NL8402755A - AZOLIC DERIVATIVES, METHOD FOR PREPARING THE SAME, PREPARATIONS CONTAINING THEM, AND USE THEREOF - Google Patents

Description

- 1 -

Azole derivatives, method of preparation thereof, preparations containing them, and use thereof.

This invention relates to azole derivatives, a process for their preparation, pharmaceutical compositions containing them, and their use as pharmaceuticals, e.g. as anti-fungal agents and as agricultural chemicals, e.g.

5 as a fungicidal.

In particular, this invention relates to azole derivatives of formula 1, wherein R 1 and R 1 independently of one another are hydrogen, halogen, nitro or unsubstituted or substituted with one or more halogen atoms of lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy and / or lower alkylthio or substituted or unsubstituted phenyl or phenoxy, R 1 is hydrogen or lower alkyl, R 1 and R 1 independently are hydrogen and / or halogen, 15 Y is CH or N, A is a polymethylene bridge with 2-7 carbon atoms and n is 0 or 1 in the form of the free base or of an acid addition salt or of a physiologically hydrolyzable and acceptable derivative.

By "physiologically hydrolyzable and acceptable derivative" is meant eg an ester of a compound according to the invention, the hydroxy group of which is esterified and which is hydrolyzable under physiological conditions and, in the case of the ester, gives an acid which itself is physiologically acceptable, ie non-toxic at the intended doses.

Lower alkyl groups occurring in the substituents preferably have 1 to 5 and in particular 1 to 3 carbon atoms, lower alkenyl and alkynyl groups preferably have 2 to 5 and especially 2 or 3 carbon atoms. Halogen 30 stands for F, Cl, Br and J. Examples of halogen-containing groups such as R ^ and R ^ are mono-, di- and tri-substituted 8402755 i-f - 2 groups such as CF ^, C ^ Cl, C ^ H ^ Cl, CBr ^ H ^, OCHF ^, SCF ^, C ^ CBr, C1C.H. and C 1 -C H 0, Examples of suitable unsubstituted groups such as R 1 and R 2 are hydrogen, halogen, CH 3, C 2 H 5, CH = CH 2, C 3 CH, OCH 3, SGH 3, C 6 H 5, C 6 H 50, and NC 4.

The compounds of formula 1 and their acid addition and physiologically hydrolyzable and acceptable derivatives can be prepared according to the invention by reacting a compound of formula 2 with a compound of formula 3, wherein t / m, Y, m and n have the definitions given above and M is hydrogen, a metal or a trialkylsilyl group, after which the compound thus obtained is isolated in the form of the free base or in the form of an acid addition salt or a physiologically hydrolysable and acceptable derivative. The reaction can be carried out in a conventional manner, for example, by treating a compound of formula 3, in which M is hydrogen, dissolved in a solvent which is inert under the reaction conditions (eg dimethyl sulfoxide) with sodium hydride and then the oxiran according to formula 2, preferably dissolved in the same solvent, and stirring the mixture at room temperature -

Examples of metals such as M are alkali metals such as sodium, and trialkylsilyl is, for example, trimethylsilyl.

The desired final product can be isolated and purified in the usual manner, and recovered in the form of the free base or in the form of an acid addition salt or of a physiologically hydrolyzable and acceptable derivative. The free base and other forms such as salts and esters can also be converted into one another in conventional ways.

The starting materials of formula 2 are new and can be prepared, for example, as indicated according to reaction schemes A, B and C, and this is also done in the usual manner, e.g. as described in the examples. The products can be isolated and purified in the usual way or directly converted further, as it suits.

* 8402755 *% - - 3 -

The other starting materials are known or can be prepared by known methods or analogously to the examples to be given below.

The compounds of formula 1 exhibit chemotherapeutic activity, and in particular they act against fungi after topical or oral administration, which in vitro from series dilution tests with concentrations between 1.5 and 100 µg / ml against fungal species of the genera Trichophyton, Aspergillus, Microsporium, Sporothrix and Candida were shown in 10 germ tube experiments with C. albicans at a concentration of 0.05 µg / ml, as well as in in vivo tests on genital mycosis in mice and rats, at doses between 3 and 25 mg / kg body weight . Thus, the compounds are indicated as pharmaceuticals, especially as anti-mycotics.

