CH366278A - Process for the preparation of new phenotiazines - Google Patents

Description

  

  Process for the preparation of new phenotiazines The present invention relates to a process for the preparation of new phenothiazines of formulas
EMI0001.0005
    in which Y represents a hydrogen atom or an alkyl radical of 1 to 4 carbon atoms, Y 'represents an alkyl radical of 1 to 4 carbon atoms, or Y and Y' together with the nitrogen atom form adjacent, a saturated heterocyclic residue, such as for example pyrrolidino-,

          piperidino-, morpholino-, piperazino-, alkyl-4-piperazino, hydroxyalkyl-4-piperazino or acyloxyalkyl-4-piperazino, B and B 'represent an aliphatic hydrocarbon radical of 2 to 4 carbon atoms with a straight chain or branched, respectively divalent, such as for example ethylene, propylene, isobutylene, tri-methylene, tetramethylene,

      or trivalent, A is a single bond or a - CH2 - group, Rl represents a hydrogen atom or an alkyl radical of 1 to 4 carbon atoms and R, an alkyl radical of 1 to 4 carbon atoms.



       The process according to the invention is characterized in that a phenothiazine of formula is reacted
EMI0001.0038
    with a compound of formula R2 - Q, one of the residues P and Q being a hydroxy group or a group of formula - OMe, Me being an equivalent of a metal, and the other being a reactive ester residue, for example a halogen atom, preferably chlorine.



  When one or both remains
EMI0001.0043
    represent a 4-hydroxyalkyl piperazino radical, this radical should be protected, for example by tetrahydropyranylation. The phenothiazines thus obtained can be converted into therapeutically tolerable acid salts and quaternary ammonium derivatives. As therapeutically tolerable acid salts, it is possible,

   mention the salts of hydrochloric, phosphoric, nitric, sulfuric, maleic, fumaric, tartaric, oxalic, - methanesulfonic, ethanesulfonic acids;

   quaternary ammonium salts are, for example, chloro-, bromo- or iodomethylates and -ethylates, chloro- and bromo-benzylates and -allylates.



       Some of the phenothiazines obtained by the process according to the invention which have an asymmetric carbon atony can exist in racemic or optically active form. Optically active isomers can be obtained starting from optically active starting materials or from the corresponding racemates by optical resolution.



  The phenothiazines obtained by the process according to the invention possess valuable pharmacodynamic properties and in particular have a powerful action on the nervous system which makes them usable in general as neuroleptics, poten- tializers of general anesthetics (for example. hexobarbital and ether) and pain relievers (eg morphine)

      and anti-emetics. Some of them are also spasmolytics or antihistamines.



  Compounds which are particularly active on the nervous system are those for which group B has the formula
EMI0002.0058
    represents a dimethylamino, diethylamino, methyl-4-piperazino, hydroxyethyl-4-piperazino or acetoxyethyl-4-piperazino radical.



  - Compounds comprising a group
EMI0002.0064
    in particular a bis- (dialkoylamino) -propyl radical and more especially bis- (dimethylamino) -2 ', 3'-propyl, are more particularly spasmolytic, which can be demonstrated experimentally by their antagonistic action of the spasm of isolated rabbit intestine caused by acetylcholine or barium chloride. Compounds in which group B represents a radical
EMI0002.0073
    are particularly interesting as antihista minics.

   It is particularly interesting in this case that the group
EMI0002.0077
    or a -dimethylamino radical. <I> Example 1 </I> In a solution of 0.84 g of potassium hydroxide in 10 cm3 of methanol, a solution of 2 g of (chloro-1 "-ethyl hydrochloride is poured in 15 minutes at room temperature. ) -3- (dimethylamino-3'-propyl) -10-phenothiazine in 20 cc of methanol.



  Then heated for 17 hours at reflux with stirring cry; after cooling, the methanol is distilled off under vacuum and the residue is taken up in 50 cm 3 of water and 50 cm 3 of ether; vigorously stirred, the ethereal layer decanted, washed with 10 cm3 of water, dried over sodium sulphate and the ether distilled off in a water bath.



  The crude oily base obtained is purified by passing through the oxalate in acetone; 1.85 g of (methoxy-1 "-ethyl) -3- (dimethyl-amino-3'-propyl) -10-phenothiazine oxalate is thus obtained, melting at 193 1940 (Maquenne block).



  (Chloro-1 "-ethyl) -3- (dimethyl-anlino-3'-propyl) -10-phenothiazine hydrochloride serving as raw material for obtaining the above product can be obtained by the action of thionyl chloride in chloroform on 1 '(hydroxy-1 "-ethyl) -3- (dimethylamino-3'-propyl) -10-phenothiazine; the hydrochloride formed is precipitated from its chloroform solution by adding ether. anhydrous; it melts at 173-174 (Maquenne block).



  <I> Example 2. </I>



  The following mixture is heated under reflux for 20 hours, while stirring
EMI0002.0114
  
    - <SEP> <SEP> hydrochloride <SEP> (chloro-1 <SEP> "- <SEP> ethyl) <SEP> - <SEP> 3 <SEP> (dimethylamino-3'-propyl) -10 phenothiazine <SEP > .. <SEP> .... <SEP>. <SEP> 5 <SEP> g
<tb> - <SEP> potash <SEP> pure <SEP> in <SEP> pellets <SEP> 2,3 <SEP> g
<tb> - <SEP> ethanol <SEP> pure <SEP> 80 <SEP> cm3 After cooling, the ethanol is distilled off under vacuum and the residue is taken up in 100 cmJ of water and 100 cm3 of ether.

   The ethereal layer is decanted and exhausted with 100 cm-1 of N hydrochloric acid; the hydrochloric extract is basified with 15 cmS of sodium hydroxide solution (d = 1.33); the oily base which precipitates is extracted with 100 cm3 and then 50 cm3 of ether; the combined ethereal extracts are washed with 2 times 20 cm3 of water and dried over anhydrous sodium sulfate.

   After distillation of the ether in a water bath, the crude base is purified by transformation into the oxalate in acetone; after recrystallization from ethanol, 2.8 g of (1-ethoxy-ethyl) -3- (dimethylamino-3'-propyl) -10-phenothiazine oxalate are obtained, melting (Maquenne) around 165-1660.

 

Claims (1)

CLAIM Process for the preparation of phenothiazines of formulas EMI0003.0019 in which. Y represents a hydrogen atom or an alkyl radical of 1 to 4 carbon atoms, Y 'represents an alkyl radical of 1 to 4 carbon atoms, or Y and Y' form, together with the adjacent nitrogen atom, a saturated heterocyclic residue, B and B 'represent an aliphatic hydrocarbon radical of 2 to 4 carbon atoms with a straight or branched chain, respectively divalent or tri valent, A is a single bond or a - CH #, - group, Ri represents a hydrogen atom or an alkyl radical of 1 to 4 carbon atoms and R2 an alkyl radical of 1 to 4 carbon atoms, characterized in that a phenothiazine of formula is reacted EMI0003.0032 with a compound of formula R2 - Q, one of the residues P and Q being a hydroxy group or a group of formula - OMe, Me being an equivalent of a metal, and the other being a residue of reactive ester. SUB-CLAIM Process according to claim, characterized in that the product is converted into a therapeutically acceptable acid addition salt.