IL41448A - Alpha alpha-diphenylimidazole-2-methanol derivatives their preparation and pharmaceutical compositions containing them - Google Patents

Description

their and compositions containing them This invention relates to useful hanol3 and addition salts to processes for their and compositions The new of the invention are those the general for more wherein are the same of different and each represents a hydrogen or halogen atom or a trifJLuoromethyl than lydrogen or tertiary butyl provided at least one them is trifluoromethyl or tertiary Rll and R12 are the same or different and each represents a hydrogen a lower alkyl a phenyl group or a substituted phenyl group and R13 hydrogen lower alkoxymethyl benzyloxymethyl or a benzenesulphonyl group optionally substituted with one or more alkyl lower phenylalkyl or phenyl methyl optionally substituted in the phenyl moiety with one or more halogen atoms or alkyl except unsubstituted benzyl and benzyloxymethyl acid addition The term with respect to alkyl and alkoxy The a of formula I have valuable therapeutic show the group compounds defined by formula those in which represents a hydrogen atom when and are atoms or one or both of them is an alkyl a lower alkoxymethyl group or a the alkoxymethyl group in which the phenyl moiety is optionally underlined meanings substituted by one or more halogen atoms or alkyl except benzyl have analgesic activity which makes the compounds useful in and the relief of pain in humans and They also optinally substitu possess antiphlogistic and antipyretic uted with one or the compounds of formula I more alkyl which R13 represents a lower alkyl a phenylalkyl groups group optionally substituted in the phenyl moiety by one or more halogen atoms or alkyl an group or a benzenesulphonyl group in which the phenyl moiety is optionally substituted by one or more alkyl or when one or both of and R12 is a phenyl group or a substituted phenyl group a lower alkoxymethyl group or a phenyl alkoxymethyl group optionally substituted in the phenyl moiety by one or more halogen atoms or alkyl groups and the other are as defined above and their acid addition are The most active compounds are those in and both are a chlorine and are hydrogen atoms or one of them is group R and R10 are hydrogen Specifically preferred compounds are and and their Within the above defined group of active preferred compounds are those in which is a gen atom or a or tertiary butyl is a hydrogen or halogen atom or a trifluoromethyl or tertiary butyl group and and 2 are drogen Specifically preferred are the compouhds in which both and are a chlorine atom or is a t group and is a hydrogen The most active and therefore most compounds are 2a methanol and 1 usually divided into two main groups according to tue type of activity A er best known representatives these groups are usually referred to as the morphin analgesics and the Analgesics of the first type exhibit the stronger activity but are known to disadvantages due to side effects such as depression of physical dependence and intestinal Analgesics of the second type are also known to cause eactions which due to the wide variety of structures of commonly classified within this group may vary from gastric lesions for the acid derivatives to agranulocytosis for The analgesic activity of the compounds of formula I has clearly been established from the results obtained in one or more of the following Test according to Carrol and using rats Carrol and Pharmacodyn 383 Test according Randall and using rats and Test according to d using rats mour and using mice and 4 Test enables a certain differentiation to be made between analgesics of morphine the aspirin in Test analgesics of both types show Test gives positive results for very strong analgesics morphine Test is not very specific In all the above mentioned test the compounds indicated above as preferred analgesics show strong activity both upon oral and parenteral The following results were obtained with chlorophenyl referred to as dose which raises the pain threshold by of Compound A in the Randall Selitto test animal body weight when administered orally the dose the dose protects of the of Compound in the Smith test 21 animal body weight for morphine it ic A special test has been performed with in order to determine whether the compound might e hibit physical dependence Test according to Saelens et Saelena et Pharmacodyn 190 affording a quick check for potential physical dependence as is found for When Compound A was with a number of analgesics belonging to the morphine the results were positive for these analgesics and negative for Compound The following observation tests have been performed in order to establish whether the compound causes certain effects inherent with the administration of Observation the behciviour of dogs upon an analgesicn It is that morphine causes dogs to vomit and also causes a depression of Neither of these reactions was caused by a slight stimulation and antagonism of narcosis and narcosis induced respiration depression was observed after administration of the compoundβ Observation the behaviour o of an Morphine causes such excitement cats that they are completely no excitement at all was caused by administration of Compound Observation the of administration of an Morphine sedates rats but activation is noted upon administration of Compound The a algesic potency the most active of the present invention is comparable with that of morphin j as the compounds do not exhibit the serious side effects of morphine they should not be called third For use as therapeutics the compounds general formula I may be used such or as acid addition salts which are not harmful to animal organism when used in therapeutic doses Such acid addition salts may be derived from inorganic such as the hydrohalic acids hydrochloric and and sulphuric and organic acids such as fumaric and acids The dosage and method of administration will depend on the mammalian species and the condition Eor use as anorexiants in adult humans the oral dosage will be from 25 to 200 mg per person The compounds with analgesic activity are suitably administered orally to humans in daily doses ranging 5 to mg per Injectable solutions for analgetic purposes will generally have a concentration ranging from to 2 According to a feature of the the of general formula I are prepared by reacting a compound of the general 5 represents an alkali metal atom or a reactive such as a group in which X represents a halogen chlorine or 4 is identical to except a hydrogen or a group beyond the scope of Ri that is easily removable for oxidation or the group or atom from the resulting complex by hydrolysis to yield a desired alcohol general formula I wherein represents a hydrogen atom or a ponding compound carrying a substituent group on a gen atom of the imidazole nucleus when in the latter case the substituent group is not identical to in the desired removing by methods known per se said substituent group if introducing group within the definition of by a method known per The reaction between the compounds of formula II and III is ferably carried out in an inert anhydrous organic solvent or solvent mixture furan and diethyl When represents an alkali metal atom it is preferred to perform the reaction at temperatures below when 5 represents a group solution of the reactants is preferably It should be understood that the definition of cludes removable groups encompassed by the definition of and when such a the compound obtained from the reaction of formula II and III may be both an intermediate and an end Examples of easily removable groups represented by in compounds of the general formula II are sulphonyl and alkoxyalkyl the me thoxymethyl group bein erred Such groups can all be by thereby affording compounds of general I wherein represents a hydrogen take place spontaneously when the product resulting from the reaction between compounds of the general formulae II and III is Active removal of a group hydrolysis may be effected by heating an aqueous solution of a resulting tertiary alcohol of the general the various symbols are as hereinbefore to which some acid or been When a group removable by vinyl or the group may be removed from the resulting tertiary alcohol by with a potassium to which some aqueous hydroxide solution has been Removal of the allyl group by oxidation is only possible when the double bond is previously shifted to the the allyl group becomes In some cases the shifting occurs concurrently with the introduction of the the appropriate imidazole compound to obtain a compound of especially in those