NO155692B - ANALOGUE PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICAL ACTIVE 1,1-DIPHENYL-2- (1,2,4-TRIAZOL-1-YL) ETHANOLD DERIVATIVES. - 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

This invention relates to the preparation of 1,1-diphenyl-2-(1,2,4-triazol-l-yl)-ethan-l-ol derivatives and their pharmacologically compatible acid addition salts which are suitable as chemotherapy

tica, especially as an antifungal, for internal or external use.

Numerous antifungal agents are known, e.g. miconazole or clotrimazole. However, their effects are

ke always.satisfactory. The purpose of the present invention is to produce new and more effective antifungals.

It has now been found that connections with the general for-

flour I

13

where one of the residues R to R represents a chlorine atom, and the others,

which may be the same or different from each other, means a hydrogen atom or a chlorine atom, and their pharmacologically compatible acid addition salts, exhibit valuable pharma-

ecological properties.

As common acids for the formation of pharmacological compatibil-

similar salts are used in particular nitric acid, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, lactic acid, succinic acid, tartaric acid

acid, citric acid, benzoic acid, salicylic acid and nicotinic acid, el-

ler they can be selected e.g. from Fortschritte der Arzneimittel-forschung, volume 10, pages 224-225, Birkhauser Verlag, Basel

and Stuttgart, 1966.

The mentioned inorganic acids are preferred, especially nitric acid or hydrochloric acid, which form especially well crystallized salts with the new compounds.

1 3

The new compounds where the residues R to R are different from each other or where the phenyl residues carry an identical substituent in a different position, exhibit an asymmetry center in the C atom which carries the hydroxyl group. Separation, isolation or preparation of a particular optical isomer can be carried out in a usual manner. Production of the optical isomers is covered by the present invention.

The compounds of the general formula I and their acid addition salts are prepared according to the invention by a compound of the general formula III

where R 1 to R 3 have the meanings given under formula I, and X means a halogen atom, preferably a chlorine or bromine atom, is reacted with 1,2,4-triazole of formula IV

and optionally the compound obtained is transferred to a pharmacologically compatible acid addition salt.

This reaction is suitably carried out with stoichiometric amounts in the presence of an acid-binding agent or with an excess of 1,2,4-triazole, both in the presence of and in the absence of a solvent or diluent.

As diluents, mainly organic solvents are used, e.g. dimethylformamide, hexamethylphosphorustriamide, acetonitrile or benzene.

An excess of 1,2,4-triazole or one of the usual acid-binding agents, such as e.g. hydroxides, carbonates or alcoholates of alkali and alkaline earth metals, especially of sodium, potassium, magnesium or calcium, besides organic bases such as e.g. pyridine or tertiary amines such as triethylamine.

The reaction temperatures can vary within a wide range. Generally, one works at temperatures from 0 to 150°C, preferably from 30 to 120°C.

Production of the starting compounds with formula III can be carried out in a manner known per se by methods for the production of tertiary alcohols from ketones or carboxylic acid derivatives and Grignard compounds, such as e.g. described in Houben-Weyl, Methoden der organischen Chemie, vol. 13/2a, 46-527 (1973).

If you e.g. uses 1-(2,4-dichlorophenyl)-1-(4-chlorophenyl)-2-chloroethan-l-ol, prepared from 2,2',4'-trichloroacetophenone and 4-chlorophenyl-magnesium bromide, and 1,2,4-triazole as starting materials, the course of the reaction can be illustrated by the following formulas:

The compounds of formula I and their salts possess excellent chemotherapeutic, especially antifungal, properties.

Suitable antimycotic agents thus contain a compound of the general formula I or pharmacologically compatible acid addition salts thereof as active ingredient, in addition to usual carriers and diluents.

The surprising antimicrobial effect in vitro was

detected against Candida albicans by the following test:

Pseudomycelium and mycelium phase test with Vandida albicans: This test takes into account that C.albicans in vivo can not only form weight cells, but also pseudomycelium and true mycelium (di- morphine). In vitro, the development of all growth phases of this microorganism and the impact of antifungal active substances are investigated in the following way: Candida albicans (Robin) Berkhout No 20/M (strain of the mycothecate, Nordmark-Werke GmbH) is inoculated with an inoculum on one side of the surface A of the nutrient medium

(brain heart infusion, Difco) and on the other hand at B as prick culture (fig.) ,

In the area with the stick culture, it is also placed on a cover glass C (microaerophilic conditions). The Petri dish D contains in the nutrient medium a geometrically stepped dilution series of the test compound in question. After incubation of these test plates (2 days, 37°C), only growth cells (yeast phase) have grown on the preparation-free control plates in the aerobic area A and in the microaerophilic area B only pseudohyphae and true hyphae.

