IL29445A - Phenoxyisoalkyl imidazolines and their preparation - Google Patents

Description

imidazolines and their preparation 2 A series of imidazoline derivatives substituted in the position by aryloxyalkyl groups incorporating a linear alkyl group are These compounds are distinguished in particular by their spasmolytic and antihistamine She present invention consists in new imidazolines of the general formula in which the phenyl radical is optionally substituted by a methylene dioxy by one or more lower alkyl lower lower alkoxy by one or more groups by one or more halogen preferably chlorine is a lower alkyl with 1 to 4 carbon and is hydrogen or a lower alkyl radical with 1 to 4 carbon and in acid addition salts compounds of formula in which the phenyl radical is optionally substituted by a lower lower alkoxy radical by a halogen preferably a chlorine and and have the same meaning as above particularly She compounds according to the invention have and unexpected pharmacological 3 The invention also consists in processes for the preparation of compounds of formula I and of their acid addition particularly physiologically acceptable By one of them a phenoxycarboxylic acid of the formula or a derivative thereof is reacted with ethylene She new imidazoline derivatives of formula I are formed either directly or in Suitable functional acid derivatives include for acid preferably the acid t imino halides or the of the corresponding the reaction may also be carried out under such conditions that the functional derivatives are only formed during the In addition to the ethylene diamine reactive of ethylene diamine may be Preferred of ethylene diamine are those which give imidazolines when reacted with carboxlic acids or their functional Examples of such compounds 4 are lene or e hylene compounds that can be concerted into ethylene diamine by treatment with ammonia can be include or its amines such as ethylene dihalidea such as or ethylene Ethylene diamine or its derivatives be used either in the form of free bases or in the of their or in quantities corresponding to times the metric the ethylene diamine may be used in the form of its sulphonic acid Where the of the acid of formula II is used as the starting material for reaction with th diamine or its to advantageously effected in the presence of hydrogen sulphide or hydrogen sulphide donors such s for example carbon reactions described above may lead to the imidazoline derivatives of formula X either directly or in For a compound corresponding to the foraula in which 5 may be formed as The substituents and may bo eliminated as from of this type or from their tautomeric forms by methods known For water can be eliminated from a compound of formula in which is OS and is hydrogen using calcium oxide s dehydrating In this the ponding derivative of formula I is formed in a high Alternatively a compound of the formula in which represents a radical that can be substituted by an amino may formed as The radical may be eliminated in the form of from a compound this type or from its tautomeric in which case the imidazoline ring is Intermediate products of this type are relatively unstable compounds when simply boiled in a suitable inert are converted into the desired imidazoline compounds of formula with elimination of cleavage reaction is particularly smooth in cases where is the reactions also produce good yields where is OH and where they are carried out under dehydrating Compounds of the formula in which and are the same or different and represent radicals that can be substituted by an amino for may also be used as intermediates in cases where the imidazoline derivatives are formed in stages If a compound of this type or its tautomeric form is treated with ammonia or ammonia the imidazoline derivatives of formula I are She reaction is particularly smooth where and represent in particular The novel imidazoline derivatives are obtained either in the of a base or in the of one of their acid addition depending upon the type of method A variety of acid addition salts can be with Acids of kind that give acceptable acid addition salts say be used in preparation of those including sulphuric alkane carboxylic acids as aci or propionic polybaslc acids as for oxalic tartaric succinic ascorbic acid or citric sulphonic acid such as methane ethane sulphonic benzene sulphonic acid or phonic aromatic carboxylic acids such as salieyclic acid or The imidazoline derivatives obtained in accordance wit invention and their acid addition salts be converte into any of pharmaceutical optionally the aid of the usual In the derivatives according to the invention are vasoactive and are utilizable in addition onic agents and in particula as vasoconstrictors in the of dropo or nasal In addition to the properties which this class of pounds is known to for example their an and spasmolytic tho novel imidasoline derivatives also sho inter alia local anaesthetic and sympathomimetic properties specific activity on the hear In the are She preparation of the novel compounds of general mula is described more fully in the following 1 100 of dry ethylmethyl ketone are added to 19 g of phe g of finely powdered carbonate and mixture is under reflux for another after which it is separated oncooling from the insoluble components present in it by filtration the residue washed with ethylme hyl ketone and the filtrate concentrated by evaporation i vacuo Ether is added to the oily the ethereal solution extracted three times with of sodium hydroxide in order to remove the excess and then with sodium thiosulphate solution in order to The product is then washed with water until it reacts neutrally and over anhydrous sodium After the solvent has been fractionation of the residual in a high vacuum gives 21 g of of the theoretical Colourless liquid of O H C H N ethyl ester chloride 11 of absolute ethanol are added to g of by the introduction of 100 chloroform dried over phosphorus of carefully dried hydrogen chloride being slowly introduced with stirring and cooling with Most of the chloroform and excess hydrogen chloride is then removed by filtration in vacuo at room and dry ether added to the residue until the ester hydrochloride is quantitatively The ester hydrochloride can yield g or of the N N The crude product of ethyl ester hydrochloride is sufficiently pure for further even without precipitation with ether hydrochloride 25 g of ethyl ester hydrochloride are added in portions to a cooled solution of of anhydrous ethylene diamine in 90 of absolute ethanol in such a way that the temperature does not exceed Q to The cooling bat is then removed and the reaction mixture heated for 1 hour on a water bath to approximately After unreacted ethylene diamine is in a cooling mixture with absolute ethanolic hydrochlic filtered off from any are insoluble in ethanol and approximately of the solvent filtered off under suction in a water pump Residual quantities of ethylene diamine dihydrochloride are precipitated in fractions by the careful addition of ethylmethyl after which the imidazoline chloride is separated off by the addition of dry Following recrystallisation from a little ethylmethyl chloride is obtained in the form of small white needles melting at S of the EXAMPLE 2 of from guaiacol with in the presence of potassium 1 g of ethylene diamine sulphonate are combined and heated for 1 hour to The reaction is accompanied by the elimination of After the reaction mixture has it is made alkaline with approximately lye and the free base extracted with The residue left after the solvent been distilled off gives of the of following recrystallisation from petroluem spirit C H N C H 7 36 N The free base may be converted into the hydrochloride in known g of hydrochloride being obtained following recrystallisation from ethan lmethyl ketone strongly hygroscopic crystals melting at N EXAMPLE of by reacting hydroquinone monomethylether with propionitrile in the presence of potassium liquid of Q 1 6 g of ethylene diamine and of carbon of imidazoline melting at to C N H N EXAMPLE g in Example 1a from and white melting at are converted into acid ethyl ester hydrochloride as in Example 1b by treatment with and g of dry hydrogen chloride In accordance with Example the hydrochloride thus obtained is reacted further isolation or purification with g of anhydrous ethylene diamine to form imidazoline White crystals melting are obtained following recrystallisation from N N EXAMPLE g as in Example 1a from and propionitrile e converted as in Example into ethyl ester hydrochloride with of absolute ethyl alcohol g of dry hydrogen chloride As in Example the chloride thus obtained is reacted and worked up without of the dissolution in absolute alcohol and the addition of absolute is reacted to give the hydrochloride again by the introduction of at least the equivalent quantity of dry hydrogen chloride The hydrochloride formed is obtained analytically pure in the form of white crystals melting at following recrystallisation from N CI N shows some more imidazolines and their salts produced by the process according 13 Almost all the compounds prepared as in Example 1 by way of the ethyl ester General formula for the compounds listed in Table 14 15 EXAMPLE 6 i Tablets are produced by mixing an appropriate binder and usual additives and the compound obtained according to Example 4 in such amounts that each tablet contains of the active EXAMPLE 7 Nose A per compound obtained according to Example 5 in a physiological sodium solution is produced and may be used as nose EXAMPLE 8 A patient suffering from an influenza with snuffing and strongly enhanced breathing through the nose obtained the nose drops according to example in a dose of 2 drops eacl and to 5 times per He was able to breath substantially without enhancement about 5 minutes after Breathing through the nose was undisturbed for about 5 undesired side effects were observed even after a regular administration through 9 insufficientOCRQuality

