DE2917244C2 - 1 - [[2- (2,4-dichlorophenyl) -2-benzyloxy] ethyl] imidazoles, processes for their preparation and pharmaceuticals containing them - Google Patents

Description

(D

where R stands for a phenyl or phenylthio radical, as well as their salts with acids.

2. Process for the preparation of the compounds according to claim 1, characterized in that dt.) One in in a manner known per se l- (2,4-dichlorophenyl> 2- (imidazol-l-yl) ethanol with a benzyl halide derivative of the general formula II

wherein R has the meaning given in claim 1 and X is chlorine or bromine, in a solvent condensed.

3. Medicaments containing at least one compound according to claim 1 as an active ingredient together with customary pharmaceutical diluents, carriers and / or other auxiliaries.

The invention relates to new l - [[2- (2,4-dichlorophenyl) -2-benzyloxy] ethyl] imidazoles, including their Salts, a process for their production and medicinal products containing them with effects against fungi, Yeast and bacteria.

The known antifungal agents such as clotrimazole (The Merck Index, 2370, page 309 and ZA 68/05392 and 69/00039) and miconazole (The Merck Index, 6043, page 805 and DE-OS 19 40 388) have the disadvantage that they are relatively toxic.

The invention is based on the object, superior pharmacological effects, in particular Due to their lower toxicity, new l - [[2- (2,4-dichlorophenyl) -2-benzyloxy] ethyl] imidazoles, to provide a process for their production and pharmaceuticals containing them.

The invention relates to l - [[2- (2,4-dichlorophenyl) -2-benzyloxy] ethyl] imidazoles in general Formula I.

V-C-O-C-T V-R

(D

where R stands for a phenyl or phenylthio radical, as well as their salts with acids.

The salts of the compounds according to the invention can be those with pharmaceutically acceptable inorganic compounds Acids, advantageously hydrochloric acid, nitric acid, sulfuric acid or phosphoric acid, or organic acids, advantageously methanesulfonic acid, p-toluenesulfonic acid, succinic acid, maleic acid, fumaric acid, citric acid or tartaric acid. Of these, those with hydrochloric acid, sulfuric acid [especially in the case of 1 - [[2- (2,4-dichlorophenyl) -2- (4-phenyl-benzyloxy)] - ethyl] imdidazole], Nitric acid, phosphoric acid [especially in the case of 1 - [[2- (2,4-dichlorophenyl) -2- (4-phenyl-phenylthio-benzyloxy)] -ethyi] -imidazole], maleic acid, methanesulphonic acid [especially in the case of l - [[2- (2,4-dichlorophenyl) -2- (4-phenylthio-benzyloxy)] ethyl] imdidazole], p-toluene sulfonic acid and citric acid [especially in the case of l - [[2- (2,4-dichlorophenyl) -2- (4-phenyl-benzyloxy) läthyrj-imdidazoll preferred. The salts with nitric acid are very particularly preferred.

The invention also relates to a process for the preparation of the compounds according to the invention, which is characterized in that l- (2,4-dichlorophenyl) -2- {imidazol-l-yl) ethanol in a manner known per se with a benzyl halide derivative of the general formula Π

ÖD ⁵

where R is as defined above and X is chlorine or bromine, is condensed in a solvent, whereupon the imidazole derivative of the general formula 1 obtained in this way, if it is obtained as the free base, converted into a salt with an acid or, if it is obtained as a salt, into the corresponding free base or is transferred to another salt.

One or more aromatic solvents can advantageously be used as a solvent Hydrocarbons, dimethylformamide, tetrahydrofuran, hexamethylphosphoramide or dimethyl sulfoxide or mixtures thereof can be used. Dimethyl sulfoxide is particularly preferably used because with this the condensation proceeds most completely, resulting in a higher yield and a purer product results. In this case it is not necessary to use the compounds obtained in the condensation of the general formula I to be subjected to purification by column chromatography, while such a cleaning when using dimethylformamide or hexamethylphosphoramide as solvent A simple filtering of the solutions of the compounds of general formula I is required a silica gel column is able to hold back the small amounts of impurities. In case of Compound of the general formula I in which R is a phenyl radical, that is to say l - [[2- (2,4-dichlorophenyl) -2- (4-phenylbenzyloxy)] ethyl] imidazole even this filtration is not necessary and the crystallization of its nitrate leads to a product which is sufficiently pure for pharmaceutical purposes.