instances where a lithium atome Otherwise the shifting is to bo brought about by previous treatment with a strong tertiary butoxide in an organic dimethyl suitable for the hydrogenation sodium with liquid may interfere with any halogen substituents on the phenyl Generally speaking ouch halogen atom are more tightly bound the smaller their atomic number and consequently use of the benzyl group a protective to when group is only recommended when the symbols than hydrogen a atom or a or The introduction of a group in a compound of formula I in which is a atom is ferably carried out by reacting the compound of formula I with appropriate alkyl aikoxymethyl substituted or unsubstituted phenylalkyl stituted or unsubstituted or substituted or unsubstituted benzene sulfonyl such as a chloride or The reaction is preferably carried out in an organic solven in the presence of a base sodium and a catalytic amount of sodium iodide or potassium Compounds of the general formula II wherein R1 a lithium atom may be prepared by reacting under a nitrogen a lithium donating for e ample with a compound of the general wherein as hereinbefore The reaction is preferably carried out in an inert anhydrous organic solvent or solvent are immediately caused to react upon a compound of the general formula III without previous isolation or The choice of groups R14 is restricted to groups as are incapable of reacting with atoms or groups represented by When or R12 is a substituted or phenyl the compound of formula I in which is a hydrogen atom is easily decomposed by The use of a protecting group that is to be removed by hydrolysis should therefore be avoided in those According to another feature of the the compounds of the general formula I prepared by reacting a compound of the general VI is a hydrogen atom or a group within the tion of or R14 and the other are as hereinbefore a compound of the general formula R2 R1 the are as hereinbe ore preferably under reaction conditions similar to those hereinbefore cribed with respect to the reaction between compounds of mulae II and removing the atom or group from the sulting complex by hydrolysis if replacing by substituent within the definition of as described The starting materials of formula VI may be prepared by wherein R16 represents an alkali metal atom or a group X represents a ably chlorine or and and are as hereinbefore with a nitrile of the general are as hereinbefore if removing the group and introducing a group by methods hereinbefore ferred reaction conditions are those described for the reaction between compounds of formulae II and III when in formula II represents an alkali metal atom or a group According to another feature of the the of general formula I that are symmetrically substituted in the phenyl the pounds of the general the various are as hereinbe ore at least one of R1 R2 R R and R bein halo en R 7representc a halogen an or group or a group O in is a metal and R12 and R14 are as hereinbefore with a compound of general formula hydrolysing the resulting o to yield a desired tertiary alcohol of general ormula X which represents hydrogen atom or a corresponding compound carrying a substituent group a nitrogen atom of the imidazole nucleus when in the latter case the substituent is not identical to the group in the desired by methods known per se said substituent if introducing a group within the definition of by a method known pe The reaction is preferably carried out heating the pound of formula XI with a molar quantit of the compound of formula in an inert anhydrous organic solvent tetrahydrofuran and diethyl The group R14 may be removed as hereinbefore Compounds of general formula XI may be prepared by reacting an imidazole derivative of the formula wherein R represents a lithium a compound of the general and 4 are as wit carbon to a salt of an acid of the general and are as hereinbefore and if converting the latter into another compound of formula in manner known For example the compound of formula XIII may be reacted with an ary alide or halide to obtain an aryl or aralk ester or with a to obtain a or with a thionyl halide to obtain an acid halide It be understood when R14represcnts an the double bond may bo shifted to the concurrently with the preparation of the compound of formula XII as described above for compounds When an or the compound of formula XI may also by reacting a of V halogenofor ate o the general j I o Hal represents a halogen atom represents i an aryl or aralkyl T e reaction is carried out by heating the reactants in a polar as or acetonitrile in the presence of a strong triet According to another feature of the invention the compounds of formula I in which a lower alkyl for the a lower alkoxyraethyl a phenylalkyl group lined meanings except benzyl substituted in the phenyl moiety by one or more halogen and methyl atoms or alkyl an alkenyl a optionally substituted alkoxymethyl group in the phenyl with one or more alkyl moiety by one or more halogen atoms or alkyl or a groups benzenesulphonyl group which the phenyl moiety is optionally substituted by one or more alkyl are prepared by introducing by a method known se the substituent corresponding compound in which is a hydrogen A suitable method is the reaction with an appropriate halide as hereinbefore described 14 The following Examples illustrate the preparation of compounds of the present EXAMPLE I Preparation of a solution of of imidazole Staab and in 300 of anhydrous tetrahydrofura and 150 of anhydrous diethyl ether at a temperature of to under a nitrogen atmosphere were added 91 of a solution of in dissolved in 150 of anhydrous diethyl Upon completion of the the mixture was kept at a temperature of to for one Next and under identical conditions as to temperature of in 200 of anhydrous tetrahydrofuran and 100 of anhydrous diethyl ether were added and the mixture was kept under the same conditions for another Cooling was stopped and the mixture was allowed to reach ambient temperature in It was then poured out into about 250 of a sodium chloride The aqueous layer was separated and the organic solvents layer was washed with of a sodium chloride dried and The residual oil was brought to crystallisation by addition of a very small amount of diethyl Purification to which some acetone Melting point of the product was B Prepar tion of A mixture of of 160 o 2 hydrochloric acid solution and about 500 of water was boiled under reflux for 5 After cooling the mixture made alkaline by addition of The precipitated solid treated with carbon in boiling toluene and crystallised from point of the product was II Preparation of Using the procedure described in Example but substituting an equivalent amount of benzophenone Picard et 20 B for the an oil obtained from which the compound crystallised upon addition of some cold diethyl It purified by boiling with petroleum ether range and next with diethyl ether followed by crystallisation frora Its melting point was Preparation of 34 of hydrochloric acid solution and 225 of water boiled under reflux for 5 After the mixture was made alkaline by addition of ammonia The base obtained was crystallised from isopropyl alcohol its melting point was Preparation of sulphonyl Using the procedure described in Example but substituting an equivalent amount of for the a reaction mixture obtained which poured into a mixture of acetic acid and The organic solvents layer was dried and The residual oil brought to crystallisatio by addition of some diethyl The solid was separated and the filtrate concentrated and again subjected to the same This course of action was repeated till five batches of solid were the last three contain the desired product in impure They were mixed and boiled with petroleura ether range Final carried out by crystallisation from Melting point of the product Preparation of 6 of concentrated hydrochloric acid 6 of water and 60 of acetic acid was boiled under reflux for The desired compound was crystallised from warm toluene containing small amount of isopropyl alcohol and thereafter frora boiling diethyl ether to which tetrahydrofuran had been Melting point of the product was 15 of the compound were dissolved in acetone and a solution of hydrogen chloride in ethanol was After addition of a small amount of petroleum ether range a precipitate was consisting of the The salt was washed with diethyl ether and crystallised from a mixture of ethanol and petroleum ether range Melting point above with decompositio EXAMPLE IV Preparation methanolo To of lithium in 150 of anhydrous diethyl ether in a nitrogen atmosphere of butyl bromide in 100 of diethyl ether added