FI70578C - ANALOGIFICATION OF THERAPEUTIC ANALYSIS OF THERAPEUTIC 1- (4-CHLOROPHENYL) -1- (2,4-DICHLOROPHENYL) -2- (1,2,4, -TRIAZOL-1-YL) -ETHANE-1-OL OCH DESS SALTER - Google Patents

Abstract

1. A 1,1-diphenyl-2-(1,2,4-triazol-1-1-yl)-ethanol of the general formula I see diagramm : EP0036153,P8,F1 where one of the radicals R**1, R**2 and R**3 is chlorine and the others, which may be identical or different, are hydrogen or chlorine, and its pharmacologically tolerated salts as antimycotics.

Description

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The present invention relates to a process for the preparation of therapeutically useful 1- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -2- (1,2,4-triazol-1-yl) ethan-1-ol and its salts. analogous method for the preparation of a therapeutically useful 1- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -2- (1,2,4-triazol-1-yl) ethan-1-ol of formula (I )

Cl 10 \ '-'I? Η / ΓΛ__ C! ^ N-CH2-C --- Y ____ / 0 (1)

Cl and its pharmacologically acceptable salts. The compound of formula (I) and its salts can be used as chemotherapeutic agents, especially against fungal infections, both internally and externally.

Numerous antifungal antifungal agents are known, for example miconazole, (L2,4-dichloro- (2,4-dichlorobenzoyloxy) phenethyl "7-imidazoline nitrate) and clotrimazole, 1- (o-chloro) -r *, β-diphenylbenzyl) imine. However, their effect is not always satisfactory.

DE-A-29 12 288 discloses imidazole compounds of similar structure which have a lower antifungal activity than the compound of the formula (I) and its salts. In addition, DE-A-26 54 890 discloses some structurally more distant triazole compounds which can be used as fungicides against plant pathogenic fungi.

Particularly suitable for the preparation of pharmacologically acceptable acid addition salts are nitric acid, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, lactic acid, succinic acid, formic acid, tartaric acid, citric acid, citric acid, benzoic acid and , Part 10, pages 224-225, Birk-5 Häuser Verlag, Basel and Stuttgart, 1966.

Particularly preferred are inorganic acids, and in particular nitric acid and hydrochloric acid, which form salts which crystallize well with the compound of formula (I).

In the compound of formula (I), the carbon atom to which the hydroxyl group is attached is a center of asymmetry. Separation, isolation or preparation of optical isomers takes place in the usual manner. Also within the scope of the invention are optical isomers and their preparation.

The process according to the invention for the preparation of a compound of formula (I) and its acid addition salts is characterized in that the compound of general formula (III)

Cl OH n 20 x-ch2-c ../ --- cl (III)! o 25 ii where X is halogen is reacted with 1,2,4-triazole

I- N

30 N tl-H UV) in a manner known per se, and the compound obtained is optionally converted into a pharmacologically acceptable acid addition salt.

ti 3 70578 This reaction is conveniently carried out using stoichiometric amounts of reactants in the presence of an acid scavenger or with an excess of 1,2,4-triazole. The reaction may be carried out with or without a solvent or diluent.

Suitable diluents are mainly organic solvents, for example dimethylformamide, hexamethylphosphoric triamide, acetonitrile or benzene.

An excess of 1,2,4-triat-10 Sol or an ordinary acid-binding agent such as hydroxides, carbonates and alcoholates of alkali and alkaline earth metals, in particular sodium, potassium, magnesium or calcium, and organic bases, such as pyridine or tertiary amines such as triethyl-15 amine.

The reaction temperature can vary within wide limits. In general, the reaction is carried out at a temperature of 0 to 150 ° C, preferably 30 to 120 ° C.

The starting materials of formula III can be prepared by known methods used for the preparation of tertiary alcohols from ketones or carboxylic acid derivatives and Grignard compounds; such methods are described, for example, in Houben-Weyl, Methoden der organischen Chemie, Vol. 13 / 2a, 46-527 (1973).

