SE196140C1

SE196140C1 -

Info

Publication number: SE196140C1
Authority: SE
Publication date: 1964-01-01

Description

Prioritet begeird frail den 1 mars 1957 (Storbritouzien) Det är kant att tiazoler av den allmanna formeln: NC—CH, HC C—CH2—CH2—X 'S' dar X betyder halogen, besitta antikonyulsiviska egenskaper. Baserna som sadana aro emellertid alltfor instahila och olosliga for att direkt kunna anvandas for terapeutiska andarnal. Man har visserligen lyckats framstalla salter av dessa tiazoler som besitta en. nagot storre stabilitet och storre lOslighet men dessa salter uppvisa dock andra egenskaper, som Ora dent olampliga for klinisk-terapeutisk anvandning. Priority given on 1 March 1957 (Great Britain) It is clear that thiazoles of the general formula: NC-CH, HC C-CH2-CH2-X 'S' where X means halogen, possess anticonyulsive properties. However, the bases as such are too unstable and insoluble to be used directly for therapeutic purposes. It has admittedly been possible to produce salts of these thiazoles which possess one. somewhat greater stability and greater solubility, but these salts still exhibit other properties which are unsuitable for clinical-therapeutic use.

Det har nu befunnits, att man genom att framstalla additionssalter med vissa tidigare icke anvanda sulfonsyror kan erhalla foreningar, som uppvisa en synnerligen god loslighet och vilka vidare aro tillrackligt stabila for att kunna anvandas for beredning ay kliniskt-terapeutiskt anvandbara lakemedel, som kunna administreras saval omit som parasiteralt. Sattet enligt uppfinningen kanneteeknas darav, att en 4-mety1-5-(fl-halogenety1)-tiazol bringas att reagera med en alifatisk monosulfonsyra med minst 2 C-atomer, t. ex. etanmonosulfonsyra eller isethionsyra, eller en alifatisk disulfonsyra, lampligen innehallande hogst tre kolatomer, t. ex. en metandisulfonsyra till bildning av additionssalter av 4-mety1--(3-halogenety1)-tiazoler med namnda sulfonsyror. Klorforeningarna och eventuellt bromforeningarna Oro att foredraga. Salterna kunna framstallas pa i och for sig kant satt genom att man omsatter i huvudsak ekvivalenta mangder av tiazolbasen och re.. spektive syra. Det Or lampligt att anvanda ett losningsmedel, som Or sá valt, att kristallisation av del bildade saltet intrader spontant. Aceton har visat sig vara speciellt lampligt som losningsmedel i detta fall, men. Oven Mgmolekylara alifatiska alkoholer samt cyklohexanol kunna med fordel an.vandas. It has now been found that by preparing addition salts with certain previously unused sulfonic acids it is possible to obtain compounds which show a particularly good solubility and which are furthermore sufficiently stable to be able to be used for the preparation of clinically therapeutically useful drugs which can be administered omit as parasitic. The process of the invention may be characterized in that a 4-methyl-5- (fl-haloethyl) -thiazole is reacted with an aliphatic monosulfonic acid having at least 2 carbon atoms, e.g. ethane monosulfonic acid or isethionic acid, or an aliphatic disulfonic acid, suitably containing up to three carbon atoms, e.g. a methane disulfonic acid to form addition salts of 4-methyl- (3-haloethyl) -thiazoles with said sulfonic acids. The chlorine compounds and possibly the bromine compounds Worry to prefer. The salts can be prepared per se by reacting essentially equivalent amounts of the thiazole base and respective acid. It is convenient to use a solvent which has been chosen so that crystallization of the salt formed occurs spontaneously. Acetone has been shown to be particularly useful as a solvent in this case, however. Mgmolecular aliphatic alcohols and cyclohexanol can also be used to advantage.

