SE178464C1

SE178464C1 -

Info

Publication number: SE178464C1
Authority: SE
Publication date: 1962-01-01

Description

Uppfinnare: R J Horclois Prioritet begard friin den 23 november 1955 (Frankrilce) Foreliggande uppfinning hanfor sig till forbattringar av terapeutiskt aktiva fentiazinderivat saint till ett forfarande for deras framstallning. Inventor: R J Horclois Priority asked for release on November 23, 1955 (Frankrilce). The present invention relates to improvements in therapeutically active phenothiazine derivatives in a process for their preparation.

Det Sr kant att olika 10-aminalkylfentiaziner besitta intressanta terapeutiska egenskaper. Omfattande forskning och experiment ha emellertid visat, att bade storleken av det terapeutiska index och arten av den terapeutiska effekt, som vissa foreningar av denrta typ uppvisa kunna radikalt ,andras (t. o. m. elimineras) genom t. 0. m. sma ,andringar i den kemiska strukturen. Sarskilt Sr detta fallet vid andringar i arten .och langden av sid.okedjan vid kvaveatomen i 10-stallning. It is clear that various 10-aminalkylphentiazines possess interesting therapeutic properties. Extensive research and experiments have shown, however, that both the size of the therapeutic index and the nature of the therapeutic effect, which some compounds of this type exhibit, can radically, others (even be eliminated) by even small, changes in the chemical the structure. In particular, this is the case with changes in the nature and length of the side chain at the nitrogen atom in the 10-position.

Sam ett resultat av forskning och experimenterande har ett nytt fentiazinderivat syntetiserats, vilket har visat sig besitta sarskilt intressanta farmakologiska egenskaper. 1 synnerhet har det visats, att det besitter framstaende spasmolytiska egenskaper i kombinalion med mindre framtradande olampliga biverkningar .an fiirut kanda fentiazinderivat. As a result of research and experimentation, a new phentiazine derivative has been synthesized, which has been shown to possess particularly interesting pharmacological properties. In particular, it has been shown to possess excellent spasmolytic properties in the combination ion with less prominent undesirable side effects than the known phenothiazine derivatives.

I overensstammelse med fOreliggande uppfinning framstalles detta nya fentiazinderfvat, namligen 10- [2,4-bis-dimetylamino-1-hutyl] fentiazin, sorn har den konventionella formeln: //\\ \7 CH2—CH—CH2—CH2--N (CH2)2 N(CF13)2 genom metylering av en amin med formeln: /Z CH, —CH —CH2— CH2—N\ z , Z van i Z-radikalerna aro antingen vateatomer eller metylgrupper, varvid atminstone en av dessa radikaler Sr en vateatom. In accordance with the present invention, this novel phentiazine derivative, namely 10- [2,4-bis-dimethylamino-1-hutyl] phentiazine, is prepared having the conventional formula: (CH2) 2 N (CF13) 2 by methylation of an amine of the formula: / Z CH, —CH —CH2— CH2 — N Sr en vateatom.

Metyleringen kan utforas under anvandning av vilket som helst konventionellt metyleringsmedel, sasom en reaktiv metylester, I. ex. en metylhalogenid eller dimetylsulfat, men utfores foretradesvis genoin anvandning av en blandning ay formaldehyd och myrsyra. The methylation can be carried out using any conventional methylating agent, such as a reactive methyl ester, I. a methyl halide or dimethyl sulfate, but is preferably carried out using a mixture of formaldehyde and formic acid.

Den nya fentiazinbasen enligt foreliggande uppfinning har utomordentlig anvandbarhet som ett spasmolytikum av papaverin-typen. I detta hanseende utgor den ett vardefullt me-del for behandling ay hi. a. amObakolit, enterokolit, oesofagism ,och kardiospasm. For terapeutiska andamal anvandes den heist i form av ett syraadditionssalt innehallande en farmaceutiskt acceptabel anion (sasom hydrokrorid eller annan hydrohalogenid, 8-klorteofyllinat, fosfat, nitrat, sulfat, maleat, fumarat, citrat, tartrat, oxalat, metansulfonat och etandisulfonat) eller •av ett kvaternart ammoniumsalt erhallet genom reaktion med en organisk halogenid (t. ex. metyl- eller etyljodid, -klorid eller -bromid eller allyl- eller bensylklorid eller -bromid) eller annan reaktiv ester. The novel phentiazine base of the present invention has excellent utility as a papaverine-type antispasmodic. In this respect, it constitutes a valuable means of treatment ay hi. a. amobacolit, enterocolitis, oesophagism, and cardiospasm. For therapeutic purposes, it is used in the form of an acid addition salt containing a pharmaceutically acceptable anion (such as hydrochloride or other hydrohalide, 8-chlorophyllinate, phosphate, nitrate, sulphate, maleate, fumarate, citrate, tartrate, oxalate, methanesulfonate or ethanesulfonate). a quaternary ammonium salt obtained by reaction with an organic halide (eg methyl or ethyl iodide, chloride or bromide or allyl or benzyl chloride or bromide) or other reactive ester.