We advantageous the condensation, especially when using the above aprotic solvents, in Presence of an alkali metal hydride or amide, which is the HyiüOxygruppe of 1- (2 ', 4'-dichlorophenyl) -2- (imidazol-l-yl) ethanol able to convert into a salt, carried out.

As another possibility, 1 or more can be used as solvent in the condensation aliphatic alcohols having 3 to 6 carbon atoms can be used. It is preferred in the presence an alkali metal alcoholate instead of the alkali metal hydride or amide worked very particularly The preferred aliphatic alcohol is tert-butanol, n-butanol or n-propanol and the preferred alkali metal IaI alcoholate is an alkali metal butylate, such as potassium tert-butylate, an alkali metal n-butylate or an alkali metal propylate used.

Preferably, the condensate :, etc. is performed as a catalyst in the presence of potassium iodide. This can advantageously be added in small amounts before the addition of the benzyl halide derivative of the general formula II.

It is preferred to carry out the condensation of 6 to 36 hours at a temperature of 20 to 100 ⁰ C. This time may also include the duration of any salt formation of the 1- (2 ', 4'-dichlorophenyl) -2- (imidazol-1-yl) ethanol.

The 1- (2 ', 4'-dichlorophenyl) -2- (imidazoll-yl) ethanol used as starting material in the process according to the invention can from l-chloroacetyl ^^ - dichlorobenzene (Beilstein, Handbuch der Org. Chem., IV. edition, Volume 7, page 28) by reducing the keto group using sodium borohydride and condensation with imidazole, the reduction and the condensation in any order can be done. The reduction can be in methanol and the condensation in dimethylformamide and methanol can be made in the presence of sodium.

The benzyl halide compounds used as starting materials in the process according to the invention general formula II are known. The preparation of 4-chloromethyldiphenyl is in Chem. Ber. 66 B (1933), 1471 and the preparation of l-bromomethyl-4-phenylthiobenzene is described 1: 1 in US Pat. No. 3,242,193.

Salts of the compounds according to the invention can be prepared by conventional procedures, for example by adding the desired acid to the free base of a compound of the general Formula 1 in an equimolar amount and subsequent crystallization of the salt thus obtained from a solvent, be performed.

Furthermore, pharmaceuticals according to the invention which 1 or more of the compounds according to the invention as Active ingredients or active ingredients together with common pharmaceutical diluents and carriers and / or other auxiliaries are provided. The compounds of the invention have namely, as already mentioned, valuable pharmacological effects against fungi, yeasts and gram-positive aerobic and anaerobic bacteria. The effectiveness is paired with a low toxicity.

There were comparative tests in which the pharmacological effectiveness and toxicity of the inventive Compounds with those of 2 very well-known antifungal agents, namely clotrimazole and Miconazole, were compared.

The results of these tests are summarized in Tables I, II and III below.

Table I shows the acute toxicity _{values (LD 50} values) of the compounds according to the invention and of the two comparison substances. The toxicity in mg / kg when administered orally to mice was determined using conventional procedures.

Table II shows the minimum inhibitory concentrations of the compounds according to the invention that were examined and the two comparative substances for fungi and yeasts. The values of the minimum inhibitory concentration were determined by the usual broth double batch dilution procedure.

The values of the minimum concentrations of the tested compounds according to the invention and both Comparisons for gram positive bacteria were also prepared using the conventional broth double batch dilution procedure determined and they are summarized in Table III

Under minimum inhibitory concentrations are those minimum concentrations which the growth of the studied fungi, yeasts and bacteria to inhibit their ability to understand.

The experimental connections were as follows:

Medium: Inoculum:

20 Temperature and incubation time:

a) With mushrooms

Sabouraud liquid with a pH of 5.7 (5 cm ³ per tube).
A 10-day-old agar culture was washed with a physiological solution containing 10% of a polyoxyethylene sorbitan raonooleate, then filtered through gauze and resuspended in the physiological solution to a dilution at which this suspension was placed in a spectrophotometer at a wavelength of 650 mn a transparency (Γ) of 50%). 0.1 cm ^{3 of} the spore suspension was used per 5 cm ^{3 of} medium. In contrast, with Aspergillus niger, a dilution of 1:10 was prepared in the physiological solution after filtration. From this dilution, too, 0.1 cm ³ per 5 cm ^{3 of} medium was used as inoculation material.

25 ° C for 7 days.