at a temperature of Upon completion of the reaction after 2 the solution was filtered and added to of dissolved in 450 of anhydrous furan and 225 of anhydrous diethyl ether at a dissolved in 300 of anhydrous tetrahydrofuran and 150 of anhydrous diethyl were added at The mixture was kept at a temperature of to for 3 allowed to return to ambient temperature and washed twice with The organic solvents layer was and 500 of glacial acetic 50 of chloric acid solution and 50 of water were The mixture was boiled under reflux for Glacial acetic acid was removed as completely as possible and water and diethyl ether were The ether layer containing unreacted ketone and the aqueouo oily layer containing the desired compound as the hydrochloride salt were The aqueous layer was made alkaline by addition of sodium hydroxide solution and extracted with diethyl The ether layer was acidified with hydrochloric acid solution and extracted with The aqueous layer was treated with activated made alkaline with 2 sodium hydroxide solution and again extracted with diethyl ethe The diethyl ether layer and concentrated and the solid obtained crystallised from isopropyl Melting point of the product was EXAMPLE V Preparation of A solution of of anhydrous was added to Grignard prepared from of magnesium and of in 150 of anhydrous The reaction mixture boiled under reflux for half an cooled and poured onto a mixture of ice and hydrochloric The solution neutralised with concentrated ammonia solution and extracted with The organic solvents layer was dried and the residue was crystallised from isopropyl Melting point of product was EXAMPLE VI Preparation of To 58 of in 200 of anhydrous tetrahydrofuran 100 ge of benzyl chloromethyl ether were added with stirring at a temperature of 0 to Cooling was discontinued after one The mixture was left standing overnight and thereafter The residue was treated with hydrocliloric acid solution and with diethyl The acidic aqueous layer was made alkaline wit potassium carbonate and extracted with chloroforme The chloroform layer was treated with activated dried and The residue was subjected to Boiling point Preparation of To a solution of of of a suspension in hexane dissolved in 75 of anhydrous diethyl ether was added with stirring at Thereafter a solution of 6 ge of in 100 of anhydrous tetrahydrofuran and 50 of anhydrous diethyl ether was added at room The mixture was kept for three hours and then extracted with a dilute acid The acidic aqueous layer was made alkaline with 2N sodium hydroxide solution and extracted with diethyl Fart of the ether was removed by evaporation and the residue washed with The ether solution was again concentrated and the desired compound crystallised from a mixture of toluene and petroleum ether range Melting point of the product was 5 C Preparation of About 17 of was boiled under reflux in a mixture of 85 of glacial acetic 5 of water and 8 5 of concentrated hydrochloric acid Acetic acid was removed by evaporation and the was liberated by addition of 2N sodium hydroxide It was crystallised from isopropyl Melting point of the product was VII Preparation of To a solution of of and of in 150 of anhydrous 51 of solution in hexane was added with stirring over a period of about one hour and at a of Stirring was continued another 2 hours at Cooling was discontinued and of benzophenone in 150 of anhydrous tetrahydrofuran was added The mixture was stirred for 6 hours at temperature and decomposed by addition of 15 of Lithium hydroxide was removed by filtration and the filtrate was A hydrochloric acid solution was added and the mixture was extracted with liberal amounts of diethyl The acidic aqueous solution was made alkaline by addition of potassium carbonate and extracted diethyl toluene and ethyl The organic solvent solutions were dried and concen The solid was purified by crystallisation from its melting point was Preparation of methanol Using the procedure described in Example VIC but substituting an equivalent amount of c lorop the was Melting point of the product was EXAMPLE VIII Preparation of Using the procedure described in but substituting an equivalent amount of benzophenone for the was Its melting point was 149 150 after crystallisa ion from B β Preparation of Using the procedure described in Example VIC but substituting an equivalent amount of phenyl for the phenyli was Its point was after crystallisation from EXAMPLE IX Preparation of Using the procedure described in IA but substituting an equivalent amount of tetrahydro enzene ether for the benzophenone f sulphonyl was Its melting point after crystallisation isopropyl Some unreacted ketone may recovered by addition of diethyl ether to the residue P eparation of Using the procedure described in IB but an equivalent amount of a bro methanoi for the Its melting point Ί after crystallisation from isopropyl of Using the procedure described in IA but substituting an equivalent amount of phenone A for the Its melting point after crystallisation toluene Preparation of Using the procedure described in Example IB but substituting an equivalent amount of pheny methanol the was Its point was after crystallisation from isopropyl XI Preparation of Using the procedure described in Example IA but substituting an equivalent amount of benzophenone for the methanol Its melting point was after crystallisation from a mixture of diethyl ether and petroleum ether range Preparation of Using the procedure described in Example IB but substituting an equivalent amount of for the ethanol Its melting point was Preparation of methanol as the hydrogen Using the procedure described Example V but substituting an equivalent amount of for the was obtained and purified by crystallisation from a mixture of toluene and petroleum ether range Melting point compound was converted into the maleate by dissolving it in diethyl ether and adding a solution of acid in the same salt was crystallised twice from a mixture of alcohol and diethyl ether and thereafter from a o acetone and diethyl Its melting point Preparation of hanol In the course of one ml of a butyl lithium solution in were added with under a nitrogen atmosphere at to a solution of g of imidazole and g of ethylenediamine in ml of anhydrous te rahydrofura Stirring was continued for another two hours at and then g of 4 obenzophenone in 00 ml of anhydrous te trahydrofuran were added The reaction mixture was kept standing overnight at room temperature and then 15 ml of water and some pieces of solid carbon dioxide The mixture was filtered ted with a mixture of diethyl ether and 2N hydrochloric The aqueous phase was made alkaline with potassium carbonate and extracted with diethyl The extract was dried over sodium sulphate and The due was extracted again with 2N hydrochloric acid and ethyl ether and the aqueous phase was made alkaline again with potassium The solid matter formed was tered off and dissolved in boiling petroleum ether range The undissolved material was filtered off and the petroleum ether was distilled The residue was taken up in a very small amount diethyl The solu tion was cooled in a mixture of carbon dioxide and acetone and the precipitate was filtered was Melting point XIV Preparation of Using the procedure of but substituting an equivalent amount of benzophenone for the f was point Preparation of Using the described in Example VIC but substituting an equivalent of the Ileltin oint Preparation of To a solution of of h and of of anhydrous tetrahydrofuran a prepared from of lithium and of butyl broraide in kO of anhydrous diethyl added with stirring at temperature of and under a nitrogen After 2 8 of in 60 of anhydrous added at The solution was kept standing overnight at room temperature and it was then decomposed with 50 of water and extracted with diethyl The extract was dried over sodium sulphate and the solvent was distilled The benzophenone starting present in the was dissolved by boiling with petroleum ether range and The residue then dissolved in a mixture of 75 of acetic of water and 75 of concentrated hydrochloric and the solution was refluxed for 5 The liquid was distilled off and the residue extracted a mixture of hydrochloric acid and diethyl The ethereal layer was dried over sodium The sodium sulphate washed with The solutions ether and acetone combined and the solvents distilled The residue was with diethyl ether and filtered with There was obtained point Preparation of Under a nitrogen atmosphere and at a temperature between and a butyllithium prepared from of lithium and of butyl bromide in 130 of anhydrous diethyl was added to a solution of of and of in 250 of