CH356457A - Process for the preparation of new phenothiazines - Google Patents

Description

  

  Process for the preparation of new phenothiazines The present invention relates to a process for the preparation of new phenothiazines, of formulas
EMI0001.0010
  
EMI0001.0011
    in which Y represents a hydrogen atom or an alkyl radical of 1 to 5 carbon atoms, Y 'represents an alkyl radical of 1 to 5 carbon atoms,

      B represents an aliphatic hydrocarbon radical, straight or branched chain, of 2 to 5 carbon atoms, such as, for example, ethylene, propylene, isobutylene, trimethylene, tetramethylene, and B 'represents an aliphatic hydrocarbon radical, with straight or branched chain, from 2 to 6 carbon atoms.



  The process according to the invention is characterized in that the ammo group of a compound of formula is alkylated
EMI0001.0030
    in which Yl represents a hydrogen atom or an alkyl radical of 1 to 5 carbon atoms,

   or at least one of the amino groups of a compound of formula
EMI0001.0034
    in which the remains. Y1 and Yi 'each represent a hydrogen atom or an alkyl radical of 1 to 5 carbon atoms, at least one of said residues being a hydrogen atom,

   by reacting said compound with a saturated aliphatic aldehyde of 1 to 5 carbon atoms and a reducing agent.



       Some of the phenothiazines obtained by the process according to the invention have in the remainder B or B 'an asymmetric carbon atom and can therefore exist in racemic or optically active form.

   Optically active phenothiazines can be obtained starting from the starting materials which are themselves optically active or from the corresponding racemates by optical resolution. The products obtained by the process according to the invention are all characterized by an activity marked on the central nervous system;

   this activity allows its use in general as anti-emetics, potentiators of general anesthetics, neuroleptics. In addition, some of them, in particular those substituted in position 10 of the phenothiazine ring by the radicals
EMI0002.0009
    exhibit very strong antihistamine activity.



       Finally, phenothiazines with two residues
EMI0002.0012
    are particularly useful as spasmolytics and local anesthetics.



  For pharmaceutical use, the products 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.



  <I> Example </I> 2.8 g of methylthio-3- (amino-3'-propyl) -10-phenothiazine dissolved in 30 cm3 of pure dioxane are neutralized with 9.2 cm3 of normal hydrochloric acid.

   22.1 cm-3 of an aqueous solution of 30% formalin and 0.2 g of platinum oxide are added to this solution, then the mixture is vigorously stirred under slight hydrogen pressure at ordinary temperature for 48 hours. . After removal of the platinum by filtration and evaporation of the solvent under reduced pressure, the residue obtained is treated with 50 cm3 of normal hydrochloric acid. The insoluble matter is filtered off and the acidic solution made alkaline with sodium hydroxide (d = 1.33).

   After extraction with ether, drying of the ethereal solution over sodium sulfate and distillation of the solvent, 0.2 g of methyl-thio -3 - (dimethylamino - 3'-propyl) -10-phenothiazine is obtained, including the picrate melts at 135o.



  The starting methylthio-3- (amino-3'-propyl) -10-phenothiazine - the acid oxalate of which melts at 198 is prepared by heating in toluene at 1100 of methylthio-3- (tosyloxy-3 ' -propyl) -10-phenothiazine with excess ammonia.



  The melting points indicated above were determined on the Kofler bench.

 

Claims (1)

CLAIM Process for the preparation of phenothiazines of formulas EMI0002.0072 EMI0002.0073 in which Y represents a hydrogen atom or an alkyl radical of 1 to 5 carbon atoms, Y 'represents an alkyl radical of 1 to 5 carbon atoms, B represents an ali phatic hydrocarbon radical, with a straight or branched chain, of 2 to 5 carbon atoms, and B 'represents an aliphatic hydrocarbon radical, straight or branched chain, from 2 to 6 carbon atoms, characterized in that the amino group of a compound of formula EMI0002.0087 in which Yl represents a hydrogen atom or an alkyl radical of 1 to 5 carbon atoms, or at least one of the amino groups of a compound of formula EMI0002.0095 wherein the Y1 and Yi radicals each represent a hydrogen atom or an alkyl radical of 1 to 5 carbon atoms, at least one of said radicals being a hydrogen atom, by reacting said compound with a saturated aliphatic aldehyde from 1 to 5 carbon atoms and a reducing agent.