Medium: Inoculum:

Temperature and incubation time:

b) In yeasts

Sabouraud liquid with a pH of 5.7 (5 cm ³ per tube).
The yeasts were grown in the Sabouraud liquid kit, all except Cryptococcus neoformans for 24 hours and Cryptococcus neoformans for 2 days. The cells were collected by centrifugation at 6500 revolutions per minute and resuspended in the physiological solution mentioned, up to a dilution at which this suspension gave a transparency (Γ) and 50% in a spectrophotometer at a wavelength of 650 nm. 0.1 cm ^{3 of} this suspension was used as inoculum for each 5 cm ^{3 of} medium.

37 ° C for 48 hours.

40 Medium: Inoculum:

Temperature and incubation time:

c) In gram-positive bacteria

Trypinsoy broth with a pH of 7.3 (5 cm ³ per tube).

The day before the experiment, the microorganisms to be examined were transferred to their respective media. After 18 hours of incubation at 37 ° C, 0.1 cm ^{3 of} a suspension of each strain in the broth in a dilution of 1: 100 were 5 cm ^{3 of} the respective media containing the compounds to be investigated in a concentration range from 0.009 to 160 y / cm ³ , vaccinated.

37 ° C for 18 hours.

50 Table I.

Acute toxicity (LD ₅₀ value) in mg / kg when administered orally to mice

l - [[2- (2,4-dichlorophenyl) -2- (4-phenyl-benzyIoxy)] - ethyl] imidazole

[Formula I with R = -C ₆ H ₅ ] (compound according to the invention)

2400

l - [[2- (2,4-dichlorophenyl) - miconazole

2- (4-phenylthio-benzyloxy)] -

ethyl imidazole

[Formula I with R = -SC ₆ H ₅ ] {compound according to the invention)

3000 870

Clotrimazole

(Comparison substance) {comparison substance / .; ·

880

Table II Effectiveness against fungi and yeast

i Minimum inhibitory concentration in y / cm ³

Pathogen cr Microorganism

l - [[2- (2,4-dichlorophenyl> -

2- (4-phenyl-benzyloxy)] -

ethyl] imidazole

l- [l2- (2,4-dichlorophynyl) -

2- (4-phenythio-benzyloxy)] -

ethyl imidazole

Miconazole

[Formula I with R = -C ₆ H ₅ ] [Formula I with R = -SC ₆ H ₅ ]

{According to the invention {according to the invention

Connection} connection}

Clotrimazole

{Comparison (Comparative substance} substance) 20th 40 20th 40 0.078 0.625 0.078 0.078 0.625 1.25 0.312 1.25 40 10 20th 40 5 5

C albicans 1040 10 C. albicans 1041 20th C. neoformans 0.312 T. mentagroph. 2538 0.156 T. mentagroph. 10 148 0.625 T. rubrum 2121 0.625 A. niger 20th P. chrysogenum 20th E. floccosum 10

Table III Effectiveness against bacteria Minimum inhibitory concentration in y / cm ³

80

80

0.156 0, i5o 0.625 0.625

10 5 5

More pathogenic Microorganism

1 - [[2- (2,4-dichlorophenyl) -
2- (4-phenyl-benzyloxy)] -
ethyl imidazole l - [[2- (2,4-dichlorophenyl) -
2- (4-phenylthio-benzyloxy)] -
ethyl] imidazole Miconazole Clotrimazole (Formula I with R = -C ₆ H ₅ ] [Formula i with R = -SC ₆ H ₅ ] (According to the invention
Link) {According to the invention
Link) (Comparative
substance) {comparative
substance) 0.039 0.039 0.312 0.312 0.039 0.018 0.312 1.25 0.156 0.156 1.25 2.5 0.156 0.078 0.625 2.5 <1.25 5.0 <U5 > 160 0312 0.078 0.625 5

S. aureus SG 511 S. aureus 10 B St. hemolyt 821 B. subtilis Cl. novyi St. hemolyt 203

The comparison between the effectiveness and toxicity of those according to the invention is particularly revealing Compounds and (i ^ nen of miconazole. In miconazole, both benzyl groups are in the 2- and 4-positions substituted by chlorine atoms, while in the compounds according to the invention the one benzyl group, which is not substituted in the 2-position is substituted in the 4-position by a phenyl or phenylthio radical. This difference leads to a considerable reduction in toxicity, which is 3 to 4 times lower for the compounds according to the invention than that of miconazole, with the compounds according to the invention Compounds the effectiveness against bacteria is also much better (sometimes even by 1 order of magnitude) than in the case of the comparison substances and against fungi and yeasts, the effectiveness of the compounds according to the invention is on average about the same as that of the comparison substances. So are the therapeutic ones Indices of the compounds according to the invention in relation to practically all bacteria examined and to for the most part also higher in relation to the fungi and yeasts examined (in some cases even by 1 order of magnitude and more) than those of the two comparison substances and, for the rest of the time, in relation to the fungi examined and yeasts higher than that of the comparison substances clotrimazole and almost the same as that of the comparison substance Miconazole.

