NO118797B

NO118797B -

Info

Publication number: NO118797B
Application number: NO15651365A
Authority: NO
Inventors: J Klosa
Original assignee: Hans Voigt Chem Pharmfabrik Dr
Priority date: 1964-01-28
Filing date: 1965-01-27
Publication date: 1970-02-16
Also published as: FR7186M; SE328300B; AT261128B; CH470382A; BE658726A; GB1099032A; DE1445975A1

Description

Fremgangsmåte ved fremstilling av nye, terapeutisk aktive, krystallinske, vannopplttselige addukter av rutinderivater. Process for the production of new, therapeutically active, crystalline, water-soluble adducts of rutin derivatives.

Foreliggende oppfinnelse angår en fremgangsmåte ved fremstilling av nye,terapeutisk aktive, krystallinske, vannopploselige addukter av rutinderivater av formelen: The present invention relates to a method for the production of new, therapeutically active, crystalline, water-soluble adducts of rutin derivatives of the formula:

hvor R og R-p som kan være like eller forskjellige, er eventuelt forgrenede alkylgrupper med 1-5 carbonatomer, eller R og R-j^ where R and R-p, which may be the same or different, are optionally branched alkyl groups with 1-5 carbon atoms, or R and R-j^

danner sammen med det nitrogenatom til hvilket de er bundet, en piperidin-, pyrrolidin- eller; morfolinring, og Z er salicylsyre, acetylsalicylsyre, nicotinsyre, isonicotinsyre, picolinsyre, aescin, form, together with the nitrogen atom to which they are attached, a piperidine, pyrrolidine or; morpholine ring, and Z is salicylic acid, acetylsalicylic acid, nicotinic acid, isonicotinic acid, picolinic acid, aescin,

orotsyre, rutin, hesperidin, coffein , theofyllin, theobromin,5-fenyl-5-ethyl-barbitursyre, 2-methyl-2-n-propyl-l,3-propandiol-l, 1-carbaminsyre, p-klorfenol, eller et i 6-stillingen med halogen, lavere alkyl eller halogen-lavere alkyl substituert 7-sulfonamido-3,<1>+-dihydro-l,2,<l>f-benzothiadiazin-l,l-dioxyd eller 7-sulfonamido-3,^-dihydro-3-benzyl-l,2,^-benzothiadiazin-1,1-dioxyd.<1>Der kommer altså ved adduktdannelse på tale slike sure grupper som er uopploselige eller tungtopploselige i vann og som bare kan gjores vannopploselige. med alkalier, slik at deres terapeutiske virkning er betraktelig innskrenket. orotic acid, rutin, hesperidin, caffeine, theophylline, theobromine, 5-phenyl-5-ethyl-barbituric acid, 2-methyl-2-n-propyl-1,3-propanediol-1, 1-carbamic acid, p-chlorophenol, or a in the 6-position with halogen, lower alkyl or halogen-lower alkyl substituted 7-sulfonamido-3,<1>+-dihydro-1,2,<l>f-benzothiadiazine-1,1-dioxyde or 7-sulfonamido-3 ,^-dihydro-3-benzyl-1,2,^-benzothiadiazine-1,1-dioxyd.<1>Thus, in the case of adduct formation, such acidic groups are in question which are insoluble or poorly soluble in water and which can only be made water soluble. with alkalis, so that their therapeutic effect is considerably reduced.

Ifolge oppfinnelsen omsettes, eventuelt in situ dannede, N-substituerte amino-methyl-rutiner av formelen: According to the invention, N-substituted amino-methyl-rutins, possibly formed in situ, are converted by the formula:

hvor R og R^er som ovenfor angitt, med de angitte sure forbindelser where R and R^ are as indicated above, with the indicated acidic compounds

Z. Z.

Det skal her pekes på at dannelsen av.de nye komplekser respektive addukter ikke kan sammenlignes med en saltdannelse i konven-sjonell betydning. It should be pointed out here that the formation of the new complexes or adducts cannot be compared to a salt formation in the conventional sense.

Det er ikke påvist, og er ikke kjent, på hvilket sted i rutin-molekylet den N-substituerte aminomethylgruppe inngår, og av den grunn betegner man disse stoffer som x-N-substituert-aminomethyl-rutin. It has not been proven, and is not known, at which place in the rutin molecule the N-substituted aminomethyl group is included, and for that reason these substances are referred to as x-N-substituted-aminomethyl-rutin.

