LU85551A1 - NOVEL AZOLIC COMPOUNDS, THEIR PREPARATION AND THEIR USE AS ANTIFUNGALS AND FUNGICIDES - Google Patents

Description

* »

The present invention relates to new azole compounds, their preparation and their use as fungicides for combating phytopathogenic fungi and for the treatment of fungal infections in humans.

The present invention relates in particular to

azole compounds of formula I

rj 10 Γ? H (A) / => / R4 (i) R1 R2 15 in which and R £ each represent, independently of one another, hydrogen, halogen, a nitro group, an alkyl group lower, lower alkenyl, lower alkynyl, lower alkoxy or lower alkylthio unsubstituted or mono-or poly-halogenated or an unsubstituted or substituted phenyl or phenoxy group, R3 represents hydrogen or a lower alkyl group, R4 and R5 each represent , independently of each other, hydrogen or halogen, Y represents CH or N, A represents a C2-C7 alkylene group and "in signifies 0 or 1, in the form of free base or in the form of 'an acid addition salt' or a physiologically hydrolyzable and acceptable derivative.

The term "physiologically hydrolyzable and acceptable" means for example an ester of a compound according to the invention in which the hydroxy group is esterified and which is hydrolyzable under physiological conditions to give, in the case of a ester, an acid which is itself physiologically acceptable, for example non-toxic at the desired doses.

The lower alkyl groups and radicals present preferably contain from 1 to 5 carbon atoms, especially from 1 to 3 carbon atoms; the lower alkenyl and lower alkynyl groups preferably contain from 2 to 5 carbon atoms, especially 2 or 3 carbon atoms. Halogen means fluorine, chlorine, bromine or iodine. As examples of halogen groups represented by R1 and R2, mention may be made of mono-di- or trisubstituted groups such as CF3, CH2CI, C2H5C1, CBr = CH2, OCHF2, SCF3, C = CBr, CIC6H4 and CI2C6H3O. Examples of suitable unsubstituted groups represented by R1 and R2 include hydrogen, halogens and the groups CH3, C2H5, CH = CH2> C = CH, 0CH3, SCH3, C6H5, C6H5O and NO2.

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

20 CH, —0 'ßfl 0' - R1 Rp '25 1 2

with a compound of formula III

ri | N (III)

30M

in which Ri a R5, Y, m and n are as defined above and M represents T hydrogen, a metal or a trialkylsilyl group, ht 3 and by isolating the compound thus obtained in the form of a free base or in the form of a addition salt of acid 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 an inert solvent under the reaction conditions, for example dimethyl sulfoxide, 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 an example of a trialkylsilyl group, mention may be made, for example, of the trimethylsilyl group.

The desired final product can be isolated and purified according to the usual methods and can be recovered in free form or in the form of an acid addition salt or a physiologically / hydrolyzable and acceptable derivative.

A \ -7 U / J "4 01, 1/1 I — l

H »M M

g - * 8- "

i Dï W

s d>:

sT

Ô »‘ «*; 1 - - i oj ri _5 ^ in "l / * i" Ö - ~ V. £ / v ^ ü -. V- <f - [| ^ sr '- ± - ": i sls V?' 5 g1 n '"Yx * i <" y <Γ 8 </> y,, es - i in uaa \. R * - u • "<3.- · -1-0 .- ^ 4-0 .- ^ = s * __j <1 <* -— 11 tfl rH CN Js.

Ό o

: T

+ nr m Ä «

Vxs / m * un ^ r / S m os a: „9_lö ü r“ N “

s ύ “l ^ V

'δ; * g - £ = υ oo / U \ 5

The free bases and the other forms such as the salts and for example the esters, can be converted one into the other according to the usual methods.

The starting materials of formula II are new and 5 can be prepared for example according to reaction schemes 1, 2 and 3 in which Ri a R5, A and n are as defined above, unless otherwise indicated, and DABCO means 1 , 4-diaza-bicyclo [2.2.2] octane. 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 usual methods or be subjected directly to the subsequent reaction.

