DE2917244A1 - 4'-SUBSTITUTED 2,4-DICHLORINE ALPHA (IMIDAZOLE-N-YLMETHYL) DIBENZYL ETHER, METHOD FOR THE PRODUCTION THEREOF, AND SUCH MEDICINAL PRODUCTS CONTAINING IT - Google Patents

Description

DR. STEPHAN G. BESZgDES PATENT ADVOCATE

S ~

AUTHORIZED REPRESENTATIVE AT THE EUROPEAN PATENT OFFICE

PROFESSIONAL REPRESENTATIVE ALSO BEFORE THE EUROPEAN PATENT OFFICE

8C60 DACKAU NEAR MUNICH

BOX 1168

MDNCHENER STRASSE 8OA Federal Republic of Germany TELEPHONE: DACHAU 4371 Postal checking account Munich (BLZ 700 100 80)

Account no. 1 368 71

Bank account no. 906 370 at the Kreis- und Stadtsparkasse Dachau-lndersdorf (bank code 700 51540) (VIA Bayerische Landesbank Girozentrale, Munich)

P 1 190

Description

-to the patent application

EECOEDATI S.A. CHEMICAL AND PHARMACEUTICAL COMPANY

Chiasso, Switzerland

concerning

4'-Substituted 2, ^ - dichloro-ptr-cimidazol-N-ylmethyl) - -dibenzyl ether, process for their production and medicinal products containing such

Me invention relates to new 4'-substituted 2,4-dichloro - «- (imidazol-N-ylmethyl) -dibenzyl ether including their salts, a process for their preparation and such Medicinal products containing, in particular with anti-fungal effects

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Yeast and bacteria.

The well-known antifungal agents, such as (imidazol-1-yl) - -o (- (o-chlorophenyl) -o (, o (-diphenylmethane {i- (o-chloro-tf, o (-diphenylbenzyl) -imidazole) [clotrimazole] (The Merck Index, 2,370, p. 309 "and South African patents 68/05392 and 69/00039) and 2,2 ', 4,4' -Tetrachlor-tf- - (imidazol-li-ylmethyl) -dibenzyl ether [miconazole] (The Merck Index, 6 043, page 805 and German patent specification 1 940 388) have the disadvantage that they are too toxic.

The invention is based on the object of superior pharmacological effects, in particular due to their lower toxicity, having new 4'-substituted ones 2,4-dichloro-o (- (imidazol-U-ylmethyl) -dibenzyl ether, a process for their production as well as medicinal products containing them.

The above was surprisingly achieved according to the invention

The invention relates to 4'-substituted 2,4-dichloro-o (- (imidazol-3J-ylmethyl) -dibenzyl ether der general formula

Cl '

Cl

909847/0618

wherein E is a phenyl or phenylthio radical, that is, ^{2,4-dichloro-1-phenyl} ^ <~ A. (imidazol-N-ylmethyl) -dibenzyiather and ^{2,4-Mchlor-4-phenylthio-l} o (- (imidazol-H-ylmethyl) - -dibenzyl ethers, as well as their salts with acids.

The salts of the compounds according to the invention can be those with pharmaceutically usable inorganic 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 2,4-dichloro-4'-phenyl-ot .- (imidazol-N-ylmethyl) - -dibenzyl ether], nitric acid, phosphoric acid [especially in the case of 2, 4-dichloro-4 ¹ -phenylthio-c <- (: iMdazdL-lT-ylmeth.yl) - -dibenzyl ether, maleic acid, methanesulfonic acid [especially in the case of 2,4-chloro-V-phenylthio-K- (imidazole -N-ylmethyl) - -dibenzyl ether], p-toluenesulphonic acid and citric acid ΓνοΓ, especially in the case of 2,4-dichloro-4 ^l -phenyl-o (- (imidazol- -N-yimethyl) -dibenzyl ether] are particularly preferred are the salts with nitric acid.

The invention also provides a method for producing the. compounds according to the invention, which is characterized in that in a known Veise 1- (2 ', V-dichlorophenyl) -2- (imidazol-N-yl) ethanol with a Halobenzyl derivative of the general formula

C-X II,

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wherein R is as defined above and X is chlorine or Bromine is condensed in a solvent, whereupon the 4'-substituted one obtained, if appropriate 2,4-dichloro-ts {- (imidazol-N-ylmethyl) -dibenzyl ether base of the general formula I converted into a salt with an acid or, if appropriate, the resulting salt Salt of the 4'-substituted 2,4-dichloro-o ;- (imidazol-N-ylmethyl) -dibenzyl ether of the general formula I into the corresponding free base of the general formula I or is converted into another salt.

