CH363028A - Process for the preparation of new phenothiazines - Google Patents

Process for the preparation of new phenothiazines

Info

Publication number
CH363028A
CH363028A CH603562A CH603562A CH363028A CH 363028 A CH363028 A CH 363028A CH 603562 A CH603562 A CH 603562A CH 603562 A CH603562 A CH 603562A CH 363028 A CH363028 A CH 363028A
Authority
CH
Switzerland
Prior art keywords
phenothiazines
preparation
sulfur atom
new
formula
Prior art date
Application number
CH603562A
Other languages
French (fr)
Inventor
Michel Jacob Robert
Louis Regnier Gilbert
Original Assignee
Rhone Poulenc Sa
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rhone Poulenc Sa filed Critical Rhone Poulenc Sa
Publication of CH363028A publication Critical patent/CH363028A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/18—[b, e]-condensed with two six-membered rings
    • C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
    • C07D279/24—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom
    • C07D279/28—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom with other substituents attached to the ring system

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

  

  
 



  Procédé de préparation de nouvelles phénothiazines
 La présente invention a pour objet un procédé de préparation de nouvelles phénothiazines de formule:
EMI1.1     
 dans laquelle X représente un atome de soufre ou un   groupe - SO - ou -502-,    B représente un radical hydrocarboné aliphatique de 2 à 5 atomes de carbone, à chaîne droite ou   ramifiée,    tel que, par exemple, éthylène, propylène, isobutylène, triméthylène, tétraméthylène, R représente un radical alcoylène et Ac représente un radical acyle.



   Le procédé selon l'invention est caractérisé en ce que   l'on    acyle un composé de formule:
EMI1.2     

 Lorsque X dans la formule du composé de départ représente un atome de soufre, on peut traiter la phénothiazine obtenue par un agent oxydant, par exemple par l'eau oxygénée en solution dans l'acide acétique, afin de transformer l'atome de soufre en   groupe -50-ou SQ-.   



   Certaines des phénothiazines obtenues par le procédé selon l'invention qui possèdent des chaînes ramifiées telles que
EMI1.3     
 peuvent exister sous forme racémique ou optiquement active. Les isomères optiquement actifs peuvent être obtenus en partant de matières premières elles-mêmes optiquement actives, ou à partir des racémiques correspondants par résolution optique.



   Les phénothiazines obtenues par le procédé selon   Invention    possèdent des propriétés pharmacodynamiques précieuses ; ce sont en particulier des antihistaminiques et des antiémétiques puissants.



   Pour l'usage pharmaceutique, les phénothiazines obtenues par le procédé selon l'invention peuvent être utilisées sous forme de sels thérapeutiquement acceptables, tels que: chlorhydrate, phosphate, nitrate, sulfate, maléate, fumarate, citrate, tartrate, oxalate, méthanesulfonate, éthanedisulfonate ou de composés d'ammonium quaternaire thérapeutiquement acceptables, tels que chloro-,   bromo- ou    iodométhylate   ou -éthylate,    chloro- ou bromobenzylate   ou -allylate.   



   Dans l'exemple qui suit, le point de fusion, sauf indication contraire, a été déterminé au banc Kofler.



   Exemple
   2,1 g    de   méthanesulfonyl -3- [(hydroxyéthyl -4"-      pipérazinyl-1")-3'-propyl]-1 0-phénothiazine,    en solution dans 21 cm3 de pyridine anhydre, sont chauffés pendant 1 h 30 à l'ébullition avec 2,8 cm3 d'anhydride acétique. On chasse ensuite le solvant en excès sous pression réduite et alcalinise le résidu obtenu  avec 20 cm3 d'une solution aqueuse de carbonate de potassium à 5 %. Après extraction au chloroforme, séchage des jus   chlorofortniques    sur carbonate de potassium anhydre et distillation du solvant sous pression réduite, on obtient 2,2 g de méthanesulfonyl3 - [(acétoxyéthyl-4"-pipérazinyl- 1") - 3'-propyl]- 10  phénothiazine    dont le dimaléate acide recristallise dans l'éthanol fond à   173-1740.   
  



  
 



  Process for the preparation of new phenothiazines
 The subject of the present invention is a process for the preparation of novel phenothiazines of formula:
EMI1.1
 in which X represents a sulfur atom or a group - SO - or -502-, B represents an aliphatic hydrocarbon radical of 2 to 5 carbon atoms, straight or branched, such as, for example, ethylene, propylene, isobutylene , trimethylene, tetramethylene, R represents an alkylene radical and Ac represents an acyl radical.



   The process according to the invention is characterized in that a compound of formula is acylated:
EMI1.2

 When X in the formula of the starting compound represents a sulfur atom, the phenothiazine obtained can be treated with an oxidizing agent, for example with hydrogen peroxide in solution in acetic acid, in order to convert the sulfur atom into group -50-or SQ-.