Claims (1)

1. 24 derivatives of the general formula in the phenyl group is optionally substituted by a by or several lower lower alkoxy groups one or several groups halogen preferably chlorine is a lower group aving from X to 4 carbon atoms and is hydrogen or a lower group having from 1 to 4 carbon and acid addition salts The of tho compounds according to any of Claims 2 to Compounds according to substantially as described herein with reference to Examples 1 to 5 and Sable 25 A process the preparation of imidazoline derivatives according to wherein a acid of the general ormula or a functional derivative in which and have the same meaning as in Claim and the phenyl ring may substituted as indicated in is reacted xfith ethylene fi if where the imidazoline is obtained as a free base it can be converted into an acid addition or where the salts of these bases are they can bo converted into the corresponding free base imidazoline A process according to Claim the nitrile of an acid of II is reacted with ethylene at an elevated temperatur if desired in the presence of carbon A process according to Claim wherein the nitrile of an acid of formula II is first converted into the ponding iaidoacid alkyl ester and the latter is reacted with ethylene diamine in the presence of a anhydrous A process according any of Claims 9 to wherein the ethylene diamine is used as the free base or in the form of a or 26 preparation of according to of Claims 1 to substantially as herein reference to Examples 1 to 5 compositions as an active according to of Claims 1 to Pharmaceutical compositions according to Clain substantially as described with reference to Examples 6 to 8 insufficientOCRQuality