One or more aromatic hydrocarbons, dimethylformamide, tetrahydrofuran, hexamethylphosphoramide or dimethyl sulfoxide or mixtures thereof can advantageously be used as the solvent. Dimethyl sulfoxide is particularly preferably used, since it is the most complete condensation solution, which leads to a higher yield and a purer product. In this case, it is not necessary to subject the 4'-substituted 2,4-dichloro-ortr (imidazol-N-ylmethyl) -dibenzyI ^- ether base obtained in the condensation to a purification by a chromatography column, while such a purification when using Dimethylformamide or hexamethylphosphoramide is required as the solvent. Simply filtering the solution of the 4'-substituted 2-, 4-dichloro-o (- (imidazol-K-ylmethyl) - -dibenzyl ether base through a silica gel column is able to hold back the small amounts of impurities -Dichlor-o <- (imidazol-N-ylmethyl) - -dibenzyl ethers of the general formula I, in which E stands for a phenyl stress, i.e. 2,4-dichloro-4'-phenyl-c <- (imidazole- ir-ylmethyl) dibenzyl ether is not

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Once this filtration is required and the crystallization of its! titrate results in one for pharmaceutical Purposes of enough pure product.

The condensation is advantageous, especially when using the above aprotic solvents, in the presence of an alkali metal hydride: or amide, · which the hydroxy group of 1- (2 ', ^ -'- dichlorophenyli - ^ - cimidazole- -If-yl) -ethanol is able to convert it into a salt.

As another possibility, 1 or more aliphatic alcohols having 3 to 6 carbon atoms can be used as solvents in the condensation. It is preferred to work in the presence of an alkali metal alcoholate instead of the alkali metal hydride or amide. Very particular preference is given to using tert-butanol, n-butanol or n-propanol as the aliphatic alcohol and an alkali tert-butoxide, such as potassium tert-butoxide, an alkali n-butoxide or an alkali propoxide, as the alkali metal alcoholate.

The condensation is preferably carried out in the presence of potassium iodide as a catalyst. This can be beneficial be added in small amounts before the addition of the halobenzyl 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. During this time, the duration of the salt formation, which may take place, of the 1- (2 ', 4'-dichlorophenyl) -2- (imidazol-ir - yl) - ethanol can also be included.

■ - 6 - ■

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The 1- (2 ', 4 -'-dichlorophenyl) -2- (imidazol-N-yl) - used in the process according to the invention as starting material -ethanol can be obtained from i-chloroacetyl ^^ - dichlorobenzene (Beilstein, Handbook of Org. Chem.j IV. Edition, Volume 7 »page 28) produced by reduction of the keto group using sodium borohydride and condensation with imidazole have been, wherein the reduction and condensation can have been accomplished in any order. The reduction can be carried out in methanol and the condensation in dimethylformamide and methanol in the presence of sodium have been made.

The halogenobenzyl compounds used as starting materials in the process according to the invention generally Formula II are known. The production of 4-chlor or methyl diphenyl is in Chem. Ber. 66B (1933), 1 4? 1 and the Production of i-bromomethyl-4-phenylthiobenzene is in U.S. Patent 3,242,193.

The preparation of salts of the 4'-substituted 2,4-dichloro - << - (imidazol-N-ylmethyl) -dibenzy 1 -ether according to the invention can be carried out by conventional procedures, for example by adding the desired acid to the 4'-substituted 2,4-dichloro-o ^ - (imidazol-N-ylmethyl) -dibenzyl ether base in equimolar amount and subsequent crystallization of the salt thus obtained from a solvent will.

Furthermore, pharmaceuticals according to the invention which contain 1 or more of the compounds according to the invention as active substances or active ingredients together with customary pharmaceutical diluents, carriers and / or Contain other auxiliary materials, provided. The inventive

909847/0618

proper connections have namely as already mentioned valuable pharmacological effects, especially against fungi, yeasts and gram-positive aerobic and anaerobic bacteria. The effectiveness is paired with a low toxicity.

There were comparative experiments in which the pharmacological effectiveness and toxicity of the invention Compounds with those of 2 well-known antifungal agents, namely (Imidazol-1-yl-o <- (o-chlorophenyl) -c *, c \ - -diphenylmethane [clotrimazole and 2,2 ', 4,4'-tetrachloro-e <- (imidazol-N-ylmethyl) -dibenzyl ether [Miconazole]] were compared.

