CH633185A5 - Antimycotic agent - Google Patents

Description

The present invention relates to an antifungal agent. It has already become known that phenoxy-tri-azolyl derivatives have good antifungal activity (see German Offenlegungsschriften 2 247 186 [Le A 14 639] and 2 324 424 [Le A 15 Ol 1]. However, their action is, in particular against Dermatophytes, not always entirely satisfactory.

35

40

Cl

20th

Q- ° -

\

X.

n

CH -

"Ni

A -

- Cl

M

jy in which

A represents a keto group or a CH (OH) group,

X represents halogen, alkyl or optionally substituted phenyl and n represents integers from 0 to 3,

and whose physiologically tolerable salts have good antimicrobial, in particular antifungal properties.

The antifungal agent according to the invention is characterized by a content of at least one 2,4-dichlorophenyl-triazolylethanol (-ol) of the general formula I.

Cl

\

- 0 - CH - A -

Cr

- Cl (i)

in which

A represents a keto group or a CH (OH) group,

X represents halogen, alkyl or optionally substituted phenyl and n represents integers from 0 to 3,

and / or their physiologically tolerable salts.

Those compounds of the formula (I) in which A represents the CH (OH) group have two asymmetric carbon atoms; they can therefore exist in the two geometric isomers (erythro and threo form), which can be obtained in different proportions. In both cases they exist as optical isomers. All isomers are claimed according to the invention.

55

60

65

Surprisingly, the 2,4-dichlorophenyl-triazolylethanols (-ols) which can be used according to the invention show better antimycotic, therapeutically useful activity than the phenoxy-tri-azolyl derivatives known from the prior art, which are the most chemically and effectively obvious compounds. The substances which can be used according to the invention thus represent an enrichment of the pharmaceutical industry.

The active compounds according to the invention are generally defined by the formula (I). In this formula, X preferably represents the halogens fluorine, chlorine, bromine and iodine, straight-chain or branched alkyl having 1 to 4 carbon atoms and phenyl optionally substituted by halogen, in particular chlorine. The index n is preferred

3rd

633 185

wise for integers from 0 to 2. A has the meaning given in the definition of the invention.

In addition to the preparation examples and the examples in Table 1, the following may be mentioned as examples of particularly effective representatives of the active compounds according to the invention: 1 - (2-chlorophenoxy) -2- (2,4-dichlorophenyl) -1 - (1,2,4 -triazole-1 -

yl) - ethane-2-one or -ol 1 - (2-isopropylphenoxy) -2- (2,4-dichlorophenyl) -1 - (1,2,4-tri-

azol-l-yl) -ethane-2-one or -ol 1 - (2-methylphenoxy) -2- (2,4-dichlorophenyl) -1 - (1,2,4-triazole-

l-yl) -ethane-2-one or -ol 1 - (2-chloro-4-methylphenoxy) -2- (2,4-dichlorophenyl) -1 - (1,2,4-

triazol-l-yl) -ethane-2-one or -ol 1 - (4-bromophenoxy) -2- (2,4-dichlorophenyl) -1 - (1,2,4-triazol-1 -

yl) -ethane-2-one or -ol 1 - (4-iodophenoxy) -2- (2,4-dichlorophenyl) -1 - (1,2,4-triazol-1 -

yl) -ethane-2-one or -ol 1 - (2,6-dichlorophenoxy) -2- (2,4-dichlorophenyl) -1 - (1,2,4-tri-

azol-l-yl) -ethane-2-one or -ol 1 - (2,5-dichlorophenoxy) -2- (2,4-dichlorophenyl) -1 - (1,2,4-tri-

azol-l-yl) -ethane-2-one or -ol 1 - (3-fluorophenoxy) -2- (2,4-dichlorophenyl) -1 - (1,2,4-triazol-1 -

yl) -ethane-2-one or -ol 1 - (3-bromophenoxy) -2- (2,4-dichlorophenyl) -l - (1,2,4-triazol-1 -

yl) -ethane-2-one or -ol 1 - (4-methylphenoxy) -2- (2,4-dichlorophenyl) -1- (1,2,4-triazole-

l-yl) -ethane-2-one or -ol 1 - (4-ethylphenoxy) -2- (2,4-dichlorophenyl) -1 - (1,2,4-triazol-1 -yl) -ethane- 2-on or -ol

