DE2228283C3 - 10-Piperazinodibenzo square bracket to b, square bracket to-thiepine, process for their preparation and pharmaceutical products - Google Patents

Description

NCH ₂ CH ₂ CH (CH ₂ J _n (I)

in which π is 2 or 3, as well as their salts. 15th

2. Process for making the compounds

according to claim 1, characterized in that

one in a conventional manner a) a secondary amine of the formula II

20th

(II)

25th

with compounds of the formula III O

(CH ₂ ) CHCH ₂ CH ₂ HaI (ΠΙ)

in which Hai is a halogen atom, alkylated or b) reactive alcohol esters of the formula IV

30th

35

(IV)

40

in which X is a halogen atom or an alkanesulfonyloxy group is, with cyclic acetals of the formula V

HN NCH ₂ CH ₂ CH (CH ₂ J _n (V)

implements or
c) enamines of the formula VI

45

50

55

60

Cl O

/ \ N NCH ₂ CH ₂ CH (CH ₂ ), (VI)

reduce), after which the products obtained

The subject matter of the invention is defined in the claims.

The compounds of the type claimed prove to be highly effective neuroleptics in animal experiments and central damping agents. This is particularly evident in the catalepsy test on rats and in the torsion bar test on mice. In both tests, the new connections are essential more effective than the well-known psychotropic remedy chlorpromazine. At the same time, their acute toxicity relatively low. The new compounds can therefore be used as psychotherapeutic agents.

The procedure specified under a) can be carried out under different conditions, for example, by heating both components to temperatures of 80 to 120 C, without solvents or in suitable inert solvents, without condensation agents (in this case the second component used in excess) or in the presence of inorganic or organic Condensation agents, especially of anhydrous alkali metal carbonates, triethylamine, pyridine.

In the process listed under b), the substitution reaction is z. B. carried out in such a way that a mixture of the reaction ^{components is heated without a reaction medium to temperatures of 50 to 150 0} C, preferably in the presence of an excess of the compound of general formula V, which then simultaneously as an acid-binding agent (ie as a condensing agent ) serves. The reaction proceeds even better (with an excess of the compound of the general formula V) in a suitable solvent, such as, for example, benzene or chloroform. Dimethylformamide, again at temperatures of 50 to 15O ⁰ C. The boiling point of chloroform, the substitution reactions are usually carried out with sufficient speed. The substitution reactions can also be carried out in the presence of condensation agents, ie substances with an alkaline reaction which bind the acid (e.g. hydrogen halide) formed during the reaction. The use of condensing agents then enables the components of the formulas IV and V to be used in equivalent amounts.

Particularly suitable condensing agents are alkali metal carbonates or bicarbonates or some tertiary ones Amines (such as pyridine, triethylamine, N-ethylpiperidine) are suitable. The output connections of the Formula IV, especially those in which X = Cl, are known (see J. O. J i 1 e k et al., Collection Czechoslov. Chem. Commun., 33 [1968], 1831, and K. Pelz et al., Ibidem, 33 [1968], 1895). The output connections of the general formula V are

partly new. Their preparation is shown in the examples described.

The reduction of the enamines of the formula Vl «e-Bite the third alternative for the preparation of compounds of formula 1 can be according to various Methods can be achieved. So for this purpose are t B. complex metal hydrides, and finally diborane Zinc in a weak acid, especially acetic acid, is applicable. The exit fireplaces of the Formula VI are new substances that are accessible by general methods of enamine synthesis. In The main question is the reaction of the corresponding ketones, i. H. of 8-substituted 11 H -dibenzo- [b, f] -thiepin-10-ones with amines of the formula V in the presence of a catalytic amount of an acid of the methanesulphonic or p-toluenesulphonic acid type with continuous removal of the water of reaction by azeotropic distillation with benzene, Toluene or xylene. A newer one with titanium tetrachloride can also be used to remove the reaction water working method can be applied.

The products obtained, i.e. H. the compounds of the formula I have a basic character "in However, they are not resistant to strongly acidic solutions. The bases let through best Purify chromatography on alumina. Their salts with "weak organic acids" are good crystallizable and relatively stable, so that it is not only used to characterize the products, but are also suitable for the preparation of appropriate dosage forms; for both purposes the maleates serve best.

The preparation of the compounds according to the invention is illustrated in the examples below.

example 1

A mixture of 10.0 g of 8-chloro-10-piperazino-10, ll-dihydrodibenzo- [b, f] -thicpine, 10.0 g of triethylamine, 15.5 g of 2- (2-chloroethyl) -l, 3-dioxane and 60 ml Toluene is refluxed with stirring for 26 hours. After cooling, it is filtered the reaction mixture and the filtrate evaporated in vacuo. The crude base obtained is (according to the Control of a sample by thin layer chromatography on aluminum oxide) sufficiently homogeneous, so that their purification by chromatography is not necessary. The whole amount of the base is dissolved in a mixture of 10 ml of acetone and 5 ml of ethanol and neutralized the solution by adding a Solution of 3.0 g of maleic acid in a little ethanol. The resulting solution is mixed with ether up to first cloudiness and lets it crystallize. On standing, 13.2 g of crystalline maleate separate out desired 8-chloro-10- {4- [2- (1,3-dioxan-2-yI) ethyl] - piperazino} - 10.11 - dihydrodibenzo - [b, f] -thiepins from, which melts at 183 to 184 ° C after recrystallization from 90% ethanol. The analysis confirms the assumed composition

C ₂₈ H ₃₃ ClN ₂ O ₆ S.