A suitable daily dose as an anti-mycotic agent is between 20 and 1500 mg. If desired, it can be administered 2 to 4 times daily over multiple doses, in unit dose form with between 5 and 750 mg of the compound, or alternatively in a sustained release form.

The compounds can be used in the form of the free base or in the form of chemotherapeutically acceptable acid addition salts, eg, as hydrochloride, bifumarate or naphthalene-1,5-disulfonate, or in the form of a physiologically hydrolyzable and acceptable derivative, which is preferably an ester. Such shapes exhibit activity of the same magnitude as the free bases.

The compounds can be mixed with conventional chemotherapeutically acceptable diluents and carriers, and optionally with other excipients, and can then be administered orally, topically, intravenously or parenterally in the form of tablets, capsules, creams, tinctures or injections.

These preparations are also within the scope of the invention.

The invention thus also relates to a method for combating infections and diseases caused by fungi, wherein a person in need thereof is provided an effective amount of a compound according to formula 1 in the invention. form of the free base or of a chemotherapeutically acceptable acid addition salt or of a physiologically isolable and acceptable derivative thereof, and this invention also relates to such compounds to be used as chemotherapeutics (and in particular as antimycotics).

The compounds of the invention in the free form or in the form of an agricultural acceptable salt or metal complex are also suitable for controlling phyto-pathogenic fungi. This anti-fungal activity can be demonstrated inter alia in in vivo tests against Uromyces appendiculatus (bean rust) on climbing beans and also against other rusts (eg Hemileia, Puccinia) on coffee, wheat, flax and decorative plates (eg Pelargoniums and Snapdragons), and against

Erysiphe cichoracearum or cucumber, as well as against other mildews (eg R. graminis f. Sp. Tritici, E. gram. F. Sp. Hordei, Podosphaera leucotricha and Uncinula recator) on wheat, barley, apples and grapes.

Preferred meanings of the symbols are and R onafhankelijk independently of one another a) hydrogen, b) halogen and especially Cl, and c) one hydrogen and the other halogen, especially F or Cl, R 3 = a) hydrogen and b ) alkyl, R4 and R <- independently of each other a) hydrogen, b) halogen and especially F or Cl, and c) one hydrogen and the other halogen, especially F or Cl, Y = a) N and b) CH , A = a) a polymethylene bridge with 2, 4 or 6 carbon-30 atoms, and b) ethylene or butylene n = a) 0 or b) 1.

Preference is given to the free bases and the acid addition salts.

Particular preference is given to the combinations of the above-mentioned meanings of the symbols.

A particular group of compounds is that according to formula 1 wherein 8 and R2 independently of one another is hydrogen, halogen, nitro or optionally halogen-substituted lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy or lower alkylthio or 5 optionally substituted phenyl or phenoxy, R 3 is hydrogen or alkyl, hydrogen or halogen, R 1 is halogen, Y is CH or N, 10 A is a polymethylene bridge of 2-7 carbon atoms, and n is 0 or 1, in the form of the free base or of an acid addition salt.

Another group of compounds is that wherein and R 2 are hydrogen or halogen, R 1 is hydrogen, R 1 and R 1. hydrogen or halogen and Y, A and n have the previously given definitions. Within this group, halogen is preferably F or Cl and there is always one hydrogen of R 1 and R 2 and of R 3 and R 4. In that case, the halogen is preferably in the para position.

A preferred compound is 1- / 1- (4-chlorophenyl) -1-hydroxy-2- (1H-1,2,4-triazolyl-methyl-1- (4-fluoro-phenylcyclopropane) in the form of the free base or of an acid addition salt or of a physiologically hydrolyzable and acceptable derivative.

The examples below illustrate the invention, in which temperatures are always in ° C.