Mange kondensasjonsprodukter mellom fenoler av forskjellige slag, primære og sekundære aminer såvel som formaldehyd, er kjent. Av slike fenolbaser er kjent at de er desto mere tungtopploselige i vann jo tallrikere hydroxylgruppene er tilstede eller jo flere kon-denserte ringer molekylet inneholder. Således er for eksempel hydro-kloridene av dialkylaminomethylnafthol meget tungtopploselig i vann. Vanligvis faller de mineral sure salter ut allerede fra 2#-ige vandige opplosninger, dessuten inntrer ved kokning i vann spaltning og harpiksdannelse. Denne harpiksdannelse er alltid desto mere sann-synlig jo storre antall hydroxylgrupper der er og desto storre molekylet er. Many condensation products between phenols of various kinds, primary and secondary amines as well as formaldehyde are known. Of such phenolic bases it is known that they are more poorly soluble in water the more numerous the hydroxyl groups are present or the more condensed rings the molecule contains. Thus, for example, the hydrochlorides of dialkylaminomethylnaphthol are very poorly soluble in water. Generally, the mineral acid salts already precipitate from 2# aqueous solutions, moreover, decomposition and resin formation occur when boiling in water. This resin formation is always all the more likely the greater the number of hydroxyl groups there and the larger the molecule.

Det var derfor å vente for en fagmann at tilsvarende baser av rutin overhodet ikke ville være i stand til å danne salter med sure forbindelser eller å danne tilsvårénde molekylærforbind- eiser, og altså slett ikke at slike salter ville være meget lett opploselige i vann. It was therefore to be expected by a person skilled in the art that corresponding bases of rutin would not be able to form salts with acidic compounds or to form complicating molecular compounds, and therefore not at all that such salts would be very easily soluble in water.

Faktisk er der i sveitsisk patent nr. 3^8.710 beskrevet visse derivater av polyoxyflavoner, aminer og formaldehyd. Ifolge eksemplet i dette patent ble hesperetin omsatt med dimethylamin og formaldehyd i vandig medium under nitrogen ved kokning idet ut-vinningen skjedde ved fortynning med vann hvorved de nye produkter falt ut og lot seg overfore til methobromider med methylbromid. Fremstillingsmåten for disse kondensasjonsprodukter viser at disse forbindelser bare har en meget begrenset vannopploselighet, slik at det heller ikke ved disse på noen måte kunne forutsees at de med vannuopploselige sure forbindelser og andre tungtopploselige forbindelser som coffein ville gi så godt vannopploselige salter respektive molekylærforbindelser. In fact, Swiss Patent No. 38,710 describes certain derivatives of polyoxyflavones, amines and formaldehyde. According to the example in this patent, hesperetin was reacted with dimethylamine and formaldehyde in an aqueous medium under nitrogen by boiling, the extraction taking place by dilution with water, whereby the new products fell out and were converted to methobromides with methyl bromide. The manufacturing method for these condensation products shows that these compounds only have a very limited water solubility, so that it could not be predicted in any way that those with water-insoluble acidic compounds and other sparingly soluble compounds such as caffeine would give such well-water-soluble salts as the respective molecular compounds.

I DAS 1.12^.95^ nevnes riktignok en opplosningsformidlende virkning av rutin på theofyllin, men på den ene side er opplosnings-formidlingen liten, og på den annen side er isoleringen av slike komplekser i krystallinsk form umulig. Dialkylaminoalkoxyrutiner, som dannes ifolge britisk patentskrift 677-^93?er ikke istand til å overfore vannuopploselige forbindelser som theofyllin til vannopploselige molekylærforbindelser. Foreliggende oppfinnelse har ingen likhet med fremgangsmåtene i DAS 1.12<1>+.95<1>+ eller britisk patentskrift 677-^93?da det ved foreliggende oppfinnelse skjer en ny dannelse av addukter mellom N-substituert-aminoalkylrutin og forbindelser av meget forskjellige forbindelsesklasser som er tungt opploselige i vann. In DAS 1.12^.95^ it is true that a dissolution-promoting effect of rutin on theophylline is mentioned, but on the one hand the dissolution-promoting effect is small, and on the other hand the isolation of such complexes in crystalline form is impossible. Dialkylamino alkoxy rutins, which are formed according to British patent specification 677-93, are not capable of converting water-insoluble compounds such as theophylline into water-soluble molecular compounds. The present invention has no similarity with the methods in DAS 1.12<1>+.95<1>+ or British patent document 677-^93?as in the present invention a new formation of adducts between N-substituted-aminoalkylrutin and compounds of very different compound classes that are poorly soluble in water.