The compounds according to the invention can be particularly useful in human therapy for topical Treatment of skin diseases or Dennatoses, such as beard lichen or Tiichophytie and candidiasis, and other infections caused by the fungi staphylococci and streptococci can be used.

The medicaments according to the invention advantageously contain the compound (s) according to the invention in an amount of 0.5 to 5% by weight, in particular 1 to 3% by weight.

The medicaments according to the invention can be in various forms, for example in the form of powders, Ointments, creams, suspensions, dispersions, gels and solutions. They are preferably in In the form of ointments, powders, glycolic solutions or gels.

The invention is explained in more detail with reference to the following examples.

example 1
l - [[2- (2,4-dichlorophenyl) -2- (4-phenylthio-benzyloxy)] ethyl] imidazole

IO

[Formula I with R = phenylthio _{radical (C 6} H ₅ -S-)]

Procedure I.

A solution of 2.57 g of l- (2 ', 4'-dichlorophenyl) -2- (imidazol-l-yl) ethanol in 10 cm ^{3 of} hexamethylphosphoramide at 25 ° C of a suspension of 0.52 g of sodium hydride ( 50% dispersion in oil) in 5 cm ^{1 of} hexamethylphosphoramide was added dropwise. When the evolution of hydrogen had ended, the salt formation was completed by heating to 50 ^° C. for 1 hour. After cooling to 25 ⁰ C 2.58 g of 1-chloromethyl-4-phenylthiobenzene were added. The temperature was increased to 50 "C and for 12 hours on the-

held this value. At the end of the reaction, the mixture was ^{poured into 200 cm 3 of} water, the product was extracted with diethyl ether, the solvent was evaporated and the residue was purified twice on a silica gel column using ethyl acetate as the eluent, the various fractions being examined by thin layer chromatography. The solvent of the middle fractions was evaporated, whereby 2.4 g of the desired l - [[2- (2,4-dichlorophenyl) -2- (4-phenylthio-benzyloxy)] - ethyl] imidazole base as yellowish 01, which in the Thin layer chromatography showed a single spot was obtained.

Analysis for C ₂₄ H ₂₀ N ₂ Cl ₂ OS:

Calculated: C = 63.30, H = 4.44, N = 6.13, Cl = 15.5, S = 7.04%;
found: C = 63.86, H = 4.24, N = 6.41, Cl = 15.29, S = 6.97%.

Procedure II

It was 0.66 g of sodium hydride (50% dispersion in oil) in a nitrogen atmosphere at 20 to 30 ⁰ C to 3.86 g of l- (2 ', 4'-dichlorophenyl> 2- (imidazol-l-yl) - ethanol was added in 15 cm ³ of dimethyl sulfoxide (dried over calcium hydride). the mixture was heated to 60 ⁰ C while stirring or shaking at 50, until gas evolution was completed. After cooling to 20 to 25 ° C 0.5 g of potassium iodide was added and a solution of 3.51 g of 1-chloromethyl-4-phenylthiobenzene in 4 cm ^{3 of} dimethyl sulfoxide was slowly added dropwise.

The mixture was stirred at 20 to 25 ⁰ C or shaken, until finishing the addition of 1-chloromethyl-4-phenylthiobenzoles terminated. The mixture was then ^{poured into 150 cm 3 of} water and extracted with diethyl ether. After drying over anhydrous sodium sulfate, an excess of a 4N nitric acid solution in diethyl ether was added to the ethereal solution. The desired product, precipitated as the nitrate, was an oil which solidified on standing. After standing for 20 hours, the ethereal liquid was decanted off and the residue was crystallized from ethanol. The nitrate thus obtained, which was not yet completely pure, was dissolved in water and an excess of sodium carbonate was added to liberate the base, which was then extracted with ethyl acetate. The obtained base was purified by filtration on a silica gel column using ethyl acetate as an eluent. The combined fractions containing the desired product were evaporated to dryness. The residue

it was dissolved in diethyl ether, converted again into the nitrate and crystallized from ethanol.