Uppfinningen belyses ay foljande exempel. The invention is illustrated in the following examples.

— — Exempel. 10- (2-dimetylamino-4-amino-1-butyl) fentiazin (10,3 g) varmes under a.terflode under 48 timmar med 30-procentig formaldehyd (10 cm3) och 98-procentig myrsyra (15 cm3) till dess irtvecklingen air koldioxid upphor. Blandningen surgores med saltsyra (d = 1,19; 7 cm3) till dess den. reagerar surt f Sr kongorottpapper och indunstas sedan till torrhet. Aterstoden lbses i vatten (50 cm3) och extraheras med eter (2 )< 50 Gino). Vattenfasen gores alkalisk med kaustik soda (d = 1,33; 10 cm3) och extraheras med ktoroform (3 X 50 cm3). 10- (2,4-bis-dimetylamino-1-butyl) fentiazin (6,2 g), destillerande vid 185° C188° C/0,5 mm Hg, erhalles. - - Example. 10- (2-Dimethylamino-4-amino-1-butyl) fentiazine (10.3 g) was heated under reflux for 48 hours with 30% formaldehyde (10 cm 3) and 98% formic acid (15 cm 3) until the evolution of air carbon dioxide ceases. The mixture is acidified with hydrochloric acid (d = 1.19; 7 cm3) until. reacts acidic f Sr kongorott paper and then evaporates to dryness. The residue is dissolved in water (50 cm 3) and extracted with ether (2) <50 Gino). The aqueous phase is made alkaline with caustic soda (d = 1.33; 10 cm 3) and extracted with chloroform (3 X 50 cm 3). 10- (2,4-bis-dimethylamino-1-butyl) fentiazine (6.2 g), distilling at 185 ° C188 ° C / 0.5 mm Hg, is obtained.

Behandling am 10-(2,4-bis-dimetylamino-1- butyl)fentiazin (4,5 g) i etanol (27 cm3) med fumarsyra (3,2 g) ger det sura difumaratet (16,7 g), som smaller mid 176° C-177° C. 10- (2-dimetylamino-4-amino-1-butyl) fentiazin (10,6 g) erhalles genom reduktion, me-deist litiumaluminiumhydrid, ay 10-(2-dimetylamino-3-cyan-1-propyl)fentiazin (12 g). Sistnamnda fOrening, mars hydroklorid smalter mid 222°-223° C, kan framstallas genom inverkan av kaliumeyanid pa 10-(3-dimetylamino-2-klor-1-propyl)fentiazin. Under loppet am reaktionen sker en isomerisering och 10- (2-dimetylamino-3-cyan-1-propyl)fentiazin erhalles i stallet for 10-(3-dimetylamino-2- cyan-1-pr opyl) fentiazin. Treatment with 10- (2,4-bis-dimethylamino-1-butyl) phentiazine (4.5 g) in ethanol (27 cm 3) with fumaric acid (3.2 g) gives the acidic difumarate (16.7 g) which narrower mid 176 ° C-177 ° C. -cyan-1-propyl) phentiazine (12 g). The latter compound, March hydrochloride melting at 222 ° -223 ° C, can be prepared by the action of potassium cyanide on 10- (3-dimethylamino-2-chloro-1-propyl) phentiazine. During the course of the reaction an isomerization takes place and 10- (2-dimethylamino-3-cyano-1-propyl) phentiazine is obtained instead of 10- (3-dimethylamino-2-cyano-1-propyl) phentiazine.

Claims

Patent claim:

A process for the preparation of a therapeutically useful phentiazine derivative, wherein an amine of the formula "z IZ ZZ NZ van in the Z radicals are either hydrogen atoms or methyl groups, at least one of these radicals having a hydrogen atom being methylated to - (2,4-bis-dimethylamino-1-butyl) fentiazine.

2. Process according to claim 1, characterized in that the methylation is carried out by means of a mixture of formaldehyde and formic acid. Request publications: Stockholm 1962. Kungl. Boktr. P. A. liorstedt & Saner. 620089