CA1115718A - Therapeutically active substituted dibenzyl ethers - Google Patents

Abstract

ABSTRACT
Therapeutically Active Substituted Dibenzyl Ethers There are provided 2,4-dichloro-4'-phenyl-.alpha.-(N-imidazolyl--methyl)-dibenzyl ether, 2,4-dichloro-4'-phenylthio-.alpha.--(N-imidazolyl-methyl)-dubenzyl ether and pharmaceutically acceptable acid addition salts thereof. These compounds show activity against some fungi, yeasts and gram positive aerobic and anaerobic bacteria.
The new compounds can be prepared by condensing 1-(2',4'--dichlorophenyl)-2-(N-imidazolyl-methyl)-ethanol with 4-chloromethyl-biphenyl), 4-bromomethyl-biphenyl, 1-phenylthio-4-chloromethyl-benzene or 1-phenylthio-4--bromomethyl-benzene in a solvent, most preferably dimethylsulphoxide.

Description

~1571~

DESCRIPTION
The invention relate~ to substituted dibenzyl ethers, to methods for their preparatlon and to pharmaceutical compositions containing them.
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The invention provides compounds of the general formula I

Cl_~CH-O-C}~2~R ~ ~

Cl .. .
I
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C 2 \~o N
wherein R represents a phenyl or phenylthio group and pharma-ceutically acceptable acid addition salts thereof. Thus, the compounds of the formula I are 2,4-dichloro-4'-phenyl-Cr(~-O imidazolyl-methyl)-dlbenzyl ether and 2,4-dichloro-4'-phenylthio-d~N-imldazolyl-methyl)-dibenzylether and pharmaceutically accéptable acid addition salts thereof.
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Pref-rred pharmaceutically acceptable acid addition salts of the compounds I include those formed from both mineral and organic acids, suah as hydrochloric, nitric, sulphuric, phos-phuri~, methane-sulphonic, succlnic, maleic, ~umaric, citric and tartaric acids~ mese salts may be prepared by conventional methQds, for example by adding to the base in equimolecular . .
amount the desired acid and then crystallizing the salt so Q obtained from a suitable solvent~

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1~15718 e compounds I and their salts are of interest for the activity they show against some fungi, yeasts and gram positive aerobic and anaerobic bacteria. The activlty is coupled with a low toxicity. The compounds of the invention have been compared with two well-known antimycotic products, clotrimazole, i.e.
Cimidazol-l-yl)-2-(o-chlorophenyl)-2,2-diphenylmethan~ , and miconazole. F
.
Particularly interesting was the comparison between the activity ' and toxicity of the compounds I and of miconazole, which is 2, 0 2', 4, 4'-tetrachloro- ~-(N-imidazolyl-methyl)-dibenzyl ether.
In miconazole both benzl groups are substituted in the 2- and 4-positions by chlorine atoms, whereas in the compounds I the benzyl group which is ~-unsubstituted is substituted in the 4-posltion by a phenyl or phenylthio group. This difference involves a notable reduction of toxicity which, for the new products, is from 3 to 4 times lower than that of miconazole, whereas the antifungal and antibacterial activity is about the same. The compounds according to the invention can be conven-ientl~''employed inihuman therapy for the local treatment of ~0 dermatosis, such as trichophytosis and candidosis, and further infections caused by fungi staphylococci and streptococci. The compound~ according to the invention may be admixed with pharmaceutically acceptable diluents or carriers to form ,j pharmaceutical compositions, which may be in any suitable form, for example powders, ointments, cream~, suspensions and '' dispersions.

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157:~8 The results obtained in biological assays are reported in Tables I, II and III.
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In Table I are reported the acute toxicity values (LD50) of the compounds I and of both the comparison substances. Toxicity, given in mg/Kg, has been evaluated per os in the mouse by con-ventional methods.

In Table II are reported the minimal inhibent concentrations (MIC) of the compounds I and of both the comparison substances.
For MIC, the minlmal concentration ls intended, able to inhibit the growth of several fungi and yeasts. The MIC values have ` been determined according to the usual two-fold serial broth `
` dllution technique.