Example I

1-f 1- (4-chlorophenyl) -1-hydroxy-2- (1H-1,2,4-triazolyl-1) ethyl J- 1- (4-chlorophenyl) cyclopropane_ 30 A solution of 1.81 g 1 2,4-triazole in 20 ml absolute dimethyl sulfoxyde was mixed with 0.63 g sodium hydride (ca 50% dispersion in mineral oil) under argon and with stirring and ice cooling and allowed to warm to room temperature in about 1 hour. To this, a solution of 0.8 g of 2- (1- (4-chlorophenyl) cyclopropyl-2- (4-chlorophenyl) oxirane in 5 ml of absolute dimethyl sulfoxide was added, followed by 24 hours at 8402755 - stirred at room temperature, before working up, the reaction mixture was poured into saturated NaCl solution and extracted with ethyl acetate, and the organic phase was dried over Na 2 SO 4 and evaporated to dryness. The crude product was dissolved in a little dichloromethane, which was diluted with ether to give colorless crystals with m.p. Mp 103-106 ° C.

The following compounds can be prepared according to Example I or in another manner indicated above.

10 ______

Ex. R ^ Rj Rg Y n Melting point _________m___ II 4-Cl Η - H 4-Cl CH 2 0 194-198 ° III 4-Cl Η - H 4-Cl N 4 0 127-135 ° 15 IV 4-Cl Η - H 4-Cl CH 4 0 155-160 ° V 4-Cl Η Η H 4-Cl N 2 1 140-150 ° VI 4-Cl Η Η H 4-Cl CH 2 1 183-185 ° VII 4-Cl Η Η H 4-Cl CH 4 1 169-172 ° VIII 4-Cl Η - H 2-F 1ST 2 0 120 ° 20 IX 4-F Η - H 4-FN 2 0 103-105 ° X 4-Cl Η - H 4-FN 2 0 125 ° XI HH-HHN 2 0 185-187 °

The starting materials required can be prepared as follows: A) 2 -ph-1- (4-chlorophenyl) cyclopropyl-7'-2- (4-chlorophenyl) oxirane (for Examples I and II) a) 1- ( 4-chlorophenyl) cyclopropanitrile.

. To a solution of 30 g of 4-chlorobenzyl cyanide in 300 ml of dry tetrahydrofuran / dimethyl sulfoxide 1: 1, cooled to 10 °, was added 79 g of ball-milled sodium hydroxide with stirring. To this mixture, 37.1 g of 1,2-dibromoethane was added with thorough stirring at a rate such that the temperature did not exceed 15 °. When all had been added, the mixture was stirred at room temperature for 45 minutes and then poured into a saturated NaCl solution and that. extracted with ethyl acetate. The ethyl acetate phases were washed together with NaCl solution, dried over Na2 SO4 and concentrated in vacuo. The residue was distilled under vacuum, bp. 92-94 ° / l, 33 Pascal. The product started to crystallize in the cooler, mp. 42-45 °.

b) 1- (4-chlorobenzoyl) -1- (4-chlorophenyl) cyclopropane.

A Grignard solution in absolute ether was made in the usual manner from 54.9 g of 4-bromo-chlorobenzene and 7.5 g of magnesium shavings. To this was added dropwise 17 g of 10 1- (4-chlorophenyl) cyclopropanitrile, after which the mixture was refluxed for 2 hours. The reaction mixture was carefully mixed with half of its volume of 6N HCl under cooling and then refluxed for 3 hours to hydrolyze the resulting ketimine.

Work-up was done by dilution with NaCl solution, extraction with ethyl acetate, evaporation to dryness and chromatography on silica gel 60 (with petroleum ether / ether 1Q; 1). A colorless oil was obtained which was homogeneous according to thin layer chromatography and NMR spectrum.

NMR (in CDCl 3): 1.25 and 1.68 (both 2h, m, CH 2>; 7.18 (4H, m), 7.25 (2H, m) and 7.70 (2H, m).

c) 1- (4-chlorophenyl) -1 - // 1- (4-chlorophenyl) -1-hydroxy-2- (phenylthioethyl-cyclopropane).

A solution of 7.46 g of thioanisole and 6.74 g of 1,4-diazabicyclo / 2,2.2 / octane ("DABCQ") in 40 ml of dry tetrahydrofuran was cooled to 0 ° C and slowly mixed under argon with a solution of 3.85 g of n-butyl lithium in n-hexane.