The other intermediate products are known or can be prepared in a similar manner to the known processes and / or to those described in the examples below.

The compounds of formula I have interesting chemotherapeutic properties, in particular antimycotic properties by local and oral application and can therefore be used therapeutically to combat infections and diseases caused by fungi. This anti-mycotic activity has been demonstrated in in vitro tests on various families and types of fungi, for example Trichophyton, Aspergillus, Microsporium, Sporothrix and Candida in serial dilution tests at concentrations between 1, 5 and 100 pg / ml and in the germination inhibition test (C. albicans) at a concentration of 0.05 pg / ml. The anti mycotic activity has also been demonstrated in vivo, for example after administration of the compounds orally at doses of between approximately 3 and 25 mg / kg in mice and in rats in which a vaginal infection has been caused. .

Thanks to these properties, the compounds of the invention can be used as medicaments, in particular as antifungals.

For their therapeutic use as antifungals, the compounds of the invention will be administered at a daily dose of between approximately 20 and 1500 mg, advantageously

AT

6 in divided doses 2 to 4 times a day in the form of unit doses each containing approximately 5 to 750 mg of active substance, or in a delayed-release form.

The compounds can be used in the form of the free base or in the form of a chemically acceptable acid addition salt, for example in the form of the hydrochloride, hydrogen fumarate or naphthalene-1,5-disulfonate. , or in the form of a physiologically hydrolyzable and acceptable derivative. These forms have the same order of activity as the free bases.

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

As medicaments, the compounds of the invention can be used in the form of pharmaceutical compositions containing the active substance in association with chemotherapeutically acceptable diluents or vehicles and, optionally, with other excipients. Such compositions, which also form part of the invention, may be presented, for example, in the form of tablets, capsules, creams, tinctures or injectable preparations, intended for administration by the oral, topical, intravenous or parenteral route. .

The compounds of the invention in free base form or in the form of salt 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, 35 wheat, flax and ornamental plants (e.g. geranium

L

* V

7 and snapdragon), and against Erysiphe cichoracearum on cucumber and other oidiums (for example E.graminis f.sp. tritici, E. gram. F. Sp. Hordei, Podosphaera leucotricha, Uncinula necator) wheat, barley, apples and vines.

The preferred meanings of the substituents are as follows:

Rl and R2 each represent, independently of one another, a) hydrogen, b) halogen, especially chlorine, or c) R1 or R2 represents hydrogen and the other represents halogen, especially F or Cl, R3 = a) hydrogen, b) an alkyl group, R4 and R5, each independently of the other, represent a) hydrogen, b) halogen, especially F or Cl or c) R4 or R5 represents hydrogen and the other represents halogen, especially F or Cl, Y = a) N, 20 b) CH, A = a) a C2, C4 or Cß alkylene group, b) an ethylene or butylene group, n = a) 0, b) 1.

Combinations of such meanings are especially preferred. Free bases and acid addition salts are preferred.

A particularly preferred group of compounds is that comprising the compounds of formula I in which R 1 and R 2 each represent, independently of one another, 8 hydrogen, a halogen, a nitro group, a lower alkyl group, alkenyl lower alkynyl, lower alkoxy or lower alkylthio optionally halogenated or an optionally substituted phenyl or phenoxy group, R3 represents hydrogen or an alkyl group, R4 represents hydrogen or a halogen, R5 represents a halogen, Y represents CH or N, A represents a C2-C7 alkylene group and 10 n signifies 0 or 1, in the form of the free base or in the form of an acid addition salt.

Another group of compounds is that comprising the compounds of formula I in which R1 and R2 represent hydrogen or a halogen, R3 represents hydrogen, R4 and R5 k 15 represent hydrogen or a halogen and Y, A and n are as defined above.

