IL31159A - Substituted benzamidines and process for the preparation thereof - Google Patents

Description

New substituted and process for the preparation thereo CHINOIN 2936 such as used throughout the specification moans straight or branched chained radicals containing preferably carbon B may stand preferably for a lower nlkoxy group as a lower particularly such comprising alkyl s of carbon atoms alkylsulphonyloxy radicals sulphonylox arylsulphonyloxy radicals optionally substituted phenylsulphonyloxy radicals such as or a nitro The R and substituents may each stand for an alkyl Said alkyl radicals may be straight or branched chained and contain preferably carbon atoms isobutyl The R and substituents may be the same or eren R and may stand particularly preferably both for When R and together with the nitrogen atom form a heterocyclic this may be preferably a piperazino or Particularly preferred benzamidine derivatives of the invention are the following wherein and have the same meaning as stated above and if desired converting a benzamidine of the Formula thus obtained into an salt or setting free a base from a or converting a salt into another salt and if desired finishing a compound of the Formula or its salt in forms ready for direct medical According to a preferred form of realization of the process according to the present invention the amine of the Formula may be used in the form of a This method is particularly suitable for the paration of It has been found that the triethylamine complex of may be converted with a secondary amine with very readily into the which may be then reacted with the nitrile to yield the corresponding Said methods may be also applied when using cyclic secondary The reaction may be conveniently in a solvent such as benzene or The having been completed the benzene or toluene is decomposed ice and The thus obtained is then washed with diluted a ids and with water order to remove the contaminating According to the process of the present invention for instance the may be prepared with a yield of in such a pure state which is suitable for direct medical use without further purification The above process which is described in details in the examples is more simple than the separation of the from compounds in ether According to said known method the amidine is separated from the amine by or the mixture of the unreacted amine and the amidine is subjected to upon the nonmiscible amidine is slurried in a solvent can take place only after the above According to another preferable form of realization our process the amines the Formula are reacted with the nitrile component in the presence of a As boron boron pentachloride and preferably aluminiumchloride can be It is highly preferred to apply minium chloride for this The reaction may be carried out conveniently in the presence of an organic solvent such as benzene or The compounds of the Formula may be converted into their The salt formation may be carried out according to methods known per se for example by adding to a solution of the benzamidine derivative formed with an organic solvent an approximately equivalent amount of the corresponding The salts may be formed with inorganic acids as hydrogen phuric phosphoric or wit acids as salicylic tartaric formic acetic propionic oleic acid or sulfonic such as naphtalene sulfonic Acoording to a further feature of the presen invention there are provided pharmaceutical and veterinary e e va ve of the Formula or a salt with a luent or Said compositions may be prepared by admixing the active ingredient with an inert diluent for example magnesium carbonate magnesium rate The compositions may be finished in forms suitable for rectal or parenteral administration and may be solid pills and positories or or liquid or injectable Said compositions may optionally contain further additives filling wetting and optionally also further therapeutically active details of our process are to be found in the It is however by no means intended to limit the scope of the invention to the Example Is A mixture S 100 ml of anhydrous benzene and triethylamine is heated to under g of ethyl bromide are dissolved in 100 ml of anhydrous benzene and 15 of said solution are poured at once into the The beginning of the reaction is indicated by the mixture becoming The ethyl bromide solution is added dropwise at The addition having been completed stirring is continued for an hour at g of butylamine are added dropwise C within 50 During the addition ethane The addition having been completed the is stirred at C for 20 whereupon solution of g of in 5 ml of anhydrous benzene is added and the is refluxed for 2 After cooling to the mixture is poured on 400 ice and 18 g of The layers are the aqueous phase is extracted with 200 of the benzene solutions are washed with 100 ml of water each and ml of concentrated hydrochloric acid are addede The aqueous layer is whereupon the benzene solution is washed twice with 100 ml of water each and is concentrated to 200 The residue diluted with 200 ml of the mixture is allowed to stand for half an the precipitated crystalline product is washed with acetone and Thus g of are According to the above process the followin amidines are prepared the corresponding starting mat e s but ami salicylate hydrochloride s t he salt of s Example To a suspension of 8 g of anhydrous aluminium chloride and 30 ml of anhydrous toluene g of are reaction mixture is a a temperature of about 0 whereupon 6 of are added and the mixture is refluxed stirring an The reaction cooled to 0 diluted with 100 ml of benzene whereupon the dark solution is cooled on a mixture of 20 ml of 6 hydrochloric and about 20 g of o The solution i separa ted and the aqueous phase is extracted ml of benzene The united solutions are washed three ti mes with 0 ml of water charcoal and evaporated to The residual thic crystalpulp is diluted 2 ml of acteone ice an The precipitated crystalline product washed three times with 10 ml of acetone each and Thus g of benzamidine ar s O f hot water 8 of the pure product melting at are Example A mixture of g of sublimated 20 ml of and 6 g of 4 is heated on a for 2 The thiok brown melt is decomposed by adding a mixture of 70 g of ice and 50 ml of 5 N hydrochloric The mixture contains a thicky The mixture is heated to clarified with charcoal and The filtrate cooled with ice for 3 whereupon the precipitated crystals are washed with 20 ml of and Thus 7 g of are Example According to the process described in Example chloride is prepared from Example According to the process in Example is prepared from Example 6 According to the method described in chloride is prepared from ile Example e The solution of insufficientOCRQuality