Dessuten har fremgangsmåteforbindelsene en klart overlegen virkning ved dyreforsok, som det fremgår av folgende tabell. In addition, the process compounds have a clearly superior effect in animal experiments, as can be seen from the following table.

Som AD^q betegnes den dose som er virksom mot dextranodem hos 50 % av rottene. Forbindelsene 1-3 var også uvirksomme ved doser på 50 % av DL^q. AD^q is the dose that is effective against dextranedema in 50% of the rats. Compounds 1-3 were also inactive at doses of 50% of DL^q.

Dette viser også en uventet farmakodyamisk virkning idet det særlig henvises til den inflammasjonshemmende virkning. This also shows an unexpected pharmacodynamic effect, with particular reference to the anti-inflammatory effect.

Ved hjelp av oppfinnelsen er det mulig,å fremstille vannopploselige salter eller addukter av forbindelser som er vannuopp- ' loselige eller tungt opploselige, uten å måtte utfore en kvater-nering. With the aid of the invention, it is possible to prepare water-soluble salts or adducts of compounds which are water-insoluble or poorly soluble, without having to perform a quaternization.

Det er overraskende at for eksempel dialkylaminomethyl-rutin er istand til med theofyllin, nicotinsyre og lignende forbindelser å danne salter i vann, som ved vanlig temperatur er 80 - 90 % vannopploselige. It is surprising that, for example, dialkylaminomethyl-rutin is able to form salts in water with theophylline, nicotinic acid and similar compounds, which at ordinary temperatures are 80 - 90% water-soluble.

Dessuten tillater slike salter, for eksempel x-diethylaminomethyl-rutin-theofyllinatet ganske spesielle anvendelses-former av theofyllin, som den perlinguale anvendelse. Det er således kjent at de kjente theofyllinsalter har meget bitter smak. Ved den nye saltdannelse er den bitre smak av theofyllinet sterkt avsvekket. Dessuten er det betydningsfullt at opplbsningene rea-gerer praktisk talt noytralt og at intet theofyllin vil falle ut selv fra 80 %- i. g opplbsning av saltene ved tilsetning av saltsyre respektive innstilling av pH på 1 - 3?hvilket alltid har vært regelen ved de tidligere salter av alkylen-diaminer, som ethylen-diamin eller ethanolamin. Foruten saltdannelsen har altså x-N-substituert-aminomethyl-rutinene spesielle opplosningsformidlende egenskaper som er uventet. Moreover, such salts, for example x-diethylaminomethyl-rutin-theophylline, allow quite special application forms of theophylline, such as the perlingual application. It is thus known that the known theophylline salts have a very bitter taste. With the new salt formation, the bitter taste of theophylline is greatly weakened. Furthermore, it is significant that the solutions react practically neutrally and that no theophylline will precipitate out even from 80% solution of the salts by adding hydrochloric acid or setting the pH to 1 - 3? which has always been the rule in the earlier salts of alkylene diamines, such as ethylene diamine or ethanolamine. In addition to salt formation, the x-N-substituted-aminomethyl-rutins therefore have special dissolution-mediating properties that are unexpected.

Ved noen salter, respektive molekylærforbindelser blir imidlertid de sure bestanddeler straks felt ved mineralsyretilset-ning, for eksempel ved orotsyresaltene blir således orotsyren straks felt ved pH 3 fra x-diethylaminomethyl-rutin-orotat. Ved det tilsvarende salicylat blir salicylsyren dog efterhvert utfelt til ca. V0 % i lopet av 6 timers henstand, mens de resterende 60 % må ut-rystes av opplosningen ved flere gangers ekstraksjon med ether. Likeledes felles rutinet bare litt efter litt fra x-N-substituert-aminomethyl-rutin-rutinatet av mineralsyrer. Den fullstendige ut-krystallisasjon fra en 50 #-ig oppløsning under tilsetning av saltsyre (pH 1-2) tar<*>*8 timer. In the case of some salts or molecular compounds, however, the acidic components are immediately precipitated by the addition of mineral acid, for example in the case of the orotic acid salts, the orotic acid is thus immediately precipitated at pH 3 from x-diethylaminomethyl-rutin-orotate. With the corresponding salicylate, however, the salicylic acid is gradually precipitated to approx. V0% in the course of 6 hours' standstill, while the remaining 60% must be shaken out of the solution by several extractions with ether. Likewise, the rutin only separates little by little from the x-N-substituted-aminomethyl-rutin rutinate of mineral acids. The complete crystallization from a 50 #-ig solution with the addition of hydrochloric acid (pH 1-2) takes<*>*8 hours.