1 - (3-methylphenoxy) -2- (2,4-dichlorophenyl) -1 - (1,2,4-triazole-

l-yl) -ethane-2-one or -ol 1 - (2-methylphenoxy) -2- (2,4-dichlorophenyl) -1 - (1,2,4-triazol-l-yl) -ethane- 2-one or -ol 5 1 - (4-chloro-2-methylphenoxy) -2- (2,4-dichlorophenyl) -1 - (1,2, 4-triazol-l-yl) -ethane-2- on or -ol 1 - (4-bromo-2-methylphenoxy) -2- (2,4-dichlorophenyl) -1 - (1, 2,

4-triazol-l-yl) -ethane-2-one or -ol 1 - (4-fluoro-2-methylphenoxy) -2- (2,4-dichlorophenyl) -l - (1,2,4-

triazol-l-yl) -ethane-2-one or -ol 1 - (4-iodo-2-methylphenoxy) -2- (2,4-dichlorophenyl) -1 - (1,2,4-

triazol-l-yl) -ethane-2-one or -ol 1 - (2,3-dimethylphenoxy) -2- (2,4-dichlorophenyl) -1 - (1,2,4-tri! s azole -1 -yl) -ethane-2-one or -ol

1 - (4-2 ', 4'-dichlorobiphenylyloxy) -2- (2,4-dichlorophenyl) -1 -

(l, 2,4-triazol-l-yl) -ethane-2-one or -ol 1 - (4-2,4'-dichlorobiphenylyloxy) -2- (2,4-dichlorophenyl) -1 - (l , 2,4-triazol-l-yl) -ethane-2-one or -ol 20 1 - (4-4'-bromobiphenylyloxy) -2- (2,4-dichlorophenyl) -1 - (1,2, 4-triazol-l-yl) -ethane-2-one or -ol 1 - (4-2-chlorobiphenylyloxy) -2- (2,4-dichlorophenyl) -1 - (1,2,4-triazol-l -yl) -ethane-2-one or -ol

The active ingredients to be used according to the invention and their salts are not yet known. However, they can be prepared according to your own proposal by using 1-bromo-2- (2,4-dichlorophenyl) -1-phenoxy-ethane-2-one of the formula II

X.

- 0 -

11

CH - CO -I

Br

- Cl

(II)

in which

X and n have the meaning given above, with 1,2,4-triazole in the presence of an inert organic solvent, for example acetonitrile, and in the presence of an acid binder, for example potassium carbonate or an excess of 1,2,4-triazole, at temperatures between 0 and 150 ° C, preferably at 60 to 120 ° C, and optionally the 1,2,4-triazolylethanones obtained in a conventional manner in the presence of a polar organic solvent, for example methanol, at temperatures between 0 and 30 ° C with complex borohydrides, for example sodium borohydride, reduced. The compounds of the formula (I) are isolated in a generally customary manner.

The l-bromo-2- (2,4-dichlorophenyl) -l-phenoxy-ethane-2-one to be used as starting materials of the formula (II) are not yet known. However, they can be prepared by known processes by reacting appropriate phenols with <a-bromo-2,4-dichloroacetophenone and then exchanging the remaining active hydrogen atom for bromine in the customary manner.

Suitable salts for the compounds of the formula (I) are salts with physiologically tolerated acids. These preferably include the hydrohalic acids, e.g. hydrochloric acid and hydrobromic acid, especially hydrochloric acid, phosphoric acid, nitric acid, mono- and bifunctional carboxylic acids and hydroxycarboxylic acids, e.g. Acetic acid, citric acid, sorbic acid, lactic acid, 1,5-naphthalene disulphonic acid.

The compounds of formula (I) and their salts which can be used according to the invention have antimicrobial, in particular 45 strong antifungal effects. They have a very broad spectrum of antifungal effects, particularly against dermatophytes and shoot fungi as well as biphasic fungi, e.g. against Candida species, such as Candida albicans, Epidermophyton species, such as Epidermophyton floccosum, such Aspergillus species, such as Aspergillus niger and Aspergillus fu-migatus, such as Trichophyton species, such as Trichophyton mentagrophytes, Microsporon species, such as Microsporillium felineum Species such as Pénicillium commune. The enumeration of these microorganisms does not in any way limit the number of germs which can be controlled, but is only of an explanatory nature.

