy-2-phenylthiolethyl-cyclopropane

  The procedure is analogous to that described under A).

  The compound is used in the next step without further purification. C) 2- (1- (4-fluorophenyl) cyclopropyl-2- (4-chlorophenyl) oxirane

  The procedure is analogous to that described under A).

  NMR spectrum (CDCl 3): 0.6-1.2 (4H, m, cyclopropane); 2.88 (1H, d, J = 5.4

  Hz) and 3.08 (1H, d, J = 5.4 Hz, -CH 20); 6.8-7.3 (8H, m, aromatics).

  C) 2- [1- (4-chlorophenyl) cyclopentyll-2- (4-chlorophenyl) oxirane (for Examples 3 and 4) The procedure is analogous to that described under A)

or B).

  a) 1- (4-chlorophenyl) cyclopentanecarbonitrile Colorless oil; E = 116 / 1.33 pascal (99% pure according to the

  high pressure liquid chromatography).

  NMR spectrum (CDCl3): 1.8-2.6 (8H, m); 7.3-7.5 (4H, m). B) 1- (4chlorobenzoyl) -1 (4-chlorophenyl) cyclopentane NMR (CDCl3): 1.62.6- (8H, m); 7.15-7.40 and 7.52-7.65

(together 8H, m).

  c) 1- (4-Chlorophenyl) -1-1- (4-chlorophenyl) -1-hydroxy-2-phenylthiolethyl-cyclopentane NMR spectrum (CDCl3): 1.2-2.3 (18H, m); 3, 22 (1H, s, OH); 3.28 and 3.83

  (each 1H, AB-q, J = 13Hz); 6.9-7.3 (13H, m).

  d) 2- [1- (4-Chlorophenyl) cyclopentyll-2- (4-chlorophenyl) oxiran NMR (CDCl3): 1.5-2.05 (8H, m); 2.74 and 3.27 (each 1H, AB-q,

  J = 5 Hz); 6.74-6.79 (2H, m); 7.06-7.27 (6H, m).

  D) 2- [1- (4-Chlorophenyl) cyclopropyl] -2- (4-chlorobenzyl) oxirane (for Examples 5 and 6) a) 1- (4-Chlorobenzoyl) -1- (4-chlorophenyl) cyclopropane a solution of Grignard according to the usual methods starting from 14.4 g of 4-bromochlorobenzene and 2 g of magnesium chips in 100 ml of anhydrous ether. 6.9 g of cadmium chloride are added and the mixture is heated Reflux for 1 hour. The ether is replaced with 100 ml of anhydrous benzene and a solution of 15 g of 1- (4-chlorobenzyl) cyclopropanecarbonyl chloride in 20 ml of benzene is added all at once to 60 ml. at reflux for 1 hour the resulting mixture, it is poured on an ice-cold solution of ammonium chloride and extracted with ethyl acetate The organic phase is washed successively with a solution of H Cl 2 N and a saturated solution of sodium hydrogencarbonate, dried over sodium sulfate and evaporated. hromatography on silica gel 60 (toluene) the title compound is obtained in the form of

clear crystals F = 92-93.

  For steps (b) and (c), the procedure is analogous to

that described under A) or B).

  b) 1- (4-Chlorophenyl) -1-1- (4-chlorobenzyl) -1-hydroxy-2-phenylthiolethyl-cyclopropane c) -2-1- (4-chlorophenyl) cyclopropyl-2- (4-chlorobenzyl) oxirane

Colorless oil.

  E) 2- (1- (4-chlorophenyl) cyclopentyll-2- (4-chlorobenzyl) oxirane (for Example 7) a) 1- (4-Chlorobenzoyl) -1- (4-chlorobenzyl) cyclopentane 5 g of 4-chloro-3- (4-chlorophenyl) propiophenone in 50 ml of a 1: 1 mixture of anhydrous tetrahydrofuran and dimethylsulfoxide cooled to 0 and the mixture is mixed with stirring with 7 g of sodium hydroxide sprayed (in a ball mill) is added to O and with vigorous stirring

  3.86 g of 1,4-di-bromobutane in 5 ml of anhydrous tetrahydrofuran.

  After removing the cooling bath, the mixture is stirred for a further 40 minutes, then poured into saturated NaCl solution and extracted with ethyl acetate. The combined organic phases are washed with chlorine. The residue is chromatographed on silica gel 60 (toluene / petroleum ether: 4: 1). The title compound is isolated from the second layer.

  main fraction as a colorless oil.