anhydrous After 2 hours a solution of 22 of in 150 of anhydrous tetrahydrofuran were added dropwise to the reaction mixture at a temperature and The reaction was stirred for one hour at and it then standing overnight at room Then 20 of water were added to the reaction and the solvents were distilled The residue dissolved in dilute liydrochloric acid and the solution was with diethyl ether and made alkaline with potassium The solid substance formed filtered off and dissolved in The solution and the residue was crystallised or Melting point 152 Preparation of A mixture of 13 of 100 of glacial acetic 10 of concentrated hydrochloric acid and 10 of for three After the liquid was distilled off and the as dissolved in a small amount of The solution was made alkaline with sodium solution and the alcohol was The remaining aqueous phase then extracted with diethyl The extract dried over sodium sulphate and the ether distilled The residue was crystallised from toluenic solution being decolorised with active There was obtained i Melting point EXAMPLE Preparation of ethanol A butyllithium prepared from of lithium and of butyl bromide in 70 of anhydrous diethyl was added at to under a nitrogen atmosphere to a solution of and of in anhydrous The reaction mixture was kept standing for 2 hours at and then 11 0 of in 75 of anhydrous tetrahydro added The temperature was Maintained at for one hour and then the reaction mixture was allowed to attain room temperature 10 of water and solid carbon dioxide added and the solvent was distilled The residue was dissolved in dilute hydrochloric the solution with diethyl ether and made alkaline with potassium The solid substance formed was iltered off and dissolved in The washed with dried over sodium sulphate and concentrated by evaporation of the The residue crystallised from isopropyl Melting point Preparation of phenyl etha ol mixture of 9 of 70 of glacial acetic 7 of concentrated hydrochloric acid and 7 of water for After the liquid was distilled off and sodium solution and a small amount of ethanol were added to the reeidue alcohol distilled and the aqueous phase was extracted diethyl The ethereal solution was washed with water and dried over sulphate and the solvent was distilled The residue was crystallised a mixture of toluene and petroleum ether range and subsequently from was Melting point Preparation of To a solution of of s in o anhydrous tetra ydrofuran 92 of butyllithium solution in was added with stirring under a nitrogen atmosphere at The reaction mixture was stirred for 2 after which anhydrous carbon dioxide gas was After being stirred for one the mixture was poured onto solid carbon The lithium salt of ca acid The salt was filtered off and washed with diethyl To a suspension of of the lithium salt and 35 of triethylamine in 150 of anhydrous of was added with stirrin under a nitrogen The mixture was for 20 hours then 300 of anhydrous toluene was added and stirring continued another hour The lithium salts formed were filtered off and the filtrate was concentrated by evaporation of solvent The containing the trimethylsilyl of was in 100 of anhydrous tetrahydrofuran and added dropwise to a re luxing solution of a Grignard compound prepared from of magnesium and of in of anhydrous was for one hour and then decomposed in ammonium chloride The precipitate was filtered off and the filtrate was extracted with s diethyl The ethereal phase was extracted with 21T hydrochloric acid and the acid extract was made alkaline with ammonia and extracted with diethyl The ethereal extract dried over sodium sulphate and the solvent distilled The residue w twice crystallised from isopropyl Melting point The compound was converted into c as described in Example XIX preparation of the ester of At a temperature of of ethyl chloroformate added to a solution of 28 of imidazole and 25 of in 125 ml0 of anhydrous The mixture was stirred at and then kept standing for two days at room The precipitated triethy hydrochloride was filtered off and washed with diethyl The filtrcite was concentrated by evaporating the solvents and the residue dissolved in diethyl The solution was dried over sodium the ether distilled off and the residue was The ethyl ester of acid was Boiling point Preparation of The wa3 dissolved in 50 of anhydrous tetrahydrofuran and added to a refluxing solution of a Grignard compound prepared from o magnesium and of in 80 of anhydrous The mixture was refluxed for one hour and then decomposed in an chloride The precipitate was filtered off and the filtrate was extracted with diethyl The ethereal phase wa3 extracted with hydrochloric acid and The residue was twice crystallised from isopropyl was Melting point A Preparatio of At a temperature of 500 of acid and of sodium hydroxide added to a solution of 31 of and in 150 of Then 29 of were added which made the temperature rise to The reaction mixture was refluxed 6 hours and The filtrate concentrated by distilling off the solvent and the residue was Boiling point Melting point of the hydrogen oxalate Preparation of is At a temperature of and under a nitrogen atmosphere of solution i were added with stirring to a solution of 28 of and 28 of tetramethylethylenediamine in 200 mi of anhydrous tetrahydro After 2 hours 50 of in 250 ml of anhydrous tetrahydrofuran were added at After bein t standing overnight the reaction mixture concentrated by distilling off the The residue was treated with hydrochloric acid and diethyl which resulted in the formation of an organic and aqueous layer an oily intermediate The aqueous and oily layers were made alkaline ammonia and extracted with diethyl The extract was dried over sodium sulphate and the solvent was distilled The oily residue was thrice recrystallised from isopropyl was Melting point Preparation of henyl To a solution of of of in 300 of anhydrous 14 of in added stirring at and under a nitrogen atmosphere over the course one Stirring was continued for 2 hours under the same after which a solution of 40 of in 300 of anhydrous tetrahydrofuran was added The reaction mixture was stirred for after which the cooling means was removed and stirring was continued overnight under the nitrogen The lithium complex obtained was then decomposed 15 of precipitate was filtered the filtrate was dried over sodium sulphate and the solvent was distilled The solid residue was twice crystallised ethyl acetate to which a small amount of ethanol had been rnethanol was Melting point Preparation of henyl To a solution of of in 180 of pyridine and 180 of inethanolic sodium 360 of aqueous potassium permanganate solution were added at 20 to After the addition was of solid potassium permanganate were added permanganate The manganese was filtered The filtrate was treated with active concentrated almost to complete dryness and poured into The solid substance filtered dissolved in war decolorised with active charcoal and precipitated by addition of The precipitate recrystallised from a mixture of acetone and Melting point EXAMPLE XXII Preparation of This compound was prepared by the procedure of 0 19 of 114 25 of butyllithium in 48 of The product was twice crystallised from a mixture of ethyl acetate and petroleum ether range Melting point Preparation of This compound prepared the procedure described Example XXI B using of 820 of aqueous potassium permanganate and 11 of solid potassium permanganate permanganate After the manganese dioxide had been filtered the excess of permanganate in the filtrate reduced to manganese dioxide by addition of sodium The precipitate was filtered off and the organic solvents were distilled The remainder of the filtrate poured into water and the oil obtained dissolved in diethyl The solution was washed four times with water and dried over sodium sulphate and the solvent was distilled The resulting oil was taken up in as little acetone as possible and brought to crystallisation by adding petroleum ether range Melting point Preparation of This compound was prepared by the procedure indicated in Example XXII using the following 10 of of butyllithium in 3 of and of The product was crystallised from ethyl Melting point Preparation of This compound was prepared by the procedure indicated in Example XXII using 8 of 250 of potassium permanganate solution and of solid potassium permanganate permanganate After removal of manganese dioxide and excess the organic solvents were distilled off and the remaining liquid was into precipitate was which was filtered off and crystallised from a mixture of isopropyl alcohol and petroleum ether range Melting point XXIV Preparation of methyl To a solution of of