Selv ora også Mannich-baser av fenoler kan gjores vannopploselige ved hjelp av mineralsyrer, var det ikke tidligere kjent fra noen av disse kjente forbindelser at de var istand til å overfore tungtopploselige forbindelser i slike salter eller molekylærforbindelser, for eksempel theofyllin, at stabile vandige oppløs-ninger kunne fåes også efter tilsetning av mineralsyrer, uten at de sure organiske forbindelser ble felt. Although Mannich bases of phenols can be made water-soluble by means of mineral acids, it was not previously known from any of these known compounds that they were capable of transferring sparingly soluble compounds into such salts or molecular compounds, for example theophylline, that stable aqueous dissolve -nings could also be obtained after the addition of mineral acids, without the acidic organic compounds being precipitated.

Foreliggende oppfinnelse er derfor overraskende og kunne ikke på noen måte forutsees. The present invention is therefore surprising and could not be foreseen in any way.

Det har nu vist seg at foreliggende fremgangsmåteprodukter kan fåes ved omsetning av x-N-substituert-aminomethyl-rutiner med de ovenfor angitte sure forbindelser Z i molarforhold 1:1, eventuelt i et opplbsnings- og fortynningsmidde1, som vann, lavere alkoholer, fortrinnsvis methanol, og inndampning av oppløsningen eller felning av de dannede salter med en egnet hoyere alkohol, som n-propanol, n-butanol, men fortrinnsvis isopropanol, et keton, som aceton, butanon, ether som diethylether, eller benzener som benzen, toluen, og lignende, eller petrolether. Man får gule krystallinske forbindelser eller også gule pulvere, som også loses i koldt vann inntil ca. 90 %. Saltene faller heller ikke ut av oppløsningene selv ved månedslang henstand. It has now been shown that the present process products can be obtained by reacting x-N-substituted-aminomethyl-rutins with the above-mentioned acidic compounds Z in a 1:1 molar ratio, possibly in a solvent and diluent1, such as water, lower alcohols, preferably methanol, and evaporation of the solution or precipitation of the formed salts with a suitable higher alcohol, such as n-propanol, n-butanol, but preferably isopropanol, a ketone, such as acetone, butanone, ether such as diethyl ether, or benzenes such as benzene, toluene, and the like , or petroleum ether. You get yellow crystalline compounds or yellow powders, which are also dissolved in cold water up to approx. 90%. The salts also do not fall out of the solutions even with a month-long delay.

Ifolge oppfinnelsen kan bestanddelene gnies med hverandre i molforholdet 1:1, fuktes med litt vann inntil oppløsning, opp-løsningen kan enten fortynnes videre med vann eller de dannede salter kan felles fra oppløsningen med et organisk, med vann bland-bart opplosningsmiddel, som isopropanol eller aceton. According to the invention, the components can be rubbed together in a 1:1 molar ratio, moistened with a little water until dissolved, the solution can either be further diluted with water or the formed salts can be precipitated from the solution with an organic, water-miscible solvent, such as isopropanol or acetone.

Ifolge oppfinnelsen kan imidlertid også rutin kokes med aminer, som dialkylamin og formaldehyd i molarforhold i en lavere alkohol, som methanol. Efterat alt er opplost, og efterat over-flødige produkter av basen, som dimethyl--, diethylamin, og lignende, er avdrevet i et svakt vakuum, tilsettes til saltdannelsen bestemte sure forbindelser Z i angitte mengder, der opphetes på nytt i 10 - 20 minutter til kokning og derpå felles den nye salt ved tilsetning av isopropanol. According to the invention, however, rutin can also be boiled with amines, such as dialkylamine and formaldehyde in a molar ratio in a lower alcohol, such as methanol. After everything has dissolved, and after excess products of the base, such as dimethyl-, diethylamine, and the like, have been driven off in a weak vacuum, acidic compounds Z determined for the salt formation are added in specified quantities, where they are heated again for 10 - 20 minutes until boiling and then add the new salt by adding isopropanol.

Som baser for dannelsen av x-N-substituert-amino-rutiner kommer på tale: dimethylamin, diethylamin, As bases for the formation of x-N-substituted-amino-routines the following are mentioned: dimethylamine, diethylamine,

dipropylamin, dibutylamin og lignende. dipropylamine, dibutylamine and the like.