Minimum inhibitory concentration refers to the concentration steps of the test preparation where 100% inhibition of the fungal growth in question is observed.

This test device makes it possible to distinguish between the minimum inhibitory concentration in the yeast phase (MHK _) and

CJ "J GclTIaS6

MHK for the pseudomycelial phase or the mycelial phase (MHKmvceifase) for Candida albicans.

While the MIC values for the yeast phase are above 128 yg/ml,

very low MHK values are obtained for the mycelial phase, as can be seen from table 1.

The antimicrobial activity in vitro against dermatophytes was investigated by an agar dilution test (lit.: P. Klein, "Bakteriologische Grundlagen der chemotherapeutischen Laboratiumspraxis"). The results of these investigations on compound 3 as an example are shown in table 2. Experimental candidosis on mice using Candiada albicans.

To determine the oral effect, groups of approximately 10 each were 20 g heavy mice pre-treated for 2 days with 50 mg/kg hydrocortisone every i.m., to achieve a good start to the infection. The mice were then infected i.v. with 500,000 Candida albicans organisms each and then treated for 4 days 2 times daily with 100 mg/kg of the test compound each time.

Alongside the infected group and the untreated control group, a group treated with the reference compounds miconazole and clotrimazole was taken as a comparison.

From table 3 it appears that at day 10 after the infection, close to 100% of the animals treated with the new compounds survive, while in the control group and among the animals treated with the reference compounds only up to 30% survive.

To investigate the intensity of action in vivo, groups of 10 mice each, as described above, were infected with Candida albicans bacteria and then treated for 4 days 2 times a day with 46.4 mg/kg (Table 4) resp. 21.5 mg/kg (Table 5) of a selection of test compounds.

Explanation to tables 3, 4 and 5:

Example no.

1 = 1,1-bis-(4-chlorophenyl)-2-Cl,2,4-triazol-1-yl)-ethan-1-ol

2 = 1,1-bis-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-ethan-l-ol hydrochloride 3= 1-(4-chlorophenyl)-1-( 2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-ethan-l-ol 4 = 1-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-2- (1,2,4-triazol-1-yl)-ethan-1-ol hydrochloride 5 = 1-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-2-(1,2,4- triazol-l-yl)-ethan-l-ol-nitrate 6 = 1-phenyl-1-(2-chlorophenyl)-2-(1,2,4-triazol-l-yl)-ethan-l-ol- hydrochloride 7 = 1-phenyl-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-ethan-1-ol hydrochloride 8 = 1-phenyl-1-(4-chlorophenyl) )-2-(1,2,4-triazol-1-yl)-ethan-1-ol nitrate 9 = 1-phenyl-1-(2,4-dichlorophenyl)-2-(1,2,4- triazol-l-yl)-ethan-l-ol 10 = 1-phenyl-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-l-yl)-ethan-l-ol- hydrochloride 11 = 1-phenyl-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-ethan-1-ol nitrate 15 = 1-(3-chlorophenyl)- 1-(2,4-Dichlorophenyl)-2-(1,2,4-triazol-1-yl)-ethan-1-ol

The results show that the new compounds with the general formula I are clearly superior in vivo to the commonly used antifungals miconazole (1-[2,4-dichloro-Ø-(2,4-dichloro-benzyloxy)phenethyl]-imidazole nitrate) and clotrimazole [1-(o-chloro-α,α-diphenyl-benzyl)-imidazole], e.g. on mice infected with Candida albicans.

Since the currently available means for the treatment of systemic mycoses are not satisfactory and since a further increase in these diseases can be expected (lit.: Infection 2^, 95

(1974); Chemotherapy 22, 1 (1976); Dtsch. Apoth. Ztg. 118, 1269

(1978), the new compounds represent a real enrichment

look at the technique.

