NO122425B - - Google Patents

Description

Analogy process for the preparation of a new pharmacodynamically active thiepine derivative.

The present invention relates to a process for the preparation of a new pharmacodynamically active thiepine derivative, 8-chloro-10-(1-piperazinyl)-10,11-dihydro-dibenzo[b,f]thiepine with formula I as well as its addition salts with inorganic or organic acids are not yet known.

As has now been found, this compound as well as its salts possess valuable pharmacological properties and a high therapeutic index. They have a central depressant effect on peroral, rectal or parenteral administration, e.g. they reduce motility, potentiate anesthesia and show a positive effect in the "test de la traction". Furthermore, they exhibit an antiemetic effect. These performance qualities, which are determined by selected standard tests [cf. R. Domenjoz and W. Theobald, Arch. Int. Pharmacodyn. 120, 450

(1959) and W. Theobald et al., Arzneimittelforsch. 17, 561 (1967)],

characterizes the compounds as suitable for the treatment of tension and irritation states. In relation to the central depressant properties, the new compounds show a smaller cataleptic effect, which was demonstrated in a standard experiment [cf. W. Theobald et al., Arzneimittelforsch. 17, 561 (1967)]. This less cataleptic intrinsic effect, alongside the pronounced central depressant properties, distinguishes these compounds. Related compounds of 8-chloro-10-(1-piperazinyl)-10,11-dihydro-dibenzo[b,f]thiepine and its salts, which are substituted in the 4-position of the piperazine ring [cf. Spofå, British patent no. 1,093,910), in relation to the central depressant properties, exhibits a significantly higher cataleptic effect and thereby affects the extrapyramidal system more strongly.

For the preparation according to the invention of the compound of formula I

one hydrolyzes a compound with the general formula II,

where Y denotes an acyl residue as in hydrolysis

can be replaced by hydrogen,

and optionally transfers the reaction product obtained with an inorganic or organic acid to an addition salt.

On hydrolysis to the hydrogen atom transferable residues Y. are acyl residues, e.g. lower alkanoyl groups, such as the acetyl group, arylcarbonyl groups, such as the benzoyl group, residues of monofunctional derivatives of the carboxylic acid or thiocarboxylic acid, such as e.g. the methoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl group, or the corresponding thiocarbonyl groups. The hydrolysis can be carried out using an alkali metal hydroxide, e.g. the potassium or sodium hydroxide, preferably at the boiling temperature either in a high-boiling hydroxyl group-containing organic solvent, such as e.g. ethylene glycol or di-ethylene glycol, or in a lower monoalkyl ether of such a glycol and especially in a lower alkanol, such as e.g. methanol or ethanol.

Starting substances with the general formula II can e.g. is prepared starting from the 8,10-dichloro-10,11-dihydro-dibenzo[b,f]thiepine described in the literature. One converts this connection e.g. with 1-piperazine carboxylic acid esters, e.g. with the methyl, ethyl, phenyl or benzyl ester, to the corresponding esters of the 4-(8-chloro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-1-piperazinecarboxylic acid. Analogously, e.g. the corresponding thiocarboxylic acid esters are prepared. Furthermore, e.g. compounds of the general formula II, which are substituted in the 4-position of the piperazine ring with a lower alkanoyl, e.g. acetyl or with an arylcarbonyl group, e.g. the benzoyl group, is also prepared analogously. One goes, e.g. from 8,10-dichloro-10,11-dihydro-dibenzo[b,f] thiepine and reacts this compound with the corresponding piperazine derivatives, e.g. with the 1-acetyl- or 1-benzoyl-piperazine.

The compound of formula I obtained by the process according to the invention is then transferred, if desired, in the usual way to its addition salts with inorganic and organic acids. E.g. one adds a solution of the compound of formula I in an organic solvent with the acid desired as salt component or with a solution of the same. Organic solvents are preferably chosen for the reaction, in which the formed salt is poorly soluble, so that it can be separated by filtration. Such solvents are e.g. methanol, acetone, methyl ethyl ketone, acetone-ethanol, methanol-ether or ethanol-ether.

For use as pharmaceuticals, instead of the free bases, pharmaceutically acceptable acid addition salts can be used, i.e. salts with such acids, whose anions are not toxic at the dosages in question. Furthermore, it is advantageous when the salts used as pharmaceuticals are easily crystallisable and not or slightly hygroscopic. For salt formation of compounds of formula I, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid and embonic acid are used.

As mentioned above, the new active substances are administered orally, rectally or parenterally. The dosage depends on the type of administration, the age and the individual condition. The daily doses of the free base or of pharmaceutically acceptable salts thereof range between 0.1 mg/kg and 10.5 mg/kg for warm-blooded animals. Suitable dosage unit forms, such as dragees, tablets, suppositories or ampoules, preferably contain 5-200 mg of the compound of formula I or of. a pharmaceutically acceptable salt of the same as active substance according to the invention.

The following example gives a more detailed account of the preparation of the new compound of formula I and of a previously undescribed intermediate product. The temperatures are indicated in degrees Celsius.

EXAMPLE

47.5 g of 1-piperazinecarboxylic acid ethyl ester are added to a solution of 28.12 g of 8,10-dichloro-10,11-dihydro-dibenzo[b,f]thiepine in 50 ml of benzene. The reaction mixture is boiled for 15 hours under reflux, cooled to 20° and 100 ml of 2-n ammonia is added. Then crude free base is precipitated. It is extracted three times, each time with 150 ml of methylene chloride-ether (1:2). The organic extract is washed with water, dried over magnesium sulphate and evaporated in vacuo. A solution of 61.0 g of powdered potassium hydroxide in 350 ml of absolute ethanol is added to the remaining crude 4-(8-chloro-10,11-" dihydro-dibenzo[b,f]thiepin-10-yl)-1-piperazinecarboxylic acid ethyl ester The clear solution obtained is boiled for 12 hours under reflux, 70 ml of water is added, it is cooled and evaporated in vacuo. The residue is taken up in ether-methylene chloride (2:1) and water, the organic phase is separated, washed with water, dried over sodium sulfate and evaporated. The residue is dissolved in 250 ml of ether and 50 ml of ethanol and the solution is neutralized with ethereal hydrochloric acid. 8-chloro-10-(1-piperazinyl)-10,11-dihydro-dibenzo[b,f] tiepin dihydrochloride is precipitated It is filtered off, washed with a little acetone, whereupon it melts at 195 - 200°.

Claims (1)

Analogous process for the preparation of a new pharmacodynamically active thiepine derivative, 8-chloro-10-(1-piperazinyl)-10,11-dihydro-dibenzo[b,f]thiepine of formula I as well as its addition salts with inorganic or organic acids, characterized by hydrolyzing a compound of the general formula II where Y means an acyl residue which can be replaced by hydrogen during hydrolysis, and optionally converts the reaction product obtained with an inorganic or organic acid into an addition salt.