NO132355B - - Google Patents

Description

The present invention relates to an analogous process for the preparation of the new 2-ethyl-2,3-dihydro-5-trifluoromethyl-1H-dibenzo[2,3:6,7]thiepino[4,5-c]pyrrole of formula I

as well as its addition salts with inorganic or organic acids.

This compound, as well as its addition salts, has interesting pharmacological properties and a high therapeutic index. It has a central depressant effect on peroral, rectal and parenteral administration, e.g. decreases denmoti-. the smallness, potentiates the effect of analgesics and narcotics, antagonizes the effect of amphetamine, acts in the traction test as an antiemetic, serotonin antagonist and lowers the body temperature. It also has an antihistamine effect. These effective qualities, which can be shown by selected standard tests [cf. R. Domenjoz and. W. Theobald, Arch. Int. Pharmaco-dyn. 120, 450 (1959), F. Raynaud, Products Pharm. 16, 99

(1961) and W. Theobald and R. Domenjoz, Arzneimittelforsch. 8, 18 (1958)], characterizes the compound as suitable for the treatment of states of tension and irritation, as well as for the treatment of psychotic conditions.

From Norwegian patent no. 127,401, tiepin and oxepin derivatives with the general formula are known:

where X means oxygen or sulphur,

Y hydrogen, chlorine, the methyl, methoxy or methylthio group and

R hydrogen, a lower unbranched alkyl group with 1-6 carbon atoms, the isopropyl or allyl group.

The compounds produced according to Norwegian patent no. 127,401 act as central depressants when administered peroral, rectal and parenteral, e.g. they reduce motility, potentiate the effect of analgesics and narcotics, antagonize the effect of amphetamine, act in the withdrawal test, act as an antiemetic, serotonin antagonist and lower body temperature. Furthermore, they exhibit an antihistamine effect.

The compound produced according to the present method exhibits a significantly greater effect with regard to orientation motility than the compounds according to Norwegian patent no. 127,401, which is evident from the following, where the compound according to the present invention (I) is compared with three compounds (II - IV ) according to Norwegian patent no. 127,401 with regard to their pharmacological activity on experimental animals during investigations of orientational motility and toxicity.

The investigations included the following compounds:

I 2-ethyl-2,3-dihydro-5-trifluoromethyl-1H-dibenzo[2,3:6,7]- thiepino[4,5-c]pyrrole methanesulfonate

II 2-isopropyl-2,3-dihydro-1H-dibenzo[2,3:6,7]thiepino-[4,5-c]pyrrole-methanesulfonate [known from example 2

d) in Norwegian patent no. 127,401,

III 2-methyl-2,3-dihydro-5-chloro-1H-dibenzo[2,3:6,7]-thiepino[4,5-c]pyrrole-methanesulfonate [known from example 3 a) in Norwegian patent no .127,401,

IV 2-ethyl-2,3-dihydro-5-chloro-1H-dibenzo[2,3:6,7]thiepino-[4,5-c]pyrrole-methanesulfonate [known from example 4 a)

in Norwegian patent no. 127,401.

Orientation motility

Groups of mice, each weighing 18 - 21 g, were placed in Plexiglass cages of 30 x 20 x 9 cm. The interruption of a light beam guided through the cages caused by the movement of the mouse is registered with the help of a photocell and a counter. The animals are placed in the cages 30 minutes after the injection of the test substance. The motility is recorded over the course of 15 minutes, and the dose is sought at which a reduction of 50% of the mean value is achieved compared to the controls (=DE^Q). The evaluations are done on semi-logarithmic paper by Schleicher and Schiill, N° 373 1/2.

Toxicity

To determine the toxicity, the compounds I - IV were given intraperitoneally to white mice in different single doses (injection rate is arbitrary).

For each dose, 5-15 experimental animals were used, whose body weight varied from 14 - 26 g. The animals were observed for a week after administration of the preparations. The DL^Q value indicates the dose which has a lethal effect on half of the treated animals.

Results

Conclusion

The toxicity values for the tested compounds lie

broadly within the same range of variation. On this basis, it turns out that the provided compounds I - IV are essentially equally toxic.

