CH373386A - Process for the preparation of new 1,3-disubstituted phenothiazine derivatives - Google Patents

Description

  

  Process for the preparation of new 1,3-disubstituted phenothiazine derivatives The invention relates to a process for the preparation of 1,3-disubstituted phenothiazine derivatives of the formula
EMI0001.0006
    where X and Y are identical or different alkyl or alkoxyl radicals, such as methyl or methyl radicals, or one of these substituents is a halogen atom, preferably before chlorine, A is a straight or branched alkylene radical with 2-6 C atoms,

          R1 and R2 denote identical or different low molecular weight alkyl radicals which, with the N atom, can form a heterocyclic ring system which can contain a further heteroatom, which is characterized in that 1,3-disubstituted phenothiazines are used the formula
EMI0001.0024
    with aminoalkyl halides of the formula
EMI0001.0026
    where Hal is a halogen atom, or 1,

  3-disubstituted phenothiazines of the formula
EMI0001.0031
    with secondary amines of the formula
EMI0001.0032
    condensed. As a secondary amine of the formula
EMI0001.0033
    you can z. B. use dimethylamine, piperidine and similar compound.



  These connections are new. With low toxicity, they have local anesthetic, sedative, ataractic and potentiating effectiveness, which z. B. is particularly marked in thiobarbiturate anesthesia.



  The condensations are advantageous in the presence of acid-binding agents such. B. alkali metals, their hydroxides, amides, hydrides, alcoholates or organometallic compounds and in an inert organic solvent, for. B. xylene performed. The condensation also takes place without solvents and without acid-binding agents.

   The alkylaminoalkyl halides can also be used in the form of their salts with strong mineral acids, but in this case an addition of acid-binding agents in appropriate amounts is necessary.



  The new compounds prepared according to the invention can be administered in the form of their water-soluble salts with organic or inorganic acids or in the form of water-soluble addition compounds.



  <I> Example 1 </I> 1.2 g of finely ground 80% sodium amide are added to a solution of 6.8 g of 1,3-dimethylphenothiazine (mp 147 ° C.) in 40 ml of xylene The mixture is heated to 130 ° C. for 2 hours while stirring. A solution of 4 g of 3-dimethylaminopropyl chloride-1 in 20 ml of xylene is then added dropwise to this over the course of 1 hour and the reaction mixture is then heated to 130 ° C. for a further 2 hours.

   After cooling, the reaction mixture is shaken out with 20 ml of a 10% strength hydrochloric acid solution, the aqueous layer is separated off, made alkaline with concentrated ammonia solution and extracted twice with 20 ml of benzene each time. The benzene extract is concentrated and the residue is distilled under reduced pressure. The 1,3-dimethyl-10- (3'-dimethylaminopropyl) phenothiazine is obtained in the form of a pale yellow, viscous liquid. Kp2 = 178 C. The hydrochloride can e.g.

   B. represent that the base is dissolved in the same weight of chlorobenzene and the equivalent of an anhydrous ethereal HCI solution is added. The hydrochloride forms colorless needles with F. 169 C.



  <I> Example 2 </I> If the 3-dimethylaminopropyl chloride-1 in Example 1 is replaced by the equivalent amount of 2-dimethylaminopropyl chloride-1, the 1,3-dimethyl-10- (2'-dimethylamino-2) is obtained '-methylethyl) - phenothiazine in a mixture with its isomer, the 1,3-dimethyl-10- (2'-dimethylamino-1'-methylethyl) - phenothiazine [cf. Charpentier and Duerot, C. r. 225, 306 (1947), 232, 415 (1951)].

       Bp 1.2-203-204 C (base); the hydrochloride forms colorless crystals (from chlorobenzene ether) with a melting point of 205 ° C (decomp.).



  <I> Example 3 </I> If the 1,3-dimethyl-phenothiazine in Example 1 is replaced by the equivalent amount of 3 chloro-1-methyl-phenothiazine (F. 139-140 C), the 3- Chloro-1-methyl-10- (3'-dimethyl-aminopropylaminopropyl) -phenothiazine. The base is at 208 ° C / 1 mm Hg; the hydrochloride melts at 177-178 C (chlorobenzene).



  <I> Example 4 </I> If the 1,3-dimethyl-phenothiazine in Example 1 is replaced by the equivalent amount of 1-chloro-3-methoxyphenothiazine (F. 132-133 C) and the 3-dimethylaminopropyl chloride 1 by the equivalent. Amount of 2-dimethylaminopropyl chloride-1, 1-chloro-3-methoxy-10- (2'-dimethylamino-2'-methyl-ethyl) -phenothiazine is obtained. The hydrochloride melts at 212 C.

 

Claims (1)

PATENT CLAIM A process for the preparation of 1,3-disubstituted phenothiazine derivatives of the formula EMI0002.0066 where X and Y are identical or different alkyl or alkoxyl radicals or one of these substituents is a halogen atom, A is a straight or branched alkylene radical with 2-6 carbon atoms, R1 and R2 are identical or different low molecular weight alkyl radicals, which are also labeled with the N- Atom is a heterocyclic ring system, which can hold another heteroatom ent, characterized in that one 1,3-disubstituted phenothiazines of the formula EMI0002.0079 with aminoalkyl halides of the formula EMI0002.0081 where Hal is a halogen atom, or 1,3-disubstituted phenothiazines of the formula EMI0002.0086 with secondary amines of the formula EMI0002.0087 condensed.