   Some of the phenothiazines obtained by the process according to the invention which have branched chains such as
EMI1.3
 may exist in racemic or optically active form. The optically active isomers can be obtained starting from starting materials which are themselves optically active, or starting from the corresponding racemates by optical resolution.



   The phenothiazines obtained by the process according to the invention have valuable pharmacodynamic properties; these are in particular strong antihistamines and antiemetics.



   For pharmaceutical use, the phenothiazines obtained by the process according to the invention can be used in the form of therapeutically acceptable salts, such as: hydrochloride, phosphate, nitrate, sulfate, maleate, fumarate, citrate, tartrate, oxalate, methanesulfonate, ethanedisulfonate or therapeutically acceptable quaternary ammonium compounds, such as chloro-, bromo- or iodomethoxide or -ethoxide, chloro- or bromobenzylate or -allylate.



   In the example which follows, the melting point, unless otherwise indicated, was determined on the Kofler bench.



   Example
   2.1 g of methanesulfonyl -3- [(hydroxyethyl -4 "- piperazinyl-1") - 3'-propyl] -1 0-phenothiazine, dissolved in 21 cm3 of anhydrous pyridine, are heated for 1 hour 30 minutes at 1 hour. 'boiling with 2.8 cm3 of acetic anhydride. The excess solvent is then removed under reduced pressure and the residue obtained is made basic with 20 cm3 of a 5% aqueous potassium carbonate solution. After extraction with chloroform, drying of the chlorofortnic juices over anhydrous potassium carbonate and distillation of the solvent under reduced pressure, 2.2 g of methanesulfonyl3 - [(acetoxyethyl-4 "-piperazinyl-1") - 3'-propyl] - are obtained 10 phenothiazine, the acid dimaleate of which recrystallized from ethanol, melts at 173-1740.

Claims (1)

REVENDICATION Procédé de préparation de phénothiazines de formule: EMI2.1 dans laquelle X représente un atome de soufre ou un groupe - 50 - ou - 502.-, B représente un radical hydrocarboné aliphatique de 2 à 5 atomes de carbone, à chaîne droite ou ramifiée, R représente un radical alcoylène et Ac représente un radical acyle, caractérisé en ce que l'on acyle un composé de formule: EMI2.2 SOUS-REVENDICATION Procédé selon la revendication, caractérisé en ce que X représente un atome de soufre et en ce que l'on traite la phénothiazine obtenue par un agent oxydant, afin de transformer l'atome de soufre en groupe -SO- ou -SO,-. CLAIM Process for the preparation of phenothiazines of the formula: EMI2.1 in which X represents a sulfur atom or a - 50 - or - 502.- group, B represents an aliphatic hydrocarbon radical of 2 to 5 carbon atoms, straight or branched, R represents an alkylene radical and Ac represents a radical acyl, characterized in that a compound of formula is acylated: EMI2.2 SUB-CLAIM Process according to claim, characterized in that X represents a sulfur atom and in that the phenothiazine obtained is treated with an oxidizing agent, in order to convert the sulfur atom into an -SO- or -SO, - group.
CH603562A 1956-04-07 1957-03-29 Process for the preparation of new phenothiazines CH363028A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR712236 1956-04-07
FR730673 1957-01-30

Publications (1)

Publication Number Publication Date
CH363028A true CH363028A (en) 1962-07-15

Family

ID=26183034

Family Applications (5)

Application Number Title Priority Date Filing Date
CH603362A CH363026A (en) 1956-04-07 1957-03-29 Process for the preparation of new phenothiazines
CH603262A CH363025A (en) 1956-04-07 1957-03-29 Process for the preparation of new phenothiazines
CH4441757A CH363346A (en) 1956-04-07 1957-03-29 Process for the preparation of new phenothiazines
CH603562A CH363028A (en) 1956-04-07 1957-03-29 Process for the preparation of new phenothiazines
CH603462A CH363027A (en) 1956-04-07 1957-03-29 Process for the preparation of new phenothiazines

Family Applications Before (3)

Application Number Title Priority Date Filing Date
CH603362A CH363026A (en) 1956-04-07 1957-03-29 Process for the preparation of new phenothiazines
CH603262A CH363025A (en) 1956-04-07 1957-03-29 Process for the preparation of new phenothiazines
CH4441757A CH363346A (en) 1956-04-07 1957-03-29 Process for the preparation of new phenothiazines

Family Applications After (1)

Application Number Title Priority Date Filing Date
CH603462A CH363027A (en) 1956-04-07 1957-03-29 Process for the preparation of new phenothiazines

Country Status (2)

Country Link
CH (5) CH363026A (en)
DK (2) DK88345C (en)

Also Published As

Publication number Publication date
CH363027A (en) 1962-07-15
CH363026A (en) 1962-07-15
CH363025A (en) 1962-07-15
DK88345C (en) 1960-01-04
CH363346A (en) 1962-07-31
DK89448C (en) 1960-08-01

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