De enligt uppfinningen framstallda salterna besitta synnerligen vardefulla terapeutiska egenskaper. Dessa Oro i huvudsak betingade av att salterna utova en modererande verkan pa aktiviteten hos hjarnbarken, och delta galler vare sig de administreras peroralt eller parenteralt. Det Or vidare mojligt att genom lampligt val av dosering och interyall mellan doserna samt vidare, nar de administreras parenteralt, genom variation av koncentrationen uppna olika grader av inverkan alit ifran djup somn, som kan vara onskyard yid storre operationer, till kortvarig inverkan som insomningsmedel. Axenledes kunna olika former av mentala rubbningar, sasom schizofreni och akuta manier, med gott resultat behandlas med foreningar, som framstallas enligt denna uppfinning och detta galler Oven olika sjukdomstillstand, som utm.arkas av konvulsiva manifestationer, i all synnerhet kunna akuta utbrott ay delirium tremens snabbt forbattras. Vare sig de anvandas fOr att astadkomma djup narkos vid operationer eller endast som somnmedel eller insomningsmedel, atfoljes uppvaknandet ay eufori, varjamte krakningar och andra obehagliga biverkningar, som annars ofta forekomma, speciellt efter narkos, Oro mycket sallsynta vid anvandningen av dessa foreningar. The salts prepared according to the invention possess extremely valuable therapeutic properties. These concerns are mainly due to the fact that the salts exert a moderating effect on the activity of the cerebral cortex, and delta grids whether administered orally or parenterally. It is further possible that by appropriate choice of dosage and interval between doses and further, when administered parenterally, by varying the concentration to achieve different degrees of effect alit from deep sleep, which may be onskyard yid major surgeries, to short-term effect as a sleep aid. Similarly, various forms of mental disorders, such as schizophrenia and acute manner, can be successfully treated with compounds prepared according to this invention and this applies. quickly improved. Whether they are used to induce deep anesthesia in surgery or only as a sleep aid or insomnia, the awakening is accompanied by euphoria, vomiting and other unpleasant side effects, which otherwise often occur, especially after anesthesia.

Uppfinningen illustreras ay foljande exempel, till vilka den dock icke Or begransad. 2— — Exempel 1: Framstallning av metandisulfonatet av 4-mety1-5- (fl-klorety1)-tiazol. 21,2 g metandisulfonsyra-dihydrat loses i minsta mojliga mangd aceton. Vidare framstalles en losning av 32,3 g 4-mety1-5-fl-kloretyl-tiazol i lika volym aceton. Den senare losningen sattes portionsvis till den forsta losningen, varvid en vit kristallinisk fanning uppkommer, som avsepareras genom centrifugering och tvdttas med kall aceton. The invention is illustrated by the following examples, to which, however, it is not limited. Example 1: Preparation of the methane disulfonate of 4-methyl-5- (fl-chloroethyl) -thiazole. 21.2 g of methanedisulfonic acid dihydrate are dissolved in the least possible amount of acetone. Furthermore, a solution of 32.3 g of 4-methyl-5-f1-chloroethyl-thiazole is prepared in an equal volume of acetone. The latter solution was added portionwise to the first solution to give a white crystalline formation, which was separated by centrifugation and washed with cold acetone.

F5reningen renas genom omkristallisation ur metanol och eter pa sa satt, att en koncenttrerad losning i metanol, som eventuellt avfargats med aktivt kol, droppvis forsattes med eter. Kristallisationen, som borjar praktiskt taget omedelbart, fullstandigas genom att blandningen far sttit vid lag temperatur. Kristallerna avsugas och tvattas med en blandning av lika volymer metanol och eter, varefter de torkas. Den vita reaktionsprodukten, som har sammansattningen C13H2006S4N2C12 smalter yid 1° C. Genom titrering kan faststallas, att saltet innehaller 64,6 % bas, vilket Overensstammer med det beraknade vardet for ett salt bestaende av 2 molekyler has och en molekyl syra. Saltet är icke hygroskopiskt under normala forhallanden. The compound is purified by recrystallization from methanol and ether in such a way that a concentrated solution in methanol, which may have been decolorized with activated carbon, is added dropwise with ether. The crystallization, which begins practically immediately, is completed by allowing the mixture to stand at low temperature. The crystals are filtered off with suction and washed with a mixture of equal volumes of methanol and ether, after which they are dried. The white reaction product, which has the composition C13H2006S4N2Cl2, melts at 1 ° C. By titration it can be determined that the salt contains 64.6% of base, which corresponds to the calculated value for a salt consisting of 2 molecules of ha and one molecule of acid. The salt is not hygroscopic under normal conditions.