The mixture was allowed to warm to room temperature and stirring was continued for an additional 40 minutes. The mixture was again cooled to 0 ° C and a solution of 7 g of 1- (4-chlorobenzoyl) -1- (4-chlorophenyl) cyclopropane in 40 ml of dry tetrahydrofuran was added dropwise and with stirring, and after removing the cooling stirred for another 45 minutes. Work-up was done by pouring into ice-cold NaCl solution, extraction 35 with ethyl acetate, evaporation to dryness and chromatography on silica gel 60 (with toluene / petroleum ether 1: 1). A colorless * 8402755 - 8 - t was obtained.

Who was homogeneous according to thin layer chromatography and NMR.

NMR (in CDClg): 0.63 and 1.30 (both 2H, m, cyclopropane-CH2); 3.04 (1H, s, OH); 3.42 and 3.83 (1H, AB-q, J = 13.1Hz, -SCH2 each); 6.8-7.4 (13H, m, aromatics).

D) 1- (4-chlorophenyl) -1 / cyclopropyl-2- (4-chlorophenyl) oxirane.

8 g of 1- (4-chloro-phenyl) -1- / 1- (4-chlorophenyl) -1'-hydroxy-2- (phenylthio) ethyl 7-cyclopropane were dissolved in 30 ml of dry dichloromethane and left for 3 hours react with 9.1 g of triethyl oxonium fluoroborate at room temperature with stirring.

Then an equal volume of 0.5 N NaOH was added and the mixture was stirred overnight. Work-up was done by separating the phases, removing the solvent and chromatographing the residue on silica gel 60 (toluene / petroleum ether 1: 1). A colorless, viscous mass was obtained which was homogeneous according to thin layer chromatography and NMR.

NMR (in CDCl 3): 0.7-1.25 (4H, m, cyclopropane); 2.92 and 3.10 (both 1H, Ab-q, J = 5.4Hz, -C2 O) and 7.0-7.3 (8H, m, aromatics). B) 21- (4-fluorophenyl) cyclopropyl J-2- (4-chlorophenyl) oxirane (for example X) _ 20 a) 1- (4-chlorobenzoyl) -1- (4-fluorophenyl) cyclopropane

A Grignard solution was made in the usual manner from 45.2 g of 4-bromochlorobenzene and 6 g of magnesium shavings in absolute ether. After the reaction was completed by refluxing for 1 hour, 6 g of absolute pyridine was added, then with stirring and dropwise 12.7 g of 1- (4-fluorophenyl) cyclopropanitrile. The whole was refluxed for 2 hours and then gently mixed with 250 ml of 6N HCl under ice-cooling with cooling and boiled for 3 hours to hydrolyze the ketimine formed.

Work-up was done by dilution with NaCl solution, extraction with ethyl acetate, evaporation to dryness and chromatography on silica gel 60 (toluene / petroleum ether 60-80 1: 1). A colorless oil was obtained, which was homogeneous according to thin layer chromatography and NMR.

NMR (in CDClg): 1.33 and 1.66 (both 2H, m, cyclopropane); 6.85-7.35 (6H, m, aromatics); 7.60-7.75 (2H, mr aromatics).

8402755

* V

- 9 - b) 1- (4-fluorophenyl} -1 - (/ 1- (4-chlorophenyl) -1-hydroxy-2- (phenythio) ethyl / cyclopropane.

Analogous to A). The compound was used in the next step without further purification.

C) 2- (1- (4-fluorophenyl) cyclopropyl-2- (4-chlorophenyl) oxirane

Analogous to A).

NMR (in CDCl 3): 0.6-1.2 (4H, m, cyclopropane) .; 2.88 (1H, d, J = 5.4 Hz), 3.08 (1H, d, J = 5 Hz, -CH 2 O) and 6.8-7.3 (8E, m, aromatics).

10 C) 2- (4-chlorophenyl) cyclopentyl (7-2- (4-chlorophenyl) oxirane (for Examples III and IV)

Analogous to A) and B).

a) 1- (4-chlorophenyl) cyclopentanitrile

Colorless oil, kp. 116 ° / l, 33 Pascal (purity according to HPLC 99%).