B e i s ρ i e 1 2

Similar to the previous example, 6.65 g of 8-chloro-10-piperazino-10,11-dihydrodibenzo- [b, f] -thiepin, 8.85 g of 2- (2-chloroethyl) -l, 3-dioxolane and 645 g of triethylamine in 45 ml of toluene (boiling under reflux for 35 hours) were used for the reaction. Work-up of the reaction mixture (separation of the triethylamine hydrochloride, evaporation of the precipitate. Chromatography of the crude product in benzene on aluminum oxide (activity II) with elution with benzene containing 5% ethanol) yields 4.1 g of 8-chloro-10 n ', 4 - [2 - (1,3 - dioxolan - 2 - yl) - ethyl] - piperazino \ - 10,11 - dihydrodibenzo - [b, f] - thiepin as a homogeneous base, which crystallized by neutralizing with maleic acid in an acetone-ethanol mixture Maleate with melting point 168 to 169 "C yields, the analysis of which confirms _{the composition C 27} H ₃₁ ClN ₂ O _{6 S.}

Example 3

Fin mixture of 20.0 g of 8,10-dichloro-10.l 1-dihydrodibenzo- [b, f] -thiepin, 25 ml of anhydrous chloroform and 27.0 g of 1- [2- (1,3-dioxolan-2-yl) ethyl] piperazine is refluxed with stirring for 8 hours. From the reaction mixture the chloroform is then distilled off. the residue is dissolved in benzene and the solution is washed thoroughly with water and evaporate the chloroform. 25.Og of 8-chloro-10-14- [2- (1,3-dioxolan-2-yl) ethyl] piperazino! -10.11-dihydrodibenzo [b, f] thiepin are obtained as residue as a crude base, which is dissolved in an acetone-ethanol mixture and by adding an equivalent amount of an ethanolic Maleic acid solution converted into the corresponding maleate, which is obtained by standing and cooling the Solution precipitates. After filtering off with suction, the product is washed with ether and crystallized from ethanol around. Mp. 168 to 169 ° C.

Serving as starting material 1- [2- (1,3-dioxolan-2-yl) ethyl] piperazine can be z. B. prepare as follows: 27.0 g of 2- (2-chloroethyl) -1,3-dioxolane and 30 g of anhydrous potassium carbonate are added to a solution of 64 g of ethoxycarbonyl} piperazine in 100 ml of 1 - butanol. The mixture is then refluxed with stirring for 12 hours. After cooling, the undissolved constituents are removed by filtration, and the filtrate is freed from butanol by evaporation under reduced pressure. The residue represents the crude 1- [2- (1,3-dioxolan-2-yl) ethyl] -4- (ethoxycarbonyl) piperazine. 30 g of potassium hydroxide and 60 ml of ethanol are added to this, and the mixture is heated hours under reflux in a bath of 120 to 130 ⁰ C. After distilling off ethanol and added; the residue is mixed with just enough water so that the solid components are brought into solution and isolated the hydrophilic product by extraction with chloroform and subsequent vacuum distillation, .

Example 4

A mixture of corresponding amounts of 8.10-dichloro-10.11 - dihydrodibenzo - [b, f] - thiepin. anhydrous chloroform and 1 - [2- (1,3-dioxan-2-yl) ethyl] piperazine is reacted by heating under reflux and stirring. Then you steam the chloroform off; the residue is dissolved in benzene and the solution is washed with water. Through Evaporation of the benzene solution gives the 8 - chlorine -10 - {4 - [2 - (1,3 - dioxan - 2 - yl) - ethyl] piperazino} -10.11 - dihydrodibenzo- [b.f] -thiepin as

crude base, which is converted into the corresponding crystalline maleal in a similar way to the previous example. Likewise, the 1 - [2 - (1,3 - dioxane - 2 - y 1> ethyl] piperazine used as starting material can be prepared in a similar way as in the previous example for the analogous dioxolane derivative is described. The 8 ■ chloro-10-; 4- [2- (1,3-dioxan-2-yl) ethyl] piperazino} -10.11 -dihydrodibenzo - [b, f] - thiepin - maleate has a melting point of m.p. 183 to 184 ° C.

Claims (1)

Patent claims: 1. 10-piperazinodibenzo- [b, f] -thiepine of the formula I. Aj, if necessary, with weak acids in the corresponding Salts transferred. 3. A pharmaceutical agent consisting of a compound according to claim 1 and pharmaceutical usual auxiliary and carrier materials.