The experimental data obtained thus show a superiority for compound I, which is prepared according to the present method, compared to the known compounds II - IV.

For production according to the invention of the compound of formula I, the compound of formula II is reacted with ethylamine and, if desired, the reaction product obtained is treated with an inorganic or organic acid in an addition salt.

The bis-bromomethyl compound of formula II is reacted with ethylamine

1 presence of a solvent. Suitable solvents are those which are inert under the reaction conditions, e.g. hydrocarbons, such as benzene or toluene, halogenated hydrocarbons,

such as chloroform, lower alkanols such as methanol or ethanol, ethereal solutions such as ether or dioxane, as well as lower alkanones such as acetone, methyl ethyl ketone or diethyl ketone.

During the reaction according to the invention of a molar equivalent of bis-bromomethyl compound with a molar equivalent of free base, 2 molar equivalents of hydrogen bromine are split off. Hydrogen bromide binds to excess ethylamine.

The starting material 10,11-bis-(bromomethyl)-2-(trifluoromethyl)-dibenzo [b,f]thiepine, which corresponds to formula II, can e.g. is prepared according to the following procedure: One starts from [o-(oc,a,oc-trifluoro-p-tolylthio)-phenyl]-acetic acid (cf. K. Pelz and M. Pro-tiva, Collect. Czechoslov. Chem. Communications 3_4 , 3936 (1969)], which is then transferred into the ethyl ester, which is condensed with diethyl carbonate in the presence of sodium to [o-(a,a,a-tri-fluoro-p-tolylthio)-phenyl]-malonic acid diethyl ester. The sodium compound of this is reacted with methyl iodide, and the disubstituted malonic acid diethyl ester obtained is hydrolysed during simultaneous decarboxylation to o-(α,α,α-trifluoro-p-tolylthio)-hydratropic acid.

IN

IN

Under the action of hydrofluoric acid at room temperature, this acid gives 11-methyl-8-(trifluoromethyl)-dibenzo[b,fjthiepin-10(11H)-one, which is converted with methylmagnesium iodide to 10,11-dihydro-10,11-dimethyl-8 -(trifluoromethyl)-dibenzo[b,fthiepin-10-ol. From the latter, during water separation by heating in a vacuum, predominantly 10,11-dihydro-lo-methyl-11-methylene-trifluoromethyl-dibenzotribeline is obtained, which on boiling with ethanolic potassium chloride is converted into 10,11-dimethyl-2- (jtr if fluoromethyl )-dibenzo[b,fjthiepine. This dimethyl compound is then brominated in the presence of dibenzoyl peroxide with N-bromosuccinimide to 10,11-bis-{bromomethyl)-2-(trifluoromethyl)-dibenzo[b,f jtiepine of formula II.

The compound of formula I obtained by the method according to the invention is then, if desired, transferred in the usual way into acid addition salts with inorganic or organic acids. E.g. one adds a solution of the compound of formula I in an organic solvent with the desired acid as a salt component or with a solution thereof. Preferably, organic solvents are chosen for the reaction, in which the obtained salts are poorly soluble, so that they 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 free bases, pharmaceutically acceptable acid addition salts can be used, i.e. salts with such acids whose anions are not toxic in the relevant dosages. Furthermore, it is advantageous when the salts used as pharmaceuticals are easily crystallizable and not or only slightly hygroscopic. For salt formation with the compound of formula I can e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, (3-hydroxy-ethanesulfonic 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.

IN

As previously mentioned, the new active substance is administered orally, rectally or parenterally. The dosage depends on the area of application, the species, the age and the individual condition. The daily doses of the free base or of pharmaceutically acceptable salts thereof are between 0.1 mg/kg and 10 mg/kg for warm-blooded animals. Suitable dosage unit forms, such as e.g. dragees, tablets, suppositories or ampoules preferably contain 2 - 100 mg of an active substance according to the invention.

The following example explains in more detail the preparation of the new compound of formula I and of previously undescribed intermediates. Temperatures are given in degrees Celsius.