In this group, the halogen preferably signifies F or Cl and one of Ri and R2 and one of R4 and R5 represents 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-tri azol el-yl) ethyl] -1- (4-fluorophenyl) cycl0- propane, in the form of a free base 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. In these examples, all temperatures are given in degrees Celsius.

EXAMPLE 1: 1-Cl (4-chlorophen.y1) -l-hydrox, y-2- (1H-1,2,4-tri azol el-yl) ethyl] -1- (4-chl orophen.yl) c.ycl opropane While stirring and cooling with ice, a solution of 1.81 g of 1,2,4-triazole in 20 ml of anhydrous dimethyl sulfoxide with 0.63 g of is mixed under an argon atmosphere. sodium hydride (approximately 50% dispersion in oil

L

r 9 mineral) and the mixture is then allowed to warm to room temperature over the course of an hour. A solution of 0.8 g of 2-C1- (4-chlorophenyl) Ucyclo-propyl-2- (4-chloropheny!) - oxirane is then added to this mixture in 5 ml of anhydrous dimethylsulfoxide and the mixture is stirred for 24 hours. at room temperature.

For the further treatment, the reaction mixture is poured into a saturated sodium chloride solution, it is extracted with ethyl acetate, the organic phase is dried over sodium sulphate and evaporated. The crude product is dissolved in a little dichloromethane and diluted with ether to give colorless crystals; F = 103-106 °.

The following compounds can be prepared by proceeding in a manner analogous to that described in Example 1 or as indicated above: 15 __. _

Ex. R. R, R, R. R- Y Asj [CH2ln n ή-îéri ^ io'ües 1 Z 3 4 5 m phySTCo-chimipues 2 4-Cl H - H 4-Cl CH 2 0 F. 194 -198 ° 3 4-Cl H - H 4-Cl N 4 0 F. 127-135 ° 20 4 4-Cl H - H 4-Ci CH 4 0 F. 155-160 ° 5 4-Cl HHH 4-Cl N 2 1 F. 140-150 ° 6 4-Cl HHH 4-Cl CH 2 1 F. 183-185 ° 7 4-Cl HHH 4-Cl CH 4 1 F. 169-172 ° 8 4-Cl H - H 2-FN 2 0 F. 120 ° 25 9 4-FH - H 4-FN 2 0 F. 103-105 ° 10 4-Cl HH 4-FN 2 0 F. 125 ° 11 HH - HHN 2 0 F. 185 -187 ° 30 The starting materials can be prepared as follows:

AT

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 tetrahydrofuran and anhydrous dimethylsulfoxide (1/1) cooled to 10 ° and the mixture is reacted with stirring with 79 g of sodium hydroxide spray and anhydrous (in a ball mill). To this mixture is added dropwise 37.1 g of 1,2-dibromoethane while stirring thoroughly so that the temperature does not exceed 15 °. The mixture is then stirred for 45 minutes at room temperature, poured into a saturated sodium chloride solution and extracted with ethyl acetate. The ethyl acetate phases are washed with NaCl solution, dried over sodium sulfate and concentrated in vacuo. The residue 15 is distilled under vacuum; E = 92-94 ° / l, 33 pascal. The product begins to crystallize in the refrigerant; F = 42-45 °.

b) l- (4-chlorobenzoyl) -l- (4-chlorophény1) cyclopropane

A Grignard solution is prepared according to the usual methods from 54.9 g of 4-bromochlorobenzene and 7.5 g of 20 magnesium shavings in anhydrous ether. To this mixture, 17 g of 1- (4-chlorophenyl) cyclopropane-carbonitrile are added dropwise and the mixture is heated at reflux for 2 hours. The reaction mixture is carefully mixed with cooling with half its volume in 6N HCl and heated under reflux for 3 hours to hydrolyze the ketimine which has formed. For the further treatment, the mixture is diluted in NaCl solution, extracted with ethyl acetate, evaporated and chromatographed on silica gel 50 (petroleum ether / ether: 10 / 1). A colorless oil is obtained which is homogeneous according to thin layer chromatography and the NMR spectrum.