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

Table I shows the acute toxicity values (ItDcQ values) of the compounds according to the invention and of the two comparison substances. The toxicity in mg / kg was indicated with oral administration Mice identified using conventional procedures.

Table II shows the minimum inhibitory concentrations of the compounds of the invention examined and both Comparative substances for mushrooms and yeasts compiled. The values of the minimum inhibitory concentrations were according to the usual broth double series dilution procedure determined.

The values of the minimum inhibitory concentrations of the investigated compounds according to the invention and both comparison substances in relation to gram-positive bacteria were also according to the conventional double series dilution

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Procedure determined and they are summarized in Table III.

Below minimum inhibitory concentrations are those Minimum concentrations that the growth of the examined To be able to inhibit fungi, yeasts and bacteria, understand.

The experimental conditions were as follows:

a) With mushrooms

Medium:

Sabouraud fluid with a pH of 5 »7 (5 cnr per tube).

Inoculation material \ A 10-day-old agar culture was washed with a physiological solution containing 10% of a polyoxyethylene sorbitan monooleate (Tween 80), then filtered through gauze and resuspended in the physiological solution, up to a dilution at which this suspension in a spectrophotometer Coleman Jr II type showed a transparency (T) of 50% at a wavelength of 650 nm. 0.1 cnr of the spore suspension was used per 5 cnr of medium. In contrast to Aspergillus niger, a 1:10 dilution was made in the physiological solution after filtering. Also from this dilution

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was used as inoculum 0.1 cnr each

■ χ 5 cnr medium used.

Ofemperainr and incubation aäauer:

25 ° C for 7 days.

b) In yeasts

Medium:

Sabouraud fluid with a pH of 5.7 (5 cnr ⁵ per tube).

Inoculation material:

The yeasts were in the Sab our aud liquid allowed to grow, all with the exception of Crypto co ecus neoformans For 24 hours and Cryptococcus neoformans for 2 days. The cells were by centrifugation at 6,500 revolutions collected per minute and resuspended in said physiological solution, up to a dilution at which this suspension in one Coleman Jr II spectrophotometer at a wavelength of 650 nm Transparency (T) of 50% was found. 0.1 cur of this suspension was used as

Inoculation material for every 5 turns.

cnr medium ver

Temperature and. Roasting ·
duration:

37 C for 48 hours.

909847/0618

/ ff

c) In gram-positive bacteria

. Medium:

Trypsin soya broth with a pH of 7.3 (5 cm ^ per tube)

Inoculation material:

The day before the experiment, the microorganisms to be examined were in their "The media concerned were transferred. After incubation at 37 C for 18 hours." with 0.1 cnr of a suspension of each strain in the broth at one dilution from 1: 100 to 5 cm of each of the media which are to be examined Compounds in one concentration

range from 0.009 to 160 vaccinated.

contained,

Qtenpeiatur \ nd

Incubation time: 37 ° C for 18 hours.

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- .11 -

Table I.

σ co oo

Acute toxicity (LDt _Q value)
in
mg / kg
when administered orally to mice 2, ^ - dichloro - ^ '- phenyl-
- «- (imidazol-N-ylmethyl) -
-dibenzyl ether
[Formula I.
with R = - CgHc]
{Connection according to the invention} -phenylthio-o ^ - (imida
zol-N-ylmethyl) dabenzyl ether
[Formula I.
with R = -.S- C ₆ H ₁ - "!
| Connection according to the inventionV chlor-af Gmidazol-N-
-ylmeth ^) - dibeaacyl ether
[Miconazole
{Vergledcihssubstanzj (Inidazol-i-ji) -oc-
- (o-cüLorph = ayl) - «ib <-
-diphenylm ethane
[\ lrgleichssubsfca3ii ^; i 2,400 3,000 870 I.
880 ^
CO

