LU86443A1 - NOVEL AZO COMPOUNDS, THEIR PREPARATION AND THEIR USE AS ANTIFUNGALS AND FUNGICIDES - Google Patents

Description

* f

The present invention relates to new azole compounds, their preparation and their use as anti-fungals and as fungicides.

In particular, the invention relates to the azole derivatives of formula I

__NOT

X * Jj sr3 T? H lA <> CB2 - Ç - 10 * 1. * 2 in which 15 and R2 independently represent hydrogen, a halogen, a nitro, lower alkenyl, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl group, or a lower alkyl or lower alkoxy group optionally substituted by one or more atoms halogen, R3 represents a lower alkyl, lower alkenyl or lower alkynyl group optionally containing one or more substituents selected from halogens and carboxy, lower alkoxycarbonyl, lower alkoxy, lower alkylthio, amino, lower alkanoylamino, lower alkoxycarbonylaminoinamin, and lower alkylamino groups lower dialkylamino, or a phenyl group optionally bearing one or more substituents chosen from halogens and lower alkyl, lower alkoxy, ami no, lower alkanoyl amino, lower alkoxycarbonylami, lower alkylamino, lower dialkylamino, 1-piperazinyl 4- (lower alkanoyl) -1-piper-2 ra zinyl, each alkyl residue contained in being able to be substituted by one or more halogen atoms, X represents N or CH and 5 n represents an integer from 2 to 5, in racemic form or in the form of enantiomers.

The lower alkyl groups contain in particular from 1 to 5 carbon atoms, preferably from 1 to 4, for example 1 or 2 carbon atoms. This also applies to the lower alkyl residue contained in other groups. The alkenyl and lower alkynyl groups contain in particular from 3 to 6 carbon atoms, especially 3 or 4 carbon atoms. By halogen is meant fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine. In the compounds of the invention, the cycloalkyl groups advantageously contain from 3 to 6 members, preferably 3 members (n = 2).

The compounds of formula I can be present in free form, in the form of salts, or in the form of metal supplements. By salt is meant an addition salt with an organic or inorganic acid, or an alcoholate. The metal complex is, for example, a complex with a metal from group Ib, IIa, 11b, VIb, V11b or VIII of the periodic table, such as copper and zinc, or with an anion such as chloride, sulfate or nitrate. Such salts and metal complexes can be prepared according to known methods from the corresponding free forms, and vice versa.

The invention also relates to a process for preparing the compounds of formula I, process according to which 3 * i

a) reacting a compound of formula II

CH 2-O fR3? - CvJ? H2) n 5 î ^ N.

(II) R1 "2 10 or a compound of formula IIa SR.,

OH I J I V-N

R4CH2 - <= - CJCH2) n 15 f "n (lia); # * · h R2 in which, R2" R3 and n have the meanings given above and R ^ represents a

eliminable group, with a compound of formula III

xlj! (III)

25M

in which X has the meaning given above and M represents hydrogen or an equivalent of a metal, or b) a compound of formula IV is reacted (formula IV see next page) - 4 - SR-.

S U

<f- = J * 2> n (IV) 5

H

R1 "2 10 in which R1, R2, R3 and n have the meanings given above, with a compound of formula III as defined above and dimethylsulfonium-methylide or dimethyloxosulfonium-methylide or a precursor of these compounds, any amino group present which can be protected by suitable protective groups which are removed after the reaction, and the compounds thus obtained are recovered in free form or in the form of salts.

Process a) can be carried out for example by reacting a compound of formula II or Ha with an azole of formula III as such (M = H) or in the form of a metal salt (M = metal), especially in the form of a salt of alkali metal, for example of sodium salt, in an inert solvent such as dimethylformamide. The operation is carried out at a temperature between room temperature and the boiling point of the reaction mixture.

Method b) can be carried out in a conventional manner, for example as described in J. Am. Chem. Soc. 84, 3782 (1982), Heterocycles 8, 397 (1977) and J. Am. Chem. Soc. 87, 1353 (1965).

The protective groups and the eliminable groups are those usually used for this type of reaction. The protective groups can be introduced and eliminated according to conventional methods.