De således erholdte nye salter og molekylærforbindelser av x-dialkyl- -aminomethyl-rutiner anvendes i form av oppløsninger, smakelige drikker, tabletter, drageer, ampuller, salver, pulvere og lignende som legemiddel ved behandling av mennesker og dyr. The thus obtained new salts and molecular compounds of x-dialkyl-aminomethyl-rutins are used in the form of solutions, palatable drinks, tablets, dragees, ampoules, ointments, powders and the like as medicine in the treatment of humans and animals.

Der skal gies noen eksempler på fremstillingen av de nye salter og molekylærforbindelser. Some examples of the production of the new salts and molecular compounds will be given.

Eksempel 1Example 1

69,6 g x-diethylaminoraethyl-rutin suspenderes i 150 ml methanol. Man tilsetter 18 g theofyllin og koker i 30 minutter slik at der inntrer praktisk talt fullstendig opplesning, derpå filtreres varmt, det gule filtrat tilsettes 100 ml isopropanol under omroring. Der faller straks ut et tykt, lysende gult'bunnfall, som efter 2-3 timers henstand antar en kornig beskaffenhet. Utbyttet er 85 g x-diethylaminomethyl-rutin-theofyllinat. Smeltepunkt: fra 230°C farveomslag til okergult, ved 255°C brunt, fra 270°C fortlopende spaltning. 69.6 g of x-diethylaminoraethyl-rutin are suspended in 150 ml of methanol. 18 g of theophylline are added and boiled for 30 minutes so that a practically complete reading occurs, then filtered hot, the yellow filtrate is added to 100 ml of isopropanol while stirring. A thick, bright yellow precipitate immediately falls out, which after 2-3 hours' rest takes on a grainy nature. The yield is 85 g of x-diethylaminomethyl-rutin-theophylline. Melting point: from 230°C color change to ocher yellow, at 255°C brown, from 270°C continuous decomposition.

9 g opploses lett i 10 ml koldt vann.9 g dissolves easily in 10 ml of cold water.

Analog med 5-fenyl-5-ethylbarbitursyre = x-diethylamino-methyl-rutin-(5-fenyl-5-ethyl-barbiturat). Smeltepunkt: over 300°C. Analogous to 5-phenyl-5-ethylbarbituric acid = x-diethylamino-methyl-rutin-(5-phenyl-5-ethyl-barbiturate). Melting point: over 300°C.

3 g er opploselig i 10 ml vann.3 g is soluble in 10 ml of water.

Eksempel 2Example 2

69,6 g x-diethylaminoraethyl-rutin ble suspendert i 150 - 200 ml methanol. Til dette ble tilsatt 13 g (0,7 g overskudd) nicotinsyre. Derpå ble reaksjonsblandingen kokt under tilbakelop i 30 minutter på vannbad til fullstendig opplosning, det ble filtrert varmt og filtratet tilsatt 300 ml isopropanol. Der falt ut et gult voluminost bunnfall som efter noen timers henstand ble kornig gult og lett filtrerbart. Utbytte: 8k g x-diethylaminomethyl-rutin-nicotinat. 10 ral vann opploser lett 8 g av denne forbindelse ved vanlig temperatur. Smeltepunkt: fra 206°C går den gule farve over i brunt, fra 300°C spaltning. 69.6 g of x-diethylaminoraethyl-rutin was suspended in 150-200 ml of methanol. To this was added 13 g (0.7 g excess) of nicotinic acid. The reaction mixture was then boiled under reflux for 30 minutes on a water bath until complete dissolution, it was filtered while hot and 300 ml of isopropanol was added to the filtrate. A yellow voluminous precipitate fell out which, after a few hours' delay, became granular yellow and easily filterable. Yield: 8k g x-diethylaminomethyl-rutin-nicotinate. 10 ral of water easily dissolves 8 g of this compound at ordinary temperature. Melting point: from 206°C the yellow color changes to brown, from 300°C decomposition.