Indications for use in human medicine include:

Dermatomycoses and systemic mycoses caused by Tri-60 chophyton mentagrophytes and other Trichophyton species, Microsporon species, Epidermophyton floccosum, shoots and biphasic fungi as well as molds.

Indications in veterinary medicine can include the following:

65 All dermatomycoses and systemic mycoses, especially those caused by the pathogens mentioned above.

The present invention includes pharmaceutical

633185

Preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more active compounds according to the invention or which consist of one or more active compounds according to the invention, and processes for the preparation of these preparations.

The present invention also includes pharmaceutical preparations in dosage units. This means that the preparations in the form of individual parts, e.g. Tablets, coated tablets, capsules, pills, suppositories and ampoules are available, the active ingredient content of which corresponds to a fraction or a multiple of a single dose. The dosage units can e.g. 1,2, 3 or 4 single doses or 1 / 2,1j3 or 1U of a single dose. A single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half or a third or a quarter of a daily dose.

Non-toxic, inert pharmaceutically suitable carriers are to be understood as solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of all kinds.

Tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays may be mentioned as preferred pharmaceutical preparations.

Tablets, coated tablets, capsules, pills and granules can contain the active ingredient (s) in addition to the usual carriers, such as (a) fillers and extenders, e.g. Starches, milk sugar, cane sugar, glucose, mannitol and silica, (b) binders, e.g. Carboxymethyl cellulose, alginate, gelatin, polyvinyl pyrrolidone, (c) humectant, e.g. Glycerin, (d) disintegrant, e.g. Agar-agar, calcium carbonate and sodium bicarbonate, (e) solution retarders, e.g. Paraffin and (f) absorption accelerators, e.g. quarterly ammonium compounds, (g) wetting agents, e.g. Cetyl alcohol, glycerol monostearate, (h) adsorbent e.g. Kaolin and bentonite and (i) lubricants, e.g. Talc, calcium * and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).

The tablets, dragees, capsules, pills and granules can be provided with the customary coatings and casings optionally containing opacifying agents and can also be composed such that they release the active ingredient (s) only or preferably in a certain part of the intestinal tract, optionally with a delay. where as embedding compounds, for example Polymer substances and waxes can be used.

The active ingredient (s) can optionally also be in microencapsulated form with one or more of the above-mentioned excipients.

Suppositories can contain the usual water-soluble or water-insoluble excipients in addition to the active ingredient or ingredients, e.g. B. polyethylene glycols, fats, e.g. B. cocoa fat and higher esters (e.g. Ci4 alcohol with C16 fatty acid) or mixtures of these substances.

Ointments, pastes, creams and gels can contain the usual excipients in addition to the active ingredient (s), e.g. B. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide or mixtures of these substances.

Powder and sprays can contain the usual excipients in addition to the active ingredient (s), e.g. B. milk sugar, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays can also contain the usual propellants, e.g. Contain chlorofluorocarbons.

4th

In addition to the active ingredient (s), solutions and emulsions can contain the usual carriers such as solvents, solubilizers and emulsifiers, e.g. Water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn oil, olive oil, castor oil and se-seed oil, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol Contain tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of Sor-10 bitans or mixtures of these substances.

For parenteral administration, the solutions and emulsions can also be in sterile and blood isotonic form.

In addition to the active ingredient (s) 15, suspensions can contain the usual carriers such as liquid diluents, e.g. Water, ethyl alcohol, propylene glycol, suspending agents e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tra-20 gant or mixtures of these substances.

The formulation forms mentioned can also contain colorants, preservatives and odor and taste-improving additives, e.g. Peppermint oil and Eu-25 calyptus oil and sweeteners, e.g. Sakharin included.

The therapeutically active compounds should preferably be present in the pharmaceutical preparations listed above in a concentration of about 0.1 to 99.5, preferably of about 0.5 to 95 percent by weight of the total mixture.

In addition to the active substances according to the invention, the pharmaceutical preparations listed above can also contain further pharmaceutical active substances.

The pharmaceutical-3S preparations listed above are prepared in a conventional manner by known methods, e.g. by mixing the active substance or substances with the carrier substance or substances.

