IL30305A - 2,2-(2-azatetramethylene)adamantane and derivatives thereof,their production and antiviral compositions containing them - Google Patents

Description

30305/2 2,2-(2-azatetramethylene)adamantane and derivatives thereof, their production and antiviral : compositions containing them N.V. PHILIPS· GLOEILAMPB FABRIBKEN "New spiro-aaate rame hylene derivatives" The' antiviral activity of compounds in vivo' may he deter-niiried hy mean's of tests on mice,, During such tests a dose of the substance to he tested is orally administered to 8 mice daily during 7 days0 At the first day of administration the animals are infected with a virus which is clouded in cages in which the mibe are housedo Since it is difficult to ascertain whether the animals fall ill or not, a dose of virus is administered such that all of the mice die during' he teste As a matter of fact, this dose is a manifold of that with a natural infeotione The mice which have died are counted twice a da 0 The number of dead mice and the instants of dying are oompared with the data obtained with a group of 18 mice which had "been infected hut did not receive the substanoe to be tested,, By means of the Wileoxon method it can then be calculated whether the substance has a significant antiviral effect,, By means of this test the antiviral activity of inter alja 1- and 2«=am.irio adamantane was. show 0 It has been found that spiro-azatetramethylene derivatives of formula I. and acid-additive salts thereof with pharmaceutically acceptable acids have a very strong antiviral activity,. In formula I, R is a infection threatens or as soon as weather conditions make an early infection probable 0 It is 'therefore preferable to administer a dose of one of the oompburids daily during1 the winter mbn'thse Since ' accination' gives immunity only after three weeks, the compounds may also he administered together with a vaccin giving protection during 'the first three weeks after vaccination,.

The compounds can he either njected o administered orally or rectally0 However, oral' administration is ^ preferred,, The treatment for adults is f rom 50' mgs to 500 nigs daily, preferably 200 mgs,, This dose may he administered at one time,, Chi dren are treated, with half a dose 0 For animals a dosage of from 10 to 1 00 mg/kg/day and preferably 0 mg/kg/day is most oommonly employed,.

The compounds of formula I may be prepared by methods which are known for the manufacture of this kind of compounds and by methods analogous ' therewith,, Accordingly the invention also relates to a method Of preparing new spiro-az te ramie ethylene derivative's and is oharao-teriaed in that compounds of formula I and salts thereof with pharmaceutically acceptable acids , in whioh formula E is a hydrogen atom, an n~alkyl group having up to 3 carbon atoms or a propargyl group, are prepared by methods which are known for the preparation of this kind of compounds or by methods analogous thereto „ and their salts, where R' is a hydrogen atom or an n-alkyl group having up to 3 carbon atoms, are obtained by reducing a where Y and Y' are double-bonded oxygen atoms or one of them represents two hydrogen atoms . This reduction may be carried out with hydrides-, such as LiAlH^, NaAlH^ or NaBH^ plus AlCl^, in an inert solvent, such as an ether, for example diethyl ethe , dioxane, tetrahydrofuran, diglyme, etc Compounds of formula III, in which Y and Y' are each a double boridedv oxygen atom, may be manufactured by starting from adaman-tan one ' and cyano acetic acid which are reacted with eachjother by the Cope methodo Treating the resultant adamantylidenecyano acetic acid with KCN in methanol results in 2~cyano»2- cyano~ methyl adamantane which may be saponified with concentrated sulphuric acid to form the dicarbonamide o This substance may be formed by means of 50 hydrochloric acid into the acid anhydrid, which may be converted with the aid of R'NIL, into a compound of formula III.