3.1 g of l - [[2- (2-dichlorophenyl) -2- (4-phenylthio-benzyloxy)] ethyl] imidazole nitrate were obtained as a white crystalline Powder obtained with a melting point of 134 ° C.

Analysis for C ₂₄ H ₂₀ N ₂ Cl ₂ OS HNO3:

Calculated: C = 55.61, H = 4.08, N = 8.11, Cl = 13.68, S = 6.18%;
found: C = 55.32, H = 4.08, N = 8.16, Cl = 13.56, S = 6.32%.

The l- {2 ', 4'-dichlorophenyl} -2- (imidazol-l-yl) ethanol used as the starting material is described as follows manufactured:

49.5 grams of sodium borohydride were slowly added to a stirred, respectively, in small portions shaken suspension of 233 g of a ^. + trichloroacetophenone in 11% methanol was added at room temperature. The solution thus obtained was stirred or shaken at room temperature for a further 2 hours and then poured into 11 5N hydrochloric acid cooled with ice. After extracting with Ethyl acetate or chloroform was extracted with water, an n-sodium hydroxide solution, then again with water until a neutral reaction is reached and finally with a saturated sodium chloride solution washed. The extract was dried and the solvent was evaporated. It was 220 g of an oil. This oil solidified on standing and this solid substance, 1- (2 ', 4'-dichlorophenyl) -2-chloroethanol had a melting point of 48 to 51 ° C.

3 Analysis for C ₈ H ₇ Cl ₃ O:

calculated: C = 42.61, H = 3.13, Cl = 47.17%; § found: C = 42.75, H = 3.19, Cl = 47.43%.

■ i] 30 g of sodium were added to a solution of 88.5 g of imidazole in 600 cm ^{3 of} methanol. Then became

Ii the solvent evaporated. The residue was dissolved in 300 cm ^{3 of} dimethylformamide and 115 bis

| fi 120 ⁰ C heated. The solution thus obtained was a solution of with stirring or shaking

ff 225 g of l- (2 ', 4'-dichlorophenyl) -2-chloroethanol obtained as described above in 400 cm ^{3 of} dimethyl

; | j formamide was added dropwise. The mixture was heated to 115 to 120 ^° C. and at this temperature for 20 minutes

? '"and, after subsequent cooling to 40 ⁰ C, were stirred vigorously, respectively

'Shake 2500 cm ^{3 of} ice water added. The product precipitated on stirring or shaking for about 2 hours, whereupon the supernatant liquid was decanted off, a further 2500 cm ^{3 of} water added

: '\ were set and after standing the whole thing was filtered. The precipitate thus obtained was dried

Κ and the toluene crystallizes. So 170 g of l- (2 ', 4'-dichlorophenyl) -2- (imidazol-l-yl) ethanol with a

i ': Melting point of 134 to 135 ⁰ C obtained.

ν / analysis for C _n Hi ₀ Cl ₂ N ₂ O:

js calculated: C = 51.38, H = 3.92, N = 10.89, Cl = 27.58%;

| .; found: C = 51.62 'H = 3.8o' N = 10J3i Cl = 27/76%. '

.ψ Example 2

§ l - [[2- (2,4-dichlorophenyl) -2- (4-phenylbenzyloxy)] ethyl] imidazole

I [Formula I with R = phenyl radical (C ₆ H ₅ -J]

% Procedure Ia

j§ A mixture of 2.02 g of potassium tert-butoxide in 30 cm ^{3 of} tert-butanol in a nitrogen atmosphere was produced

manufactured at 20 to 25 ° C. Then 3.86 g of 1- (2 ', 4'-dichlorophenyl) -2- (imidazol-N-yl) ethanol prepared as described in connection with Example 1 were added. The solution was refluxed for 1 hour and then cooled to 20-25 ° C. 3.03 g of 4-chloromethyldiphenyl were added and the solution was refluxed again for 5 hours. After cooling to 20 to 25 ° C., the whole was poured into water and the l - [[2- (2,4-dichlorophenyl) -2- (4-phenyl-benzyloxy)] ethyl] imidazole base was extracted with ethyl acetate. The extract was washed with diethyl ether and the solvent was evaporated. The residue was dissolved in 80 cm ^{3 of} diethyl ether and left to stand overnight. The insoluble substances were filtered off and the filtrate was treated with nitric acid dissolved in diethyl ether. An oil which solidified on standing was obtained. The residue consisting of l - [[2- (2,4-dichlorophenyl) -2- (4-phenylbenzyloxy)] ethyl] imidazole nitrate was crystallized from ethanol or ethyl acetate.