If 1- (2,4-dichlorophenyl) -1- (4-chlorophenyl) -2-chloroethan-1-ol prepared from 2,2 ', 4'-trichloroacetophenone and 4-chlorophenylmagnesium bromide is used as starting material, and 1,2,4-triazole, the reaction can be described by the following scheme: 30 Cl

Cl, ·. \

Il · / 7 \ I> · // V \ C1 N ^ N-H + X-CH2-c _ / ^ Λ-ci -HC1 ^ N CU2 ~ C Λ ^ ^ φ ..... Φ ‘n ci L1 4 70578

The compounds of the formula I and their salts have excellent chemotherapeutic properties, in particular antifungal properties.

The surprising antimicrobial activity was tested against 5 Candida albicans organisms in vitro by the following experiment:

Pseudomycel and mycelium phase test with Candida albicans In this test, it is considered that Candida Albi-10 cans can form pseudomycel and right mycelium (dimorphism) in vivo in addition to shrinkage cells. In vitro, the development of all growth stages of this microorganism and the effect of antifungal agents on them can be tested as follows: Candida albicans (Robin) Berkhout No. 15 20 μM strain (Normark-Werke GmbH mycotein strain) is inoculated with nutrient medium (Brain Heart Infusion, Difco) to surface A and as a culture to point B (figure).

Cover plate C (microaerophilic conditions) is placed at the injection site. Petri dish D contains the test compound in a geometrically decreasing dilution series in the nutrient range-20. The test plates are incubated (2 days, 37 ° C), with control plates free of test compounds showing only shrinkage cells (yeast phase) in aerobic area A and pseudohyps and real hyphae in microaerophilic area B.

The minimum inhibitory concentrations of the test compounds were considered to be those concentrations of the test compound at which 100% inhibition of each fungal growth was observed.

With this experimental set-up it is possible to distinguish the minimum inhibitory concentration of the yeast phase of the microorganism Candida 30 albicans

(MHK, .. c.) And the pseudomycelic phase or equivalent mysee huvaase J c J J

minimum phase concentration (MHK... ...

myseelifaasi)

Yeast phase MHC values were found to be greater than 128 pg / ml, whereas mycelial phase MHK values were very low, as shown in Table 1.

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Table I

j = 1t 5 il-v ^ N-CHj- Ηζ Jh ^ j x 2

R

1 2 3 in Eg R R R Salt MHK,. LDrn (mouse) 10 mycelium- 50 No. phase p.o. (mg / kg) _ (ug / ml) _ 1 2-C1 4-Cl 4-Cl - <0.125> 4000 2 2-C1 4-Cl 4-Cl HCl <0.125> 1000 15 3 2-C1 4-Cl 4-Cl HNO 3 <0.125> 1000

The in vitro antimicrobial activity against dermatophytes was determined by an agar dilution assay (literature: P. Kelin's "Bacteriologische Grundlagen der chemotherapeu-20o tischen Laboratoriumspraxis"). The results of this experiment using the compound of Example 1 as a test compound are shown in Table 2.

Table 2 25

Microsporon-la j it: MHK (yug / ml) M. audouinii no. 4 0.25 M. ferrugineum no. 5 0.5 30 M. canis no. 167 4 M. canis no. 168 2 M. canis no. 169 8 6 70578

Table 2 (continued)

Trichophyton species; MHK (μg / ml) 5 T. shoenleinii no. 9 0.25 T. violaceum no. 10 2 T. mentagroph. Well. 159 0.125 T. mentagroph. Well. 172 0.25 T. mentagroph. Well. 173 0.25 10--

Epidermophyton species: E. floccosum no. 157 16

Experimentally induced Candida albicans infection in mice

To determine oral efficacy, groups of 10 mice (20 g each) were pretreated for 2 days at 50 mg / kg animal per hydrocortisone (intramuscularly) to obtain good infection. Mice were then infected intravenously with 500,000 Candida albicans each, and the mice were then orally administered twice daily with 100 mg / kg of the test compound for four days.

In addition to the infected group and the untreated control group, one group was treated with miconazole and one group with clotrimazole for comparison.

It can be seen from Table 3 that after 10 days of infection, 100% of the animals treated with the compounds of the invention were still alive, while up to 30% of the animals in the 30 control and control groups were still alive.