* i - 5 -

The compounds of formula I have an asymmetric carbon atom and can therefore exist in the form of enantiomers or their mixtures which can be separated according to known methods. When optically active starting materials are used, corresponding fine products are obtained. The invention relates equally to the two substantially pure enantiomers as well as to their mixtures, the (+) enantiomer being preferred when Ri = Cl or Br, R2 = H, R3 = CH3 and n = 2.

In the compounds of formula I, the substituents preferably have the following meanings:

Rl and R2 = a) hydrogen b) halogen R3 = a lower alkyl group, especially a methyl group,

X = a) N

B) CH and n = 2.

The preferred compounds of formula I are those containing a combination of these characteristics.

The compounds of formula II are new compounds. They can be prepared from the compounds of formula IV, in a manner analogous to method b). The compounds of formula Ha can be prepared for example according to known methods from the compounds of formula II.

The compounds of formula IV are partly new. They can be prepared according to known methods, for example a) by reacting a compound of formula V

Hal 0 i 30 ΐ-Wn v R1 R2 in which Ri, R2 and n have the meanings given above and Hal represents a halogen, - 6 -

with a thiol of formula VI

HS-R3 (VI) 5 in which R3 has the meaning given above, in free form, advantageously in the presence of a base, or in the form of a salt, or

b) reacting a compound of formula IX

10 0 1 - “” Λ.1 - “15 xSv R] R2 in which R] _, R2, n and Hal have the meanings given above,

with a halogen, for example Br2 in a mixture of ether and dioxane, which gives a compound of formula VIII

O Hal 25 C - CH - (CH2) n - Hal ô 0/1111 R1 R2 30 in which R] _, R2, n and Hal have the meanings given above,

compound which is reacted with a thiol of formula VI, in free form advantageously in the presence of a base or in the form of a salt, which gives a compound of formula VII

- 7 - 0 SR3 c - CH - (CH,) - »al (Vil) 5 A: R1 R2 which is then subjected to cyclization.

When the preparation of the starting materials is not described, these are known or can be obtained by methods analogous to the known methods or those described in the present application.

The end products and starting materials can be isolated and purified according to known methods.

The compounds of the invention have interesting biological properties, in particular anti-fungal properties, and can therefore be used therapeutically for the treatment of fungal infections in humans and in animals. This rapid anti-fungal activity has been demonstrated by in vitro tests, for example by serial dilution tests on various families and species of fungi, such as yeasts, molds and dermatophytes, at concentrations between about 0.6 and about 50 pg / ml, and also by in vivo, e.g. systemic, tests, by oral administration at doses between about 0.1 and 10 mg / kg twice daily, at rats in which intravaginal infection has been caused with Candida albicans.

Thanks to these properties, the compounds of the invention can be used as anti-fungals. For this use, the dose administered will depend on the compound used, the mode of administration and the treatment desired. However, satisfactory results are generally obtained when the compounds of the invention are administered at a daily dose of between approximately 0.5 and 10 mg / kg, advantageously in divided doses 2 to 4 times per day, or in a sustained release form. In human therapy, the corresponding daily dose will be between 40 and 700 mg of active substance; the appropriate unit doses for oral administration include, for example, between 10 and 700 mg of active substance.

The compounds of the invention can be used in free form or in the form of pharmaceutically acceptable salts (addition salts of acids or alcoholates). In general, the salts have the same order of activity as the free forms. As examples of acid addition salts, mention may be made of the hydrochloride, the hydrogen fumarate and the naphthalene-1,5-disulfonate.

The invention therefore relates to the compounds of the invention, in free form or in the form of salts acceptable from the pharmaceutical or veterinary point of view, for use as medicaments, in particular as anti-fungals.

As medicaments, the compounds of the invention can be used in the form of pharmaceutical or veterinary compositions containing the active substance in association with inert, pharmaceutically acceptable carriers or diluents 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 to be administered by the oral, topical, intravenous or parenteral route. 25 teral.

The compounds of the invention, in free form or in the form of salts or metal complexes acceptable in agriculture, are also suitable for combating phytopatogenic fungi. This fungicidal activity has been demonstrated, inter alia, in in vivo tests against Uromyces appendicula-tus (bean rust) on ream beans, against other rust fungi (e.g. Hemileia, Puccinia) on coffee, wheat, flax and ornamental plants (for example geranium and snapdragon), and against Erysiphe cichoracearum 35 on cucumber and other powdery mildew (for example E. graminis f. sp.