midazole and of anhydrous tetrahydrofuran 51 a lithium solution in added over the course of one hour at and under a nitrogen After the addition was stirring was continued for another two The cooling means then removed and of of anhydrous were added The mixture was stirred for 6 hours at room temperature and it was then decomposed with 15 of The precipitated lithium was filtered off and the filtrate was concentrated by distilling off the 2 chloric acid was added to the after which the mixture extracted with diethyl The aqueous phase made alkaline with sodium hydroxide The precipitate formed filtered washed with water and twice crystallised from a mixture of isopropyl alcohol and range 40 Melting point EXAMPLE Preparation of imidazole hydrogen At a temperature of 500 of picrinic acid and 22 of sodium hydroxide were added to a suspension of 83 of i Bredereck and 80 in 600 of Then 41 05 mo of ere added dro with which made the temperature rise to The reaction mixture refluxed for 2 hours and it wa then with water and diethyl The ethereal phase was dried over sodium sulphate and the solvent distilled An ethereal solution of oxalic added to the the precipitate was filtered off and four times crystallised from xsopropyl Melting point Preparation of hydrogen Under a nitrogen atmosphere and at a butyllithium prepared from of lithium and of butyl in 50 ml of diethyl was added stirring to a solution of of imidazole and of in 100 of anhydrous The mixture was stirred for 2 hours and then of dichlorobensophenone anhydrous furan were added The reaction mixture wa3 kept standing overnight and it then poured onto ice and extracted with diethyl extract was dried over sodium sulphate and the solvent distilled The residue was thrice crystallised from ether range solution of of the substance in 100 of glacial acetic 10 of concentrated hydrochloric acid and 100 of was refluxed for 5 liquid distilled off and ethyl alcohol was added to the residue until a clea solution The solution with ammonia and extracted with diethyl The extract dried over sodium sulphate and the solvent distilled The residue wa dissolved in diethyl and tho solution extracted with hydrochloric extract made alkaline with ammonia and extracted with diethyl The ethereal solution dried over sodium sulphate and the ether distilled To residue an ethereal solution of maleic acid The precipitate filtered off an thrice crystallised from isppropyl hydroge was Melting point EXAMPLE Preparation of mothyl Under a nitrogen atmosphere and at 38 of a butyllithiura solution in were added over the course 45 minutes to a mixture of mol of tetramothylethylenediamine and 7 of in 100 of anhydrous The mixture stirred for another two the same conditions and then g of in 100 ml of anhydrous ran were added After the addition was the mixture stirred for 2 hours posed with of the precipitate was filtered off and the filtrate was dried over sodium sulphate and The solid residue was crystallised from isopropyl alcohol methoxymethyl was Melting point Preparation of e A mixture of g of g of sodiumhydroxide mg of picric acid and ml of acetonitrile was heated to under Then g of freshly distilled allyl chloride were added The mixture was for 5 hours and The filtrate was concentrated and water and diethyl ether were added to the The ethereal phase was washed with dried over sulphate and The residue was was Boiling point Preparation of In the course of half an hour ml lithium in exane were added dropwise under a nitrogen atmosphere at to to a solution of g of and g of in 150 ml of anhydrous The mixture was stirred for another two hours under the same Then a solution of g of 4 in 100 ml of anhydrous was added dropwise and after completion of the the mixture was stirred for other The cooling means were removed and the mixture was kept standing overnight at room temperature under the nitrogen The reaction mixture was then posed by stirring half an hour with 20 ml of The organic phase was washed with dilute hydrochloric acid until it was clearly washed with water and dried sodium The solvent was tilled off under The residue was ved in a small amount of diethyl ether with a little By addition of petroleum ether range a solid was which was filtered off and twice crystallised from isopropyl 5 1 was Melting point Preparation of 4 methanol At 4 ml of a aqueous permanganate lution were added dropwise in the course of one hour to a solution of 1 6 7 g of in a mixture of 220 ml of pyridine and 2 20 ml of 0 5N ethanolic sodium Then 4 4 g of potassium permanganate were added in small portions to reaction The reaction ture was kept standing overnight at room temperature The manganese dioxide formed was filtered the filtrate was decolorized with sodium metabisulphite and active charcoal and the solvent was distilled off under reduced The residue was suspended in The aqueous phase was extracted with diethyl the extract was dried over sodium sulphate and The residue was dissolved in as little as possible boiling isopropyl leum ether range was which caused 4 to The product was crystallised from a mixture of propyl alcohol and petroleum ether range Melting point Preparation of 2 ichiorophenyl methoxymethyl To a solution of 6 g 0 0676 of dazole and g 0 0676 of lenediamine in ml of anhydrous tetrahydrofu an were ded dropwise a nitrogen atmosphere at 43 ml 0 070 of lithium solution in solution was stirred at for one Then 23 g 0 0676 of 2 2 4 4 as and Yuan Ting 5 6 40 50 ml of anhydrous were added The was stirred another hour at and one night at room temperature The reaction mixture was decomposed with ml of water and extracted with diethyl The organic phase was dried over sodium sulphate and concentrated and the residue was extracted with a mixture of hydrochloric acid and diethyl ether on which a solid substance was which was crystallised from a mixture of isopropyl alcohol and diethyl The product appeared to be the hydrochloride of the desired contaminated with the compound methoxymethyl Ammonia diethyl ether were added to liberate the The ethereal was concentrated and the residue times crystallised from a mixture of isopropyl and petroleum ethe range 2 ophenyl Preparation of 2 methanol A solution of 10 g of 2 phenyl in ml of glacial acetic 15 of concentrated hydrochloric acid and 15 ml of refluxed for two hours and then The residue was dissolved in a small amount of a mixture of e hanol and 2 hydrochloric acid and the solution was extracted with diethyl The extract was dried over sodium sulphate and the ether was distilled Diethyl ether and petroleum ether range were the solid substance was filtered off and twice crystallised from isopropyl alcohol a little was Melting point E I Preparation of methoxymethyl This compound was prepared by the procedure described in Example XXVII using the following g of 1 g 5 of in 250 ml of anhydrous 70 ml of butyl lithium in g of Vingiello and Soc in 1 0 ml of anhydrous After decomposition of the reaction mixture with 25 ml of the organic phase was separated washed thrice The solvent was distilled off and the residue was suspended in a small amount of cold diethyl The solid substance was filtered off and twice crystallised from methoxymethyl was Melting point Preparation of A mixture of g of ml of glacial acetic ml of concentrated hydrochloric acid and 15 ml of water was refluxed for The reaction mixture was treated with active charcoal and The residue was dissolved in diethyl ether and the solution was washed with To the ethereal phase an ethereal solution of oxalic acid was The precipitate thus was crystallised from ethanol with a small amount of The base was liberated by addition of sodium hydroxyde and extraction with diethyl The ether was distilled off and the residue was crystallised from isopropyl As the product obtained contained crystal isopropyl it was dissolved in diethyl The ethereal phase washed with water and dried over sodium sulphate and the ether was distilled was Melting point The melting point was not sharp but the and the titrations and the elementary analysis were in conformity with the desired structure Thin layer graphy revealed only one of 2 methoxyme hy1 hanol At and nitrogen atmosphere 44 ml of lithium solution in was added dropwise under stirring to a solution of 7 g of imidazole and 8 1 g of in 100 ml of anhydrous The mixture was stirred for one hour and then of 2 none in ml of anhydrous te added at The solution was stirred one hour at and kept standing overnight at room Then 50 ml of added and the solid matter formed was filtered The filtrate was extracted with tetrahydrofuran diethyl The organic phase was dried over sodium phate and the solvents