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Table 3 (Dosage: 2 x 100 mg / kg color)

The number of pre-surviving animals mark the day after infection 5 _1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

1 10 10 10 10 10 10 10 10 10 10 2 10 10 10 10 10 10 10 10 10 10 3 10 10 10 10 10 10 10 10 10

Miconazole 10 10 88642211

Clotrimazole 10 10 10 9 8 6 5 5 4 3 10

Check 10 10 87432111

To test the in vivo efficacy, groups of 10 mice were infected with Candida albicans microorganisms as above. Mice were then administered 46.4 mg / kg (Table 4) or 21.5 mg / kg (Table 5) of selected test compounds twice daily for 4 days.

Table 4

Dosage: 46.4 mg / kg twice daily)

Pre- Surviving animal count ---- 20 mark days after infection nQ'_ 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

1 10 10 10 10 10 10 -10 10 10 10 2 10 10 10 10 10 10 10 10 9 9 3 10 10 10 10 10 10 10 9 9 9 25 Clotrimazole 10 10 98876643

Check_10 10 87431111_

Table 5 (Dosage: 21.5 mg / kg twice daily)

Pre- Surviving animal count ---- 50 mark days after infection no._1. 2. 3. 4. 5. 6. 7. 8. 9. 10_ 1 10 10 10 10 10 10 10 10 10 10 2 10 10 10 10 10 10 10 10 10 10 3 10 10 10 10 10 10 10 10 10 10

Clotrimazole 10 10 95532 200 35 Control_10 10 85311100__ 70578

The results show that the compounds according to the invention are clearly more potent in vivo against, for example, the test organism Candida albicans than miconazole, (1- / 2,4-dichloro-5H '- (2,4-dichlorobenzoyloxy) phenethyl] imidazoline nitrate, which is commonly used as antifungal agent. ti) and clotrimazole, 1- (o-chloro-X, N-diphenylbenzyl) imidazole.

Since the drugs used so far have not given satisfactory results in systemic mycoses and it is therefore to be expected that these diseases will continue to increase (literature: Infection 2, 95 (1974); Chemotherapy 22, 1 (1976); Dtsch. Apoth. Ztg. 118, 1269 (1978)), the compounds of the invention must be regarded as a real medical advance.

The compounds of the invention are particularly suitable for the oral and topical treatment of fungal infections in humans and animals.

. Diseases in humans and animals that can be treated with them include, for example: dermatomycoses, dermatophytosis and systemic mycoses, which cause in particular species belonging to the following dermatophytes: epidermophytes, Microsorum or Trichophyton, yeasts such as Candida species, and molds, Species belonging to Aspergillus, Mucor or Absidia.

The compounds according to the invention can be used alone or in combination with other known active ingredients, in particular antibiotics.

Chemotherapeutic preparations are prepared by mixing the active ingredient with conventional solid, semi-solid or liquid carriers and diluents and using conventional excipients used in pharmaceutical technology, the choice of these agents depending on the desired route of administration, i.e. externally or internally administered (35 see, e.g., LG Godman, A. Gilman, The Pharmacological Basis of Therapeutics).

it.

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Formulations suitable for internal and external use include, for example, tablets, dragees, capsules, pills, aqueous solutions, suspensions and emulsions, optionally sterilized solutions for injection, anhydrous emulsions, suspensions and solutions, ointments, creams, pastes, lotions, powders, gels, .

In order to achieve good results, it has generally proved advantageous in both human and veterinary medicine to administer the active ingredient in an amount of about 10 to 250 mg / kg body weight in 24 hours, preferably in several divided doses. However, it may be necessary to deviate from said dosage range depending on the severity of the disease and the type of preparation, as well as the mode of administration, the time of administration or the means of administration by which the medicament is administered. In some cases, doses lower than those mentioned above can be used, while in other cases the above-mentioned doses must be exceeded. The optimum dose and mode of administration required will be readily determined by one skilled in the art based on his or her skill.

Preparations for external topical use contain from 0.5 to 5% by weight, preferably from 1 to 2% by weight, of active ingredient. In the case of oral medicaments, the unit dose suitably contains 50 to 250 mg of active ingredient. Generally, the medicine is taken 1 to 4 times a day.