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Table II

Effectiveness against fungi and yeast
Minimum concentration
.. in
tf / cm ³ latnogerBr
Mitaoorgsnismis 2,4-dirinlor-4'-jbenyl -
- «• - (imdd azol-N-ylmetnyl) -
-dibeazylätfaer
£ j? Annell
with R = - C ₆ H ₅ ]
In accordance with the
^ indving] · 2,4-di £ 5hlor-4'-rfaenyl-
MUo- o (.- Oiiidazol-ii-yl-
me1 ^ l) -dibeaayläth er
[Formula I.
with R- - SQ ₆ H ₅ ]
(In accordance with the invention,
birctUQg} 2,2 ', 4,4'-0fetra-
chlorine - «(- \ imidazole (Imidazole-1 - ^.) - o <-
-Cn- rWnrphpnyl) - 0 ^ 06-
—D T [^ ftnyl τη fi + Jh an
rCLotrinazolJ
■ (Vagledchs-
aabstanz ^ j C. albicans 1040 10 80 [iliconazolj
{Comparative
aabstaaz} 40 C, riThVvns 1 Π41 20th . 80 20th 40 C neoibnnans 0.312 - 0.156 20th 0.625 T. meatagpo ^ i. 2,538 0.156 0.156 0.078 0.078 T. m> entagrqcfcL 10 148 0.625 0.625. 0.078 1.25 T. rubrum 2 121 0.625 0.625 0.625 1.25 A. niger 20th 10 0.312 10 P. chrysogenum 20th 5 40 40 E. floccosum 10 5 20th 5 5

- 13 -

- 13 -

Table III

Effectiveness against bacteria
Minimum concentration
in '■, ■,
. ... ... i / orn ^ Patnogenic
Mikcooicgardsmis 2, ^ -Bid & Qr * - * »· ¹ -pbecQrl-,
«-Ptr ^ CimJd azi oHJ-ylroeüQrl) -
[lOnnell
with S: -G ₆ H ^ l '
{Et ^ nduog ^ size Vea> 2, ^ ΜΛοΐν-4 '-tibsoyl · -
me% l) - dibenayläfciit er
[FacmeX I.
. TBttH * - S-CgHcI
{EriUndungggemaS e "\ fe r-
DXSdÄlg} 2,2 ', 4,4'-0fet3? & -
cbJor - «<- (3jnida25ol
-ylme1 ^^ - K3ibeDzy] ätha?
[lliccxiaziol]
{yerglsidas ·
aubstaaz} · ^: (Imiriazole, -1 - ^.) - o <-
~ d jpb.enylmetihian
rbljotrinazolj
{Vgglgichs- »
piVx ^ harpji. «Ρ
O
co
OP
* -
ς>
Φ
~ » S # aureus SG 511 0.039 0.039 0.312 0.312, S. aureus 10 B 0.039 ο, οΐδ 0.312 1.25 St. aemolyt; 821 0.156 0.156 1.25 '2.5 B. subtilis 0.156 0.078 0.625 2.5 Cl. novyi <1.25 5.0 <1.25 > 16Q St ν * hterooO ^ 203 0.312 0.078 0.625 5

Especially revealing is the comparison between the efficacy and toxicity of the compounds of the invention and those of 2,2 ', ^ - jV tetrachloride - "* - - (imidazole-N-methyl) -dibenzyläther [" miconazole] In 2 _r 2'. , 4,4'-tetrachloro (- (imidazol-: iI-ylmethyl) - -dibenzyl ether [miconazole) are both benzyl groups in the 2- and 4-positions substituted by chlorine atoms, while in the compounds according to the invention the one benzyl group, which is unsubstituted 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 in the case of the compounds according to the invention is 3 to 4 times lower than that of 2,2 ', ^, ^' - retrachlor-oi-cimidazol-N-ylmethyl) - -dibenzyl ether [Miconazole! Is, the effectiveness of the compounds according to the invention against bacteria is also much better (in some cases even Λ order of magnitude) than in the comparison substances and against fungi and yeasts di The effectiveness of the compounds according to the invention is on average about the same as that of the comparison substances. Thus, the therapeutic indices of the compounds according to the invention with regard to practically all bacteria investigated and for the most part also with regard to the fungi and yeasts investigated are higher (in some cases even by 1 order of magnitude and more) than those of the two comparison substances and the remainder in relation to higher than that of the comparison substance (imidazol-1-yl) -— * - (o-chlorophenyl) -cA, o {-diphenylmethane (clotrimazole) and almost the same as that of the comparison substance 2.2 · »4- , 4 · -Tetrachlor-ot- (imidazol-If-ylmethyl) - -dibenzyl ether (Miconazole).

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The compounds according to the invention can be particularly useful in hunian therapy for topical Treatment of skin diseases or dermatoses, such as beard lichen respectively Trichophytia and candidiasis, -and. further through 'The fungi staphylococci and streptococci caused infections are used.

