LU86001A1 - NEW AZOLIC COMPOUND, ITS PREPARATION AND ITS USE AS ANTIFUNGAL AND FUNGICIDE - Google Patents

Description

- 1 -

The present invention relates to a new azolic compound, a process for the preparation of this compound and its use as an antifungal and fungicide.

5 In particular, the invention relates to enan

evogyrous tiomer 1 of the compound of formula I

Cl ·! " OH CH, 1! Η2-Η3 <] 10 Λ CH3

Cl in free form or in the form of a SET or a metalic complex.

15 British patent applications Nos. 2 1 36 423-A and 2 064 520-A each describe a broad class of derivatives of triazole and imida-zole. However, these documents do not specifically mention the (-) enantiomer according to the invention 2 ° or its advantageous antifungal properties.

The invention also includes a process for preparing the compound of the invention in free form or in the form of a salt or a metal complex, process according to which a

25 compound of formula II

30 hrs

M

In which M represents hydrogen, a metal or a tri alkylsi 1 y1e group,

with the levorotatory enantiomer of a compound of formula III

5 CH- '3/1

CH2 ~ “f ï N III

to 10 or a reactive functional derivative of this compound, and the compound thus obtained is recovered in free form or in the form of a salt or a metalic complex.

The process can be carried out in a conventional manner, for example as described in British Patent Application No. 2,136,423-A or as described in the examples below.

The compound of the invention is obtained in free form or in the form of a salt or a metal-2 Π lique complex. By salt is meant an addition salt with an organic ‘or mineral acid.

The salts or the metal complexes can be obtained according to known methods from the corresponding free form, and vice versa.

25

The compound of the invention, in free form or in the form of a salt or metal complex, can be isolated from the reaction mixture and be purified according to known methods.

The starting materials of formulas II and III are known or can be obtained according to known methods from known starting materials.

The compound of the invention, in free form or in salt form acceptable from the pharmaceutical or veterinary point of view, has interesting biological properties, in particular an antifungal activity, and can therefore be used in human or veterinary therapy such as medi-5 for the treatment of fungal infections in humans or animals. This antifungal activity has been demonstrated by in vitro tests, for example by serial dilution tests on various families and species of fungi, such as 1 evures, moi si ssures and dermatophytes, at concentrations of between approximately 0, 4 and approximately 100> μg / ml, and also by in vivo tests, for example by systemic application by the oral route of doses of between approximately 0.4 and 100 mg / kg in mice in which an intra infection has been caused. -vaginal with Candida albicans.

Thanks to these properties, the compound of the invention can be used in human or veterinary therapy as an antifungal. For this use, it will be administered at a daily dose advantageously between 70 and 2000 mg, for example in divided doses 1 to 4 times per day in the form of unit doses, or in a sustained-release form. Unit doses suitable for example for oral administration contain between 17.5 and 2000 mg, preferably 17.5 to 500 mg of active substance.

In the tests described above, it was found that the levorotatory enantiomer according to the invention has a considerably better activity than the corresponding racemate or dextrorotatory (+) enantiomer. For example, in it - 4 - the Candida albicans vaginitis model in rats, the following cure rates were observed after two oral applications.

Dose (mg / kg) Racemate Enantiomer (-) Enantiomer (+) 5 1.6 93 l 93% 2% 0.8 73% 84% 3% 0.4 41% 72% 0%

The compound of the invention can be used in the form of a free base or in the form of an addition salt with a pharmaceutically acceptable mineral or organic acid. In general, the salts have the same order of activity as the free forms. As acids for the formation of acid addition salts there may be mentioned hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, fumaric acid and naphthalene acid -1-5 -disulfonic.

The invention therefore relates to the compound of the invention, in free form or in the form of a pharmaceutically or veterinary acceptable salt, for use as a medicament, in particular as an antifungal.

The invention also relates to a medicament containing, as active substance, the compound of the invention in free form or in the form of a pharmaceutically or veterinary acceptable salt.

30

As a medicament, the compound of the invention can be used in the form of pharmaceutical or veterinary compositions containing the active substance in combination with pharmaceutically or veterinary inert carriers or diluents, and optionally with d other excipients. Such compositions, which also form part of the invention, can be presented, for example, in the form of tablets, capsules, creams, tinctures or injectable preparations intended for administration by oral, topical, intravenous route. or parenteral.

The compound of the invention, in free form or in the form of a salt or metal complex acceptable in agriculture, is 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 ornamental plants (e.g. geranium and snapdragons), and against Erysiphe cichoracearum on cucumber and other powdery mildew (eg E. graminis f. sp. tritici. E. gram. f. sp. hordei, Podosphaera leuco-tricha, Uncinula recator) on wheat , barley, 25 apples and vine.

In the following example which illustrates the invention without in any way limiting its scope, the temperatures are given in degrees Celsius.