The MIC values of the products under examination and of both ; comparison substances, re~erred to a certain number of gram positive bacteria and determined according to the conventional two-fold serial broth dilution technique, are reported in Table III.
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Experimental condltions were as follows:
~ For Fun~
`~ 20 Medium. Sabouraud liquid pH 5.7 (5 ml per tu~e) ;~ Inoculum: A ten days agar culture was washed with a physio-loglcal solution containing 10% Tween* 80, then flltered through gauze and again suspended in physiological solution ,, i i :, .
* Trade Mark

- 3 -~1571B

until the solution showed on a Colemln Jr II ~pectrophotometer, at a wavelength of 650 nm, a 50% transparence (T) (0.1 ml of spore suspension per ml). For Aspergillus niger, after filtration, a 1/10 dilution in physiological solution was prepared. 0.1 ml of this dilution constituted the inoculum for 5 ml.
Temperature and incubation time: 25C for 7 days.

For Yeasts Medium: Sabouraud liquid pH 5.7 (5 ml per tube) 0 Inoculum: Yeasts were grown ln Sabouraud liquid for 24 hours - (Cryptococcus neoformans ~or 2 days). Cells were collectedby centrifugation at 6500 rpm and again suspended in physio-logical solution so as to have a suspension giving on a Coleman Jr II spectrophotometer, at a wavelength of 650 nm, a 50~ tran~parence (T). 0.1 ml of this suspension constituted the inoculum for 5 ml.
Temperature and lncubatlon time: 37C for 48 hours.
;
For Gram Positlve Bacteria ; Medium: Tryptic soy broth p~ 7.3 (5 ml per tube) . ~ .
0 Inoculum: The day before the test, the microorganisms to be tested were transplanted in their xespective media~ After 18 hours incubation at 37C, 0.1 ml of a 1:100 diluted suspension of each strain in broth, were inoculated in S ml of medium containing the products ~' `

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~ ~ 5 '' under examination at a serial concentration of from 0.009 to 160 mcg/ml.
Temperature and incubation time: 37C for 18 hours.

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T A B L E I
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Acute toxicity (LD 50) per OS in the mouse in mg/Kg.
. - . .
Formula I Formula I Miconazole Clotrimazole I R=C6H5 I : R=C6H5S
... . _ _ - _ T A B L ~ - II
,~ _ Antimycotic activity (MIC) in mcg~ml . . __ _ .
Phatogenous Formula I Formula I Miconazole Clotrima-Agent R = C6~5 6 5 zole C.Albicans R 5 40 5 10 C.Albicans Gr~ne~thal 5 40 5 10 C.Albicans 1040 10 80 20 40 C.Albicans 1041 20 80 20 40 C.Neoformans 0,312 0,156 0,078 0,625 T.Mentagroph.2538 0,156 0,156 0,078 0,078 T.Mentagroph.10148 0,625 0,625 0,625 1,25 1 T.Mbntagroph.5865 1,25 1,25 0,31 0,62 T.Verrucosum 10 1,25 2,5 1,25 ; T. ~ubrum 2121 O,625 O,625 O,312 1,25 M. Canls 28 20 2,5 5 2,5 R
A. Niger 20 10 40 10 P. Chrysogenum 20 5 20 40 E. Floccosum 10 5 5 5 '~ ~ . _ .' ~ `

1~157~ e t:
T A B L E III

Antibacterial activity (MIC) in mcg/ml Phatogenou~ Formula I Formula I Miconazole Clotrimazole Agent 6 5 6 5 S.aureus SG 511 0,039 0,039 0,312 0,312 S.aureus 10 B 0,039 0,018 0,312 1,25 Str.hemolyt 821 0,156 0,156 1,25 2,5 B. subtilis0,156 0,078 0,625 2,5 Cl.novyi< 1,25 5,0 < 1,25 > 160 Str.hemolyt 203 0,312 0,078 0,625 ., .