Advantageous is or are in the medicaments according to the invention the (s) according to the invention Compound (s) in an amount of 0.5 to 5% by weight, in particular 1 to 3% by weight, contain.

The "invented medicaments can be used in various forms, for example in the form of powders, ointments, creams, suspensions, dispersions, Gels and solutions. They are preferably in the form of ointments, powders, glycolic solutions or gels.

The invention is explained in more detail by means of the following examples.

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example 1

2,4-DiCIiIOr-V -phenyl thio - * - (imidazole-JU- -ylmethyl) -dibenzyl ether

^ Formula I with E = phenylthio radical 7CgHc - S procedure I.

A solution of 2.57 S 1- (2 ', V-phenyl) -2- (imidazol-N-yl) ethanol in 10 cnr hexamethylphosphoramide at 25 ° C in a suspension of 0.52 ε sodium hydride (50% -ige dispersion in oil) in 5 cm * hexamethylphosphoramide was added dropwise. As was die'Wasserstoffentwicklung completed, the salt formation was completed by 1 hour heating at 50 ⁰ C. Tray for cooling to 25 ° C, 2.58 g of 1-chloromethyl-4-phenylthiobenzene was added. The temperature was increased to 50 ^° C. and held at this value for 12 hours. At the end of the reaction, the mixture was poured into 200 ml 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, giving 2.4 g of the desired 2,4-dichloro-4 * -phenylthio-ος- (imidazol-N-ylmethyl) -dibenzyl ether base as a yellowish oil, which showed a single spot on thin layer chromatography , was obtained.

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29172U

Zn

-rf-

Analysis:
For C ₂₄ H ₂₀ N ₂ Cl ₂ OS

Calculated: C = 63.30%, H = '4.44%, N = 6.13%, Cl S = 7.04%;

found: C ■ = 63.86%, H = 4.24%, N = 6.41%, Cl 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 ° C to 3.86 g of 1- (2 ^l , 4 ^l -dichlorophenyl) -2- (iiaidazol-N -yl) - -ethanol in 15 cm * dimethyl sulfoxide (dried over calcium hydride) was added. The mixture was heated to 50 to 60 ° C. with stirring or shaking until the evolution of gas ceased. After cooling to 20 to 25 ° C., 0.5 g of potassium iodide was added and a solution of 3.51 g of i-chloromethyl-4-phenylthiobenzene in 4 cnr dimethyl sulfoxide was slowly added dropwise. The mixture was stirred or shaken at 20 to 25 ° C. until the addition of the i-chloromethyl-4-phenylthiobenzene was complete. The mixture was then poured into 150 cubic meters of water and extracted with diethyl ether. After drying over anhydrous sodium sulfate, an excess of a 4 η nitric acid solution in diethyl ether was added to the ethereal solution. The desired product precipitated as nitrate was an oil,

-. 18 909847/0618

which got stuck while standing. After standing for 20 hours, the essential liquid became decanted off and the residue crystallized from ethanol. The nitrate thus obtained, which was not yet completely pure, it was dissolved in water and there was an excess of Sodium carbonate was added to liberate the base, which was then extracted with ethyl acetate became. The obtained base was purified by filtration on a silica gel column using Purified ethyl acetate as the eluent. The combined containing the desired product Fractions were evaporated to dryness. The residue was dissolved in diethyl ether, again converted into nitrate and crystallized from ethanol,

3.1 g of 2,4-DiChlor-V-phenylthio-o ^ - (imidazol-N-ylmethyl) -dibenzyl ether nitrate were obtained as a white crystalline powder with a melting point of 134 ⁰ O.

Analysis:

For C ₂₄ H ₂₀ N ₂ Cl _{2 5}

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%.

09847/0618

29172A4 23,

The 1- (2 ', 4'-dichlo: rphenyl) - 2- (imidazol-N - yl) ethanol used as the starting material has been manufactured as follows:

There were 49.5 S sodium borohydride slowly in small portions to a stirred or shaken suspension of 233 g c <, 2,4-trichloroacetophenone added in 1 l of methanol at room temperature. The solution thus obtained was another 2 hours stirred or shaken at room temperature and then in 1 l of a 5N hydrochloric acid cooled with ice poured. After extracting with ethyl acetate or chloroform, the extract was washed with water, a η sodium hydroxide solution, then again with water until the neutral reaction is reached and finally washed with a saturated sodium chloride solution. The extract was dried and the solvent was evaporated. 220 g of an oil were obtained. This oil became while standing solid and this solid substance, 1- (2 ', V-dichlorophenyl) -2-chloroethanol had a melting point of 48 to 51 ° C