- 9 - tritici, E. gram. f. sp. hordei, Podosphaera leucotricha, Uncinula necator) on wheat, barley, apples and vines.

The following examples illustrate the present invention without in any way limiting its scope. In these examples, all 5 temperatures are indicated in degrees Celsius.

Example 1: a- (4-chorophenyl) -a- (1-methylthio) cyclopropyl-1H-1,2,4-triazol-1-ethanol [method b)] To a suspension of 3.2 g of hydride sodium (50¾) in 120 ml of anhydrous dimethylformamide, 14.8 g of trimethylsuifoxonium iodide are added in portions and stirring is continued for 45 minutes. A solution of 3.2 g of sodium hydride (50%), 120 ml of anhydrous dimethylformamide and 4.6 g of 1,2,4-triazole added in portions is prepared simultaneously, and the mixture is also stirred for 45 minutes and combined with the suspension mentioned above. To this mixture, a solution of 10.6 g of 4-chlorophenyl-1-methylthiocyclopropylketone in 50 ml of anhydrous dimethylformamide is then added dropwise at room temperature. The reaction mixture is stirred for 7 days at room temperature and the solvent is removed at 50 ° under a vacuum of 20 1 Torr, the oily residue is partitioned between chloroform and water, the combined organic phases are washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. After chromatography on silica gel (ethyl acetate), the title compound is obtained in the form of colorless crystals melting at 131-133 °.

Example 2: ot- (4-bromophen.yl) -g- (1-meth.ythi o) cycl opropyl-1H-1,2,4-triazol-1-ethanol [process b) 3 By proceeding in a similar manner to that described in Example 1, the title compound is obtained; melting point = 125-127 °.

- 10 - * »

Example 3: (+) - a- (4-chlorophenyl) -a- (1-methylthio) cyc1opropyl-1H-1,2,4-triazol-1-ethanol (process a)]

A mixture of 129 mg of alcohol (+) - 4-chloro-α- (1-methylthio) cyclopropyl-a-methyloxymethyl-5-benzyl, of 53 mg of 1,2,4- is stirred for 4 hours at 70 °. triazole, 105 mg of potassium carbonate and 10 ml of anhydrous dimethylformamide. The mixture is then poured into water, it is extracted with ethyl acetate, the organic phase is dried over magnesium sulphate and evaporated. The residue obtained is chromatographed on silica gel with ethyl acetate. Colorless crystals are thus obtained, melting at 112-114 °; [a] 20 (acetate) + 40.2 °.

Example 4: (-) - a- [4-chlorophenyl) -a- (l-meth, y1 thi o) cyclopropyl-1H-1,2,4-triazol-l-ethanol [process a)]

By proceeding in a similar manner to that described in Example 15, we obtain the title compound; [a] 20 (acetone) = - 40 °.

The starting materials can for example be obtained as follows: A) 4-chlorophenyl-1-methylthi ocyclopropylketone (for Example 1) 20 a) 4-chlorophenyl-3-chloro-1-bromopropylketone

65.1 g of 4-chlorophenyl-3-chloropropylketone are dissolved in a mixture of 120 ml of anhydrous ether and 60 ml of anhydrous dioxane, the mixture is heated to boiling and treated with 48 g of bromine. After stirring for 30 minutes at room temperature, the reaction mixture is poured into 300 ml of ice and extracted with ether. The combined organic phases are dried over sodium sulfate and evaporated. The solid residue is crystallized from petroleum ether, F = 67-69 °. b) 4-chlorophenyl-3-chloro-1-methylthiopropylketone 30 A to a suspension of 10.6 g of sodium methanethiolate in 200 ml of anhydrous 1,2-dimethoxyethane, 45.25 g of 4 are added dropwise with stirring -chlorophenyl-3-chloro-1-bromopropyl-ketone in 100 ml of anhydrous 1,2-dimethoxyethane, while maintaining the temperature below 30 °. The reaction mixture is stirred for 2 hours at room temperature and diluted carefully in 150 ml of water and 250 ml of ether. The organic phase is washed with water, dried and evaporated. The title compound thus obtained is purified by chromatography on a column of silica gel (n-hexane / ethyl acetate = 98/2). A colorless oil is thus obtained; Rf = 0.12 (n-hexane / ethyl acetate = 98/2).

c) 4-chlorophenyl-1-methylthiocyclopropylketone

A solution of 10.86 g of potassium hydroxide in 45 ml of methanol is reacted dropwise with a solution of 24.3 g of 4-chlorophenyl-3-chloro-1-methylthiopropylketone in 45 ml of metanol. The reaction mixture is stirred for 1 hour at room temperature, concentrated in a rotary evaporator, distributed between toluene and water, the combined organic phases are washed with water, dried and dried. evaporates. After crystallization of the oily residue in petroleum ether, colorless crystals are obtained, melting at 30-32 °.