  NMR spectrum (CDCl3): 1.6-2.4 (8H, m); 3.15 (2H, s); 6.8-7.8 (8H, m). For steps (b) and (c), the procedure is analogous to

that described under A) or B).

  b) 1- (4-Chlorophenyl) -1-1- (4-chlorobenzyl) -1-hydroxy-2-phenylthiolethylcyclopentane

Colorless oil.

  c) 2- [1- (4-Chlorophenyl) cyclopropyl] -2- (2-chlorobenzyl) oxirane The oily crude product is reacted without further purification. F) 2- [1- (4-Chlorophenyl) cyclopropyl] -2- (2-fluorophenyl) oxirane (for Example 8) The procedure is analogous to that described under A) or B). a) 1- (2-fluorophenyl) cyclopropanecarbonitrile E = 660 / 13.33 pascal NMR spectrum (CDCl3): 1.40 and 1.69 (each 2 H, m, cyclopropane);

7.05-7.4 (4H, m, aromatics).

  b) 1- (4-Chlorobenzoyl) -1- (2-fluorophenyl) cyclopropane NMR Spectrum (CDC 13): 1.35 and 1.80 (each 2H, m, cyclopropane);

6.8-7.6 (8H, m, aromatics).

  c) 1- (2-Fluorophenyl) -1-1- (4-chlorophenyl) -1-hydroxy-2-phenylthiolethyl-cyclopropane NMR Spectrum (CDCl 3): 0.50-0.85 (2H, m, cyclopropane) ); 1.34 (2H, m, cyclopropane); 3.10 (1H, s, -OH); 3.50 and 3.96 (each 1H, dq,

  J = 13.5 Hz and 1.8 Hz, -SCH 2); 6.8-7.3 (13H, m, aromatics).

  d) 2- [1- (4-Chlorophenyl) cyclopropyl] -2- (2-fluorophenyl) oxirane NMR spectrum (CDCl3): 0.55-1.15 (4H, m, cyclopropane); 2.93 (1H, d,

  J = 5.4 Hz); 3.14 (1H, dd, J = 5.4 and 2.0Hz, CH 2 O); 6.9-7.2 (8H, m, 20 aromatic).

  G) 2- [1- (4-fluorophenyl) cyclopropyl] -2- (4-fluorophenyl) oxirane (for Example 9) The procedure is analogous to that described under A) or B). a) 1- (4-fluorophenyl) cyclopropanecarbonitrile E = 66 '/ 13.33 pascal NMR spectrum (CDCl3): 1.35 and 1.70 (each 2H, m, cyclopropane);

7.0-7.4 (4H, m, aromatics).

  b) 1- (4-fluorobenzoyl) -1- (4-fluorophenyl) cyclopropane

  NMR spectrum (CDCl3): 1.30 and 1.66 (each 2H, m, cyclopropane); 6.8-7.85 (8H, m, aromatics).

  c) 1- (4-Fluorophenyl) -1-1- (4-fluorophenyl) -1-hydroxy-2-phenylthiolethyl-cyclopropane NMR Spectrum (CDCl3): 0.48-0.85 (2H, m, cyclopropane) ; 1.32 (2H, m, cyclopropane); 3.07 (1H, s, -OH); 3.43 and 3.86 (each 1H, AB-q, J = 13.1Hz, -SCH 2); 6.8-7.3 (13H, m, aromatics). d) 2-E 1- (4-fluorophenyl) cyclopropyl-2- (4-fluorophenyl) oxirane NMR spectrum (CDCl3): 0.6-1.2 (4H, m, cyclopropane); 2.90 (1H, d, J = 5.4 Hz); 3.08 (1H, d, J = 5.4Hz, -CH 20); 6.8-7.3 (8H, m, aromatics).

Claims (8)