were distilled Diethyl ether was added to the semisolid residue and the solid matter was tered This product was combined wit the solid matter obtained the addition of The substance was twice crystallised from acetone with a small amount of 2 1 thoxyme was Melting point Preparation of A solution of 1 g of ol ml of glacial acetic 15 ml of concentrated hydrochloric acid and 15 ml of water was refluxed for 5 The dark brown solution was and water was added to the The mixture was then made alkaline by addition of ammonia and extracted with diethyl The organic phase was separated decolorized with active dried over sodium sulphate and the ether was distilled The solid residue was twice crystallised from rewashed with petroleum ether once tallised from isopropyl 2 was Melting point E XXI Preparation of phenylimidazole This compound was prepared by the procedure described in Example XXVII the following g of g of ml of anhydrous 62 ml of butyl lithium in g of in ml of anhydrous tetrahydrofuran The reaction mixture was decomposed with 75 ml of The solid matter formed was filtered off and the aqueous phase of the filtrate was The organic phase was The residue appeared to be identical to the solid matter filtered The combined solid substances were crystallised from isopropyl et y1 was Melting point Preparation of 2 hanol A mixture of g of 90 ml of glacial acetic 9 ml of water and 9 ml of concentrated chloric acid was refluxed for The acetic acid was distilled off and residue was dissolved in a mixture of water and The solution was made alkaline with 2N aqueous sodium the alcohol was distilled off and the aqueous solution was The filtrate was tracted with diethyl ether and the extract was over sodium sulphate and The residue and the solid filtered off were combined and crystallised from acetone with a small amount of was Melting point Preparation of ha ol A of S of freshly distilled allyl 7 g 5 of according to Example g of sodium g of picric acid and 50 ml of acetonitrile was refluxed for 5 The warm action mixture was filtered and water added to the The precipitate formed was filtered washed with water and petroleum ether range and three times crystallised from isopropyl chioropheny1 as Melting point 1 Preparation of a At a temperature of to and under a nitrogen 25 ml of butyl lithium in hexane were added to a solution of g of and g of in 75 ml of anhydrous The mixture was stirred for 2 hours and then g of 4 4 dissolved in 75 ml of anhydrous tetrahydrofu an were added dropwise under the same The reaction mixture was stirred for 2 hours at to and kept standing overnight at room temperature under the nitrogen Then 25 ml of water and a small amount of acetic acid were added to the reaction mixture and the liquid was distilled Water was added to the residue and the was filtered The product was crystallised from a mixture of isopropyl and petroleum ether range was Melting point E IV Preparation of thanol This compound was prepared by the procedure described in Example using the following g of g of g 25 ml of butyl lithium in The compound was crystallised from a mixture of acetone and V Preparation of A solution of g of Soc 5 in 60 ml of tetrabyd was added dropwise at to under a phere to mol phenyl lithium from 1 g of lithium and g of bromobenzene in 70 ml of diethyl The reaction mixture was stirred fo one hour and then g of benzophenone in ml of tetrahyd o u were added The reaction mixture was stirred under the nitrogen atmosphere for two at to and for 15 hours at room The mixture was then poured into a mixture of ice and The aqueous phase was twice extracted with diethyl ether and the combined extracts were The residue was taken up in diethyl ether and the undissolved solid matter starting was filtered The ether was tilled off and the residue was again taken up in a small amount of diethyl The undissolved which now appeared to be the desired was filtered This procedure the ether and taking up the residue in ether was repeated a few times and the solid materials filtered off were The substance was crystallised from isopropyl alcohol with a small amount of was Melting point VI Preparation of 1 methanol A solution of 0 of to a phenyl lithium prepared from 1 67 g 0 24 of lithium and g 0 of bromobenzene in 80 ml of anhydrous diethyl The mixture was heated for about one hour until a brightly homogenous solution was Subsequently a of 25 1 g 0 1 of in 60 ml of anhydrous added in the course of one hour at a rature between and The reaction mixture was stirred for 1 5 hours at room under the nitrogen atmosphere and it was then poured on 200 g of The aqueous phase was saturated with sodium chloride and the organic phase separated off and The residue dissolved in a small amount of acetone the solution was acidified with hydrochloric Then some toluene was added and the precipitate filtered The product was thrice crystallised from a mixture of isopropyl alcohol and petroleum ether range was Melting point Preparation of Following the procedure Example but substituting an equivalent amount of 4 Picard and 9 the a reaction mixture was which was poured into a mixture of ice and sodium The organic phase was separated dried over sodium phate and the solvent was distilled Diethyl ether was added to the residue and the undissolved material ting of the desired was filtered The product was crystallised from isopropyl was Meltin point 7 Preparation of The reaction procedure of Example XXXVI was repeated with instead of 4 The ketone was added at a between and mixture was stirred overnight at room temperature and then poured on 200 ml of The aqueous phase was with sodium chloride and the organic phase was separated The solvents distilled off diethyl ether was added to the The undissolved material was filtered off and thrice crystallised from a mixture of chloroform and petroleum ether range 4 was Melting point XXXIX Preparation of ophenyl The reaction procedure of Example XXXVIII was repeated with instead of The reaction mixture was poured on ice and organic phase was separated off and The was dissolved in smal amount of acetone and 2N hydrochloric acid was added The mixture was extracted with diethyl ether and the extract was concentrated and the residue was shaken with sodium hydroxide solution on which the desired compound product filtered and twice tallised from a mixture of acetone and petroleum ether ling range and twice from 1 was ting point Preparation of A solution of 20 ml butyl lithium in in JO of diethyl ether was added dropwise under a nitrogen to a solution of g of imidazole Soc 4000 in 100 ml of diethyl After the addition was the reaction mixture was stirred for another hour at room Then a solution of g of in 75 ml of anhydrous diethyl ether was added The reaction mixture was for 3 hours and it was then poured into 200 ml of The ethereal layer was rated dried over sodium sulphate and the ether was tilled The residue crystallised from a mixture of ethanol and petroleum ether range was Melting point Preparation of A solution of 2 0 08 mol of but l lithium in to a solution of g of imidazole in ml of anhydrous diethyl The tion mixture was stirred for one hour and then a solution of g of in diethyl ether was added The reaction mixture was stirred hours and it was then poured into a mixture of ice and The solid matter was filtered off and lised from was Melting point E of oxalate 1 A mixture of of g of sodium hydroxide and ml of acetonitrile was stirred for one Then of picric acid in water and a few crystals of potassium iodide added to the The homogenous reaction mixture obtained was heated to and at this temperature a solution of g of in 50 ml of acetonitril e added The reaction mixture was then refluxed for 4 After the solid matter was tered The solvent was evaporated and the residue was The boiling range of the main fraction was This product was dissolved in anhydrous ethyl ether and an ethereal solution of oxalic acid was which caused the desired oxalate to The salt was crystallised from Melting point Preparation of 1 In the course of one 64 ml 05 of butyl lithium in were added dropwise at to and under a nitrogen to a solution of 1 g of 1 from the late described under g of tetramethylethylenedia ine in 150 ml of anhydrous The reaction mixture was stirred for hour and then a suspension of g of 4 none in 0 ml of anhydrous tetrahydrofuran was added ly under the same reaction Stirring was continued for one hour and then the cooling means was removed and the reaction mixture was kept standing overnight at room 20 of water were added and the organic phase was separated and The residue was suspended in a mixture of water and diethyl