B) 4-bromophenyl-1-methylthiocyclopropylketone (for example 2)

The procedure is analogous to that described under A).

a) 4-bromophen.yl -3-chl oro-1-bromopropyl ketone 20 F = 92-94 °.

b) 4-bromophen.yl-3-chloro-1-methylthioprop.ylketone Rf = 0.13 (n-hexane / ethyl acetate = 98/2) c) 4-bromophen.yl -1-methyl thi oc. ycl oprop.yl ketone F = 43-45 °.

C) Al cool 4-chloro-α- (1-methylthi o) cyclopropyl-α-mesyloxymethyl-benzyl (for examples 3 and 4) a) 1- (4-chlorophenyl) -1- (1-methylthi o) cyclopropyl-oxi ranne To a suspension of 0.73 g of 80% sodium hydride in 50 ml of anhydrous dimethylformamide, 5.34 g of trimethylsulfoxonium iodide are added in portions and the mixture is stirred for 45 minutes. A solution of 5 g of 4-chlorophenyl-1-methylthiocyclopropylketone in 25 ml of dimethylformamide is then added dropwise and the mixture is stirred for 18 hours at room temperature. The mixture is then concentrated in vacuo 35 (1 Torr) and the residue is taken up in a mixture of water and ethyl acetate. The organic phase is separated, dried over magnesium sulfate and evaporated. A colorless oil is thus obtained. IH-NMR spectrum: 7.1-7.6 (m, 4H); 2.76-3.0 (AB system, 2H); 1.98 (s, 3H); 0.7-1.3 (m, 4H).

5 b) 4-chloro-a-hydroxymethyl-a- (1-methylthio) cyclopropyl-benzyl alcohol

0.2 g of 1- (4-chlorophenyl) -1- (1-methylthio) cyclopropyl-oxirane is stirred for 20 hours at 60 ° with a 0.3 molar solution of potassium hydroxide in a 4: 1 mixture of dimethyl sulfoxide 10 and water. The mixture is then diluted with 50 ml of water and extracted with ethyl acetate. The extract is dried over sodium sulfate and evaporated. The crude product can be purified by chromatography on silica gel with a 4: 1 mixture of hexane and ethyl acetate. Colorless crystals are thus obtained, melting 15 at 86-91 °.

c) Separation of the optical isomers To 2.65 g of the racemic product in 50 ml of piridine, 2.67 g of (-) camphoric acid chloride are added in portions under cooling with ice water and the mixture is stirred. blend for 20 hours at room temperature. The mixture is poured onto ice-cold dilute sulfuric acid, it is extracted with ethyl acetate, the organic phase is dried over magnesium sulphate and evaporated. The mixture of diastereomeric esters is separated by chromatography on silica gel with a 4: 1 mixture of hexane and ethyl acetate.

Diastereomer A: F = 122-124 °, [a] 20 (acetone) = + 28 °.

Diastereomer B: F = 125-127 °, (acetone) = -43.5 °.

2 g of the diastereomer A are stirred for 15 hours at the reflux temperature with 3 g of a strongly basic ion exchanger in a mixture of methanol and water. After filtration and evaporation, the dextrorotatory enantiomer is obtained in the form of colorless crystals melting at 60-62 °; [a ^ O (acetone) = + 79.7 °.

1 »- 13 - d) Alcohol (+) - 4-chloro-α- (l-methylthiο) cyclopropy1-α-mesyloxy- methyl-benzyl A 1,27 g of alcohol (+) -4-chl oro-α - hydroxymethyl-a- (1-methyl -thio) cyclopropyl-benzyl in 20 ml of anhydrous pyridine, 0.68 g of mesyl chloride is added dropwise under cooling with ice water. The mixture is stirred for 2.5 hours at 0-5 ° and it is poured onto ice-cold dilute sulfuric acid, it is extracted with ethyl acetate, the organic phase is dried over magnesium sulfate and it is evaporated, which gives a colorless oil.