EXAMPLE

a) Dissolve 23.2 g (0.05 mol) 10,11-bis-(bromomethyl)-2-(trifluoromethyl)-dibenzo[b,fJthiepine in 100 ml abs. benzene. This

the reading is added dropwise over the course of one hour at 40° to a solution of 40 g (approx. 0.9 mol) of ethylamine in 200 ml of methanol.

The reaction mixture is stirred for a further 2 hours at 50° and the solvent and excess ethylamine are then distilled off.

100 ml of water is added to the residue and the suspension obtained is extracted with ether. The ethereal solution is washed with water, dried over potassium carbonate and evaporated to dryness in vacuo. The residue is recrystallized in ethanol and gives the pure 2-ethyl-2,3-dihydro-5-(trifluoromethyl)-1H-dibenzo[2,3:6,7]thiepino[4,5-c]pyrrole with m.p. 104 - 106°.

8.68 g (0.025 mol) of the base obtained is dissolved in 25 ml abs. acetone and 2.40 g (0.025 mol) of methanesulfonic acid are added, after which the methanesulfonate crystallizes out. 2-Ethyl-2,3-dihydro-5-(-': (trifluoromethyl)-1H-dibenzo[2,3:6,7]thiepino[4,5-cJpyrrole-methanesulfonate is recrystallized in ethanol.

The starting material 10,11-bis-(bromomethyl)-2-(trifluoromethyl)-dibenzo[b,fJthiepine is prepared as follows: b) 224.0 g (0.725 mol) [o-(a,a,a-trifluoro -p-tolylthio)-phenylj-acetic acid is dissolved in 2000 ml abs. ethanol and add 100 ml

6,5-n ethanolic hydrochloric acid. The reaction mixture is refluxed for 5 hours, the solvent is evaporated in vacuo and the oily residue is taken up in ether. The ethereal solution is extracted with water, saturated sodium bicarbonate solution and again with water. The ethereal phase is dried over magnesium sulphate, the solvent is evaporated in vacuum and the oily residue is distilled in high vacuum. The pure [o-(α,α,α-trifluoro-p-tolyl-thio)-phenyl]-acetic acid ethyl ester boils below 0.01 torr at 132-135°; n^° = 1.5415.

c) 234 g (0.69 mol) of the ester obtained according to b) is dissolved in 200 ml of diethyl carbonate and added dropwise over the course of 20 minutes

to a solution of 16.3 g (0.71 mol) of sodium in 800 ml of diethyl carbonate. The reaction mixture is stirred for one hour at 100°, and then the released ethanol is distilled off (maximum internal temperature 125°). The reaction mixture is then cooled to room temperature, poured into one liter of ice water and acidified with 2-n hydrochloric acid to pH 3. The organic phase is then taken up in ether, washed with water and evaporated after drying with magnesium sulfate in vacuum. The residue obtained (287 g) consists of [o-(α,α,α-trifluoro-p-tolylthio)-phenylj-malonic acid diethyl ester, which is further used as a crude product.

d) 285 g (0.69 mol) of the crude [o-(α,α,α-trifluoro-p-tolylthio)-phenyl]-malonic acid diethyl ester are dissolved in 800 ml abs. ethanol and

a solution of 15.9 g (0.69 mol) of sodium in 800 ml of abs. ethanol. The reaction mixture is further stirred for one hour at room temperature. Then 147.0 g (1.03 mol) of methyl iodide are added dropwise into the liquid

30 minutes. After the addition of the methyl iodide is finished, boil

the reaction mixture for 6 hours under reflux. A solution of 84.g (1.50 mol) of potassium hydroxide in 690 ml of water in ldpet of 30 minutes at reflux temperature. The mixture is boiled for 20 hours under reflux and then the ethanol is distilled off over the course of 3 hours from the reaction mixture. The residue is cooled, poured into 2 liters of ice water and extracted three times with benzene. The alkaline, aqueous phase is acidified with conc. hydrochloric acid (pH =1) and extracted twice with ether. The. ethereal phases are washed with water, dried over magnesium sulfate and evaporated in vacuo. The obtained residue is distilled in hdy vacuum. The pure o-(α,α,α-trifluoro-p-tolylthio)-hydratropic acid boils at 155 - 160°/0.0l torr.