Exempel 2: Framstallning av etan-1,2-disulfonatet av 4-mety1-5-(j9-klorety1)-tiazol. 226 g etandisulfonsyra-dihydrat loses i minsta mojliga mangd aceton och losningen filtreras. Vidare framstalles en losning av 323 g 4-mety1-5-p-kloretyl-tiazol i lika volymer aceton. Den forsta lbsningen sattes portionsvis till den senare under kraftig omrorning. Kristallisationen, som borjar spontant, far fortsatta och fullstandigas vid lag temperatur, varefter den bildade fallningen avsepareras och tvattas med kall aceton och torkas i luft vid rumstemperatur eller vid 37° C. Produkten renas genom att losas i metanol och till metanollosningen sattes efter kylning samma volyrn eter, varefter kristallisationen far fullstandigas vid lag tenaperatur. 50 g av saltet fordrar for omkristallisering 100 ml metanol och sammavolym eter. Efter torkning smalter saltet vid 124° C och har sammansdtt- ninaen 14 C 22 06 S4N2C12. Det innehaller 62,9 - % bas, vilket Or i overensstammelse med vad som beraknas for ett salt bestaende av 2 molekyler bas och 1 molekyl disulfonsyra. Saltet är icke flyktigt och ej heller hygroskopiskt under normala forhallanden. Example 2: Preparation of the ethane-1,2-disulfonate of 4-methyl-5- (β-chloroethyl) -thiazole. 226 g of ethanedisulfonic acid dihydrate are dissolved in the least possible amount of acetone and the solution is filtered. Furthermore, a solution of 323 g of 4-methyl-5-p-chloroethyl-thiazole is prepared in equal volumes of acetone. The first solution was added portionwise to the latter with vigorous stirring. The crystallization, which begins spontaneously, is allowed to proceed and complete at low temperature, after which the precipitate formed is separated and washed with cold acetone and dried in air at room temperature or at 37 ° C. The product is purified by dissolving in methanol and after cooling the same was added. volyrn ether, after which the crystallization is allowed to complete at low temperature. 50 g of the salt require for recrystallization 100 ml of methanol and co-volume of ether. After drying, the salt melts at 124 ° C and has a composition of 14 C 22 06 S 4 N 2 Cl 2. It contains 62.9 -% base, which Or in accordance with what is calculated for a salt consisting of 2 molecules of base and 1 molecule of disulfonic acid. The salt is neither volatile nor hygroscopic under normal conditions.

Pa samma satt kan man aven framstalla etan-1,2-disulfonatet med any5ndning av metanol eller butanol som losningsmedel. Aven andra organiska losningsmedel, sasom andra lagmolekylara alifatiska alkoholer och cyklohexanol kunna med fOrdel anvandas som losningsmedel vid saltframstallningen.In the same way, the ethane-1,2-disulfonate can also be prepared with the use of methanol or butanol as solvent. Other organic solvents, such as other low molecular weight aliphatic alcohols and cyclohexanol, can also be used to advantage as solvents in the salt preparation.

Claims

Patent claim:

1. Prepared to prepare new, therapeutically valuable salts of 4-methyl-5- (fl-haloethyl) -thiazoles, characterized in that a 4-methyl5- (8-haloethyl) -thiazole is reacted with an aliphatic monosulfonic acid having at least 2 C atoms, e.g. ethane monosulfonic acid or isethionic acid, or an aliphatic disulfonic acid, suitably containing up to three carbon atoms, e.g. a methane disulfonic acid to form addition salts of 4-methyl-5- (fl-halethylethyl) -thiazoles with said sulfonic acids.

2. S5.tt according to claim 1, characterized in that the thiazole and the acid are reacted in approximately equivalent amounts.

Shit according to claim 1 or 2, characterized in that the reaction is carried out in the presence of a solvent, preferably an organic solvent.

Salt according to any one of the preceding claims, characterized in that 4-methyl-1- (§-chloroethyl) -thiazole is reacted with ethanedisulfonic acid.