The present invention also includes the use of the active compounds according to the invention and of pharmaceutical preparations which contain one or more active compounds according to the invention in human and veterinary medicine for preventing, ameliorating and / or curing the above-mentioned diseases.

The active substances or the pharmaceutical preparations can be administered locally, orally, parenterally, intraperitoneally and / or rectally, preferably parenterally, in particular intravenously.

In general, both in human and in veterinary medicine, it has proven advantageous to use the active compound (s) according to the invention in total amounts of about 10 to about 300, preferably 50 to 200 mg / kg of body weight per 24 hours, optionally in the form of several Individual doses 55 to achieve the desired results.

However, it may be necessary to deviate from the doses mentioned, depending on the type and body weight of the object to be treated, the type and severity of the disease, the type of preparation and the application of the drug, and the period or interval within which the administration takes place. In some cases it may be sufficient to make do with less than the above-mentioned amount of active ingredient, while in other cases the above-mentioned 65 amount of active ingredient has to be exceeded. The optimum dosage and type of application of the active ingredients required in each case can easily be determined by any person skilled in the art on the basis of his specialist knowledge.

Example A Antifungal In Vitro Efficacy Description of the Experiment: The in vitro tests were carried out in a serial dilution test with germinocula with an average of 5 × 104 germs / ml of substrate. Served as a nutrient medium

5 633185

a) for dermatophytes and molds: Sabouraud's milieu d'épreuve b) for yeasts: meat extract and glucose broth. The incubation temperature was 28 ° C, the incubation

The duration was 24 to 96 hours.

Table A In Vitro Antifungal Efficacy

Active ingredient MIC values in - // ml nutrient medium

Trichophy- Candida Pénicillium Aspergillus Mikrospo-Torulopsis tonmentagr. albicans commune species ronfelineum glabrata

Cl - ^ - 0-CH-CO-C (CHj) 3

At

Li

(known)

P-

Cl - ^^ 0-CH-C0-C (CH3 ^

Ah

N U

(known)

P-

ci- © -o-ch-co - @ - ci

40> 100 100 100

\

if

N-

il

40> 100 100 100

4 * -> 100 100 «

4> 64> 64> 64 64

(known)

9H

H3C00C - ^ - 0-CH-CH-C (CH3) 3 4

N - -i)

(known)

C \ OH

v (

H3 C- <y) -0-CH-CH-C (CH3) 3

. -

IÏ _ ii

(known)

OH

Cl- ^ V-O-CH-CH- ^ S 64 64> 64

''!

N-

(known)

64> 64> 64 64

633185

6

Table A

Antifungal In Vitro Effectiveness (continued)

Active ingredient 'MIC values in y / ml nutrient medium

(Compounds from Example No.) • Trichophy-Candida Pénicillium Aspergillus Mikrospo-Torulopsis c. tonmentagr. albicans commune species ronfelineum glabrata

2 '4 32> 64> 64 32 -

3 4 8> 64 64 32

5 <1 32> 64> 64 - 32

14 4 8> 64 64 32 32

15 <1 32> 64> 64 <1 1

16 <1 8> 64> 64 4 1

* = 90% growth inhibition

Production Examples Example 1

Cl-

Cl

-O-CH-CO-

i

■ N-

-Cl r

"N

N-

S03H

Example 2

Cl

\

Cl-

-O-CH-CO

i

C.

N—

II

n> -ci x HCl

2o thaline disulfonate (l, 5) the base is released by adding sodium hydrogen carbonate solution, taken up in ethyl acetate and converted with ethereal hydrochloric acid into the hydrochloride, which crystallizes after long standing in ether. Quantitatively l- (4-chloro-25 phenoxy) -2- (2,4-dichlorophenyl) -l- (1,2,4-triazol-l-yl) -ethane-2-one hydrochloride of melting point 138 is obtained -140 ° C.