1 H-NMR spectrum: 7.2-7.65 (m, 4H); 4.5-5.22 (AB system, 2H); 3.0 (s, 3H); 1.52 (s, 3H); 0.5-1.4 (m, 4H).

[a] 20 = + 57.4 °.

D

The (-) isomer can be obtained in an analogous manner.

Claims (11)

1, - The azole derivatives of formula I ΪΠι T? H lA, CH2 "f" Cv3H2, n »J» p ^ R2 in which Rl and R2 independently represent hydrogen, a halogen, a nitro group, lower alkenyl, lower alkylthio, lower alkyl sulfinyl or lower alkylsulfonyl, or a lower alkyl or lower alkoxy group optionally substituted by one or more halogen atoms, R3 represents a lower alkyl, lower alkenyl or lower alkynyl group optionally containing one or more substituents selected from halogens and carboxy groups, lower alkoxycarbonyl, lower alkoxy, lower alkylthio, amino, lower alkanoylamino, lower alkoxycarbonylamino, lower alkylamino and lower dialkylamino, or a phenyl group optionally bearing one or more substituents chosen from halogens and lower alkyl, lower alkoxy, amino, lower alkanoylamino, lower alkoxycarbonylamino, alkylam lower ino, lower dialkylamino, 1-piperazinyl and 4- (lower alkanoyl) -1-30 piperazinyl, each alkyl residue contained in R3 can be substituted by one or more halogen atoms, X represents N or CH and n represents a number integer from 2 to 5, in racemic form or in the form of enantiomers, and their salts. * »« - 15 - 2. A compound according to claim 1, in which R1 and R2 independently represent hydrogen or a halogen, R3 represents a lower alkyl group and n signifies 2. 3. A- (4-chlorophenyl) -a- (1-methylthio) cyclopropyl-1H- 1,2,4-triazol-1-ethanol, in free form or in salt form. 4. A- (4-bromophenyl) -a- (l ~ methylthio) cyclopropyl-1H- 1,2,4-triazol-1-ethanol, in free form or in salt form. 5. (+) - a- (4-chlorophenyl) -a - [(1-methylthio) cyclo-propyl1-1H-1,2,4-triazol-1-ethanol, in free form or in salt form , 6. (-) - a- (4-chlorophenyl) -a- (1-methylthio) cyclo-propyl-1H-1,2,4-triazol-1-ethanol, in free form or in salt form. 7. A process for the preparation of the compounds specified in claim 1, in free form or in the form of salts, characterized in that a) a compound of formula II CH is reacted, - O i 3 20 X / (II) XC <- C <CH2) n 1 ^ M 25 R1 or a compound of formula Ha SR, OH I I% 30 R.CH, - C - C (CH,) 42 I ^ 2 “(lia) W! R1 R2 * t - 16 - in which Ri, R2, R3 and n have the meanings given in claim 1 and R4 represents an eliminable group, with a compound of formula III --N * 'J! • N- * M in which X has the meaning given in claim 1 and M represents hydrogen or an equivalent of a metal, or b) a compound of formula IV is reacted SR-. ? U, cC (CH,) I w 2 "(IV) 15 ¢ 3 20 wherein Ri, R2, R3 and n have the meanings given in claim 1, with a compound of formula III as defined above and dimethylsulfonium- methylide or dimethyloxosulfonium-methylide or a precursor of these compounds, each friend group no present being able to be protected by appropriate protective groups which are eliminated after the reaction, and the compounds thus obtained are recovered in free form or in the form of salts. 8. A compound according to any one of claims 1 to 6, in free form or in the form of a pharmaceutically acceptable salt, for use as a medicament. »I #‘ «i - 17 - 9. A compound according to any one of claims 1 to 6, in free form or in the form of a pharmaceutically acceptable salt, for use as an anti-fungal. 10. A pharmaceutical composition, characterized in that it comprises a compound specified in any one of claims 1 to 6, in free form or in the form of a pharmaceutically acceptable salt, in association with a pharmaceutically acceptable vehicle or diluent . 11. Products and processes in substance as above described with reference to the examples cited.