EksempelExample

6,9 g x-diethylaminomethyl-rutin ble gnidd med 1,8 g theobromin. Blandingen ble omrort med 20 ml vann på dampbad i 10 minutter og omrort ytterligere 3 til k timer ved vanlig temperatur. Der inntrådte fullstendig opplosning. Man filtrerer fra en blakning og tilsetter enten filtratet isopropanol eller aceton og feller 6.9 g of x-diethylaminomethyl-rutin was rubbed with 1.8 g of theobromine. The mixture was stirred with 20 ml of water on a steam bath for 10 minutes and stirred for a further 3 to 10 hours at ordinary temperature. Complete dissolution occurred. One filters from a blank and adds either isopropanol or acetone to the filtrate and traps

derved theobrominatet ifolge eksempel 1 eller fortynner det efter onske med vann eller damper den vandige opplosning inn i vakuum til sirupkonsistens, hvorved efter gnidning med isopropanol, kry-stallisasjon inntrer. Smeltepunkt: fra 260°C begynner spaltning under brunfarvning. thereby the theobrominate according to example 1 or dilutes it as desired with water or evaporates the aqueous solution into a vacuum to a syrup consistency, whereby after rubbing with isopropanol, crystallization occurs. Melting point: from 260°C decomposition begins during browning.

Eksempel * fExample * f

66,<*>+ g vandig rutin (handelsvare) suspenderes i 150 ml methanol, man tilsetter 6 g dimethylamin (overskudd) hvorved fullstendig opplosning av rutinet inntrer. Derpå tilsettes h ml av en 37 /6-ig formalinopplosning og det hele oppvarmes i 30 minutter på vannbad til kokning. Derpå avdestilleres h- 0 ml methanol i vakuum hvorved overskudd av dimethylamin såvel som formalin går over. 66.<*>+ g of aqueous rutin (commercial product) is suspended in 150 ml of methanol, 6 g of dimethylamine (excess) is added, whereby complete dissolution of the rutin occurs. Then h ml of a 37/6 formalin solution is added and the whole is heated for 30 minutes in a water bath until boiling. Then h-0 ml of methanol is distilled off in a vacuum whereby excess dimethylamine as well as formalin is transferred.

Derpå tilsettes den gule opplosning 17 g orotsyre og der kokes i ytterligere 30 minutter på vannbadet. Man filtrerer varmt og feller x-dimethylaminomethyl-rutin-orotsyresalt som et gult pulver med 200 ml isopropanol. Utbytte: 83 g. Smeltepunkt: fra 2<1>+0°C spaltning. Produktet er opploselig i vann inntil 70 %. 17 g of orotic acid is then added to the yellow solution and boiled for a further 30 minutes in the water bath. Filter hot and precipitate x-dimethylaminomethyl-rutin-orotic acid salt as a yellow powder with 200 ml of isopropanol. Yield: 83 g. Melting point: from 2<1>+0°C cleavage. The product is soluble in water up to 70%.

Analog med x-diethylaminomethyl-rutin = x-diethylamino-methyl-rutin-orotat: smeltepunkt l80°C under oppblæring, brun farve, fra 230°C spaltning. Analogous with x-diethylaminomethyl-rutin = x-diethylamino-methyl-rutin-orotate: melting point l80°C during swelling, brown colour, from 230°C decomposition.

Analog ifolge eksempel 1 = x-morfolinomethyl-rutin-salicylat, smeltepunkt: fra 230°C brunt, fra 250°C spaltning. Utbytte 85 %, opploselig inntil 90 % i vann, smak behagelig sot. Analog according to example 1 = x-morpholinomethyl-rutin-salicylate, melting point: from 230°C brown, from 250°C decomposition. Yield 85%, soluble up to 90% in water, pleasant soot taste.

Analog: x-piperidinomethyl-rutin-coffein, utbytte 95 % i smeltepunkt: fra 260°C spaltning, opploselig inntil 80 % i vann. Analogue: x-piperidinomethyl-rutin-caffeine, yield 95% in melting point: from 260°C decomposition, soluble up to 80% in water.

x-diethylaminomethyl-rutin-2-methyl-2-n-propyl-l,3-propan-diol-1,1-carbamat, smeltepunkt over 300°C, 2 g loses i 10 ml vann ved 18 - 20°C. x-diethylaminomethyl-rutin-2-methyl-2-n-propyl-1,3-propane-diol-1,1-carbamate, melting point above 300°C, 2 g are dissolved in 10 ml of water at 18 - 20°C.

Eksempel 5Example 5

13,8 g x-diethylaminomethyl-rutin ble suspendert i ca.13.8 g of x-diethylaminomethyl-rutin was suspended for approx.

