CS261345B1 - (E) -N-Methyl-3- (6,11-dihydrodibenzo / b, e / thiepine-11-ylidene) propylamine N-phenylaceterates and their Hydrochlorides - Google Patents

Abstract

The solution falls into the field of synthetic drugs. Its subject is N-phenacyl derivatives of (E)-N-methyl-3-(6,ll-dihydrodibenzo/b,e/- thiepin-ll-ylidene)propylamine and their hydrochlorides. As phenacyl, both the unsubstituted phenacyl group itself and 4-chlorophenacyl are used in their molecules. The substances according to the invention showed moderate effects with very low acute toxicity in antireserpine tests on animals and further in in vitro tests (affinity to binding sites for imipramine and desipramine in the rat hypothalamus). Their therapeutic effect is similar to that of known antidepressant preparations (prothiaden, northiaden), with the advantage being higher lipophilicity (allowing easier penetration into the brain) and rapid metabolism to effective northiaden. They are therefore useful in the therapy of mental depression. They can be prepared by substitution reactions of (E)-N-methyl-3-(6,11-dihydrodibenzo[b,e]thiepin-11-ylidene)propylamine with phenylacyl halides; the hydrochlorides are prepared by neutralization of the base with hydrogen chloride.

Description

The present invention relates to the N-phenyl-derivatives of (E) -N-methyl-3- (6, U-dihydrodibenzo [b, e] thiepin-11-ylidene) propylamine of formula (I)

WITH.

(I), ch ₃ in which R represents a hydrogen atom or a chlorine atom, and their hydro-chlorides.

The compounds of formula I and their hydrochlorides show efficacy in animal and block-pharmacological tests, which is considered an indication of antidepressant efficacy in mentally ill patients. Thus, it is expected that these compounds will be useful in psychiatric medical practice in depressed patients. The individual tests used are listed below together with the doses of compounds of formula I which have shown efficacy. All dosages refer to oral administration.

(E) -N-Phenacyl-N-methyl-3- (6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propylamine (I,

RH) was tested in the form of the hydrochloride. Its acute toxicity in mice is very low; doses of 1 g / kg do not produce any toxic symptoms yet. In the rotating rod test in mice, the substance induces ataxia (incoordination effect) at extremely high doses; _5Q ED = 584 mg / kg. The undesired central damping effect is therefore very low. In the reserpine-induced hypothermia antagonist assay in mice, the substance exhibits a distinct effect at doses far from toxic; Egg 134 mg / kg. Reserpine-induced ptosis in mice is inhibited by the test substance starting at a dose of 300 mg / kg. The agent further potentiates the toxicity of yohimbine in mice, a typical antidepressant effect; ED-. - 241 mg / kg. Finally, the substance inhibits slightly the binding of 4 nmol.l ^-3 ( ³ H) imi ^3U- i 3 pramine (at 100 nmol.l inhibits binding by 35 t) and further binding of 4 nmol.l (H) desipramine (both in rat hypothalamus brain); XC ₅₀ - 263 nmol.l ³ .

(E) -N- (4-Chlorophenacyl) -N-methyl-3- (6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propylamine (I, R-Cl) was also tested in the form of the hydrochloride. There is also minimal toxicity in the acute toxicity test in mice since doses of 1 g / kg do not induce lethality or any toxic symptoms. In the rotating rod test in mice, the substance is discoordinating ineffective up to a dose of 500 mg / kg; the 1000 mg / kg dose induced ataxia in 20% of the animals. The undesired central damping effect is therefore even lower than that of the fabric. The antagonistic effect against reserpine ptosis in mice is demonstrable at up to 1000 mg / kg, which is still non-toxic. In the yohimbine potency toxicity potentiation test in mice, the drug was administered at doses of 100, 250, 500 and 1000 mg / kg; the highest dose potentiated the toxicity of yohimbine statistically significantly in 50% of the animals in the experiment, so this dose is approximately equal to the ED _en dose. Similarly to the foregoing, this compound slightly binds to 4 nmol.l of (H) imipramine and (H) desipramine in the rat brain hypothalamus; the respective values of the mean inhibitory concentrations of IC ₅₀ are 263 nmol.l ^-3 , respectively. 581 nmol.l ^-3 .