Analysis:

For C ₈ H ₇ Cl ₅ O

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

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30 g of sodium were added to a solution of 88.5 6 imidazole in 600 cur of methanol. The solvent was then evaporated off. The residue was dissolved in 300 cnr dimethylformamide and heated to 115 to 120 ° C. The resulting solution was stirred or shaken to a solution of 225 g of 1- (2 ', 4' obtained as described above. -Dichlorphenyl) -2-chloroethanol were added dropwise in 400 cnr dimethylformamide. The mixture was heated to 115 to 120 ⁰ C and maintained at this temperature for 20 minutes and after subsequent cooling to 40 C 2500 cur ice water were added with vigorous stirring or shaking. The product precipitated on stirring or shaking for about 2 hours, after which the supernatant liquid was decanted, a further 2,500 cubic meters of water was added and, after standing, the whole was filtered. The resulting precipitate was dried and the toluene crystallized g 1- (2 ', 4'-dichlorophenyl) -2- (imidazol- -N-yl) -ethanol with a melting point of 134 to 135 ° C were obtained.

Analysis:
For C ₁₁ H

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

found: C = 51.62%, H = 3.80%, N = 10.73%, Cl = 27.76%.

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Example 2

2,4-DiChIOr- ^ ¹ -phenyl-ri-Cimidazol-N -ylmethyl) -dibenzyl ether

Formula I with R = ehenyl radical

Procedure Ia

A mixture of 2.02 g of potassium tert was used. butyl at in 30 cnr tert-butanol in a nitrogen atmosphere 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 heated and then cooled to 20-25 ° C. 3 »03 g of 4-chloromethyldiphenyl were added and the solution was again heated to boiling under reflux for 5 hours. After cooling to 20 to 25 ° C, the whole thing was poured into water and the 2,4-dichloro-4'-phenyl-eC- (imidazoΙ-ΐΓ-ylmethyI) -dibenzyl ether base extracted with ethyl acetate. The extract was washed with diethyl ether and the solvent was evaporated. The residue was dissolved in 80 ml 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 2,4- dichloro ^ '- phenyl - ^ - cimidazol-N-ylmethyl) -dibenzyl ether nitrate

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existing residue was crystallized from ethanol or ethyl acetate.

Thus were as product 4.3 g of 2,4-dichloro-4'-phenyl <x- (imidazol-N-ylmethyl) -dibenzyläthernitrat which proved by thin layer chromatography to be pure and have a melting point 140-141 ⁰ C. had received.

Analysis:
For C ₂₄ H ₂₀ N ₂ Cl ₂ O. ENT ₅

Calculated: C = 59.25%, H = 4.35%, H "= 8.64%, O1 = 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 6 sodium metal in 20 cnr n-propanol, 4.1 g of 1 - '(2 ^l , 4 ^l -Dichlorophenyl) -2- (imidazole-IT- prepared as described in connection with Example 1) yl) ethanol 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 heated to boiling under reflux. 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.

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-25 -

The insoluble residue was filtered off and the clear ethereal solution thus obtained was treated with a mixture of nitric acid and diethyl ether. The 2,4-dichloro-4'-phenyl- <X- (imidazol-II-ylmethyl) -dibenzyl ether nitrate obtained in this way was crystallized from ethanol. The product was 2.1 g of 2,4-dichloro-4 ^f -phenyl-o (- (imidazole-N- -ylmethyl) -dibenzyl ether nitrate with the same properties as those prepared by the above procedure Ia, which was a single in thin layer chromatography Stain showed received.

Procedure II

It was 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- (imidazol-H-yl) ethanol in 15 cnr dimethyl sulfoxide (dried over calcium hydride) was added. The mixture was heated to 50 to 60 ° C heated until the evolution of gas ceased. Then the mixture was cooled to 20-25 ° C. It 0.5 g of potassium iodide were added and a solution of 3 × 3 g of 4-chloromethyldiphenyl in 7 cm of dimethyl sulfoxide (dried over calcium hydride) was added dropwise. The whole thing was done at 20 bis for about 20 hours Stirred or shaken 25 ° C and poured into water. The product was made with Ethyl acetate extracted and then treated in the manner described in Procedure I.

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Thus 4.6 g of 2,4-dichloro-4 ¹ -phenyl - & £ ■ - (imidazol-N-ylmethyl) -dibenzyl ether nitrate with the same properties as those prepared according to procedure I above are obtained.