NMR spectrum (CDCl3): 1.25 and 1.68 (each 2H, m, CH2); 7.18 (4H, m); 7.25 (2H, m); 7.70 (2H, m).

h 11 c) 1- (4-chlorophenyl) -1- [1- (4-chlorophenyl) -1-hydroxy-2-phenylthio] -ethyl-cyclopropane

Cooled to 0 ° and under an argon atmosphere a solution of 7.46 g of thioanisole and 6.74 g of 1,4-diazabicyclo- [2.2.2] 5 octane ("DABCO") in 40 ml of tetrahydrofuran anhydrous and mixed slowly with a solution of 3.85 g of n-butyllithium in n-hexane. The mixture is allowed to warm to room temperature and continues to stir for 40 minutes. The mixture is further cooled to 0 ° and a solution of 7 g of 1- (4-chlorobenzoyl) -1- (4-chlorophenyl) cyclo is added dropwise with stirring. propane in 40 ml of anhydrous tetrahydrofuran and, after removing the condenser, stirring is continued for 45 minutes. The subsequent treatment is carried out by pouring the mixture into an ice-cold NaCl solution, it is extracted with ethyl acetate, it is evaporated and the residue is chromatographed on silica gel 60 (toluene / petroleum ether: 1/1). A colorless oil is obtained which is homogeneous according to thin layer chromatography and the NMR spectrum.

NMR spectrum (CDCl3): 0.63 and 1.30 (each 2H, m, cyclopropane-CH2); 3.04 (1H, s, 0H); 3.42 and 3.83 (each 1H, AB-q, 0 = 13, 1Hz, -SCH2); 6.8-7.4 (13H, m, aromatics).

d) 2- [1- (4-ch1orophenyl) cyc1opropyl] -2- (4-ch1orophen.yl) oxirane

8 g of 1- (4-chlorophenyl) -1- [1- (4-chlorophenyl) -1-hydroxy-2-phenylthio] ethyl-cyclopropane are dissolved 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. An equal volume of 0.5N sodium hydroxide is then added and the mixture is stirred overnight. For the further 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 and colorless mass is obtained which is homogeneous according to thin layer chromatography and the NMR spectrum.

NMR spectrum (CDCl3): 0.7-1.25 (4H, m, cyclopropane); 2.92 and 3.10 35 (each 1H, AB-q, 0 = 5.4Hz, -CH2O); 7.0-7.3 (8H, m, aromatics).

/ - 12 B) 2- [1- (4-fluorophenyl) cyclopropyl3-2- (4-chlorophenyl) oxirane (for Example 10) a) 1- (4-chl orobenzoyl) -1- (4-f 1 uorophén.yl) cyclopropane

A Grignard solution is prepared according to the usual methods from 45.2 g of 4-bromochlorobenzene and 6 g of magnesium shavings in anhydrous ether. After reacting at reflux for 30 minutes, 6 g of anhydrous pyridine and then 12.7 g of 1- (4-fluorophenyl) cyclopropanecarbonitrile are added dropwise and with stirring. The mixture is heated at reflux for 2 hours, carefully mixed under ice cooling with 250 ml of 6N HCl and heated at 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, evaporated and the residue is chromatographed on silica gel 60 [1: 1 mixture of toluene and petroleum ether (E = 60-80 °)]. A colorless oil is obtained which is homogeneous according to thin layer chromatography 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-f1uorophén.yl) -l- [l- (4-ch1orophény1) -l-hydroxy-2-phenyl-thiolethyl-c.yclopropane

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) c, ycloprop, yl] -2- (4-chl or ophenyl) oxi ranne

The procedure is analogous to that described under A). NMR spectrum (CDC13): 0.6-1.2 (4H, m, cyclopropane); 2.88 (1H, d, J = 5.4 Hz) and 3.08 (1H, d, J = 5.4 Hz, -CH2O); 6.8-7.3 (8H, m, aromatics).