The solid matter formed filtered off and the ethereal was separated dried over sodium sulphate and The residue was twice crystallised from 1 Preparation anol To a suspension of g of according to Example in ml of 500 of picric 300 mg of potassium iodide and 1 g of sodium hydroxide were added at The reaction mixture was stirred for one hour and then g of methyl iodide in 25 ml of acetonitrile added at The mixture was for four the solvent was distilled off and the residue was extracted with a mixture of water and diethyl The solid matter was filtered off and the ethereal phase was dried over sodium sulphate and Diethyl ether was added to the residue and the solid matter filtered The two portions of solid material combined and twice crystallised from isopropyl alcohol and twice from toluene and rewashed with petroleum range Melting point of phehy1 ano1 of lithium solution in were added with stirring at and under a gen atmosphere to a solution of 1 g of tho imidazole and g of tetramethylethylenediamine in 75 ml of anhydrous Stirring was continued for 1 5 hours and then 2 9 g 0 009 1 of 4 trifluoromethyl in ml of anhydrous tetrahydrofuran were added dropwise under the same which made the colour change from light red into very dark The reaction mixture was kept standing overnight at room temperature and it was then decomposed by addition of 40 ml of The mixture was extracted with ether and the tract was The residue was extracted with a mixture of 2 N hydrochloric acid and diethyl The ethereal phase was dried over sodium sulphate and the ether was distilled The residue was boiled a few times petroleum ether range to remove ketone starting material and it was then once tallised from a mixture of toluene petroleum ether range and twice from petroleum ether range was Melting point Preparation of 1 A mixture of 25 ml of 9 2 g of according to Example and 1 5 g of sodium hydroxide was stirred one To the now homogenous reaction of picric acid and a few crystals of potassium iodide added and the mixture was heated to A solution of 2 g benzyloxymethyl chloride in 50 ml of acetonitrile was then added dro wise and the reaction mixture was subsequently the filtrate was concentrated The residue was suspended in water and the suspension was tracted with diethyl The extract was dried over sodium sulphate and the ether was distilled The solid residue obtained was crystallised from isopropyl The product was then boiled four times with 75 ml of petroleum ether range the petroleum ether being decanted each after which it was once again crystallised from isopropyl The substance was dried in vacuo for hours at 1 was Melting point The invention includes within scope pharmaceutical compositions as the active at lea3t one of the therapeutically active compounds of general formula or acid addition salt in association with a cally acceptable The compositions may any of the forms customarily employed for administration of therapeutic Tablets and pills may be formulated in the usual manner with one or pharmaceutically acceptable diluents or for example lactose or include materials of a lubricating for example calcium or magnesium Capsules made of absorbable such as contain tho active substance alone or in admixture with a solid or liquid The or an acid addition salt may also be in a form suitable for parenteral as a suspension or emulsion in sterile or an organic licpid ueually employed for injectable for example a vegetable oil such as olive or a sterile solution in or an organic Preparation of hanol j 3 of magnesium and g ethyl bromide were converted into Grignard in 50 ml of anhydrous te the course of 5 minutes a solution of g of dazole in 20 of anhydrous an was added with stirring to the refluxing after which the reaction mixture was refluxed for another two A suspension of g of 4 ml anhydrous was then added and as continued for 24 The whole procedure was carried out under a nitrogen After the reaction mixture was into mixture of and ammonium chloride The mixture was then extracted with diethyl and the extract was washed with sodium and The solid residue was twice tallised from a mixture of alcohol and dimethyl E Preparation of 1 A solution of g of methanol according to Example III and 3 g sodium hydroxyde in 250 ml of acetonitrile was refluxed for one hour ith Then 500 mg of picric a few crystals of potassium iodide and a solution of g of benzyl in 100 ml of acetonitrile were fluxing was then continued for 4 hours with The reaction mixture was kept standing The tate formed was off and dissolved in 3 liter of diethyl This solution was washed with a saturated sodium chloride decolorized with active dried over sodium sulphate and The residue was crystallised from a mixture of methanol and diethyl was Melting point The following Example illustrates the preparation of a pharmaceutical 50 g of sieved i through a 40 mesh sieve of meshes g of 101 and 1 g of purified silicon are mixed together and gelatin capsules are filled each with 101 of the mixture so that each capsule contains 50 mg of active insufficientOCRQuality

Claims (1)

1. CLAIMS 2. II.1973 for" more wherein R1-R10 are the same of different and each than one of Rc and R..-R.,- represents a hydrogen or halogen atom or a trifluoromethyl 3 o 1U other than or tertiary butyl group, provided at least one of them is hydrogen. halogen, trifluoromethyl or tertiary butyl, Rll and R12 are the same or different and each represents a hydrogen atom, a lower alkyl group, a phenyl group or a habgen- substituted phenyl group and R13 represents: ; a) hydrogen, benzyl, alkenyl, lower alkoxymethyl , enzyloxymethyl or a benzenesulphonyl group optionally substituted with one or more alkyl groups; 2. II.1973 ,^except unsubstituted benzyl and benzyloxymethyl; and their acid "addition salts. 2. a,a-Diarylimidazole-2-methanols according to Claim 1, in which R13 represents a hydrogen atom or - when Rll and R12 are hydrogen atoms or one or. both of them is an alkyl group - a lower alkoxymethyl group or a phenyl ( lower) - ' 41448/2 alkoxymethyl group in which the phenyl moiety is optionally substituted by one or more halogen atoms or alkyl groups and the other R-symbols are as defined in Claim 1, and their acid addition salts. 3. a , a-Diarylimidazole-2-methanols according to claim 1, in which R13 represents a lower alkyl group, a phenylalkyl group optionally substituted in the phenyl moiety by one or more halogen atoms or alkyl groups, an alkenyl group or a benzenesulphonyl group ( in which the phenyl moiety is optionally substituted by one or more alkyl groups) or -when one or both of Rll and R12 is a phenyl group or a halogen substituted phenyl group - a lower alkoxymethyl group or a phenyl (lower) alkoxymethyl group optionally substituted in the phenyl moiety by one or more halogen atoms or alkyl groups and the other R-symbols are as defined in claim 1, and their acid addition salts. Compounds according to claim 5 in which and RQ both are a chlorine atom, R 1 and Ri 2 are hydrogen atoms or one of . them is a p-c loroptienyl group and R1 , R2 , R4 , R5 , R6 , 7 , R9 and R1 0 are hydrogen atoms. a , L--Bis( -chlo ophenyl) -1 -vinyl midazole- 2-methanol and its acid addition salts. 1 -Benzyl-U U-DI 3(p-chlorophenyl) imidazole- 2-metha ol and its acid addition salts. Coapounds according to claim 2 in which R 3 is a haloge atom or a trifluoromethyl" or tertiary "butyl group, Re is ■ . - 41448/3 alkoxymethyl group in which the phenyl moiety is optionally substituted by one or more halogen atoms or alkyl groups and the other R-symbols are as defined in Claim 1, and their 2.11.1973 acid addition salts. for the underlined 3. a , a-Diarylimida-30.ie-2-methanols according to claim 1, meanings in Claims 2 and in which R13 represents a lower alkyl group , a phenylalkyl 3 except benzyl and group optionally substituted in the phenyl moiety by one or benzyloxy methyl, more halogen atoms or alkyl groups , an alkenyl group or a optionally subs ituted benzenesulphonyl group ( in which the phenyl moiety is with one or more alkyl optionally substituted by one or more alkyl groups) or -. groups when one or both of Rll and R12 is a phenyl group or a halogen substituted phenyl group - a lower alkoxymethyl group or a phenyl (lower) alkoxymethyl group optionally substituted in the phenyl moiety by one or more halogen atoms or alkyl groups and the other R-symbols are as defined in claim 1, and their acid addition salts. Co pounds according to claim 3 in which R3 and Rs both are a chlorine atom, R1 1 and R1 2 are hydrogen atoms or one of . them is a p-chlorophenyl group and R1 , R2 , R . R5 , R6 , R7 , 9 and R1 0 are hydrogen atoms. ,ii-Bi£j(p-chlorophenyl) - 1 -vinylimidazole- 2-r.ie h3.nol and its acid addition salts. , 1 -3enzyl-a-u-bls( O-chl0rophenyl) imidaiiole- 2-methanol and its acid addition salts. Compounds according to claim 2 in which 3 is a halogen atom or a trifluorome hyl or tertiary butyl group, ,R8 i a hydrogen or halogen atom or a trii'luoromethyl or tertiary butyl group, and R1 , R2 , R4 , R5 , R6 , R7 , R , R1 0 , R1 1 and R1 2 are hydrogen atoms, and their acid addition ■ salts. a . Compounds according to claim 7 in which both R3 and Rs are a chlorine atom or R3 is a trifluo ornethyl group and R8 is a hydrogen atom. 9 . a ,a-Bis(p-c.hlorophenyl)imidazole- 2-methanol and its acid ■addition salts. 