Example 3

Cl

35

Cl-

., -0-CH-CH-

y / i I

-Cl

244.6 g (0.62 mol) of l-bromo-l- (4-chlorophenoxy) -2- are added to 149 g (2.13 mol) of 1,2,4-triazole in 1500 ml of acetonitrile at the boil. (2,4-dichlorophenyl) -ethane-2-one added dropwise. The mixture is heated under reflux for 40 hours. The solvent is then distilled off in vacuo, the residue is taken up in 1000 ml of methylene chloride and extracted with three times 500 ml of water. The aqueous phase is shaken out again with 500 ml of methylene chloride. The combined methylene chloride phases are dried over sodium sulfate and concentrated by distilling off the solvent in vacuo. The residue is dissolved in 300 ml of acetone and mixed with 100 g of 1,5-naphthalenedisulfonic acid hexahydrate in 200 ml of acetone. 270 g (41.3% of theory) of 1- (4-chlorophenoxy) 2- (2,4-dichlorophenyl) -1- (1,2,4-triazol-1-yl) -ethane-2-one are obtained -naphthalenedisulfonate- (1,5) melting point 198 ° C.

If

N-

NN

OH

'N

x HCl

40

From the l- (4-chlorophenoxy) -2- (2,4-dichlorophenyl) -1 - (1,2,4-triazol-1 -yl) -ethane-2-one-naph- obtained according to Example 1

226 g (0.42 mol) l- (4-chlorophenoxy) -2- (2,4-dichlorophenyl) -1 - (1,2,4-triazol-l -yl) -ethane-2-one-naphthalenedisulfonate- (1,5) (Example 1) are slurried in 500 ml of methylene chloride, treated with 1000 ml of saturated sodium hydrogen carbonate solution and stirred for 5 hours. The isolated organic phase is dried over sodium sulfate and concentrated in vacuo. The residue is taken up in 1.51 methanol, 17 g (0.45 mol) of 50 sodium borohydride are added in portions of about 1 g at about 0 to 5 ° C. and the mixture is stirred for 15 hours at room temperature. 200 ml of concentrated hydrochloric acid are then added dropwise at 0 ° C. and the mixture is stirred again at room temperature for 15 hours. The reaction mixture is then stirred into 1000 ml of saturated sodium hy-S5 bicarbonate solution, the aqueous phase is extracted with two 500 ml of methylene chloride and the organic phase with two 200 ml of water. The combined organic phases are dried over sodium sulfate and concentrated by distilling off the solvent in vacuo 60. The remaining oil is dissolved in 800 ml of ether and an excess of dry hydrogen chloride is added. 113.5 g (64% of theory) of 1- (4-chlorophenoxy) -2- (2,4-dichlorophenyl) -1- (1,2,4-triazol-1-yl) -ethane-2- are obtained. ol hydrochloride as a mixture of isomers from melting point 65-157-172 ° C.

The following compounds of Table 1 are obtained analogously to the examples mentioned above.

E.g.

4th

5

6

7

8th

9

10th

11

12

13

14

15

16

17th

18th

19th

633 185

Table 1

- 0 - CH - A

- Cl

n,?

N II

A

Melting point (° C)

CO

173-83 (x HCl)

CO

205-08 (x HCl)

CO

138 (dec.) (X HCl)

CO

83-86

CO

176 (x HCl)

CO

140-42 (x HCl)

CO

86-88

CO

172 (x HCl)

CO

138 (x HCl)

CO

156 (x HCl)

CH (OH)

68-85 (x HCl), isomer gem.

CH (OH)

148-50 (x HCl),

CH (OH)

170-74,

CH (OH)

139-43 (x HCl),

CH (OH)

171-73,

CH (OH)

155-58 (x HCl),

x "

2,4-Cl2

4- © - «

4-F 2,6-Cl2

3-C1

4-CH3 4-Cl, 2-CH3 4-J

2,4-Cl2

-Cl

4-4-F

3-C1

Claims (2)

633185 2 PATENT CLAIMS 1. Antifungal agent, characterized by a content of at least one 2,4-dichlorophenyl-triazolylethanone (-ol) of the general formula I. Cl - 0 - CH - A - G - Cl (I) in which A represents a keto group or a CH (OH) group, X represents halogen, alkyl or optionally substituted phenyl and n represents integers from 0 to 3, and / or their physiologically tolerable salts. 2. A process for the preparation of an antifungal agent, characterized in that 2,4-dichlorophenyl-triazolylethanols (ole) according to the formula in claim 1 are mixed with inert, non-toxic, pharmaceutically suitable excipients. It was found that the new 2,4-dichlorophenyl-triazolylethanols (-ols) of the general formula I 25th 30th