Compounds of formula III9 where Y is a double-bonded oxygen atom and X1 represents two hydrogen atoms, may also be obtained from 2-cyano-2~cyanomethyl adamantane0 To this end, the substance is hydrogenated with hydrogen and Raney-nickel to obtain 2»cyano-2-(2-aminoethyl ) adamantane which is alkylated, ΡΗ¥0 258Ο Ce if desired, wit an alkyl chloride having up tp 3 carbon atoms0 The nixrile group is ' subsequently hydrolysed with sulphuric acid and the resulting 2-(2-aminoethyl)adamantane carb©xj3icacid-2 is cyclised wit thionylbhloride or dioyclohexylcarbodiimidee Compounds 'of formula ΊΙΙ, where Y represents two hydrogen atoms and Y1 represents a double-bonded oxygen atom , may also be obtained when starting from adamantanone0 To this end, this substance is reacted, according to Reformatzki, with an ester of acid0 A moleoule of water is extracted from the reaction product with the aid of, for example, thionylchloride i pyridine0 The resulting adamantylidene-acetic acid ester is subsequently saponified with lye' and converted into the acid chloride using 'PCL-, in benzene0 The reaction product may be converted into the corresponding acetimide with the aid of ammonia or an amine R'NHgo The resulting substance may then be converted into the desired compound using dimethyloxbsulphonium-methylide in dimethyl sulphoxide0 Compounds of formula IV arid their salts, where R" is an n<=alkyl group having up to 3 carbon atoms or a propargyl group, may be manufactured by alkyla*?: ting 2,2-=(2-azatetramethylehe )adamantane0 This may be effected by reacting the substance with a halide R"Hal or a.sulphate R'^SO^, preferably in an alkaline inert solvent, for example, in triethyl-amine, pyridine, KOH or KgCO^ in benzene οϊ' methanolo Compounds of formula V arid their salts, where' E"' represents an n-alkyl group having up to 3 oarb n atoms, may also "be manufactured by reductively alkylating 2,2-(2-azatetrajnethylene )adamantane0 This reaction may be oarried out with formaldehyde, aoet -aldehyde, propional- ' dehyde and, for example, Pt/H2, Raney«*iickel/H2, formio aoid, UaBH^ or the like0 The' compounds of formula V can also "be obtained "by acyla-ting and then reducing 2,2-(2-azatetramethylene)adamantane<, To this end, the substance may be reaoted with either formio aoid or the anhydride or a halide of aoetic acid or propionio acid,, . . a.

The resulting amide may be reduced, for example, with hydride, for example, L AlH^0 2,2-(N=propargyl='2~azatetramethylene)adamantane and its salts pound of formula 71 where R^ represents the group -CBr ■* CH"2 or the group -CHBr-CHgBr,, The reaotiori may be carried out with NaNH2 in fluid ammonia or i toluene, xylene arid the like0 The substance of formula VI in whioh R.j represents the group ~CB »CH2 may be obtained by ooupling 2, 2-(2-azatetramethylene)adamantane with 2,3-dibrom:Q .propene-1 and the substance of said formula in which represents the group -CHBr-CHgBr by reacting 2,2-(N-allyl-2-azatetramethylene) adamantane, manufactured by a method described for the synthesis of oompounds of formula III, with bromine in water0 - ~ with formaldehyde and acetylene. The reaction may he carried out ' at a temperature between 3Q°C and 40°C and an acetylene pressure of + 10 atm. under the influence of *cuprochloride in acetic acid. 2 ,2-(2-azatetramethylene )-adamantane and its salts may, at least, methyl be obtained by heating salts of 2-aminoethyl-2-aminoe fcyi..-ada-mantane to temperatures above their melting- point „ This reaction may be carried out in the absence of a solvent.

The substances may be given a form suitable for administration in the usual manner. Thus 'they can be mixed with, .or dissolved in, inert solid or fluid' carrier material s<. It is. thus possible to obtain tablets,' pills, coated tablets, suppositoria, powders, suspensions, injection liquids, capsules and the like. If desired, it is possible to provide them with other medicines, vitamins or dyes0 Suitable carrier materials are, for example, water, glycerin, chalk, calcium phosphate, lactose and powder sugar (saccharose) or mixtures of these substances. The use of sugars as carrier material affords the advantage of a pleasing taste.

Tablets and coated. tablets may also contain swelling agents which readily cause disintegration of the composition in water. As such may be used, for example, potato starch, maize starch, arrow root (amylun marantae), carboxy methyl cellulose. Furthermore libricants can be used, such as talc, magnesium stearate and calcium stearate.

Compounds such as, for example, methyl-p-hydroxybenzoate , propyl-p-hydroxybenzoate and benzyl alcohol may be added as preservatives. Suitable surfaoe~active substances are, for example., mono- or tri-esters of, for example, lauric acid, palmitic acidp stearic acid, ricinic acid and oleic acid with a poly-alcohol such as, for example, sorbitan, manitan, mannide and glycerol and also polyoxyethylene derivatives of inter alia the said esters.