NMR (in CDCl3): 1.8-2.6 (8H, m) and 7.3-7.5 (4H, a).

b) 1- (4-chlorobenzoyl) -1- (4-chlorophenyl) cyclopentane.

NMR (in CDCl3): 1.6-2.6 (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- (phenylthio) ethyl cycloopenopene NMR (in CDCl3: 1.2-2.3 (18H , m), 3.22 (1H, s, OH), 3.28 and 3.83 (both 1H, AB-q, J = 13 Hz), 6.9-7.3 (13H, m).

d) 2--1- (4-chlorophenyl) cyclopentyl] 1- (4-chlorophenyl) oxirane NMR (in CDCl 3) 1,5 1.5-2.05 (8H, m); 2.74 and 3.27 (both 1H, AB-q, J = 5 Hz); 6.74-6.79 (2H, m) and 7.06-7.27 (6H, m).

D) 1- (4-chlorophenyl) cyclopropyl J-2- (4-chlorobenzyl) oxirane (for examples V and VI) _ a) 1- (4-chlorobenzoyl) -1- (4-chlorophenyl) cyclopropane 30 In the usual manner a Grignard solution was made from 14.4 g of 4-bromochlorobenzene and 2 g of magnesium shavings in 100 ml of absolute ether. 6.9 g of powdered cadmium chloride was added and the mixture was refluxed for 1 hour. The ether was replaced 8402755 ____________ ________________ - 10 10 10 10 10 10 10 10 10 - - door door door door door door door door 10 droog droog benz en en en en en en en en en en en en en en en en en en en en en en en en het het en en en het het en en en het het en het en en en het het en en en het het het het ether ether ether ether ether ether ether ether ether ether ether ether ether ether ether ether ether ether ether ether ether ether ether ether ether ether ether ether ether ether ether ether by 8 by 8 with the solution of ether. That mixture was refluxed for one hour and poured into ice-cold ammonium chloride solution and extracted with ethyl acetate. The organic phase was extracted successively with 2N HCl and with saturated NaHCO 2 solution, dried over Na 2 SO 2 and evaporated to dryness. Chromatography on silica gel 60 with toluene gave colorless crystals of the title compound with m.p. 92-93 ° C.

Steps b) and c) were analogous to A) and B).

b) 1- (4-chlorophenyl) -1- / 1- (4-chlorobenzyl) -1-hydroxy-2- (phenylthio) ethyl / cyclopropane c) 2- ^ 1- (4-chlorophenyl) cyclopropyl ^ -2- (4-chlorobenzyl) oxirane 15 Colorless oil.

E) 2- [~ 1- (4-chlorophenyl) cyclopentyl] - 2- (4-chlorobenzyl) oxirane (for example VII) a) 1- (4-chlorobenzoyl) -1- (4-chlorobenzyl) cyclopentane One to 0 ° C cooled solution of 5 g of 20 4-chloro-3- (4-chlorophenyl) propiophenone in 50 ml of dry tetrahydrofuran / dimethyl sulfoxide 1: 1 was mixed with 7 g of sodium hydroxide ground in a ball mill with stirring. 3.86 g of 1,4-dibromobutane in 5 ml of dry tetrahydrofuran was added with stirring at 0 ° C. After removing the cooling bath, the mixture was stirred for an additional 40 minutes and then poured into saturated NaCl solution. The mixture was extracted with ethyl acetate and the organic phases were washed together with NaCl solution and dried over Na 2 SO 4 and evaporated in vacuo. The residue was chromatographed on silica gel 60 with toluene / petroleum ether 4: 1. The title compound was isolated from the second main fraction as a colorless oil.

NME (in CDCl3): 1.6-2.4 (8H, m); 3.15 (2h, s) and 6.8-7.8 (8H, m). Steps b) and c) were analogous to A) and B).