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` The invention fur~her provides a method for the preparation of compounds of the general formula I as hereinbefore defined, the method comprising condensing in a solvent 1-(2',4'-dichlorophenyl)-2-(N-imidazolyl)--ethanol with a halobenzyl compound of the general - formula V

R ~ CH2X V
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10 wherein R has the meaning previously ascribed to it and X represents a chlor~ne or bromine atom.

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As solvent, aromatic hydrocarbon, dimethylformamiae, tetrahydrofuran, hexæmethylphosphoramide and~or a mix.ure thereof can be employed, but it has been verified that condens~tion is more complete if dimethyl-sulpho~ide is used. This leads to a higher yield and to ; a purer proauct. In this case it is not necessary to ~j~ submit the base obtained from condensation to a `~` purification through chromatographic column, whereas ~ ~ said purification is necessary using as solvents .,~ .. ~
` dimethylformamide or hexamethylphosphoramide. A simple filtration of the base solution through a silica gel ~; column is in fact able to retain the small amounts of . .. .
impurities. For the compound I, in which R represents a phenyl sroup, not even the filtra~ion is necessary, and crystallization of the nitrate leads to a product ~ suf iciently pure for pharmaceutical purposes. With the ,.~; , ... ~ , " . - . ., .. . , . ~ ~ , .; . .

~1571~
g aprotic solvents specified above, there is usually used an alkali metal hydride or amide! which is able to salif~ the hydroxy group of the ethanol derivative.

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Alternatively the condensation solvent may be an S aliphatic alcohol having from 3 to 6 carbon atoms, such as t-butanol, and in this case the alkali metal hydride or amide should be replac~d by an alkali metal alcoholate, for example potassium t-~utylate.

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A further very useful expedient is to add smali amounts of potassium iodide as catalyst before adding the halobenzyl derivative.

~he 1-(2',4'-dichlorophenyl)-2-(N-imidazolyl)-ethanol may be prepared from l-chloroacetyl-2~4-dichloro-benzene tBeils.ein-Han~buch der O_g. Chem. IV ed.vol.7, page 28) by reduction of the keto group using sodium borohydride and condensation with imidazole. The reduction and condensation can be effected in either order. The reduction may be effected in methanol and the condensation may be effected n dimethylformamlde and methanol ln the presence of sodium. The halobenzyl compounds of the , general Cormula V are known. The preparation of 4-chloro-`I methyl-biphenyl is described in Chem. Ber. 66B, 1471, i 1~33 and the ~reparation of 1-bromomethyi-4-phenylthio-j~ -benzene is described in United Sta.es Patent Specification ;¦ 2~ No. 32~2193.

Examples 1 to 4, which follow, illustrate the invention .. . while Examples A and B describe the preparation of the starting materials used in Examples 1 to 4.

EX~MPLE A
1-(2',4'-dichlorophényl)-2-chloro-et~anol 49.5 g of sodium borohydride were added slowly and in j smaIl parts to a suspension of 233 g of 1-(1'-hydroxy-2'-- -chloro-ethyl)-2,4-dichloro-benzene in 1 litre of methanol ! stirred at room temperature. The solution thus obtained was stirred at room t~mperature for a further two hours, ¦ and it was then poured ~nto 1 litre of 5~ hydrochloric i acid cooled with ice. After exiraction with ethyl 1~ acetate or chloroform, the ~xtract was washed with water, ¦~ with lN sodium hydroxide, then again with water until neutrality, and finally witn a satllrated sodium chlor~de solution. The extract was aried, the solvent evaporated o'f and 220 g of an oil were obtained. The oil solidified on standing and the solid melted at 48-51C.
Analysis ~or C8~7C130 C% H% Cl%
'. ~ 20 Calculated 42.61 3.13 47.17 Found : 42.75 3.19 47.43 ~ , .
EX~IPLE B