PEN 2580 C.

Preparations aocording to the invention may have, for example, the following compositions s Suspension for in.iection 100 gins* of 2,2-(2-azatetramethylene)adamantane 1,80 gmso of methyl-p-hydroxybenzoate 0,20 mso of propyl~p-hydroxybenzoate ■ 9,0 gmso of sodium chloride 4,0 mso of polysorbate 80 UoS.Po water up to 1000 mlso Tablet 335 m So of lactose 60 m So of potato starch mgSo of magnesium stearate m So of gelatin Suppository 200 mgSo of 2, 2~( 2-azatetramethylene )-adamantane o sulphuric acid 1 00 m So of suppository mass Manufacture of in.iection liquid 1o80 gmso of methyl-p-hydroxybenzoate , 0o20 gms. of propyl-p-hydroxy-benzoate and 9°0 gms0 of sodium chloride were dissolved in OO fflls of boiling water for injection... Another J00 mis of water for . injection were added to the solution, followed by cooling to 30° Co The resulting solution had added to it a solution of 4o0 gmso of polysorbate 80 U.S0P0 in water of 40°C for injection,. The mixture was stirred until a homogeneous liquid was obtained and then cooled down to 20° Co The pH»value was adjusted between 6o and 7» using 0o N-hydrochloric acid p0ao, whereafter the solution was supplemented with water for injection up to 1000 PHN 2580 C. sterilized in an autoolave (for an hour at 1 1 0°C ) and cooled to room temperature, while stirring, under' aseptic conditions. 1 00 gmso of 2 , 2 - ( 2~azatetramethylene) adamantane' with a particle size of 1 m^u to 1 0 m' were' sterilized "b 'dry he.ating at 1 50°C for 1 hour. After cooling, the substance was suspended in 800 mis. of the liquid obtained in accordance with the above. rescriptiono The suspension was supplemented with a similar liquid up to 1000 mis., stirred until it was homogeneous and worked up into ampoules of 2 mis, each. . .. . . ..

Manufacture of tablets 200 gms. of 2 p 2-(N~methyl-2'=azatetramethylene)"adamantane HC1, 335 gms. of lactose and 30 gms.. of potato, starch were mixed until a homogeneous mixture was obtainedo The mixture was wetted with a solution of gelatin in water. The moist mass was granulated and dried at 45 whereafter the mass was again gra-nulatedo Subsequently the granules were mixed with 25 gms. of talc, 5 ms. of stearate and 30 gms. of potato starch. The resulting mixture was compressed to form tablets of 65Ο mgm. each. Manufacture of coated tablets The manufacture of coated tablets was carried out in a similar . manner as for tablets, except that biconvex instead of flat tablets were formed and provided with a sugar and glassy layer. Manufacture of suppositories 200 gms. of 2 , 2- ( 2-azatetramethylene)-adamantane sulphuric acid sieved through a 100 —mesh sieve were added, while stirring, to 1 0 gms. of suppository mass heated to 37?C° After a homogeneous paste had been obtained, the mixture was worked up into suppen forms of 1 . 5 mis. each.

Examples. _1_a Adamantylidene°-2-c.yanoacetic-acid ethylester PHN 2580 C. 0.7 gms. of ammonium acetate in 1 β 14 mis. of glacial acetic acid were added to 1 gms of adamantanone dis&olved in 50 mis of benzene o The mixture was boiled with reflux, while stirring, for 3 hours. The water produced was collected in a water separator. The benzene layer was washed once with a solution of soda and. washed twice with water. The benzene was dried on MgSO^ and then removed in vacuo. The residue was recrystallised from 75$ ethanol. Melting point between 80o5° C and 82° Co . ' 1b 2-Gyano~2-cyanomethyladamantane 64 gms. of KCN in 140 mls0 of water were added to a solution of 100 gms. of adamanthylidene=2-cyanoacetic-acid ethyl ester in 800 mis. of ethanol. The mixture was stirred at 6 °C for 16 hours. After cooling, the deposit was sucked off, washed wit 7 $ ethanol and dried on a steam bath. The filtrate was evaporated to a small volume. The resulting solid material was filtered, washed with 0$ ethanol and dried..

