CS260095B1 - (e)-11-(3-methylaminopropylidene)-6,11-dihydrodibenzo/b,e/thiepine-2-carbonitrile and its oxalate - Google Patents

Description

The invention relates to (E) -11- (3-methylaminopropylidene) -6,11-dihydrodibensyl (b, e) thiepine-2-carbonitrile of formula I

CH ₂ NH ₃ and its oxalate.

The compound of formula I, which has been tested by biochemical-pharmacological methods in the form of its hydrogen oxalate, suggests the properties of a potential antidepressant to a somewhat unusual efficacy profile. While basically it lacks antireserpine and centrally suppressing o

effects in in vivo assays, show high affinity for the (H) imipramine binding sites in the rat brain hypothalamus. This affinity is expressed by the mean inhibitory concentration

IC 50 = 17.49 nM (( ² H) imipramine used at 4 nM). This affinity is considerably selective, since inhibition of 4 nM / H / desipramine binding in the same brain structure is much weaker;

IC ₅₀ = 1967 nM.

Selectivity of this type suggests that the compound of Formula I is a 5-hydroxytryptamine reuptake inhibitor in the brain, which is considered a prerequisite for one type of antidepressant activity. Like other tricyclic antidepressants, the compound of Formula 1 exhibits a central anticholinergic action, which exhibits considerable affinity for muscarinic receptors in rat brain. 0.5 nM (H) -hinuclidylbenzilate was used as ligand; the mean inhibitory concentration of the compound of formula I against the binding of this ligand is expressed as = 347 nM.

At a dose of 10 mg / kg p.o. the substance does not affect the likomotor activity of the mice in the Dews test. At a dose of 25 mg / kg p.o. has no significant antireserpine effect in the ptosis test in mice and at a dose of 50 mg / kg p.o. does not significantly inhibit reserpine-induced gastric ulceration in rats. Thus, substance I can be characterized as an atypical antidepressant.

The compound of formula I is accessible by synthesis using compounds of formulas II to VI

II, III, r ^and R ¹ 1 = Br, = Br, R - R ² 2 = ch ₃ = cooc ₂ h ₅ iv, R = Br, R « = H IN, VI, R ¹ R ¹ = Br, = CN, R ² = R ² - CO (CH ₂ ) ₃ OH = CO (CH ₂ ) ₃ OH

, with R and R substituents being indicated as starting material and as intermediates. The preferred substance is (E) -N, N-dimethyl-3- (2-bromo-6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propylamine of formula II, the preparation of which is described as a homogeneous trans-isomer in čs. copyright certificate 247 593.

Reaction of this material with ethyl chloroformate in boiling benzene affords partial demethylation to give an oily carbamate of formula III. It can be used for further work without characterization and is treated in the crude state by hydrolysis with a boiling, highly concentrated, preferably 40 to 50% solution of potassium hydroxide in ethanol. In high yield, an oily N-methyl-3- (2-bromo-6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propylamine of formula IV is obtained which yields the crystalline hydrochloride and whose 1 H MNR spectrum confirms that The (E) -configuration was retained during the transformations. Base IV is then liberated from the crystalline hydrochloride salt with aqueous ammonia and treated with butyrolactone in boiling xylene in the presence of 2-pyridone.

The crude 4-hydroxybutyramidine derivative of formula (V) is isolated from the obtained mixture by chromatography on silica gel and reacted with copper (I) cyanide in hexamethylphosphoric triamide at 150 ° C. The crude intermediate (VI) obtained is purified again by chromatography and subjected without gentle hydrolysis to dilute sulfuric acid in dioxane at 90 ° C. Chromatography of the crude product on alumina yields the desired base of Formula I which is oily and whose NMR spectrum indicates that it consists predominantly of the (E) -isomer and is only partially contaminated with the (Z) -isomer.

