CS263999B1 - 4,9-dihydrothieno [2,3-c] -2-benzothiepine series amines and their salts - Google Patents

Abstract

The solution falls into the field of synthetic drugs. Its subject is amines of the 4,9-dihydrothieno/2,3-c/-2-benzothiepin series and their salts, of which in particular N,N-dimethyl-3-(4,9-dihydrothieno/2,3-c/-2-benzothiepin-4-yl)propylamine hydrochloride shows in a number of pharmacological and biochemical tests the pharmacodynamic profile of an antidepressant and a thymoleptic. It is therefore considered a drug against mental depressive states. The substances according to the solution are accessible by reduction of the respective tertiary alcohols or olefinic amines with hydroiodic acid in boiling acetic acid in the presence of red phosphorus. The obtained oily bases are converted into crystalline salts by neutralization reactions, which are also the subject of the solution.

Description

The invention relates to amines of the 4,9-dihydrothieno [2,3-c] -2-benzothiepine series of formula (I)

wherein R is 3-dimethylaminopropyl or 1-methyl-4-piperidyl, and salts thereof with pharmaceutically acceptable inorganic or organic acids.

The compounds of formula (I) are novel and exhibit typical thymoleptic effects in pharmacological and biochemical tests, which usually correlate with antidepressant effects in patients. Thus, the compounds of formula I and their salts can be considered as antidepressant drugs and as such are tectinically important.

A typical compound of the invention is 4- (3-dimethylaminopropyl) -4,9-dihydrothieno [2,3-c] -2-benzothiepine, which has been pharmacologically evaluated as hydrochloride. The doses given below are all based on a recalculation. Its acute toxicity in female mice by intravenous administration is given by a mean lethal dose of LD50 = 28.2 mg / kg. The toxic symptoms observed in the determination of LD 50 are respiratory problems and seizures. The substance has only a very slight discoordination effect in the rotating rod test in mice; the median effective dose of the ED50 is 60 mg / kg when administered orally (with a maximum at 15 min after administration and with resolution of symptoms within 2 h). Centrally damping effect is practically absent, which is very advantageous. When evaluating the effect on spontaneous locomotor activity in mice, the Dews ray method shows activities; it certainly does not have a dampening effect. In the reserpine ulcer test in rats, the compound exhibits a statistically significant antiireserfill effect from an oral dose of 10 mg / kg. From the same oral dose, the substance significantly antagonizes reserpine ptosis in mice. At doses of 5, 10 and 25 mg / kg orally, it significantly antagonizes reserpine hypothermia in mice; the median effective dose D 50 is 17.5 mg / kg after the rat perfenazine catalepsy test has an intense anticataleptic effect at an oral dose of 40 mg / kg; even at a dose of 20 mg / kg, the anticataleptic effect is evident. The substance effectively potentiates yohimbine toxicity in mice; ED 50 = 10.8 mg / kg po The effect in this test and many others is well comparable to that of the classic tricyclic antidepressant imipramine. Finally, the substance exhibits a distinct affinity for the ( ³ H) imipramine and ( ³ H) desipramine binding sites in the rat hypothalamus. The mean inhibitory concentration of 4 nM / ³ H / 1mipramine binding IC 50 is 169.4 nM and 512 nM for nM / ³ H / desipramine binding inhibition. Thus, the substance has an overall pharmacodynamic profile of a classical tricyclic antidepressant.

The compounds of the formula I according to the invention are accessible by reducing the tertiary aminoalcohols of the formula II

(H) wherein R is the same as in Formula I, or olefinic amines of Formula III

wherein R ¹ is 3-dimethylaminopropylidene or 1-methyl-4-piperidylidene. Hydroiodic acid in a boiling mixture with acetic acid is best suited for the reduction. To recover the hydrogen iodide, red phosphorus is added to the reaction mixture.

Reduction reactions of the base of formula I obtained are oily, but provide crystalline hydrochlorides or other salts, for example maleates. In the form of salts, crystallization is purified to analytical purity and either spectra of these salts or homogeneous bases released therefrom are measured for identification. Both analytical and spectral data confirm the identity of the substances described. The starting materials of formulas (II) and (III) are generally known and the ethereal references to them are given in the examples. These are intended only to illustrate the preparation possibilities of the compounds according to the invention.

Example 1

N, N-dimethyl-3- (4,9-dihydrothieno [2,3-c] -2-benzothiepin-4-yl) propylamine

A mixture of 120 ml of acetic acid, 75 ml of 55% hydroiodic acid, 13.9 g of red phosphorus and 33.8 g of N, N-dimethyl-3- (4,9-dihydrothieno / 2,3-c) -2-benzothiepine hydrochloride 4-ylidene) propylamine (Protiva M. et al .: Collect. Czech. Chem. Commun. 29, 2161, 1964; Rajsner M. et al .: Collect, Czech. Chem. Commun. 39, 1366, 1974) Stir and reflux for 3 h under a nitrogen atmosphere. The cooled mixture was filtered, the filtrate was diluted with water (400 ml), basified with 25% sodium hydroxide solution while cooling, and extracted with dichloromethane. Work-up of the extract yielded a non-homogeneous residue, which was chromatographed on a column of 120 g of silica gel (Merck 60). Elution with chloroform gave 14.9 g (49%) of the desired homogeneous oil base. Neutralization with hydrogen chloride in ethanol / ether gives the hydrochloride, which crystallizes from ethanol / ether and melts at 172-173 ° C in pure state. A completely homogeneous oily base is obtained by decomposing the hydrochloride with dilute aqueous ammonia, extracting with ether, and treating the extract by conventional means. Its ¹ H NMR spectrum confirms its identity.

Example 2

4- (1-methyl-4-piperidyl) -4,9-dihydrothieno (2,3-c-2-benzothiepine)

Mixture of 45 ml of acetic acid, 45 ml of 57% hydroiodic acid, 5.6 g of red phosphorus and 13.3 g of 4- (1-methyl-4-piperidyl) -4,9-dihydrothieno [2,3-c] -2 -benzothiepine-4-ol (Rajšner M. et al .: Collect. Czech. Chem. Commun. 32, 2,854, 1967; Polivka Z. et al .: Collect. Czech. Chem. Commun. 48, 623, 1983) The mixture was stirred and refluxed for 3.5 h. A similar treatment as in the previous example yielded 13.5 g of an inhomogeneous base which was chromatographed on 80 g of silica gel (Merck 40). Elution with chloroform first removes 0.9 g of a mixture of less polar components, after which it is eluted from the column of 8.0 g (63%) of the desired homogeneous oil base. Neutralization with hydrogen chloride in ethanol / ether gives the hydrochloride, which crystallizes from ethanol and melts in the pure state at 279-290 ° C. His analysis and spectra confirm the identity. Hydrogen maleate is then prepared from the liberated base by neutralization with maleic acid, which crystallizes from a mixture of ethanol and ether and melts at 151-153 ° C.

Claims (1)

The amines of the 4,9-dihydrothieno [2,3-c] -2-benzothiepine series of formula (II) OF THE INVENTION wherein R is 3-dimethylaminopropyl or 1-methyl-4-piperidyl, and their salts with pharmaceutically acceptable inorganic or organic acids.