10. ,a-Bis(p-chlorophenyl)-i -methoxymethylimidazole-2-metha- nol and its acid addition salts. 11. -Phenyl-a-( p-trifluoromethylphenyl) imidazole- 2-methanol and its acid addition salts.- T2. 1 -(Methoxyme.thyl )-u-phenyl-u-(g-trifluoromethylphenyl) imidazole- 2-methanol and its acid addition salts. 3. Process for the preparation of a ,a-diarylimidazole-2-me- thanols as claimed in claim 1 , characterized in that a compound of the formula RI5 (wherein R15 represents an alkali metal atom or a reactive organo-metal group, R14 is identical to R13 , except a hydrogen atom, or a removable group beyond the scope of R13 and R11 and R12 are as defined in claim 1) is reacted with a compound of the' general formula (wherein R1 -R10 are as defined in claim 1), the group or atom R15 is removed from the resulting organo-metal complex by hydrolysis to yield a desired tertiary alcohol of general formula I given in claim 1 wherein R13 represents a hydrogen atom or a corresponding compound carrying a substituent group R14 on a nitrogen atom of the imidazole nucleus and, when in the latter case the substituent. group is not identical to R15 in the desired product, said substituent group is removed and, if desired, a group within the definition of †3 is introduced by a method laiown per se and the base obtained is, if desired, converted into an acid addition salt. Process according to claim 1j, characterized in that in formula II R15 represents a lithium atom or a group MgX, in which X represents a halogen atom. Process according to claim 13, characterized in that the reaction between the compounds of formulae II and III is carried out in an inert anhydrous organic solvent or solvent mixture. Process according to claim 15, characterized in that, when R15 represents an alkali metal atom, the reaction is carried out at a temperature below 0°C. 41448/3 Process accordin:; to claim 15, charac erized in that, when R15 represents a group HgX (wherein X is as defined in claim I.4) the solution of the reactant.s is refluxed. j ΐλ. Process according to claim 13 wherein as a last step a 5 group R13 is introduced, charac erized in that said step is performed by reacting a compound of the formula I given in claim 1, wherein R1 represents a hydrogen atom and the other Ιΐ-symbols are as defined in claim 1 , with 2. II.1973 a compound of the formula R13X, wherein R13 is a lower alkyl lined"^^ 9rou ' a lower alkoxymethyl group, a phenylalkyl group optionally alkyl groups) and X is as defined in claim 14. 19. process according to claim 18, charac erized in that the reaction is carried out in an organic solvent 'in the presence of a base. 20. Process according to claim 19, characterized in that the reaction is carried out in the presence of a catalytic amount of sodium iodide or potassium iodide. 21.' Process for the preparation of u , -diarylimidazole ■•^-methanols as claimed in claim 1 , characterized in that a compound of the formula wherein R13 ' is a hydrogen, atom or a group within the definition of R13 (defined in claim 1) or R14 (defined in claim 13). and the other R-symbols are as defined in claim 1 , is reacted with a compound of the formula (wherein the R-symbols are as defined in claim 1 and 1 ) the group or atom R15 is removed from the resulting orga-no-metal complex by hydrolysis to yield a desired tertiary alcohol of general formula I given in claim 1, wherein R13 represents a hydrogen atom, or a corresponding compound carrying a substituent group R131 on a nitrogen atom of the imidazole nucleus and, when in the latter case the substituent group is not identical to R13 in the desired product, said substituent is removed and, if desired, a group within the definition of R13 is introduced by a method known per se and the base obtained is, if desired, converted into an acid addition salt. · Process according to claim 21 , characterized in that in formula VII R15 represents a lithium atom or a group MgX, in which X represents a halogen atom. Process according to claim 21 , characterized in that the reaction between the compounds of formula VI and VII is 41448/2 carried out in an inert anhydrous organic solvent or solvent mixture. Process according to claim 2>, characterized in that, when R15 represents an alkali metal atom, the reaction 5. is carried out at a temperature below 0°C. Process according to claim 23, characterized in that, when R15 represents a group HgX -(wherein X is as .defined in claim 14) the solution of the reactants is refluxed. Process according to claim 21 wherein as a last step a group R13 as defined in Claim 18 is introduced by the process accord to any of Claims 18 to 20. Process for the preparation of a ,a-diaryliinidazble-2- methanols of the general formula (wherein the various R-synibols are as defined in claim 1 } at least one of R1 , R2, R3 , R4 and R5 being halogen, tri- fluoromethyl or tertiary butyl *),characterized in that a compound of the general formula 41448/2 ^ " R1 2 R1 1 \ ■ (wherein R1 η .represents a halogen atom, an alkoxy,' aryloxy, aralkoxy or silyl ox . group or a group ON in which Γί is a ■metal atom, and R1 1 , R1 2 and R1 4 are as defined in claims 1 and 1 3 ) is reacted with a compound of the formula VII given in claim 21 , the group or atom R1 5 is removed from the resulting organo-metal complex by hydrolysis .'to yield a desired tertiary alcohol -of general formula I given in claim 1 wherein R1 5 represents a hydrogen atom or a corresponding compound · carrying a substituent group R1 4 on a nitrogen atom of the imidazole nucleus and, when in the latter case the substituent group is not identical to R1 3 in the desired product, said substituent group is removed and, if desired, a group within the definition of R1 3 is' introduced by a method known per se.and the base obtained is, if desired, converted into an acid addition salt. 28. Process according to claim 27, characterized in that in formula VII R15 represents a lithium atom or a group MgX, in which X represents a halogen atom. 29. Process according to claim 27, characterized in that the reaction between the compounds of formulae XI and VII is carried out in an inert anhydrous organic solvent or solvent mixture. 30. Process according to claim 29, characterized in that, when R15 represents an alkali metal atom, the reaction is carried out at a temperature below 0°C. 31. Process according to claim 29, characterized in that, when R15 41448/3 32. Process according to claim 27 wherein as a last stzp a group R13 is introduced by the method according to Claims 18-20. 33. Process for t e preparation of a , a-diarylimidazole-2-methanols of the formula. I given in claim 1, wherein R13 is a lower alkyl 2 II 1973 9rouP I a lower alkoxymethyl group , a penylalkyl group optionally linedn(^er su^st^-tu^-e(^ phenyl moiety by one or morehalogen atoms or meanings alkyl groups an alkenyl group, a phenyl (lower) alkoxymethyl andZ^ group (optionally substituted in the phenyl moiety by one or methvl°X^ more halogen atoms or alkyl groups) or a benzenesulphonyl group optionally substituted ^n which the phenyl moiety is optionally substituted by with one or more alkyl one or more ^ikyl groups) and the other symbols are as defined *O lOS in claim 1, characterized in that the substituent R13 is introduced in the corresponding compound in which R13 is a hydrogen atom, by a method known per se. . 34. Process according to claim 33, characterized in that the compound of formula I wherein R13 is a hydrogen atom, is reacted with a compound of the formula R13X, wherein R13 is as defined in Claim 30 and X is as defined in Claim 18 by the method according to Claims 18-20. 35. Pharmaceutical compositions, characterized in that they contain, as active ingredient, at least one of the therapeutically active a , -diarylimidazole-2-methanols claimed in claim 1 , or a nontoxic addition salt thereof, in association with a pharmaceutically acceptable carrier. '