The compounds of formula (I) are derivatives, respectively. analogs of known antidepressants of prothiaden (Metyšová J. et al., Arzneim.-Forums. 13, 1039, 1963) and northiaden (Metyšová J. et al., Arzneim.-Forums. 15, 524, 1965). With these preparations, the compounds according to the invention are less effective (in terms of intensity of action), but at the same time they are far less toxic, so that the therapeutic breadth remains the least. In addition, the compounds of the invention are much more lipophilic than the above-mentioned preparations, allowing them to penetrate the brain more rapidly and to have a faster onset of action. The presence of the phenacyl residue in the molecules of the new substances furthermore requires their rapid metabolism to the highly active northiaden: the binding of phenacyl to the nitrogen atom is very labile and the removal of this residue from the molecule is certainly due to both hydrolytic and oxidative mechanisms. Thus, the compounds of formula (I) may also be considered as a prodrug of northiadene, which is chemically (E) -N-methyl-3- (6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propylamine, i.e. the secondary amine of this series .

The compounds of formula (I) according to the invention are accessible from (E) -N-methyl-3- (6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propylamine (Rajsner M. et al., Collect. Czech. Chem. Commun.

34, 1963, 1969) by substitution reactions with phenacyl halides and 4-chlorophenacyl halides. These substitution reactions do not change the configuration at the double bond, so that the products of formula (I) also belong to the (E) trans-configuration, as demonstrated by infrared spectra. The substitution reactions can be performed in various ways. Preferred is the process described in the examples, wherein said secondary amine is treated with said halides (suitable for chlorides or bromides) in the presence of anhydrous alkali carbonates in boiling chloroform. The bases obtained, which are oily, are purified by chromatography on silica gel and converted by neutralization with hydrogen chloride into the crystalline hydrochlorides which are also part of the invention. The substances described in the invention are novel; their identity was assured by analytical and spectral methods. The examples are merely illustrative of the preparation possibilities of the compounds of the invention.

Example 1 (E) -N-phenacyl-N-methyl-3- (6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propylamine (I,

R = H)

To a stirred mixture of 14.1 g of (E) -N-methyl-3- (6,11-dihydrodibenzo [b, e] thiepine-11-ylidene) propylamine, 25 ml of chloroform and 5.3 g of sodium carbonate were added over 15 min. a solution of 7.7 'g ^of phenacyl chloride (commercial product) in 15 ml of chloroform. The reaction is slightly exothermic. The mixture was stirred at room temperature for 2 h and then refluxed for 30 min. After cooling, it is diluted with 50 ml of dichloromethane, the solid is filtered off and washed with dichloromethane.

The filtrate was evaporated under reduced pressure and the inhomogeneous residue was chromatographed on a column of 50 g of silica gel (Merck). Unchanged phenacyl chloride is eluted with a mixture of 90% benzene and 10% chloroform. Subsequent elution with chloroform alone elutes 9.9 g of the desired oily base, which is dissolved in 22 ml of chloroform and acidified with a solution of hydrogen chloride in ether. Further addition of ether leads to the precipitation of crystalline hydrochloride. After standing overnight, it is filtered off with suction and recrystallized from a mixture of ethanol and ether, m.p. Mp 189-193 ° C.

Example 2 (E) -N- (4-Chlorophenacyl) -N-methyl-3- (6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propylamine (I, R = Cl)

To a stirred solution of 11.2 g of (E) -N-methyl-3- (6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propylamine in 30 ml of chloroform was added 5.8 g of anhydrous potassium carbonate and then slowly 9.35 g of 4-chlorophenacyl bromide (Collet A., Bull. Soc. Chim. Fr. (3) 21, 69, 1899).

The mixture was stirred at room temperature for 1 h and then heated at reflux for 2 h. After cooling, the mixture was diluted with 50 ml of chloroform and washed with 50 ml of water. After drying with potassium carbonate, the chloroform solution was evaporated and the residue was chromatographed on a column of 150 g of silica gel (Merck 40). The fractions obtained by eluting with benzene are discarded and the product is then eluted with mixtures of benzene and chloroform and finally with chloroform alone. 8.4 g (48%) of an oily base are obtained, which is converted, as in the previous case, to crystalline hydrochloride (5.7 g). After recrystallization from ethanol / ether, it melts at 190-194 ° C.

Claims (1)

N fenacylderiváty (E) -N-methyl-3- (6, ll-dihydro-dibenzo / b, e / thiepin-l l-ylidene) propylamine of formula I CH ₃ wherein R is a hydrogen or chlorine atom, and their hydrochlorides.