Example 3

Salts of 2,4-dichloro-4'-phenylthio-oCr- - (imidazol-N-ylmethyl) -dibenzyl ether and 2,4-dichloro- ^ · · -phenyl-cX-cimidazole-N- -ylmethyl) -dib enzylether

Salts of 2,4-dichloro-4'-phenylthio-o <- (imidazol-N-ylmethyl) -dibenzyl ether were obtained by reacting the free 2,4-dichloro-V-phenylthio-o (- (imidazol-N-ylmethyl ) -dibenzyl ether base in solution in ethanol with an alcoholic solution of the desired acid and subsequent crystallization of the salt thus obtained from a solvent. The free 2, ^ - dichloro ^ ¹ -phenylthio- <x ^ (imidazole-N- -ylmethyl) - dibenzyl ether base was obtained according to example 1, procedure I or by liberating the nitrate prepared according to example 1, procedure II by treatment with sodium carbonate, extraction with diethyl ether and evaporation.

Salts of 2,4-dichloro-4 -'-phenyl- - <Kr- (imidazol-N-ylmethyl) -dibenzyl ether produced.

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909847/0618

ze

-9S- 29172ΑΛ

In the following Table IV are the crystallization solvents, elemental analysis And the melting points of salts of 2,4 — dichloro-4- '-phenylthi ο -o <- (imidaz oil -N-ylmethyl) -dibenzyl ether compiled.

In the following Table V the same data of salts of 2,4-dichloro-4'-phenyl-tx ^ (imidazole- -N-ylmethyl) - dibenzyl ether compiled

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909847/0618

co

co co

σ> co

- 26 Table IV

salt iristalLisa—
rissns.laaooßj-
middle Enamel
Point Calculated C. H N Cl S. Found C. H N Cl S. 2 4 Tyir-h1rir> -4l-Thm-a-hM η « ! sopiqpamL 181 to 185 ⁰ C 58.61% 4.30% 5.69% 21.62% 6.51% 58.42% 4.31% 5.67% 21.40% 6.79% - (iioijszol-ii-yjmethyl) -
-dibenzjiääierliydiuciiLorid Ethanol 117 to 118 ⁰ C 58.85% 4.23% 4.90% 12.41% 5.61% 58.615 * 4.50% 4.77% 12.24% 5.91% -dibeazylätäbsrmaLeiaat EthantiL 153 to 155 ° C 54.45% 4.39% 5.08% 12.86% 11.63% 54.21% 4.32% 4.78% 12.97% 11.94% -dibaazyjattermatöBQSuLfonat Ethanol 127 to 128 ⁰ C 59.33% 4.50% 4.46% 11.30% 10.22% 59.43% 4.49% 4.43% 11.63% 10.44% - (inudazol-N-ylmethyl) -di-
ben ^ jaöEr-p-tolvDlsulfjnat Ethanol 143 to 145 ⁰ C 52.09% 4.19% 5.06% 12.81% 5.79% 51.86% 4.18% 5.12% 12.90% 5.91% -CLmidaaiL-li-ylmethyl) -

'JD

- 27 Table V

salt KristaHisa-
middle Sctomelz -
, puakt Calculated C. H N Cl S. Found C. H N Cl S. ι
2,4-Mchlor-4'-itoenyl-c * -
- (imdazol- ^ N-jemethyl) -dl- · ν
bereylätiiertcdrociilar id itiylacetat 171 to 172 ° 0 62.69% 4.60% 6.09% 25, 15% 62.4036 4.80% 5.86% 25.18% 2,4-DküLQr-4'-iBayl-oC-
- (iniäaaaL-il-ylineti ^ l) -dibenziji-
Etiiersulfat Ethanol 72 to 80 ⁰ C 55.28% 4.25% 5.57% 15.60% 6th, 15% 5A * 99> 5.90% 5.25% 15.48% 6.25% 2,4-didilar-4 * -ihenyl- <x.-
—Fimidflfpl ^ if-vl mf # T7l) -di— Ethanol 128 to 129 ° C 62.55% 4.48% 5.19% 15.14% 62.05% 4.19% 4.91% 15.51% benzyl acetate Ethanol 182 to 184 ⁰ C 64.25% 4.87% », 8396 12.25% 5.55% 65.81% 4.82% 4.54% 12.52% 5.65% 2,4-dicblor-4 ^l -pbeä3yl- (X -
- (imidazol-K-ylmeiiiyl) -dl -
benzyl ether p-toiboilsilfonate Ethanol 150 ⁰ C 58.55% 4.58% 4.55% 11.52% 58.97% 4.47% 4.61% 11.60% ρ. ü. — pictilop — t-WlvaT / l - «- - (iraLda2aL-iiy] aBtiiyl) -di-
benzy] fltbar egg kicked

