CH542875A - Process for the preparation of hydroxyalkylpiperazino derivatives of the dibenzo- (b, f) -thiepin series - Google Patents

Description

  

  
 



   The present invention relates to a process for the preparation of hydroxyalkylpiperazino derivatives of the dibenzo- (b, f) -thiepin series of the general formula I.
EMI1.1
 wherein
R is a hydrogen, a halogen atom, a trifluoromethyl radical, an alkyl, alkoxy or alkylthio group having 1 to 4 carbon atoms and n is an integer from 2 to 3, and salts thereof.



   These substances show a pronounced pharmacodynamic effectiveness, which enables their use as neurotropic and psychotropic remedies. In particular, they have a moderate to very strong central depressant activity, in some cases they are cataleptically highly effective, they also develop a high hypothermic effectiveness, potentiate the hypnotic effect, and also have antiserotinin, antihistamine and vasodilating effectiveness.



   A typical example of the compounds of the formula I is 8-methylthio-10-14- (3-hydroxypropyl) -piperazino] -10.1 1-dihydrodibenzo- (b, f) -thiepin, which is pharmacologically in the form of its dihydrochloride dihydrate was checked. Its acute toxicity in mice after intravenous administration (LD ,,) is 44 mg / kg). In the torsion bar test after intravenous administration in mice, the substance causes disturbances in the coordination of movements even in very small doses; the mean effective dose in this test (ED ,,) at the time of maximum effect (40 minutes after administration of the substance) is 0.11 mg / kg; furthermore, the substance potentiates thiopental anesthesia in mice after ontravenous administration.



   The threshold dose, which statistically significantly prolongs thipental sleep, is 0.025 mg / kg.



  The substance is also highly effective in the catalepsy test in rats; the dose which triggers catelepsy in 50% of the animals after intraperitoneal administration (ED50) is 0.62 mg / kg. As early as 0.1 mg / kg, after intraperitoneal administration, the substance has an antiserotinic effect in rats in in vivo experiments. In the administration of 10 mg / kg i.p.



  the substance does not affect the reserpintose in mice; after oral administration of the dose of 50 mg / kg it antagonizes the ulcerogenic effect of reserpine in rats in a statically insignificant manner. Finally, a marked antihistamine effect in guinea pigs in vivo in the histamine dopoxication test, as well as a marked hypothermic, vasodilating and significant anti-inflammatory effect were found with this substance.



   Compared with the well-known neuroleptic preparation chlorpromazine, the substance mentioned is five times more effective in the test of the torsion bar, ten times more effective in the test of thiopental anesthesia potentiation, about thirteen times more effective in the catalepsy test; at the same time it is only slightly more toxic, so that its index of action exceeds that of chlorpromazine several times.



   The process according to the invention for the preparation of the compounds of the general formula I, characterized in that secondary amines of the general formula II
EMI1.2
 where R is the same as in formula I, with alkylene oxides of the general formula III
EMI1.3
  wherein m is 1 or 2, reacts, after which the basic products obtained are converted into corresponding salts, if appropriate by neutralization with inorganic or organic acids.



   The reactions with the mentioned alkylene oxides, i.



  specifically with ethylene oxide or trimethylene oxide, can even at room temperature, in suitable inert solvents, such as ethers. aromatic hydrocarbons, etc., and provide the isolated bases in high yields.



   Further details of the process according to the invention, which relate in particular to carrying out the reaction and isolating the products, can be seen from the following examples.



   Example I.
Gaseous ethylene oxide is introduced into a solution of 8.9 g of 10-piperazino-10, 1 l-dihydrodibenzo (b, f) thiepin in 60 ml of absolute benzene with stirring at room temperature until the increase in weight is 1, 5 g. The reaction mixture is then heated under reflux for 2 hours at 60 ° C. and finally benzene is distilled off. The crystalline residue is stirred with a little ethanol and filtered off with suction. 9.5 g of 10- [- (2-hydroethyl) piperazino] are obtained. -10, 11-dihydrodibenzo- (b, f) -thiepin, which, after recrystallization from aqueous ethanol, melts at 108 to 110 ° C. By neutralizing with maleic acid, the base yields the corresponding maleate, which melts at 129 to 130 ° C.