1-(2',4'-dichloro~henYl)-2-(N-imidazolYl)-ethanol .
30 g of sodium were added to a solution of 88.5 g of im~dazole in 600 ml of methanol; the solvent was then eva?orated ofr. The residue was dissolved in 300 ml of !.,~ ~ ,, , 7~

dimethylformamide and heated to 115-120C. To the I solution so obtained was added, dropwise and under !: stirring, a solution of 225 g of 1-(2',4'-dichlorophenyl)-I -~-chloro-2th~nol in ~0 ml of dim2thyl.0rmamid2. The ; 5 mixture was heated to 115-120C and maintained at that I temperature for 20 minutes and, after subsequent cooling ¦ to 40C, 2500 ml of iced water were added under vigorous ¦- stirring. The product precipitated under stirring over -'¦ a period of about two hours, the upper liquid was then ,.~ , 1~ 10 decanted off, a further 2500 ml of water were added and, '~1` . . .
i~ after standing, the whole was filtered. The precipitate .hus obtained was dried and crystallized from toluene.
' 170 g of the desired product, melting at 134-135C, was obtained.
Ar.alysis for CllHloC12N20 C~ ~% N% ' Cl%
Calculated 51.38 3.92 10.89 27.58 Pound ' 51.62 3.80 10.73 27.76 ~;
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-dibenzyl'e~her'C}: ~-C6H5S)' .: , ~
'~SETEOD I
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~ A solution of 2.57 g of 1-~2',4'-dichlorophenyl)-2-(~-- -imidazolyl)-ethanol, prepared as described in Ex~mple B, ~ in 10 ml of hexzmethylphosphoramide was dropped at 25C
; a~:; into a suspension of 0.52 g o~ sodiu~ hydride (50% in oil) in 5 ml of hexamethylphosphoramide. When hydrogen ; e.~ission W25 over, tha salification wzs comDleted ~Y
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:~ ~ , ~ 111571~ 5 heating for 1 hour at 50C. After cooling to 25C, 2.58 g of ¦-1-chloromethyl-4-phenylthio-benzene were added. The temperature was raised to 50C and maintained at that temperature 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 off and the residue was purified twice on a silica gel column, using ethyl acetate as eluant and testing the various fractions by TLC. The solvent was evapora-ted off the middle fractions to give 2.4 g of the desired base ; 0 as a yellowish oil, showing a single spot on TLC.
~- Analysis for C24H20N2C12OS

C% H% N% C1% S~
Calculated 63.30 4.44 6.13 15.57 7.04 Found 63.86 4.24 6.41 15.29 6~97 METHOD II
0.66 g of sodium hydride (50% in oil) were added at 20-30C
and under nitrogen atmosphere to 3.86 g of 1-(2',4'-dichloro-phenyl)-2-(N-imidazolyl)-ethanol ln 15 ml of dimethylsulphoxide (dried on calcium hydride).

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~0 The mixture was heated under stirring at 50-60C until gas emission was over. After cooling to 20-2SC, 0.5 g of potassium iodide were added and slowly a solution of 3.51 g of 1-chloromethyl-4-phenylthio-benzene in 4 ml of dimethylsulphoxide was dropped in. The mixture was .,j,,, .

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stirrea at 20-25C until addition of the l-chloro-methyl-4-phenylthio-benzene was over. The mixture was then poured into 1~0 ml of water and extracte~ with diethyl ether. To the etheric solution, after drying on anhydrous sodium sulphate, was added excess 4N nitric . .
acid solution in diethyl ether: the desired product precipitated as ni~rate, an oil which solidified on standing~ After standing for 20 hours, the etheric liquid was decanted off and the residue was crystallized '- 10 from ethanol. m e nitrate .hus obtained, not completely ` pure, was dissoIved in water and excess sodium carbonate .:~
'~ was added in order to iiberate the base which was then extracted with ethyl acetate. The base~obtained by '' filtration, was purified on a'silica gel column using' ethyl acetate as eluant.~' The combined fractions containing ~ the desired product were evaporated to dryness. The '~ 'residue was dissol~od in diethyl ether, again transforme~
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into the n~tra.e and crystallized from ethanol. ~
. . , ield: 3.1 g of a white crystalline power, melting at 134C.
. .
Analysis for C24H20N2C120 ~HN03 ~: C% H% N% Cl% S%
`1 ~ Calculated 55.61 4.08 8.11 13.68 6.18 , .
; Found 55.3Z 4.08 8.16 13.56 6.32 EXA~LE 2 2,4-Dichloro~ phenyl-~-(N-imidazolyl-methyl)-di~enzyl e her ~ j . .