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29172U

Example 4
Drug e1

A) ointment

2,4 ~ diclilor-4-phenyl thio- oil (imidazol-N-ylmethyl) dibenzyl ether extract 2 g

Lanolin 20 g

Vaseline to supplement 100 g

B) Glycolic solution

2,4-dichloro-4- ¹ -phenyl thio- - <* - (imidazol-N-ylmethyl) -

-dib enzyläthemit rat 2 g

Propylene glycol for

Fill up to 100 cm

C) powder

2, ^ - dichloro- ^ '-phenyl thio- -e (- (imidazol-N-ylmethyl) ~

dib enzyläthemit rat 2. G

Lanolin 1.5 g

Soybean lecithin 2 g

Talc to supplement 100 g

90 9 8A7 / 0618

- 2H9 -

D) gel

2,4-dichloro-V -phenyl thio- - «<- (imidaz ol-Üf-ylme tliyl) -

-dibenzyl ether nitrate 2 g

High molecular weight carboxyvinyl polymer (Carbopol) 2 g

Water 2 g

Polyethylene glycol for

Add to 100 g

Triethanolamine in one

amount required to achieve a pH of about 3

Claims

809847/0618

Claims (1)

Claims 4'-Substituted 2,4-dichloro-cx - (imidazole- -U-ylmethyl) -dibenzyl ether of the 'general formula H. where E stands for a phenyl or phenylthio radical and their salts with acids. 2.) Compounds according to claim 1, characterized in that that they contain salts with hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, Maleic acid, methanesulphonic acid, p-toluenesul- fonsäure or citric acid are. 5.) Process for the preparation of the compounds according to claim Λ or 2, characterized in that in a known manner 1- (2 ^!, 4- ^l -dichlorophenyl) -2- (imidazol-] J-yl) - ethanol with a halobenzyl derivative of the general formula §09847 / 0618 II wherein R is as defined in claim 1 and X is chlorine or bromine, in one Solvent condenses, whereupon the obtained 4'-substituted 2,4-DiChIOr-OC- (imidazol-N-ylmethyl) - -dibenzyl ether base of the general formula I converted into a salt with an acid or optionally the resulting salt of the 4'-substituted 2,4-dichloro-o <- (imidazole- -N-ylmethyl) -dibenzyl ethers of the general Formula I in the corresponding free base of the "general formula I or in another Salt transferred. 4.) Process according to claim 3, characterized in that the solvent used is 1 or more aromatic Hydrocarbons, dimethylformamide, Tetrahydrofuran, hexamethylphosphoramide or dimethyl sulfoxide or mixtures thereof used· 5.) 'Method according to claim 3 or 4-, characterized characterized in that the condensation is carried out in the presence of an alkali metal hydride or amides. 6.) The method according to claim 3, characterized in that the solvent 1 or more aliphatic alcohols with 3 to 6 Carbon atoms used. - 32 909847/0618 7 ·) Process according to claim 3 or 6, characterized in that the condensation carries out in the presence of an alkali metal alcoholate. 8.) Process according to claim 3, 6 or 7, characterized in that the alcohol is tert-butanol., N-butanol or n-propanol and the alkali metal alcoholate is an alkali tert-butoxide, alkali n-butoxide or alkali n -propylate used, 9.) Method according to claim 3 to 8, characterized in that that the condensation is carried out in the presence of potassium iodide as a catalyst. 10.) Process according to claim 3 to 9, characterized in that the condensation is carried out for 6 to 36 hours at a temperature of 20 to 100 ^° C. 11.) Medicines, characterized by a content of 1 or more Verbähdurgen according to claim. 1 oiler 2 as an active ingredient or active ingredients together with conventional pharmaceuticals Diluents, carriers and / or other auxiliaries. 12.) Medicament according to claim 11, characterized in that it is the connection (s) according to Claim 1 contains in an amount of 0.5 to 5 wt .-%. - 33 809847 / 061.8 13.) Medicines after. Claim 11 or 12, characterized in that it is available as an ointment, powder, glycolic solution or Gel is present. 809847/0618