Example: (-) - a- (4-chlorophenyl) -ot- (l-cyclo-20 propyl-1-methylethyl) -lH-1,2,4-triazole-1-ethanol

0.5 g of (-) - 2- (4-chlorophenyl) -2- (1-cyclopropyl-1-methylethyl) oxirane is stirred for 2 days at room temperature with triazole-sodium (6) prepared from 0.29 g of 1,2,4-triazole and 0.1 g of NaH) in 5 ml of anhydrous dimethylformamide. The resulting mixture is evaporated in vacuo and the residue is taken up in water and dichloromethane. The organic phase is isolated, washed with water, dried over magnesium sulfate and evaporated. The crude product thus obtained can be purified by recrystallization from n-hexane or chromatography on silica gel with ethyl acetate. White crystals are obtained, melting at 104-105 °; [a] p ° = -87.5 °.

The levorotatory or (-) enantiomer according to the invention has the absolute configuration "R" and can therefore be called R (-) - a- (4-chlorophenyl) -a- (1-cyclopropyl-1- methyl-ethyl) -1H-1,2,4-triazole-1-ethanol p 20

Cl 25

The starting material can be prepared as follows: a) Alcohol 4-chloro-α- (1-cyclopropyl-1-methylethyl) -a- (4-methylphenylsulfinylmethyl) - benzyl 30 A solution of the lithium salt of diisopropylamine in tetrahydrofuran (prepared from 14.4 ml of 1.6 N butyllithium in hexane and 2.37 g of diisopropylamine in 120 ml of anhydrous tetrahydrofuran), dropwise added

V

- 7 - drop at -5 ° 3.1 g of methyl R (+) sulfoxide and p-tolyl in 75 ml of tetrahydrofuran and the mixture is stirred for one hour at -5 °. Then 4.6 g of 1- (4-chlorophenyl) -2-cyclopro-5 pyl-2-methyl-propane-l-one is added, which increases the temperature to 0 °, the mixture is allowed to return to at room temperature and treated with 40 ml of saturated aqueous ammonium chloride solution.

The organic phase is separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate and evaporated. The residue is chromatographed on silica gel with the n-hexane / ethyl acetate system in order to separate the two diastereoisomers A-1 and A-2.

20 Al = colorless oil, [a] Q = + 115 ° (acetone) 20 A-2 = colorless oil, [a] p = + 48 ° (acetone) b) Alcohol (-) - 4-ch 1oro-α- (1-cyclopropyl-1-methyl-20 ethyl) -g- (4-methylphenylthlomethyl) -benzyl A 2.8 g of compound Al prepared under a) and 1.77 g of CoCl 2 OH 6 in 120 ml of absolute ethanol , 0.75 g of NaBH 3 are added slowly, in portions and at -10 °. Stirring is continued for 2 hours at room temperature, and then 3N hydrochloric acid is added until the aqueous phase turns pink. The mixture is extracted with diethyl ether, the ethereal phase is washed with = a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated. The crude product thus obtained can be purified by chromatography on silica gel with toluene. A colorless oil is thus obtained, 2η ♦ ν - 8 - [α] ρ = -15.7 ° (acetone).

c) (-) - 2- (4-chlorophenyl) -2- (1-cyclopropyl-1-methylethyl) oxirane 5 A 1 g of alcohol (-) - 4-chloro-a- (1-cyclopropyl- 1- methylethyl) -a- (4-methylphenylthiomethyl) - ben-zyl in 10 ml of anhydrous dichloromethane, 1.37 g of triethyloxonium tetrafluoroborate are added at 0 ° and the mixture is stirred for two and a half hours. Room temperature. After adding 5 ml of a 10% aqueous NaOH solution, the mixture is stirred for two and a half hours at room temperature and the organic phase is separated.

The organic phase is washed with water, dried over magnesium sulphate and evaporated. The crude product thus obtained can be purified by chromatography on silica gel with, as eluent, a mixture in equal parts of toluene and n-hexane *, white crystals are obtained, melting at 57-58 °, 20 [a] p5 = (acetone)

Claims (8)

1. The levorotatory enantiomer of the compound of formula I ^ 3 OH CH, 1, M-îkl 9ch3 Cl in free form or in the form of salt or metal com-plex. 2. R - (-) - a- (4-chlorophenyl) -a- (l-cyc1o-propyl-I-methylêthy1) -1 H-1,2,4-tri azole-l - ethanol, in free form or in the form of a salt or a metal complex. 3. A process for the preparation of the compound specified in claim 1, in free form or in the form of a salt or metal complex, characterized in that a compound of formula II is reacted 20 N-il II U * M in which M represents hydrogen, a metal or a tri alkylsilyl group, 25 with the levorotatory enantiomer of a compound of formula III OR .CL "3 A Ch2 - P- Ä CH3 III 30 X Μ w * - 10- “or a reactive functional derivative of this compound, and the compound thus obtained is recovered in free form or in the form of a salt or a metalic complex. 4. A compound according to claim 1 or 2, in free form or in the form of a pharmaceutically acceptable salt, for use as a medicament. 5. A compound according to claim 1 or 2, in free form or in the form of a pharmaceutically acceptable salt, for use as an antifungal. 6. A medicament, characterized in that it contains, as active substance, a compound according to I5 of claim 1 or 2 in free form or in the form of a pharmaceutically acceptable salt. 7. A pharmaceutical composition, characterized in that it comprises a compound according to claim 1 or 2 in free form or in form? Π ume of a pharmaceutically acceptable salt, in association with a pharmaceutically acceptable diluent or vehicle. 8. Products and processes in substance as described above with reference to the examples cited.