A second amount of substance was obtained from the residue by shaking it with 4 0 mis. of water and 50 mis. of 2N 0H, then shaking with diethylether and evaporating the ether solution to dryness. Melting point of the two fractions between 126.5°C 1 c 2, 2~(2-oxa°°1 «.5"diketotetramethylene )adamantane 76 gms. of 2=cyano~2=cyanomethyladamantane were dissolved in 750 mis. of concentrated sulphuric acid heated to 90°C. The solution was shaken for minutes and then poured on 12 litres of ice.

The liquid was neutralised with 50$ natron lye, followed by heating above steam for 1 hour. The solid material was than filtered, washed with water and dried. The resulting substance was then introduced into 2 litres of concentrated hydrochloric acid and heated above steam. After the substance had dissolved ΡΗΝ 2580 C< completely8 there was heated for another' 1-jjr hours. After cooling, the deposit was sucked off and washed with water. -The substanoe was dissolved in litres of boiling benzene, the benzene layer was separated from a water layer formed and ccoled down to.10°C The crystallisate was sucked off · and washed with benzene. Melting point between 226CC and 229°C. " 1 d 2 , 2-( 2°aza»1 , 3~diketotetrameth.yleneQadamantane 52.1 gms. of 2 , 2- ( 2-oxa~1 , 5-diketO'tetramethylene)adamantane were melted in an atmosphere of ammonia, the ammonia being passed through at a rate of 4 litres/hour for 4 hours. The substance was recrystallised from ·§■ litre of ethanol. Melting point between 187°C and 189°C. 1e 2 , 2~( 2°azatetramethylene )adamantane .HCl 40 gms. of LIAIH^ were dissolved in 1 litre of absolute tetrahy-drofuran. 45 <> 1 gms of 2 , 2-( 2=aza~1 s 3=diketotetramethylene )adaman-tane were added in small portions to this solution, followed.Vby refluxing for 85 hours. The complexes were subsequently decomposed using 55 mis. of water, the hydroxides sucked off, boiled twice with half a litre of diethylether and again sucked off„ 90 mis of N HCl were, added to the filtrate and the washing liquids. The liquid was evaporated in vacuo to 100 mis and then heated to boiling point* After cooling, the crystallisate was sucked off9 washed with ethanol and dried above K0Ho. Melting point between 252°C and 254° 0. 2a 2-(N°me thylcarboxamidomethylJj^2°carboxyadamantane 6.60 gms. of 2 , 2~( 2~oxa~1 ,3~diketotetramethylene)adamantane were dissolved in 100 mis of hot benzene and added, while stirring, to an equimolar amount of me h lamine in 60 mls0 of benzene heated to a temperature between 60°C and 65°C0 After stirring for half an hour at 60°C, the deposit was sucked' off and washed ° ° ΡΗίτ 2580 c: 2b 2 .2-(N-methyl-2∞aza~1 ? 5-diketotetrametnylene )adamantane 6 gms of 2-(N-methylcarboxamidome'thyl ) -=2-carboxyadamantane were heated in an atmosphere of nitrogen up to -1 °C above' -its melting. point for 50 minuteso The substance ,· .after cooling, was recrys- 5 tallised from ethanolo Melting point between 2'1 4°C and 216°C. 2c 2 , 2-(N-methyl-2-azatet-ramethylene )°adamantane oHCl.. ms. of 2 , 2-(lT»meth l~2-=aza-1 9 "diketO--tetrame-thyle e)-adaman-. tane were dissolved in 1 00 mis. of tetrahydrofura 0 LiAlH^ was. added to the solution in a- 1 00 excess, followed by refluxing for 5 days. The complexe^ were then decomposed with the aid of approximately 6 mis. of water. The- deposited hydroxides were sucked off, boiled twice with 50 mis, of ether and then filtered-.

The collected filtrates were added to 1 0 mis. of .2½- N alcoholic hydrochloric acid« The mixture was . evaporated in vacuo to 10 mls0 and then 1 5 heated to boiling., Ethanol was added to an amount such that a clear solution is obtained. After the solution had been evaporated to dryness, the residue was crystallised from ethanol/benzene 1810 Melting point between 267®<C and 268eC0 3. 2 a 2~(N-methyl-2°azatetramethylene)adamantane_h drochloride 2 mis, of a formalin solution ( 37 ) and 200 mgs. of platinum oxide were added to a solution of 1.2 gms. of 292- ( 2=azatetra=' methylene )adamantane in mis. of 6$ ethanol. The reaction mixture was shaken under Hg ( 4 at.) for 1 6 hours, whereafter the catalyst was filtered off. The filtrate was acidified with hydro- 25 chloric acid and then evaporated to dryness in vacuo0 After crystallisation of the resulting residue from ether 1 s 1 2, 2~(]J=>meth l-2~azatetramethylene)~ adamantane hydro» chloride was obtained. Melting point between 265eC and 267°C.