1571~ -(I: R-C6H5) METHO~ I
A mixture consisting of 2.02 g of potassiu~ t-butylate in 30 ml o~ t-butanol was pre~ared at 20-25C and ~n nitrogen atmosphere. 3.86 g of 1-(2',4'-dichlorophenyl)--2-(N-imidazolyl)-ethanol, prepared according to Example B, were added. The solution was refluxed for 1 hour and then cooled to 20-25C. 3.03 g of 4-chloro-methyl-biphenyl were added, and the solution was again refluxed for S hours. Af.er aooling to 20-25C the whole was poured into water and the base extracted with ethyl acetate. Th~ ~xtract was washed with diethyl ether and the solvent evaporated off. The residue was dissolved in diethyl ether (80 ml) and left to stand overnight. ~he insoluble s~bstances were filtered off and the fil.rate was tr~*ed wi~h nitric acid dissolved in diethyl ether.
~n oil, which solidified on stanaing, was obtainea. The res~due, consis,ing of 2,4-dichloro-4l-phenyl-K-~--imidazolyl-methyl)-dibenzyl ether nitrate, was crystallized ~rom ethanol or ethyl acetate. A
product (4.3 g), shown to be pure on TLC and melting 140-141C, was obtained.
Analysis for C24H20N2C120~HN03 C% R% N~ Cl%
Calcula.ed 59.25 4.35 8.64 14.57 Found 59.17 4.14 8.61 14.46 .
..

" l~lS718 METHOD I (a?
To a solution of 0.37 g of sodium metal in 20 ml of n-propanol,

4.1 g of (1-(2',4'-dichlorophenyl)-2-(N-imidazolyl)-ethanol were added and the mixture was refluxed for two hours under stirring. After cooling to room temperature, 0.5 g of potassium iodide and 3.25 g of 4-chloromethyl-biphenyl were added under stirring and the mixture was again refluxed. At the end of the reaction, the mixture was'filtered off and washed wlth ethanol. The filtrate was evaporated to dryness ~0 and the residue dissolved in diethyl ether. The insoluble - residue was filtered off and the clear etheric solution thus obtained was treated with a mixture of nitric acid and diethyl ether. The 2,4-dichloro-4~-phenyl-C~-(N-imidazolyl-methyl)--dibenzyl ether nitrate so formed was crystallized from ethanol~
A product ~2.1 g) having the same characteristics as that prepared according to the previous method and showing a single spot on TLC was obtained.

METHOD II
, 0.66 g of sodium hydride were added, under nitrogen atmosphere '` ~0 and at 20-25C, to a solution of 3.86 g of 1-(2',4'-dichloro-phenyl)-2-(N-imidazolyl)-ethanol in 15 ml of dimethylsulphoxide (dried on calcium hydride). The mixture was heated at 50-60C

.;~ until gas emission was over. The mixture was then cooled to 20-25C, 0.5 g of pot'assium iodide were added and a solution of , ~
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lil57~3 ` -16-3.03 g of 4-chloromethyl-b~phenyl in 7 ml of dimethylsulphoxlde (dried on calcium hydride) was droppea in. The whole was stirred for about 20 hours at 20-25 &
an~ tnen pour~d into wa~er. The product was extracted with ethyl acetate and then treatea as descrlbed in Me.hod I. Yield 4.6 g.