So were 4.3 g of l - [[2- (2,4-dichlorophenyl) -2- (4-phenyl-benzyloxy)] - ethyl] imidazole nitrate, which was found to be pure on thin layer chromatography and had a melting point of 140 to 141 ° C, obtain.

Analysis for C ₂₄ H ₂₀ N ₂ Cl ₂ O ■ HNO ₃ :

Calculated: C = 59.25, H = 4.35, N = 8.64, Cl = 14.57%; found: C = 59.17, H = 4.14, N = 8.61, Cl = 14.46%.

Procedure Ib

There were added to a solution of 0.37 g of sodium metal in 200 cm ^{3 of} n-propanol, 4.1 g of l- (2 ', 4'-dichlorophenyl) -2- (imidazole-l- prepared as described in connection with Example 1) ylhthanol was added and the mixture was heated to boiling for 2 hours with stirring or shaking and under reflux. After cooling to room temperature, 0.5 g of potassium iodide and 3.25 g of 4-chloromethyldiphenyl were added with stirring or shaking and the mixture was again At the end of the reaction, the mixture was filtered and washed with ethanol. The filtrate was evaporated to dryness and the residue was dissolved in diethyl ether. The insoluble residue was filtered off and the clear ethereal solution thus obtained was mixed with a mixture of The 1- [L2- (2,4-dichlorophenyl) -2- {4-phenylbenzyloxy)] ethyl] imidazole nitrate thus obtained was crystallized from ethanol. The product obtained was 2.1 g of l - [[2- (2,4-dichlorophenyl> 2- (4-phenyl-benzyloxy)] -ethyl / imidazole nitrate with the same properties as those prepared according to the above procedure Ia, soft TLC showed a single spot.

Procedure II

There were 0.66 g of sodium hydride (50% dispersion in oil) in a nitrogen atmosphere at 20 to 25 ° C to a solution of 3.86 g of 1- (2 ', 4'-dichlorophenyl) -2- (imidazole-l -yl) ethanol in 15 cm ^{3 of} dimethyl sulfoxide (dried over calcium hydride) was added. The mixture was heated to 50 to 60 ^° C. until the evolution of gas had ended. Then the mixture was cooled to 20-25 ° C. 0.5 g of potassium iodide were added and a solution of 3.03 g of 4-chloromethyldiphenyl in 7 cm ^{3 of} dimethyl sulfoxide (dried over calcium hydride) was added dropwise. The whole was stirred or shaken for about 20 hours at 20 to 25 ° C and then poured into water. The product was extracted with ethyl acetate and then in the process

ίο wisely I treated way described.

Thus 4.6 g of l - [[2- (2,4-dichlorophenyl-2- (4-phenylbenzyloxy)] ethyl] imidazole nitrate with the same properties were obtained as obtained by that prepared by procedure I above.

15 Example 3

Salts of l - [[2- (2,4-dichlorophenyl) -2- (4-phenylthio-benzyloxy)] ethyl] imidazole and
! - [[^ - (i ^ -Dichlorphenyl ^ - ^ - phenyl-benzyloxy ^ -ethylhydazole

Salts of l - [[2- (2,4-dichlorophenyl) -2- (4-phenylthio-benzyloxy)] ethyl] imidazole were obtained by reacting of the frt; en l - [[2- (2,4-dichlorophenyl) -2- (4-phenylthio-benzyloxy)] - ethyl] imdidazole base in solution in ethanol with an alcoholic solution of the desired acid and subsequent crystallization of the resultant Salt made from a solvent. The free l - [[2- (2,4-dichlorophenyl) -2- (4-p! Ienylthio-benzyloxy *] - ethyl, imidazole base was according to Example 1, Procedure I or by releasing it after the Example 1, procedure II Nitrate produced by treating with sodium carbonate, extracting with Obtained diethyl ether and evaporation.

Salts of l - [[2- (2,4-Dichloφhenyl) -2- (4-phenyl-benzyloxy)] - ethyl] imidazole were prepared analogously.
The following Table IV summarizes the crystallization solvents, the elemental analysis and the melting points of salts of '- [[2- (2,4-dichlorophenyl) -2- (4-phenylthio-benzyloxy)] - ethyl] imidazole.