P-HN 2580 C is 2 ? 2- (H-ace tyl -2-azatetrame th 1ene )adamantane 2.45 gms. of 2 , 2-(2-azatetramethylene )adamantane were dissolved in 5 mis. of acetic acid anhydride . The reaction mixture was heated to 100°C and, after cooling, poured into -15 mis. of water. After heating at 80°C for several minute's and coolin to room temperature, the reaction mixture was extracted with chloroform. The extract was washed with a solution of sodium'b carbonate and with water and, after drying, on sodium sulphate- evaporated to dryness. The residue is crystallised from petroleum ether (40°G - 50°C) at ~20°C. The product obtained had a melting point between 43°C and 45°Co . . . . 2 2.. 3377 nniiss.. ooff 22ss22--((NN--aacceettyyll~~22--aazzaatteettrraammeetthhyylleennee))aaddaammaannttaannee wwaass aaddddeedd iinn ssmmaallll ppoorrttiioonnss ttoo aa ssttiirrrreedd ssuussppeennssiioonn ooff 11 ggnmu. ooff LLiiAAllHH^^ iinn 4400 mmiiss.. ooff aabbssoolluuttee tteettrraahhyyddrrooffuurraann,,.. AAfftteerr tthhee rreeaacc¬ttiioonn mmiixxttuurree hhaadd bbeeeenn bbooiilleedd ffoorr 1166 hhoouurrss uunnddeerr aa rreefflluuxx ccoooolleerr wwiitthh tthhee eexxcclluussiioonn ooff mmooiissttuurree 99 iitt wwaass ccoooolleedd ddoowwnn99 wwhheerreeaafftteerr aa mmiixxttuurree ccoonnssiissttiinngg ooff 33 mmiiss.. ooff tteettrraahhyyddrrooffuurraann aanndd 33 mmllee ooff wwaatteerr iiss sslloowwllyy ddrrooppppeedd iinn wwhhiillee ssttiirrrriinngg.. TThhee rreeaaccttiioonn mmiixxttuurree wwaass tthheenn ssuucckkeedd aanndd tthhee rreessiidduuee iinntteennsseellyy wwaasshheedd wwiitthh aabbssoolluuttee tteettrraahhyyddrrooffuurraann.. TThhee ffiillttrraattee wwaass aacciiddiiffiieedd wwiitthh aa ssoolluuttiioonn ooff HHCC11 iinn ddiieetthhyylleetthheerr.. TThhee ccrryyssttaalllliisseedd pprroodduucctt wwaass ffiilltteerreedd aanndd rreeccrryyssttaalllliisseedd ffrroomm eetthhaannooll//ddiieetthhyylleefcfchheerr 11ss11.. AA ssuubbssttaannccee wwaass oobbttaaiinneedd hhaavviinngg aa mmeellttiinngg--ppooiinntt bbeettwweeeenn 226666°°CC aanndd 226688eeCC.. 16.44 mse of 2 , 2-(2~azatetramethylene )adamantane were dissolved in 0 mis. of absolute ethanol and 35 mis. of triethylamine were added to the solution. Subsequentl · 1 7 gms, of propargylbromide were dropped inp while cooling in. ice and stirring9 within +_ 5 minutes., The reaction mixture was heated to boiling and cooled down immediately thereafter to room temperature . Crystallised product was sucked off. The filtrate was evaporated to dryness and 50 mis,, of water were added to the residue 0 The resulting emulsion was extracted with the aid of diethylether and, after washing with water and drying on Na^SO^ 9 the extract was acidified with etheric hydrochloric acid„ The deposit produced was sucked off and crystallised twice from water, A crystalline product was obtained having a melting point between 225°C and 226°C (sealed tube ) o 6f ., 2-aminoe thyl-2-aminome thyladamantane-dihydrochloride 6 ml So of 3o8,5 n alcoholic hydrochloric acid and 200 mgs0 of platinum oxide were added to a solution of 2 gms0 of 2*-cyano-2-cyanome hyl adamantane in 2 mls» of ethanol 0 The reaction mixture was shaken under (4 at0 ) for " 6 hours, followed- by filtering off the catalyst,, The filtrate was evaporated to dryness in vacuo, Crystallisation of the resulting residue from ethanol /diethyle her yielded 2-aminoe hyl-2-aminomethyladamantane di hydro chloride of melting point 281°C to 283°C 6bo 2 2-( 2 agate trame thylene )adamantane 0 HC1 1 „ 5 niSo of 2-amonoe hyl -2-aminome thyl -adamantane dihydrochloride were heated to 350 C in a metal bath for 3 minute s» The residue was dissolved in water and washed once with 15 mis. of diethylethe , The aqueous solution. as made basic by adding 6 mls0 of 2 n NaOH and extracting twice with diethylether 0 The collected extracts were washed once in water5 dried on magnesium sulphate and acidified with alcoholic hydrochloric acid to produce a weakly acid reaction. The crystallised p oduot was filtered off and recrystallised from ethanol/ diethylether ( 1 S 1 ) „ The resulting product melted at 252°C to 254°C„