C) 2- [1- (4-chlorophenyl) cyclopentyl] -2- (4-chlorophenyl) oxirane 30 (for examples 3 and 4)

The procedure is analogous to that described under A) or B).

13 a) l- (4-chlorophény1) cyclopentane-carbonitrile

Colorless oil; E = 116 ° / 1.33 pascal (pure at 99¾ according to high pressure liquid chromatography S).

NMR spectrum (CDCI3): 1.8-2.6 (8H, m); 7.3-7.5 (4H, m).

5 b) 1- (4-chlorobenzo.y1) -1- (4-chlorophenyl) cyclopentane

NMR spectrum (CDCl3): 1.6-2.6- (8H, m); 7.15-7.40 and 7.52-7.65 (set 8H, m).

c) 1- (4-chlorophenyl) -1- [1- (4-chlorophenyl) -1-hydroxy-2-phenylthio] -ethyl-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) cyclopenty1] -2- (4-chlorophenyl) oxirane NMR spectrum (CDCl3): 1.5-2.05 (8H, m); 2.74 and 3.27 (each 1H, AB-q, J = 5Hz); 6.74-6.79 (2H, m); 7.06-7.27 (6H, m).

D) 2-Çl- (4-chlorophenyl) cycloprop.y1] -2- (4-chlorobenzyl) oxirane (for Examples 5 and 6) a) 1- (4-chlorobenzoy1) -1- (4-chlorophenyl). yl) c, yc1opropane

A Grignard solution is prepared according to the usual methods from 14.4 g of 4-bromochlorobenzene and 2 g of 20 magnesium shavings in 100 ml of anhydrous ether. 6.9 g of pulverized cadmium chloride are added and the mixture is heated under reflux for 1 hour. The ether is replaced by 100 ml of anhydrous benzene and a solution of 15 g of 1- (4-chlorobenzyl) cyclopropane-carbonyl chloride in 20 ml of benzene is added all at once to the 60th. The resulting mixture is heated to reflux for 1 hour, poured onto an ice-cold ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed successively with a 2N HCl solution and a saturated sodium hydrogencarbonate solution, dried over sodium sulfate and evaporated. After chromatography on silica gel 60 (toluene), the title compound is obtained in the form of colorless crystals. M = 92-93 °.

14

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-phen.ylthio] -eth.yl-cyclopropane 5 c) 2- [1- (4-chloropheny1) cyclopropyl] -2- (4-chlorobenz.yl) oxirane Colorless oil.

E) 2- [1- (4-chlorophenyl) cyclopentyl3-2- (4-chlorobenzyl) oxirane (for example 7) a) l- (4-chlorobenzo.yl) -l- (4-chlorobenzyl) cyclopentane 10 Dissolve 5 g of 4-chloro-3- (4-chlorophenyl) propio-phenone in 50 ml of a 1: 1 mixture of tetrahydrofuran and anhydrous dimethyl sulfoxide cooled to 0 ° and the whole is mixed with stirring with 7 g of sodium hydroxide pulverized (in a ball mill). 3.86 g of 1,4-di-bromobutane in 5 ml of anhydrous tetrahydrofuran are added at 0 ° and with vigorous stirring.

After removing the cooling bath, the mixture was stirred for a further 40 minutes, then poured into saturated NaCl solution and extracted with ethyl acetate. The combined organic phases are washed with sodium chloride, dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel 60 (toluene / petroleum ether: 4/1). The title compound is isolated from the second 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). 25 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-phenylthio] -ethyl-c. encyclopentane

Colorless oil.

C) 2- [1- (4-chlorophenyl) cyclopropyl3-2- (2-chlorobenzyl) oxirane

The crude oily product is reacted without further purification.

h 15 F) 2-Ü- (4-chl orophenyl) ο \ κ: 1ορπ) ρ.ν1] -2- (2- · Π uorophenyl) oxirane (for Example 8)

The procedure is analogous to that described under A) or B).