In the following Table V are the same data of salts of 1- [[2- (2,4-dichlorophenyl) -2- (4-phcnylbenzyloxy)] ethyl] imidazole compiled.

Table IV

Crystallization solvent

Melting point, ⁰ C Calculated, % C H

Cl

Found,% C H

l - [[2- (2,4-dichlorophenyl) - isopropano!

2- (4-phenylthio-benzyloxy)] - ethyl] imidazole hydrochloride

l - ([2- (2,4-dichlorophenyl) ethanol

2- (4-phenylthio-benzyloxy)] - ethyl] imidazole maleate

l - [[2- (2,4-dichlorophenyl) ethanol

2- (4-phenylthio-benzyloxy)] - ethyl] imidazole methanesulfonate

l - [[2- (2,4-dichlorophenyl] -ethanol

2- (4-phenylthio-benzyloxy)] - ethyl] imidazole p-toluenesulfonate

l - [[2- (2,4-dichlorophenyl) ethanol

2- (4-phenylthio-benzyloxy)] - ethyl] imidazole phosphate

Table V

181 to 183 58.61 4.30 5.69 21.62 6.51 58.42 4.31 5.67 21.40 6.79

117 to 118 58.85 4.23 4.90 12.41 5.61 58.61 4.50 4.77 12.24 5.91

153 to 155 54.45 4.39 5.08 12.86 11.63 54.21 4.32 4.78 12.97 11.94

127 to 128 59.33 4.50 4.46 11.30 10.22 59.43 4.49 4.43 11.63 10.44

143 to 145 52.09 4.19 5.06 12.81 5.79 51.86 4.18 5.12 12.90 5.91

Crystallization Melting Calculated,%

solvent point, ⁰ C q ^

Cl

Found,% C II

1- (12- (2,4-dichlorophenyl) ethyl acetate

2- (4-phenyl-benzyloxy)] - ethyl] - imidazole hydrochloride

1 - [[2- (2,4-dichloropheny I) - ethanol

2- (4-phenyl-benzyloxy)] - ethyl] - imidazole sulfate

l - [[2- (2,4-dichlorophenyl) ethanol

2- (4-phenyl-benzyloxy)] - ethy I] - imidazole maleate

l - [[2- (2,4-dichlorophenyl) ethanol

2- (4-phenyl-benzyloxy)] - ethyl] - imidazole-p-toluenesulfonate

l - [[2- (2,4-dichlorophenyl) ethanol

2- (4-phenyl-benzyloxy)] ethy I] imidazole citrai

up to 172 62.69 4.60 6.09 23.13

62.40 4.80 5.86 23.18

72 to 80 55.28 4.25 5.37 13.60 6.15 54.99 3.90 5.25 13.48 6.23

up to 129 62.35 4.48 5.19 13.14

62.05 4.19 4.91 13.51

182 to 184 64.25 4.87 4.83 12.23 5.53 63.81 4.82 4.54 12.52 5.63

150 58.55 4.58 4.55 11.52

58.97 4.47 4.61 11.60

Example 4 Drugs

A) ointment

1- Q2- (2,4-dichlorophenyl) -2- (4-phenylthio-benzyloxy)] ethyl] imidazole nitrate lanolin

Vaseline to supplement too

B) Glycolic solution

! - [P ^ j ^ dichlorophenyl ^ -i ^ phenylthio-benzyloxy ^ -ethylJ-iniidazole nitrate Propylene glycol to fill up

C) powder

l - [[2- (2,4-dichlorophenyl) -2- (4-phenyltbio-benzyloxy) 3-ethylhemidazole nitrate lanolin

²⁰ soybean lecithin

Talk to complement too

D) gel

HR - ^^ Dichlorphenyl ^ - ^ - phenylthio-benTyloxyfl-äthylj-imidazole nitrate High molecular weight colloidal carboxyvinyl polymer (Carbopol) water
Polyethylene glycol to complement triethanolamine in one to achieve

a pH of about 3 required amount

2 G S. 20th G G 100 G G 2 G G 100 cm ³ G 2 G G 1.5 g 2 100 2 2 2 100

10

Claims (1)

IS20253G 40 50 claims: 1. l - [[2- {2,4-dichlorophenyl> 2-ben2yloxy] ethyl] imidazoles of the general formula I.
H