Claims (1)

1o A method of manufacturing spiro-azatetramethylene derivatives, characterized in that oompounds of formula I and salts thereof with pharmaceutically acceptable . acids, in which formula R is a hydrogen atom, an n-alkyl group having up to '3 carbon atoms or a propargyl group;, are prepared by methods which are known for the preparation of this S?in.d of oompounds or by methods analogous thereto,, o A method as claimed in Claim 1 , characterized in that compounds of ormula II where R' is a hydrogen atom or an n-alkyl group having up to 3 carbon atoms, and salts thereof with pharmaceutically acceptable acids are manufactured by reducing a compound of formula III V where Y and Y' each, represent a double-"bonded ossjrgen &torn ¾¾·.. one of them represents two hydrogen atoms,, 3c A method as olaimed in Claim 1 , characterized in that compounds of formula IV where R" represents an n-alkyl group having up to 3 carbon atoms, or a propargyl group and salts thereof with pharmaceutically acceptable aoids are manufactured by alkylating 2,2-(2-azatetra-methylene)adamantane with a compound R"Hal or R'^SO^, where Hal is a halogen atom0 o A method as claimed in Claim 1 , characterized in that oom«= pounds of formula V where R"' represents an n-alkyl group having up to 3 carbon atoms, and salts thereof with pharmaceutically acceptable acids are manufactured by reductively alkylating 2,2-(2-azatetrame~ thylene )adamantane0 5„ A method as claimed in Claim 1, characterized in that compounds of formula V where R"' represents an n-alkyl group having up to 3 carbon atoms, and salts thereof with pharmaceutically acceptable acids are manufactured by acylating and then reducing 2, 2—( 2-azatetra-methylene)adamantane0 -6. A method as claimed in Claim t , characterized in that 2 , 2-(ltf-propargy -2- azatetramethylene )adamantane- and salts, thereof with pharmaceutically acceptable acids are ■ manufactmred by dehydrobrominating a compound of formula VI where .^ represents the group -CBr=>CH2 or the group -CHBr-CHgBr. 7. A methqd as claimed in Claim 19 characterized in that 2, 2-(N-propargyl-2-azatetramethylene)adamantane and salts thereof with pharmaceutically acceptable acids are manufactured by reacting 2,2-(2-azatetrame.thylene)adamantane with formaldehyde and acetylene.. 8. A method as claimed in Claim 1,. characterized in that 2,2-(2-azatetramethylene )adamantane and salts thereof with pharmaceutically acceptable acid are obtained by heating 2-aminoethyl-2-amino-methyl adamantane or salts thereof at temperatures above their melting point 0 im 1. and salts thereof with pharmaceutica y acceptable acids0 10o 2, 2- ( 2-azatetramethylene )adamantane and salts thereof with pharmaceutically acceptable acidSo 11 o 2ip2~(N-methyl-2-azatetramethylene )adamantane and salts thereof with pharmaceutically acceptable acids „ ■ 12. 2,2-(N-ethyl-2-azatetramethylene)adamantane and salts thereof with pharmaceutically acceptable acids „