The new compounds are particularly suitable for oral or external treatment of fungal infections in humans and animals.

As indication areas for humans and animals are e.g. dermatomycoses, dermatophytoses and systemic mycoses, especially caused by dermatophytes, such as species of the genera Epidermophytes, Microsporum or Trichophyton, yeasts such as species of the genus Candida, and molds such as species of the genera Aspergillus, Mucorella or Absidia.

The compounds can be used alone or together with other active substances, especially antibiotics.

The production of the chemotherapeutic agents or preparations, with usual solid, semi-solid or liquid carriers or diluents and the usual "used pharmaceutical-technical auxiliary substances according to the desired form of administration with a suitable dosage for internal or external use, takes place in the usual way way, especially by mixing (see L.G. Godman,

A. Gilman, The Pharmacological Basis of Therapeutics).

As preparations for internal and external use, e.g. mention is made of tablets, dragees, capsules, pills, aqueous solutions, suspensions and emulsions, possibly sterile, injectable solutions, non-aqueous emulsions, suspensions and solutions, ointments, creams, pastes, liquids, powders, gels, spray preparations etc.

In both human and veterinary medicine, it has usually proven to be advantageous to administer the active ingredient or active ingredients in amounts of approx. 10 to approx. 250 mg per kg body weight within 24 hours, preferably in the form of several single administrations to achieve the desired results. However, it may be necessary to deviate from the dosages mentioned,

and then depending on the nature and degree of the disorder, the nature of

the preparation and the administration of the agent, as well as the time or interval during which the administration takes place. Thus, in some cases it may be sufficient to use less than the above-mentioned amounts of active ingredient, while in other cases one must exceed the specified amounts of active ingredient. Determining the optimum dosage and administration form for the active substances required at any given time can easily be carried out by any professional.

For external, local application, the preparation contains 0.5 to 5, preferably 1 to 2% by weight of active substance. For oral administration, quantities of 50 to 250 mg are normally used as single doses. Usually, the active ingredient is administered 1 to 4 times a day.

The usual galenic administration forms, such as tablets, can e.g. is produced by mixing the active substance with known excipients, e.g. inert diluents, such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, calcium carbonate, calcium phosphate or milk sugar, disintegrants, such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and/or agents for to achieve a depot effect, such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also consist of several layers.

Similarly, dragees can be produced by coating cores produced analogously to the tablets with agents that are usually used in dragee coatings, e.g. collidon or shellac, gum arabic, talc, titanium dioxide or sugar. The dragéover coating can also consist of several layers, using the excipients mentioned above for tablets.

Solutions or suspensions with the new active substances can also contain taste-enhancing agents, such as saccharin, cyclamate or sugar as well as e.g. flavoring substances such as vanillin or orange extract. In addition, they may contain suspending aids such as sodium carboxymethyl cellulose, or protective substances such as p-hydroxybenzoates. Capsules contain active ingredients, e.g. is produced by mixing the active ingredient with an inert carrier, such as milk sugar and sorbitol, and encapsulating it in gelatin capsules.

Ointments, pastes, creams and jellies for external use may contain the usual carriers, e.g. animal and vegetable fats, waxes, paraffins, starches, gum tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide or mixtures of these substances.

Powders and spray preparations can contain, in addition to active ingredients, the usual carriers, e.g. milk sugar, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Spray preparations can also contain the usual propellants, e.g. chlorofluorocarbons.

Solutions and emulsions can contain, in addition to the active substance or substances, the usual carriers such as solvents, dissolution mediators 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 seed oil, olive oil, castor oil and sesame oil, glycerol, glycerol formal, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan or mixtures of these substances.

Example 1

58.6 g of 1-bromo-4-chlorobenzene in 250 ml of diethyl ether are reacted with 8 g of magnesium shavings at boiling temperature, and then 12.4 g of chloroacetic acid ethyl ester are added dropwise at 0 to 10°C. After stirring for 1 hour at room temperature, the reaction mixture is treated with ice and aqueous ammonium chloride solution. The organic phase is poured over sodium sulphate and evaporated in vacuo. The oily reaction product is then stirred with 20.8 g of 1,2,4-triazole and 8.4 g of sodium bicarbonate for 2 hours in a melt at a bath temperature of 130°C, and then the mixture is shaken out with water and chloroform after cooling. The organic phase is dried with sodium sulfate, evaporated, and the residue is triturated with diethyl ether. After recrystallization from 1,2-dichloroethane, 17.3 g of crystalline 1,1-bis-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-ethan-1-ol are obtained with m.p. . 14 4°C.

