CH335403A - Process for the preparation of new piperazine derivatives - Google Patents

Description

  

  <B> Process for </B> Preparation <B> New Piperazine Derivatives </B> The present invention relates to a process for the preparation of novel therapeutically active piperazine derivatives.



  These new compounds are amino-1-alkyl (phenothiazinyl-10 ') 4-alkyl piperazines which have the general formula
EMI0001.0011
    In this formula, X represents a hydrogen or halogen atom or an alkyl or lower alkyloxy, phenyl, phenoxy, benzyl or benzyloxy radical, preferably in position 3 of the ring of the phenothiazine (Beilstein number rotation);

  <I> A </I> and <I> AI </I> are the same or different and each represent a divalent straight or branched chain saturated aliphatic radical containing from 2 to 4 carbon atoms; R and RI are identical or different and each represents a lower alkyl radical, or one of the two radicals R and RI is a hydrogen atom and the other a lower alkyl or cyclo-alkyl radical, or else, R and RI form with the adjacent nitrogen atom a heterocyclic radical such as pyrrolidino, piperidino, or morpholino. The piperazine nucleus can, in addition,

   be substituted by one or more lower alkyl radicals.



  By lower alkyl radical is meant a radical containing not more than 4 carbon atoms.



  The process according to the invention is characterized in that one reduces a compound of formula
EMI0001.0026
    in which <I> B </I> denotes the radical <I> A </I> or a radical <I> A.-CO </I> such that A.-CH2 is identical to A, and <I> BI </I> designates the radical <I> AI </I> or a CO-A3 radical such that -CH2A <I>; </I> is identical to <B> <I> AI, </I> < / B> at least one of the radicals <I> B </I> and <I> BI </I> being reducible.



  This reduction is preferably carried out by means of lithium aluminum hydride, in a solvent such as tetrahydrofuran. The bases which correspond to formula I can be converted into addition salts with acids (for example hydrochlorides) into quaternary ammonium salts (for example haloalkylates) or into the addition derivatives which they form, for example, with 8-chloro-theophylline, by known methods. The products obtained by carrying out the process according to the invention, their salts and their derivatives, have valuable therapeutic properties which allow them to be used in human and veterinary medicine.

      The following examples illustrate the process according to the invention. The indicated melting points were determined in the Kofler block. <I> Example 1: </I> 6.5 g of [(3-chloro-phenothiazinyl-10 ") - 2 'ethyl] -1 (piperidinoacetyl) -4 piperazine are hydrogenated in 30 cml of tetrahydrofuran with 45 cm- 'of an ethereal solution at 1.811 / o of lithium aluminum hydride added over half an hour. The mixture is heated at reflux for 6 hours.

   It is left overnight in 2011, then treated with 1 cm3 of water, then 1 cm3 of 15% sodium hydroxide, then 4 cm3, 4 em3 and 30 cc of water. 100 cm3 of ether are added. It is filtered through Supercel and exhausted with 3 times 50 cm3 of ether. After drying the ethereal layer over sodium sulfate and concentrating, 6.5 g of crude base are obtained. The mixture is treated with 3.5 g of maleic acid in 70 cm 3 of ethyl acetate. a mixture of 350 cm 3 of ethanol and 45 cm3 of water.

   5.4 g of [(3-chloro-phenothiazinyl-10 ") -2 'ethyl] -1 (piperidino-2' ethyl) -4 piperazine trimaleate are obtained, melting at 2400.



  [(3-chloro-phenothiazinyl-10 ") - 2 'ethyl] -1 (piperidinoacetyl) -4 piperazine is obtained, giving a dipicrate melting at 130 by heating in a water bath for 5 hours pipé ridine with [ (3-chloro "phenothiazinyl-10") - 2 'ethyl] -1 chloroacetyl-4 piperazine.



  The latter product is prepared by heating at reflux in toluene for 2 hours the chloroacetyl chloride with chloro-3 [(piperazinyl-1 ") - 2 'ethyl] -10 phenothiazine. <I> Example 2 </I> In operating as in Example 1, replacing the piperidine with monocyclohexylamine, the trimaleate of [(3-chloro-phenothiazinyl-10 ”) is obtained

  -2 'ethyl] -1 (cyclohexyl-amino-2' ethyl) -4 piperazine which, after recrystallization from ethanol, melts at 2161).



  [(3-Chloro-phenothiazinyl-10 ") -2'ethyl] -1 (cyclohexylaminoacetyl) -4 piperazine dimaleate melts at 1341).

 

Claims (1)

CLAIM Process for the preparation of aminoalkyl-1- (phenothiazinyl-10 ') - alkyl-4-piperazines of general formula EMI0002.0081 in which X represents a hydrogen or halogen atom or an alkyl or lower alkyloxy, phenyl, phenoxy, benzyl or benzyloxy radical; <I> A </I> and <I> AI </I> are identical or dif ferent and represent a saturated divalent straight or branched chain aliphatic radical containing from 2 to 4 carbon atoms; R and RI each represent a lower alkyl radical, or else R is a hydrogen atom and RI is a lower alkyl or cycloalkyl radical or else R and RI together with the adjacent nitrogen atom form a heterocyclic radical, the piperazine ring which may, in addition, be substituted by one or more lower alkyl radicals, characterized in that a compound of formula is reduced EMI0002.0089 in which <I> B </I> denotes the radical <I> A </I> or an A2-CO radical such as AZ-CH, or identical to A, and BI denotes the A1 radical or a CO-A3 radical such as -CH., A; be identical <I> to </I> A1, at least one of the radicals <I> B </I> and BI being reducible. SUB-CLAIM Process according to claim, characterized in that the base obtained is converted into an acid addition salt.