Conventional galenic formulations, such as tab-25 tablets, may be prepared by mixing the active ingredient with known excipients such as inert diluents, such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, calcium carbonate, calcium phosphate, lactose, and lactating agents. corn starch and alginic acid, binders such as starch and gelatin, lubricants such as magnesium stearate and talc and / or with depot agents such as carboxypolymethylene, carboxymethylcellulose, cellulose acetate phthalate and polyvinate acetate phthalate The tablets may also consist of several layers.

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Similarly, dragees can be prepared by coating cores obtained analogously to the preparation of tablets with conventional dragee coatings, such as collidone or shellac, acacia, talc, titanium dioxide or sugar. The dragee coating may consist of several layers, in the preparation of which the excipients mentioned above in connection with the preparation of tablets may be used.

The solutions and suspensions may contain, in addition to the compounds of the invention, flavoring agents, such as saccharin, cyclamate, or sugar, as well as flavoring agents, such as vanillin or orange flavoring. They may also contain suspending aids, such as sodium carboxymethylcellulose, or preservatives, such as p-hydroxybenzoate. Capsules containing the active ingredients can be prepared by mixing the active ingredient with inert carriers such as lactose or sorbitol and enclosing the mixture in gelatin capsules.

Ointments, pastes, creams and gels for topical use may contain, in addition to the active ingredient, conventional carriers} these include, for example, animal or vegetable fats, waxes, paraffins, starches, tragacanth, cellulose derivatives, silicones, benzonite, silicon-25 acid, talc. and zinc oxide and mixtures of these substances.

Powders and sprays may contain, in addition to the active ingredient, conventional carriers such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. The sprays may additionally contain conventional propellants such as chlorofluorocarbons.

The solutions and emulsions may contain, in addition to the active ingredient, conventional carriers such as solvents, solubilizers and emulsifiers, e.g. , oils, especially cottonseed oil, corn oil, peanut-5 oil, olive oil, castor oil or sesame oil, glycerol, glycerol formal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures thereof.

Example 1 1- (4-Chlorophenyl) -1- (2,4-dichlorophenyl) -2- (1,2,4-triazol-1-yl) ethan-1-ol 1-bromo-4-chlorobenzene ( 29.3 g) and Mg chips (4 g) are reacted at boiling temperature in 250 ml of diethyl ether, 22.4 g of 2,2 ', 41-trichloroacetophenone are then added dropwise to the reaction mixture. After 1 hour, aqueous NH 4 Cl is added to the mixture, the organic phase is washed neutral, dried over sodium sulfate and evaporated in vacuo. the oily reaction product is stirred in a melt with 1,2,4-triazole (20.8 g) and sodium hydrogen carbonate (3,4) at a bath temperature of 130 ° C for 2 hours, the mixture is cooled and ice water and chloroform are added, the mixture is shaken. The organic phase is dried over sodium sulfate, evaporated to dryness and the residue is triturated with diethyl ether. 22.8 g of crystalline title compound are obtained, m.p. 187 ° C.

25 C16H12Cl3N3 ° <368'67)

Calculated,%: C 52.13 H 3.28 Cl 28.85 N 11.40

Found,%: C 52.06 H 3.45 Cl 29.4 N 11.27.

Example 2 1- (4-Chlorophenyl) -1- (2,4-dichlorophenyl) -2- (1,2,4-30 triazol-1-yl) ethan-1-ol hydrochloride By treating the base prepared in Example 1 with hydrochloric acid in diisopropyl ether gives the title compound, m.p. 130 ° C.

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Example 3 1- (4-Chlorophenyl) -1- (2,4-dichlorophenyl-2- (1,2,4-triazol-1-yl) -ethan-1-ol nitrate By treating the compound prepared in Example 1 with 5,100- % nitric acid in diisopropyl ether gives the title compound, mp 176 ° C.

il

Claims (1)

X-CVC - <^ J ^ C1 uii) i 25 ^ 1 where X is halogen is reacted with 1,2,4-triazole ----- N | (IV) 30 Ν ^^, Ν-Η in a manner known per se, and the compound obtained is optionally converted into a pharmacologically acceptable acid addition salt.