50 ml methanol. Derpå ble h g (lite overskudd) acetylsalicylsyre i fast form tilsatt porsjonsvis under roring. Alt så nær som en liten rest opplostes med en dyp brun-gul farve. Derpå ble det oppvarmet på vannbad ved hO - 50°C i nok 10-15 minutter under omroring, det ble filtrert og filtratet tilsatt 100 ml aceton. Der felles straks et dypt gult bunnfall, som efter noen timers henstand kry-stalliserte, det ble avsuget, vasket med isopropanol, og ved opplosning i varm methanol og fornyet felning kan x-diethylaminomethyl- rutin-acetylsalicylatet renses. Utbytte var 95 % i smeltepunkt: sintret ved l80°C under farveskiftning, farven blir brun og spaltning foregår, ved 250°C mork harpiks. Smaken er behagelig sot. 50 ml of methanol. Then h g (slight excess) acetylsalicylic acid in solid form was added in portions while stirring. Anything as close as a small residue dissolves with a deep brown-yellow color. It was then heated in a water bath at h0 - 50°C for another 10-15 minutes with stirring, filtered and 100 ml of acetone added to the filtrate. There immediately falls a deep yellow precipitate, which after a few hours' delay crystallized, it was suctioned off, washed with isopropanol, and by dissolving in hot methanol and renewed precipitation, the x-diethylaminomethyl-rutin-acetylsalicylate can be purified. Yield was 95% in melting point: sintered at 180°C during color change, color becomes brown and cleavage takes place, at 250°C dark resin. The taste is pleasantly sooty.

Eksempel 6Example 6

13,8 g x-diethylamino-methyl-rutin ble suspendert i 100 ml methanol. Man tilsetter 12,6 g rutin, oppvarmer under omroring ved 50 - 60°C på vannbad i 20 minutter slik at fullstendig opplosning inntrer, farven er brungul. Derpå blir oppløsningen tilsatt 100 ml isopropanol under omroring. Der felles et lysende gult bunnfall som efter noen timers henstand suges av og vaskes med isopropanol. Rensning ved opplosning i methanol og felning med isopropanol. Utbytte 95 %. Opploselig i vann ved vanlig temperatur itil 70 %. Smeltepunkt: fra 260°C går den lysende gule farve i brun, fra 300°C spaltning. 13.8 g of x-diethylamino-methyl-rutin was suspended in 100 ml of methanol. 12.6 g of rutin are added, heated with stirring at 50 - 60°C in a water bath for 20 minutes so that complete dissolution occurs, the color is brownish yellow. 100 ml of isopropanol is then added to the solution while stirring. A bright yellow precipitate falls which, after a few hours' rest, is sucked off and washed with isopropanol. Purification by dissolving in methanol and precipitation with isopropanol. Yield 95%. Soluble in water at normal temperature up to 70%. Melting point: from 260°C the bright yellow color changes to brown, from 300°C decomposition.

Analog med p-klorfenol og x-piperidino-methyl-rutin medAnalogous with p-chlorophenol and x-piperidino-methyl-rutin with

85 %- ±g utbytte: i 85%-±g yield: i

x-piperidino-methyl-rutin-p-klorfenolat, smeltepunkt fra 230°C under fremad skridende spaltning, 3,5 g loses, i 10 ml vann ved 18 - 20°C. x-piperidino-methyl-rutin-p-chlorophenolate, melting point from 230°C during progressive decomposition, 3.5 g dissolved in 10 ml of water at 18 - 20°C.

Eksempel 7Example 7

13,8 g x-diethylaminomethyl-rutin ble suspendert i 60 ml methanol. Derpå ble 5,8 g 6-klor-7-sulfonamido-3,^-dihydro-l,2, h-benzothiadiazin-1,1-dioxyd som var godt pulverisert, tilsatt under omroring. Mann oppvarmer i 15 - 20 minutter på vannbad ved h0 - 50°C hvorved alt går i opplosning. 13.8 g of x-diethylaminomethyl-rutin was suspended in 60 ml of methanol. Then 5.8 g of 6-chloro-7-sulfonamido-3,3-dihydro-1,2,h-benzothiadiazine-1,1-dioxide which was well powdered was added with stirring. Man heats for 15 - 20 minutes in a water bath at h0 - 50°C whereby everything dissolves.

Ved tilsetning av isopropanol felles analogt .med eksempel 1. Utbytte: 17,5 g x-diethylaminomethyl-rutin-6-klor-7-sulfonamido-3,^-dihydro-l,2,^-benzothiadiazin-l,1-dioxyd, som gult krystall-pulver, meget lett opploselig i vann, smeltepunkt: fra 270°C spaltning. By adding isopropanol, proceed analogously to example 1. Yield: 17.5 g x-diethylaminomethyl-rutin-6-chloro-7-sulfonamido-3,^-dihydro-1,2,^-benzothiadiazine-1,1-dioxyd , as yellow crystalline powder, very easily soluble in water, melting point: from 270°C decomposition.