35 8402755-11 - b) 1- (4-chlorophanyl) -1- / 1- (4-chlorobenzyl) -1-hydroxy-2- (phenylthio) ethyl 7-cyclopentane

Colorless oil.

c) 2- (4-chlorophenyl) cyclopropyl_77-2- {4-chlorobenzyl) -5 oxirane_i___

The crude oily product was reacted without further purification.

F) 2- / 1- (4-chlorophenyl) cyclopropyl 7-2- (2-fluorophenyl) oxirane (for Example VIII) Analogous to Ά) and B).

a) 1- (2-fluorophenyl) cyclopropanitrile Kp »66 ° / 13.33 Pascal NMR (in CDCl 3): 1.40 and 1.69 (both 2H, m, cyclopropane); 7.05-7.4 (4H, m, aromatics).

B) 1- (4-chlorobenzoyl) -1- (2-fluorophenyl) cyclopropane NMR (in CDCl 3): 1.35 and 1.80 (both 2H, m, cyclopropane); 6.8-7.6 (8H, m, aromatics).

c) 1- (2-fluorophenyl) -1- / 1- (4-chlorophenyl) -1-hydroxy-2- (phenyl-thio) ethyl 7cyclopropane 20 NMR (in CDCl 3): 0.50-0.85 (2H , m, cyclopropane); 1.34 (2H, m, cyclopropane); 3.10 (1H, s, -OH); 3.50 and 3.96 (both 1H, dq, J = 13.5 Hz and 1.8 Hz, -SC ^) and 6.8-7.3 (13H, m, aromatics).

d) 2- / 1- (4-chlorophenyl) cyclopropyl-7-2- (2-fluorophenyl) oxirane NMR (in CDCl 3): 0.55-1.15 (4H, m, cyclopropane); 2.93 (1H, d, 25 J = 5.4 Hz); 3.14 (1H, dd, J = 5.4 and 2.0 Hz, -CH 2 O); 6.9-7.2 (8H, m, aromatics).

G) 2- / 1- (4-fluorophenyl) cyclopropyl 7-2- (4-fluorophenyl) oxirane (for Example IX)

Analogous to A) and B).

A) 1- (4-fluorophenyl) cyclopropanitrile Kp. 66 ° / 13.33 Pascal NMR (in CDCl 3): 1.35 and 1.70 (both 2H, m, cyclopropane); 7.0-7.4 (4H, m, aromatics).

8402755 µm - 12 - b) 1- (4-fluorobenzoyl) -1- (4-fluorophenyl) cyclopropane NMR (in CDCl 3): 1.30 and 1.66 (both 2H, m, cyclopropane); 6.8-7.85 (8H, m, aromatics).

c) 1- (4-fluorophenyl) -1- / 1- (4-fluorophenyl) -1-hydroxy-2- (Enyl-5 thio) ethyl / cyclopropane NMR (in CDCl 3): 0.48 -0.85 (2H, m, cyclopropane); 1.32 (2H, m cyclopropane); 3.07 (1H, s, --OH); 3.43 and 3.86 (both 1H, AB-q, J = 13.1 Hz, -SCH ^) and 6.8-7.3 (13H, m, aromatics).

d) 2- / 1- (4-fluorophenyl) cyclopropyl-7-2- (4-fluorophenyl) oxirane 10 NMR (in CDCl 3): 0.6-1.2 (4H, m, cyclopropane); 2.90 (1H, d, J = 5.4 Hz); 3.08 (1H, d, J = 5.4 Hz, -CH 2 O) and 6.8-7.3 (8H, m, aromatics).

84 0 27 5 5

Claims (8)