C16H13C12N3° (334'22>

Example 2

By treating the base from example 1 with hydrogen chloride dissolved in diisopropyl ether, 1,1-bis-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-ethan-1-ol hydrochloride is obtained with m.p. 117°C.

Example 3

29.3 g of 1-bromo-4-chlorobenzene in 250 ml of diethyl ether are reacted with 4 g of magnesium shavings at boiling temperature, and then 22.4 g of 2,2<1>,4'-trichloroacetophenone are added dropwise. After 1 hour, cleavage is carried out with aqueous ammonium chloride solution, the organic phase is washed neutral, dried over sodium sulphate and evaporated in vacuo. The oily reaction product is stirred with 20.8 g

1,2,4-triazole and 3.4 g of sodium bicarbonate in melt for 2 hours at 130°C bath temperature and shaken with ice water and chloroform after cooling. The organic phase is dried over sodium sulphate, evaporated and triturated with diethyl ether. 22.8 g of crystalline 1-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-ethan-1-ol with m.p. 187°C.

C16H12C13N3° (368.67)

Example 4

By treating the base from example 3 with hydrogen chloride dissolved in diisopropyl ether, 1-(4-chlorophenyl)-1-(2,4-di-chlorophenyl)-2-(1,2,4-triazol-1-yl) -ethan-l-ol hydrochloride with m.p. 130°C.

Example 5

By treating the base from example 3 with 100% nitric acid dissolved in diisopropyl ether, 1-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl) -ethane-l-ol nitrate with m.p. 17 6°C.

Examples 6 to 16

Analogous to examples 3 to 5, the following compounds were synthesized: 6. 1-phenyl-1-(2-chlorophenyl)-2-(1,2,4-triazol-1-yl)-ethan-1-ol hydrochloride, m.p. . 134°C. 7. 1-phenyl-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-ethan-1-ol hydrochloride, m.p. 208°C. 8 . 1-phenyl-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl),-ethan-1-ol nitrate, m.p. 201°C. 9. 1-phenyl-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-ethan-1-ol, m.p. 203°C. 10. 1-phenyl-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-ethan-1-ol hydrochloride, m.p. 183 C. 11. 1-phenyl-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-ethan-1-ol nitrate, m.p. 214°C. 12. 1-(2-chlorophenyl)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-ethan-1-ol hydrochloride, m.p. 228°C. 13. 1-(2-chlorophenyl)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-ethan-1-ol, m.p. 161°C. 14. 1-(2-chlorophenyl)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-ethan-1-ol hydrochloride, m.p. 195°C. 15. 1-(3-chlorophenyl)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-ethan-1-ol, m.p. 149°C. 16. 1-(3-chlorophenyl)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-ethan-1-ol hydrochloride, m.p. 135°C.

DLj-q orally in mice

DAS2623129, Example 17: 4368.20 mg/kg

The invention " 3: > 4690 mg/kg (at this dose no dead animals).

Claims (4)

1. Analogy method for the preparation of pharmacological active compounds of the general formula I where one of the residues R 1 to R 3 means a chlorine atom, and the others, which may be the same or different, means a hydrogen atom or a chlorine atom, and their pharmacologically compatible salts, characterized in that a compound with the general formula III where R 1 to R 3 have the meanings given for formula I, and X means a halogen atom, is reacted with 1,2,4-triazole, and the compound obtained is optionally transferred to a pharmacologically compatible acid addition salt. 2. Process as stated in claim 1 for the production of 1,1-bis-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-ethan-1-ol, characterized in that it is used a starting 1 2 material of formula III where R is hydrogen, R is chlorine and R 2 is p-chloro. 3. Process as stated in claim 1 for the production of 1-phenyl-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-ethan-1-ol, characterized in that a starting material with formula III is used where R and R are both chlorine, and R is hydrogen. 4. Method as stated in claim 1 for production of 1-(4-chlorophenyl-)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-ethan-l-ol, characterized in that a starting material of formula III is used, where R and R are both chlorine, and R is p-chloro.