   Example 2
In a solution of 10.5 g of 8-chloro-10-piperazino-10, 1 1-dihydrodibenzo- (b, f) -thiepin in 50 ml of absolute benzene, an ice-cold solution of 1, 5 g of ethylene oxide in 20 ml of absolute ether.



  The temperature of the reaction mixture is then gradually increased to moderate reflux. The reaction mixture is heated for a further 2 hours in a bath kept at 50 to 60 ° C. and the solvents are then distilled off under reduced pressure. The oily residue (11.5 g) represents the crude 8-chloro-10- [4- (2 hydroxyethyl) piperazino] -10.1 1-dihydrodibenzo- (bf) thiepin. Benzene mixture is poured over with a petroleum ether the crystallization of the residue.



  After recrystallizing the crude product from 90% ethanol, the pure base is obtained in the form of the hemihydrate with a melting point of 103 to 105 "C. Neutralizing with maleic acid gives the corresponding maleate with a melting point of 165 to 166" C.



   Example 3
A solution of 2.5 g of trimethylene oxide in 10 ml of absolute benzene is added dropwise with stirring to a solution of 8-methylthio-10-piperazino-10.11 dihydrodibenzo- (b, f) -thiepine in 80 ml of absolute benzene. The reaction mixture is refluxed for 3 hours and then benzene is evaporated off under reduced pressure. The residue represents the crude base of X-methylthio-lO-14- (3-hydroxypropyl) -piperazino] -10, 11-dihydrodibenzo- (h, f) -thiepine (yield: 12.0 g).

  The base is obtained completely pure by recrystallization from a benzene petroleum ether mixture, it then melts at 93 to 95 "C. Neutralizing with hydrogen chloride gives the corresponding dihydrochloride, which crystallizes from aqueous ethanol in the form of the dihydrate and is at 223 to 226" C melts.



   Example 4
In a manner analogous to the above examples, the reaction of 10-piperazino-10, 1 (), 11 l-dihydrodibenzo- (b, f) -thiepin with trimethylene oxide is carried out and the desired 10- [4- ( 3-Hydroxypropyl) -piperazinoj-10, 11-dihydrodibenzo- (b, f) -thiepin, the base of which melts at 138 "C and the maleate at 156" C.



      Example S.
The reaction of 8-chloro-10-piperaziono-10,11 dihydrodibenzo- (b, f) -thiepin with trimethylene oxide is carried out in a manner analogous to that in the preceding examples, and the desired 8-chloro-10- [4 - (3-hydroxypropyl) piperazino) -10, 11 -dihydrodibenzo- (b, f) -thiepine, the base of which melts at 109 to 112 "C and the di (hydrogen maleate) at 139 to 140" C.

 

   Example 6
The reaction of 8-methoxy-1 () -piperazino-10,11 dihydrodibenzo- (b, f) -thiepin with trimethylene oxide is carried out in a manner analogous to that in the preceding examples, and the desired 8-methoxy-10- [ 4- (3-hydroxypropyl) -piperazino] -10, 11 -dihydrodibenzo- (b, f) -thiepin, the di- (hydrogen maleate) of which melts at 113 to 114 "C (ethanol).

 

Claims (1)

PATENT CLAIM Process for the preparation of hydroxyalkylpiperazino derivatives of the dibenzo- (b, f) -thiepin series of the general formulas EMI2.1 wherein R is a hydrogen, a halogen atom, a trifluoromethyl radical. an alkyl, alkoxy or alkylthio group having 1 to 4 carbon atoms, and n is an integer from 2 to 3, and salts thereof, characterized. that secondary amines of the general formula II EMI3.1 where R is the same as in formula I, with alkylene oxides of the general formula III EMI3.2 in which m is 1 or 2, after which the basic products obtained are converted into corresponding salts, if appropriate by neutralization with inorganic or organic acids.