A compound according to formula 1, wherein and R 2 independently of each other are hydrogen, halogen, nitro 5 and / or unsubstituted and / or lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy or lower alkylthio and / or al then unsubstituted phenyl or phenoxy, R 1 is hydrogen or lower alkyl, R 1 and R 1 are independently hydrogen and / or halogen, Y is CH or N, A is a polymethylene bridge of 2-7 carbon atoms, and n is Q or 1 in the form of the free base or of a acid addition salt or 15 of a physiological, hydrolyzable and acceptable derivative. 2. A compound according to claim 1, wherein a) R 1 and R 1 independently of each other hydrogen, halogen, nitro and / or optionally halogen-substituted lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy or lower alkylthio and / or optionally substituted phenyl or be phenoxy, R 1 is hydrogen or alkyl, R 1 is hydrogen or halogen, R 5 is halogen, Y is CH or N, 25. is a polymethylene bridge of 2-7 carbon atoms, and n is 0 or 1, or b ) Rj, R ^, R ^ and Rj. independently hydrogen or halogen and R ^ is hydrogen, or c) and R ^ are hydrogen, R ^ and R ^ are independently hydrogen or halogen, and R ^ is hydrogen, or d) R. and R are hydrogen R0 and R are independently 14. d are F or Cl and R ^ is hydrogen, or e) and R are. in the para position and represent F or Cl, R 4 and R 4 are hydrogen and R 4 is hydrogen, in the form of the free base or of an acid addition salt or of a physiologically hydrolyzable and acceptable derivative. * 8402755 si - IH- 3. One of the following compounds: 1- / H4-chlorophenyl) -1-hydroxy-2- (1H-1,2,4-triazolyl-1) ethyl-7-1- (4-chlorophenyl) cyclopropane; 1- / 1- (4-chlorophenyl) -1-hydroxy-2- (1H-1,3-imidazolyl-1) ethyl J-5 1- (4-chlorophenyl) cyclopropane; 1- / 1- (4-chlorophenyl) -1-hydroxy-2- (1H-1,2,4-triazolyl-1) ethyl-7-1- (4-chlorophenyl) cyclopentane; 1- / 1- (4-chlorophenyl) -1-hydroxy-2- (1,1-1,3-imidazolyl-1) ethyl-1- (4-chlorophenyl) cyclopentane; 1- / 1- (4-chlorophenyl) -1-hydroxy-2- (1H-1,2,4-triazolyl-1) ethyl 7-1 (4-chlorobenzyl) cyclopropane; 1- / 1- (4-chlorophenyl) -1-hydroxy-2- (1H-1,3-imidazolyl-1) ethyl-7-1- (4-chlorobenzyl) cyclopropane; 1- / 1- (4-chlorophenyl) -1-hydroxy-2- (1H-1,3-imidazolyl-1) ethyl 7-15 1- (4-chlorobenzyl) cyclopentane; 1- / 1- (4-chlorophenyl) -1-hydroxy-2- (1H-1,2,4-triazolyl-1) ethyl-7-1 (2-fluorophenyl) cyclopropane; 1- / 1- (4-Fluorophenyl-1-hydroxy-2- (1H-1,2,4-triazolyl-1) ethyl-7-1- (4-fluorophenyl) cyclopropane, in the form of the free base or of an acid addition salt or of a physiologically hydrolyzable and acceptable derivative. 4. 1- / 1- (4-chlorophenyl) -1-hydroxy-2- (1H-1,2,4-triazolyl-1) ethyl 7-1- (4-fluorophenyl) cyclopropane, in the form of the free base or of an acid addition salt or of a physiologically hydrolyzable and acceptable derivative. 5. 1- / 1- (4-chlorophenyl) -1-hydroxy-2- (1H-1,2,4-triazolyl-1) ethyl-7-1-phenylcyclopropane, in the form of the free base or of an acid addition salt or of a physiologically hydrolyzable and acceptable derivative. A chemotherapeutic composition comprising a compound according to any one of claims 1 to 5 in the form of a free base or of a chemotherapeutically acceptable acid addition salt or of a physiologically hydrolyzable and acceptable derivative thereof. 7. A process for the preparation of a compound according to claim 1 and of the acid addition salts and the acids. Physiologically hydrolyzable and acceptable derivatives thereof, characterized in that a compound of formula 2 is reacted with a compound of formula 3, wherein R through R, Y, A and n have the definitions given above, And wherein M is hydrogen, a metal or a trialkylsilyl group, the compound thus obtained is isolated in the form of the free base or of an acid addition salt or of a physiologically hydrolyzable and acceptable derivative. 8. A compound of formula 2 as defined in claim 7. 8402755 i-Improvement of errata in the specification pertaining to patent application No. 84.02755 Ned. proposed by applicant dd. 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