5 a) 1- (2-fluorophenyl) cyclopropanecarbonitrile E = 660 / 13.33 pascal

NMR spectrum (CDCl3): 1.40 and 1.69 (each 2H, m, cyclopropane); 7.05-7.4 (4H, m, aromatics).

b) 1- (4-chlorobenzo.yl) -1- (2-fluorophenyl) cyclopropane NMR spectrum (CDCl3): 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-phenylthi0] -ethyl-cyclopropane

NMR spectrum (CDCI3): 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, 0 = 13.5 Hz and 1.8 Hz, -SCH2); 6.8-7.3 (13H, m, aromatics).

d) 2- [1- (4-chlorophenyl) cyclopropy1] -2- (2-fluorophenyl) oxirane NMR spectrum (CDCl3): 0.55-1.15 (4H, m, cyclopropane); 2.93 (1H, d, J = 5.4Hz); 3.14 (1H, dd, J = 5.4 and 2.0 Hz, -CH20); 6.9-7.2 (8H, m, 20 aromatics).

G) 2- [1- (4-f1uorophenyl) cyclopropyl] -2- (4-f 1 uorophenyl) oxirane (for 11 example 9)

The procedure is analogous to that described under A) or 8).

25 a) 1- (4-f 1 uorophenyl) c.yc1opropanecarbonitrile E = 66,713.33 pascal

NMR spectrum (CDCI3): 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).

/ U

/ /

V

16 c) 1- (4-fluorophenyl) -! - [! - (4-fluorophenyl) -1-hydroxy-2-phenylthio] -ethyl-cyclopropane

NMR spectrum (CDCI3): 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, 5 J = 13.1 Hz, -SCH2); 6.8-7.3 (13H, m, aromatics).

d) 2- [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 = 5.4 Hz, -CH2O); 6.8-7.3 (8H, m, aromatics).

/ i ^ \

Claims (12)