Analogt fra x-dibutylaminomethyl-rutin og 6-trifluormethyl-7-sulfonamido-3, h-dihydro— 3-benzyl —1,2,^-benzothiadiazin-l,1-dioxyd fåes det tilsvarende x-n-dibutylaminomethyl-rutin-6-trifluormethyl-7-sulfonamido-3,^-dihydro- 3-benzyl -1,2,^-benzothiadiazin-l,1-dioxyd, utbytte 85 %, smeltepunkt: fra 250°C begynner spaltning, Analogously from x-dibutylaminomethyl-rutin and 6-trifluoromethyl-7-sulfonamido-3,h-dihydro-3-benzyl-1,2,^-benzothiadiazine-1,1-dioxyd the corresponding x-n-dibutylaminomethyl-rutin-6- trifluoromethyl-7-sulfonamido-3,^-dihydro-3-benzyl-1,2,^-benzothiadiazine-1,1-dioxyd, yield 85%, melting point: from 250°C decomposition begins,

3 g loses i 10 ml vann ved 18 - 20°C.Dissolve 3 g in 10 ml of water at 18 - 20°C.

Eksempel 8Example 8

13,8 g x-diethylaminomethyl-rutin ble opplost i ca. 80 ml methanol. 11 g aescin ble tilsatt og blandingen oppvarmet ved 60 - 70°C til opplosning. Efter inndampning i vakuum eller ved felning med aceton fikk man et gult, i vann lett opploselig krystallmel som var x-diethylaminomethyl-rutin-aescin. Smeltepunkt: 156 - 160°C under spaltning. 13.8 g of x-diethylaminomethyl-rutin was dissolved in approx. 80 ml of methanol. 11 g of aescin was added and the mixture heated at 60-70°C to dissolve. After evaporation in a vacuum or by precipitation with acetone, a yellow, water-soluble crystalline powder was obtained which was x-diethylaminomethyl-rutin-aescin. Melting point: 156 - 160°C during decomposition.

Ovenstående komplekssalt kan også fremstilles direkte under anvendelse av et vandig methanolisk ekstrakt av hestekastanjer. Hestekastanjer ekstraheres med 80 %- ig methanol. Fra dette ekstrakt avdestilleres methanolet i vakuum. I det vandige residuum be-stemmes aescin-innholdet, den beregnede mengde x-diethylamino-methyl-rutin tilsettes, blandingen oppvarmes kort for å opplose tilsetningen og derpå inndampes den dannede filtrerte opplosning i vakuum. Man får et gult krystallinsk pulver av x-diethylamino-methyl-rutin-aescin, som er lett opploselig i vann. The above complex salt can also be prepared directly using an aqueous methanolic extract of horse chestnuts. Horse chestnuts are extracted with 80% methanol. From this extract, the methanol is distilled off in a vacuum. In the aqueous residue, the aescin content is determined, the calculated quantity of x-diethylamino-methyl-rutin is added, the mixture is heated briefly to dissolve the addition and then the formed filtered solution is evaporated in vacuo. A yellow crystalline powder of x-diethylamino-methyl-rutin-aescin is obtained, which is easily soluble in water.

Claims

Procedure for the production of new, therapeutically active, crystalline, water-soluble adducts of rutin derivatives of the formula:

where R and R^ , which may be the same or different, are optionally branched alkyl groups with 1-5 carbon atoms, or R , and R-. together with the nitrogen atom ti 1 to which they are bound, form a piperidine, pyrrolidine or morpholine ring, and Z is salicylic acid, acetylsalicylic acid, nicotinic acid, isonicoti n acid, picolinic acid, aesciti, orotic acid, rutin, hesperidin, caffeine, theophylline , theobromine, 5-phenyl-5-ethyl-barbituric acid, 2-methyl-2-n-propyl-1,3-proparidiol-1, 1-carbamic acid, p-chlorophenol, or a halogen lower alkyl or halogen-lower alkyl substituted 7-sulfonamido-3^-dihydro-1,2,^-benzothiadiazine-1,1-dioxyd or 7-sulfonamido-3,^-dihydro-3-benzyl-1 , 2,1 +-benzothiadiazine-1,1-dioxyd, i c a r a c t e r .1 s e r t by possibly forming in situ N-substituted aminomethyl routines of the formula:

in which R and R^ are as indicated above, are reacted with the indicated acidic compounds Z.