Claims (1)

1. ■31159/2,. -butylbenzamidine is reacted with 2,2 ihydroxy~l,l» dlnapht yl-iaethane-5-5'-dicarboxyiic acid, to, yield the corresponding embonate. M.p. % 162°C. _ \ : CLAIMS . a saturated heterocyclic ring v/hich may' optionally contain as a further heteroatom an oxygen atom or an optionally jalkyl-substituted nitrogen atom. . if desired finishing the compou ds of the Formula I. i or their salts in forms ready for direct medical use. 18. Process according to claim 17, which comprises usin the amine of the Formula III. in the form of a Grig-, nard compound. 19· Process according to Claim 17, which comprises reacting,the amine of the Formula III. in the presence of " a- Lev/is acid. 20. Process according to Claims 17 and 19, which comprises using anhydrous aluminium chloride, as Lewis acid.. 21. Process according to any of Claims 17-20, which com- " prises carrying out the reaction in the presence of a hydrocarbon solvent, o 22. Process according to any of Claims 17-21, which com- : prises converting a compound of the Formula I. into a salt formed with an inorganic acid, such as b^£iro- hal-©g-©*iic acids, sulphuric acid, phosphoric acid or with organic acids, such as salicylic acid, tartaric acid, formic acid, acetic acid, propionic acid, embon- ic acid, oleic acid, maleic acid, fumaric acid or sul- phonic acids, such as naphtfealene-sulphonic acid. 23· Pharmaceutical compositions for both human and vete- . rinary use comprising at least one benzamidine derivative of the Formula I. (wherein A,B,D,R and have the same meaning as stated in Claim 1) or a salt thereof together with a non-toxic diluent or carrier. 24. Pharmaceutical compositions according to Claim 23, .comprisin one or more of the benzamldine-derivatives claimed in any of Claims 2-16, together with a non- "'■·...■.' toxic diluent or carrier. 23» Process for the preparation of pharmaceutical and * veterinary compositions according to Claims 23 or 24, which, comprises admixing a compound of the Formula I. or a sal thereof with suitable inert solid or liquid non-toxic diluents or carriers and optionally with further additives such as filling agents, emulsifiers, wetting agents, and optionally . with further therapeutically active compounds and finishing the compositions in forms ready for oral, parenteral, or rectal administration. 26.. Process according to Claim 25, which comprises finish- . ing the compositions in the form of tablets, pills, coated pills, capsules, suppositories, solutions, emulsions, suspensions or injectable preparations.. 27. Benzamidine derivatives as claimed in Claims 1-16 substantially as described in any of Examples 1-7· 28. A process as claimed in any of Claims 17-22 substantially as described in any of Examples 1-7· 29. Pharmaceutical' and veterinary compositions as claimed in Claims 23-24- whenever prepared by the process claimed in Claims 25-26.