.
Salts of 2,4-dichloro-4'-phenylthio~ (N-imidazolyl-methyl)--dibenzyl ether were prepared by reacting the free base, di-ssolved in ethanol, with an alconol solution of the desired acid ana subseauently crystallizing the salt so obtained from a suitable solvent. The free base was prepared according ~o Example 1, Method I, or by liberation ~rom its nitrate, prepared according to Method II, by treatment wit~ sod~um carbonate, extraction with diethyl ether and evaporation.

In Table IV the soIvents of crystallization, the elementai analysis and the ~elting points of some salts are reported.

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In Table V are listed the same data for some salts of 2,4-dichloro-4'-phenyl~ N-imidazolyl-methyl)-~ibenzyl ; ether, obtained using the methods described above.
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Pharmaceutical antifungal and antibacterial formulations, comprising active compounds according to the invention at concentrations of from O.S to 5% by weight, preferably from 1 to 3% by weight, in admixture with pharmaceutically acceptable diluents or..carriers, were prepared. Examples of the composition of an ointment, a powder, a glycolio solution and a gel are given below.
Ointment 2~4-aichloro-4~-phenylthio~ N-imidazolyl-methyl)--dibenzyl ether nltratP 2 g Lanolin 20 g Vaseline q.s. to 100 g Glycolio solu'ion 2,4-dichloro-4~-phenyl'hio-~-(N-imidazolyl-methyl~- :
-dibenzyl ether nitrate 2 g Propylene Glycol ~.s. to 100 ml '.

Powder :: 2,4-dichloro-4~-phenylthio-~-~N-imidazolyl-met~yl~--dibenzyl ether nitrate 2 g Lanolin 1.5 g Soybean lecithin 2 g Talc q.s. to 100 g . .
. ' ~ 157~3 G
2,4-dichloro-4'-phenylthio-K-(N-imidazolyl-methyl)--dibenzyl ether nitrate 2 g Carbopol . 2 g Water 2 g Po}yethylene glycol q.s. to 100 g Triethanolamine q.s. to about pH 3 ~: ' . ' ' ' ,, , f , . ; . ,, :,, : ,,.:; . .: .,: . '::.

Claims (6)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a compound of the general formula I, I

wherein R represents a phenyl or phenylthio group, and pharma-ceutically acceptable acid addition salts thereof, which comprises condensing 1-(2',4'-dichlorophenyl)-2-(N-imidazolyl)-ethanol with a halobenzyl derivative of formula V, V .

wherein R has the meaning previously ascribed to it and X represents a chlorine or bromine atom, and isolating the product thus obtained as free base or reacting it with a pharmaceutically acceptable salt-forming acid.

2. A compound of the general formula I and its pharmaceutically acceptable acid addition salts whenever prepared by the process of claim 1 or by any obvious chemical equivalent thereof.

3. A process for preparing 2,4-dichloro-4'-phenylthio-.alpha.-(N-imidazolyl-methyl)-dibenzyl ether or a pharmaceutically acceptable acid addition salt thereof, which comprises condensing 1-(2'-4'-dichlorophenyl)-2-(N-imidazolyl)-ethanol with l-chloro-methyl-4-phenylthio-benzene and isolating the product so formed or reacting it with a pharmaceutically acceptable salt-forming acid.

4. 2,4-dichloro-4'-phenylthio-.alpha.-(N-imidazolyl-methyl)-dibenzyl ether and its pharmaceutically acceptable acid addition salts whenever prepared by the process of claim 3 or by any obvious chemical equivalent thereof.

5. A process for preparing 2,4-dichloro-4'-phenyl-.alpha.-(N-imidazolyl-methyl)-dibenzyl ether or a pharmaceutically acceptable acid addition salt thereof, which comprises condensing 1-(2',4'-dichloro-phenyl)-2-(N-imidazolyl)-ethanol with 4-chloro-methyl-biphenyl and isolating the product so formed or reacting it with a pharmaceutically acceptable salt-forming acid.

6. 2,4-dichloro-4'-phenyl-.alpha.-(N-imidazolyl-methyl)-dibenzyl ether and its pharmaceutically acceptable acid addition salts when-ever prepared by the process of claim 5 or by any obvious chemical equivalent thereof.