Neutralization with oxalic acid dihydrate in ethanol gives a crystalline hydrogen oxalate which has been identified as a hemihydrate melting at 202-204 ° C. Further details of the procedure for preparing the compound of Formula I are given in the example:

A solution of 12.6 g of (E) -N, N-dimethyl-3- (2-bromo-6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propylamine (literature cited) in 40 ml of benzene is added dropwise with stirring at 75 ° C to a solution of 4.73 g of ethyl chloroformate in 20 ml of benzene and the mixture was refluxed for 1 h.

After cooling, the mixture was washed with water, filtered, washed with 50 ml of 10% sulfuric acid and again with water.

It is dried over solid potassium hydroxide and evaporated under reduced pressure. The oily residue (12.57 g of crude compound of formula III) was added to a solution of 9.0 g of potassium hydroxide in 11 ml of ethanol, and the mixture was heated under reflux in a bath at 125-130 ° C for 2 h. After cooling, the mixture was diluted with 50 ml of water and extracted with benzene. The extract was shaken with 50 ml of 10% hydrochloric acid to convert the basic product into the aqueous phase.

The acidic aqueous layer was basified with a slight excess of 20% sodium hydroxide solution and the product was isolated by extraction with benzene.

The extract was dried over anhydrous potassium carbonate and evaporated. 8.3 g (68%) of practically homogeneous (oily) (E) -N-methyl-3- (2-bromo-6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propylamine (IV) are obtained. This was dissolved in ethanol and converted to the hydrochloride (7.52 g) by the addition of a slight excess of a solution of hydrogen chloride in ether. Crystallization of this material from ethanol yields a pure product which is produced at 264-268 ° C. Aqueous ammonia releases a completely pure base which is isolated by extraction with ether and used in the next step.

A mixture of 9.65 g of base the previous formula IV, 5.7 g of 2-pyridone (Cava Μ. P. Bhattacharyya NK J. Org. Chem., 23rd ^»1287, 1958) in 13 ml of butyrolactone and 50 ml of xylene was boil under reflux for 4 h. The mixture was filtered and the filtrate was partitioned by shaking between benzene and dilute aqueous ammonia. The benzene phase is dried over potassium carbonate and evaporated. The residue is chromatographed on a column of 250 g of silica gel. The less polar components of the mixture were washed with benzene and then with chloroform. The mixture of chloroform and ethanol was eluted with 10.0 g of the crude hydroxyamide of formula V, which was dissolved in 20 ml of hexamethylphosphoric triamide, 4.5 g of copper (I) cyanide was added, and the mixture was heated to 150 ° C for 12 h. After cooling, it is partitioned by shaking between benzene and dilute aqueous ammonia, the benzene phase is washed with water, dried over potassium carbonate and evaporated.

The residue is chromatographed on a column of 300 g of neutral alumina (activity II). From the chloroform fraction, 3.85 g of a homogeneous oil, corresponding to the cyanoamide of formula VI, is obtained. They are subjected to hydrolysis without characterization. Dissolve in 100 mL of dioxane, add 100 mL of 10% sulfuric acid and heat at 90 ° C for 4 h. The dioxane was evaporated, the acidic aqueous solution was washed with benzene and basified with aqueous ammonia. The liberated base is extracted with benzene and the benzene evaporation residue is chromatographed on 100 g of alumina (neutral, activity II). Benzene and then chloroform eluted with 2.24 g (27%) of the oily base of Formula I.

Neutralization with oxalic acid dihydrate in ethanol gives 2.15 g of hydrogen oxalate which crystallizes from ethanol as a hemihydrate; m.p. Mp 202-204 ° C. The NMR spectrum of the base released from the pure oxalate shows that it is an almost pure (E) -isomer; the admixture of the (Z) -isomer is slight.

Claims (1)

OBJECT OF THE INVENTION (E) -11- (3-methylaminopropylidene) -6,11-dihydrodibenzo [b, e] thiepine-2-carbonitrile of formula I and its oxalate. Severography, n. P., MOST Price 2,40 Kčs