  An azole compound of formula I Y, OH c A 1 R CHC C C R 1 R 2   wherein R 1 and R 2 each independently represent hydrogen, halogen, nitro, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy or lower unsubstituted alkylthio, or mono or polyhalogenated or unsubstituted or substituted phenyl or phenoxy, R 3 is hydrogen or lower alkyl, R 4 and R 5 are each, independently of one another, hydrogen or halogen; Y is CH or N, A is C 2 -C 7 alkylene and n is 0 or 1;   in free base form or in the form of an acid addition salt or a physiologically hydrolyzable and acceptable derivative.   A compound according to claim 1, characterized in that a) R 1 and R 2 are each, independently of one another, hydrogen, halogen, nitro, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy or optionally halogenated lower alkylthio or optionally substituted phenyl or phenoxy, R 3 is hydrogen or alkyl, R 4 is hydrogen or halogen, R 5 is halogen, Y is CH or N, A represents a C 2 -C 7 alkylene group and n represents O or 1, or b) R 1, R 2, R 4 and R 5 each represent, independently of each other, hydrogen or halogen, R 3 represents hydrogen or c) R 1 and R 4 represent hydrogen, R 2 and R 5 each represent, independently of one another, hydrogen or halogen, R 3 represents hydrogen or d) R 1 and R 4 represent hydrogen, R 2 and R 5 each represent, independently fluorine or chlorine, R 3 represents hydrogen or e) R 2 and R 5 are in the para position and represent fluorine or chlorine, R 1 and R 4 represent hydrogen, R 3 represents hydrogen, in free base form or in the form of an acid addition salt or a physiologically hydrolysable and acceptable derivative 3 An azole compound, characterized in that it is chosen from 1-11- (4-chlorophenyl) -1-hydroxy-2- (1H-1,2,4-triazol-1-yl) ethyl-1- (4-chlorophenyl) cyclopropane; 1-11- (4-chlorophenyl) -1-hydroxy-2- (1H-1,3-imidazol-1-yl) ethyl-1- (4-chlorophenyl) cyclopropane; 1-11- (4-chlorophenyl) -1-hydroxy-2- (1H-1,2,4-triazol-1-yl) ethyl-1- (4-chlorophenyl) cyclopentane; 1-11- (4-chlorophenyl) -1-hydroxy-2- (1H-1,3-imidazol-1-yl) ethyl-1- (4-chlorophenyl) cyclopentane; 1-11- (4-chlorophenyl) -1-hydroxy-2- (1H-1,2,4-triazol-1-yl) ethyl-1- (4-chlorobenzyl) cyclopropane; 1-11- (4-chlorophenyl) -1-hydroxy-2- (1H, 1,3-imidazol-1-yl) ethyl-1- (4-chlorobenzyl) cyclopropane; 1-11- (4-chlorophenyl) -1-hydroxy-2- (1H-1,3-imidazol-1-yl) ethyl-1- (4-chlorobenzyl) cyclopentane; 1-E 1- (4chlorophenyl) -1-hydroxy-2- (1H, 1,2,4-triazol-1-yl) ethyl-1- (2-fluorophenyl) cyclopropane; and 1- [1- (4-fluorophenyl) -1-hydroxy-2- (1H-1,2,4-triazol-1-yl) ethyl] -1- (4-fluorophenyl) cyclopropane,   in free form or in the form of an acid addition salt or a physiologically hydrolyzable and acceptable derivative.   1- [1- (4-Chlorophenyl) -1-hydroxy-2- (1H-1,2,4-triazol-1-yl) ethyl] -1- (4-fluorophenyl) cyclopropane, in free base form or in form an acid addition salt or a derivative   physiologically hydrolyzable and acceptable.   1- [1- (4-Chlorophenyl) -1-hydroxy-2- (1H-1,2,4-triazol-1-yl) ethyl] phenyl-cyclopropane, in free base form   or in the form of an acid addition salt or a physiologically hydrolyzable and acceptable derivative.   A process for the preparation of a compound according to claim 1, its acid addition salts and its physiologically hydrolysable and acceptable derivatives, wherein a compound of formula II is reacted. (II) R 1 R 2 with a compound of formula III I N (III)   In which R 1 to R 5, Y, A and N are as defined in claim 1, and M represents hydrogen, a metal or a trialkylsilyl group, and the compound thus obtained is isolated in the form of a baselibre or under form of an acid addition salt or a physiologically derived hydrolyzable and acceptable.   7 Azole compounds specified in any one of   Claims 1 to 5, in free base form or in the form of a chemotherapeutically acceptable acid addition salt or   of a physiologically hydrolyzable and acceptable derivative, for use as drugs.   8 A medicament, characterized in that it contains, as active substance, an azole compound specified in one   any of claims 1 to 5, in free base form or   in the form of a chemotherapeutically acceptable acid addition salt or a physiologically hydrolyzable derivative and acceptable.   A pharmaceutical composition, characterized in that it comprises an azole compound specified in any one of   1 to 5, in free base form or in the form of a chemotherapeutically acceptable acid addition salt or a   physiologically hydrolysable and acceptable derivative, in combination with a chemotherapeutically acceptable diluent or vehicle. A compound of formula II CH 2 (A) R 4 (1) C-C / (II) R 1 R 2   wherein R 1 and R 2 each independently of one another is hydrogen, halogen, nitro, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy or lower unsubstituted alkylthio or mono or polyhalogenated or unsubstituted or substituted phenyl or phenoxy, R 3 is hydrogen or lower alkyl, R 4 and R 5 are each, independently of one another, hydrogen or halogen, A represents a C 2 -C 7 alkylene group and n means O or 1.