e) 187 g (0.574 mol) of o-(α,α,α-trifluoro-p-tolylthio)-hydratropic acid is introduced in approx. 700 ml anhydrous hydrofluoric acid and

dissolves. The mixture is stirred for 12 hours at room temperature and then the hydrofluoric acid is evaporated at 25 - 30°. The residue obtained is dissolved in benzene and extracted with water and 2-n sodium carbonate solution. The organic phase is dried over magnesium sulfate and evaporated to dryness in vacuo. The residue obtained is recrystallized in pentane. The pure 11-methyl-8-(trifluoromethyl)-dibenzo[b,f]thiepin-10(11H)-one melts at 107 - 108°.

f) 57 g (0.185 mol) 11-methyl-8-(trifluoromethyl)-dibenzo[b,f] thiepin-10(11H)-one are dissolved in 200 ml abs. benzene and added dropwise

at -5 to 0° over the course of 2 hours to one of 8.8 g (0.37 mol) magnesium and 52.5 g (0.37 mol) methyl iodide in 500 ml of ether freshly prepared Grignard solution. The mixture is then stirred for one hour at room temperature and 12 hours at 45-50. After sufficient cooling, the contents of the flask are poured into a solution

100 g of ammonium chloride in one liter of ice water and extracted with ether. The ethereal phases are washed with water, dried over magnesium sulphate and evaporated in vacuo. The obtained crude 10,11-dihydro-10,11-dimethyl-8-(trifluoromethyl)-dibenzo[b,f]thiepin-10-ol is a viscous oil.

g) 50.8 g (0.157 mol) of the crude 10,11-dihydro-10,11-dimethyl-8-(trifluoromethyl)-dibenzo[b,f]thiepin-10-ol are heated for 6 hours in

vacuum at 190°. The crude product is dissolved in ether and purified by chromatography on 700 g of neutral silica gel (grain size 0.05 - 0.3 mm, Merck) eluting with petroleum ether. The eluted product (42.5 g) is dissolved in 400 ml abs. ethanol and boil

after adding 80 g of potassium hydroxide 12 hours under reflux. The ethanol is then extensively evaporated in a vacuum and the residue is shaken off with ether and water. The ether-containing phases are washed neutrally with water, dried over magnesium sulphate and the solvent is evaporated in vacuo. The oily residue obtained is distilled under high vacuum. The pure 10,11-dimethyl-2-(trifluoromethyl)-dibenzo [b,fJthiepine boils at 125 - 130°/0.01 torr and exhibits a m.p. of 63 - 65°.

h) 9.81 g (0.03 mol) of 10,11-dimethyl-2-(trifluoromethyl)-dibenzo[b,f]thiepine is dissolved in 100 ml of abs. carbon tetrachloride. 11.2 g (0.063 mol) N-bromosuccinimide is added to the solution

and 0.1 g of dibenzoylperoxide. While stirring and lighting with

a UV lamp heats the mixture to boiling. After 30 minutes, the reaction is complete (the succinimide floats over the carbon tetrachloride) and the mixture is cooled to room temperature. The succinimide is filtered off, washed out with carbon tetrachloride and the filtrates are shaken out with dilute sodium bicarbonate solution.

The organic phase is then washed neutrally with water, dried over magnesium sulphate and the solvent is evaporated in vacuo. The residue is recrystallized in ether-petroleum ether. The pure 10,11-bis-(bromomethyl)-2-(trifluoromethyl)-dibenzo[b,fthiepine melts at 144-146°.

Claims (1)

Analogous process for the preparation of the new therapeutically active 2-ethyl-2,3-dihydro-5-trifluoromethyl-1H-dibenzo[2,3:6,7]thiepino[4,5-c]pyrrole of formula I as well as its addition salts with inorganic or organic acids, characterized by reacting the compound of formula II with ethylamine, and optionally transfers the obtained reaction product with an inorganic or organic acid to an addition salt.