1. An azolic compound of formula I jl N I? H (A) / = 5 / R4 (!) 10 Ri h in which R1 and R2 each independently represent hydrogen, halogen, nitro group, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy or lower alkylthio unsubstituted or mono- or poly-halogenated or an unsubstituted or substituted phenyl or phenoxy group, R3 represents hydrogen or a lower alkyl group, R4 and R5 each represent, independently of one another, hydrogen or a halogen, Y represents CH or N, A represents a C2-C7 alkylene group and n signifies 0 or 1, in the form of a free base or in the form of an acid addition salt or of a physiologically hydrolyzable derivative and acceptable. 2. A compound according to claim 1, characterized in that a) R 1 and R 2 each represent, independently of one another, hydrogen, a halogen, a nitro group, a lower alkyl group, lower alkenyl, lower alkynyl, lower alkoxy or lower alkylthio optionally halogenated or an optionally substituted phenyl or phenoxy group, L ^ \ 18 R3 represents hydrogen or an alkyl group, R4 represents hydrogen or a halogen, R5 represents a halogen, Y represents CH or N, 5. represents a C2-C7 alkylene group and n signifies 0 or 1, or b) R1, R2> R4 and R5 each represent, independently of each other, hydrogen or a halogen, "R3 represents Hydrogen or 10 c) Ri and R4 represent hydrogen, R2 and R5 each represent, independently of one another, hydrogen or a halogen, R3 represents hydrogen or d) Ri and R4 represent l , R2 and R5 each represent, independently of each other, the 15 fl uor or chlorine, R3 represents hydrogen or e) R2 and R5 are located in the para position and represent fluorine or chlorine, Rl and R4 represent hydrogen, R3 represents hydrogen, in the form of the free base or in the form of an acid addition salt or of a physiologically hydrolyzable and acceptable derivative 3. An azolic compound, characterized in that it is chosen from l- [l- (4-chlorophenyl) -l-hydroxy-2- (1H-1,2,4-triazole-1-yl) - ethyl3-1- (4-chlorophenyljcyclopropane; 1- [1- (4-chlorophenyl) -1-hydroxy-2- (1H-1,3-imidazole-1-yl) -ethyl] -1- (4-chlorophenyl ) cyclopropane; 1-D- (4-chlorophenyl) -1-hydroxy-2- (1H-1,2,4-tri azole-1-yl) -30 ethyl] -1- (4-chlorophenyl) cyclopentane; 1- [1- (4-chlorophenyl) -1-hydroxy-2- (1H-1,3-imidazole-1-yl) -ethyl] -1- (4-chlorophenyl) cyclopentane; 1- [1- (4-chlorophenyl) -1-hydroxy-2- (1H-1,2,4-triazole-1-yl) - / ethyl 3-1- (4-chlorobenzyl) cyclopropane; - \ L- 19 le l- [ l- (4-chlorophenyl) -1-hydroxy-2- (1H, 1,3-imidazole-1-yl) -ethyl] -1- (4-chlorobenzyl) cyclopropane; 1- [1- (4-chlorophenyl ) -l-hydroxy-2- (1H-1,3-imidazole-1-yl) -ethyl3-1- (4-chlorobenzyljcyclopentane; 5 1e 1- [1- (4-chlorophenyl) -l-hydroxy-2- (1H, 1,2,4-triazole-1-yl) - ethyl3-1- (2-fluorophenyl) cyclopropane; and 1- [1- (4-fluorophenyl) -l-hydroxy-2- (1H-1 , 2,4-triazole-1-yl) -ethyl3-1- (4-fluorophenyl) cycl opropane, s in free form or in the form of an acid addition salt or a physiologically hydrolyzable and acceptable derivative. 4. 1- [1- (4-chlorophenyl) -1-hydroxy-2- (1H-1,2,4-triazole-1-yl) ethyl3-1- (4-fluorophenyl) cyclopropane, in base form free or in the form of an acid addition salt or a physiologically hydrolyzable and acceptable derivative. 5. 1- [1- (4-chlorophenyl) -1-hydroxy-2- (1H-1,2,4-triazole-1-yl) ethyl3-1-phenyl-cyclopropane, in free base form or in form of an acid addition salt or a physiologically hydrolyzable and acceptable derivative. 5. A process for the preparation of a compound according to claim 1, of its acid addition salts and of its physiologically hydrolyzable and acceptable derivatives, characterized in that a compound of formula II is reacted Ô s R1 R2 with a compound of formula III 30 rs! M h (III) 7 to 20 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, 5 and the compound thus obtained is isolated in the form of a free base or in the form of an acid addition salt or of a physiologically hydrolyzable and acceptable derivative. 7. The azole compounds specified in any one of claims 1 to 5, in the form of the free base or in the form of a chemotherapeutically acceptable acid addition salt or a physiologically hydrolyzable and acceptable derivative, for use. use as medicines. 8. A medicament, characterized in that it contains, as active substance, an azolic compound specified in any one of claims 1 to 5, in the form of a free base or in the form of an acid addition salt chemotherapeutically acceptable or a physiologically hydrolyzable and acceptable derivative. 9. A pharmaceutical composition, characterized in that it comprises an azolic compound specified in any one of claims 1 to 5, in the form of a free base or in the form of a chemotherapeutically acceptable acid addition salt or a physiologically hydrolyzable and acceptable derivative, in association with a chemotherapeutically acceptable diluent or vehicle. 10. A compound of formula II CÜT / (A) / = / "" l "c— (ii) ô s R1 R2 U /, 35 i 21 in which Rl and R2 each represent, independently of one of l other, hydrogen, halogen, nitro, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy or lower alkylthio unsubstituted or mono- or polyhalogenated or an unsubstituted or substituted phenyl or phenoxy group , T R3 represents hydrogen or a lower alkyl group, R4 and R5 each represent, independently of one another, hydrogen or a halogen, A represents a C2-C7 alkylene group and n signifies 0 or 1. 11. Products and processes in substance as above described with reference to the examples cited. A. 9