CS263998B1 - 3-/11-methyl-6,11-dihydrodibenzo/b,e/thiepin-6-yl/-propylamines and hydrogenmaleinates them - Google Patents

Abstract

The solution is in the synthetic field drugs. Its subject matter is N-methyl- and N, - N-dimethyl-3- (11-methyl-6,11-dihydrodibenzo / b, e) thiepin-6-yl) propylamine and their hydrogen maleate. Named substances according to the invention exhibit a pharmacological profile of thymoleptics and are useful as anti-drugs mental depression. Their preparation comes out from 11-methyl-6,11-dihydrodibenzo / b, e / - thiepine, which is converted to 6-carhanion by treatment with butyllithium by alkylation 3-dimethylaminopropyl chloride; results in one of the listed substances according to solution. The second one is obtained from this substance demethylation by action of ethyl chloroformate and subsequent alkaline hydrolysis non-isolated carbamate. Gained substances are mixtures of stereoisomers that are \ t it is purified either by chromatography or by crystallization hydrogen maleate. 1 H NMR spectra (was used to ensure a rough structure, first, to determine the stereoisomer content in mixtures.

Description

The present invention relates to 3- (11-methyl-6,11-dihydrobenzo [b, e] thiepin-6-yl) propylamines of formula I

wherein R is methyl or hydrogen, and their hydrogen maleate.

The compounds of the invention are novel and their hydrogen maleate compounds exhibit thymoleptic properties in animal tests, which usually correlate with antidepressant efficacy in patients. The compounds of formula (I) and their maleate compounds may therefore be considered as potential drugs against mental depressive states.

The compounds of the formula I according to the invention have two chiral centers in their molecules. Thus, the crude products obtained by synthesis are mixtures of two stereoisomers. These mixtures can be characterized by ¹ H NMR spectra and the components can be determined. Chromatography of the crude bases leads to elimination of the minor component and the substance will then, by ^f H NMR spectra appear as homogeneous. The invention relates both to mixtures of stereoisomers corresponding to formula I and to individual homogeneous stereoisomers.

For the two substances according to the invention, pharmacological data are provided which confirm their thymoleptic character:

N, N-Dimethyl-3- (11-methyl-6,11-dihydrodibenzo [b, e] thiepin-6-yl) propylamine (I, R = CH 3) was tested as hydrogen maleate. When administered orally, it is very toxic in mice; up to a dose of 500 mg / kg appears to be non-toxic and does not even have a depressant effect. In a rotating rod test in mice it shows a slight incoordinating effect; ED 50 = - 35 mg / kg p.o. In the reserpine ptosis test in mice, it exhibits a significant antireserpine effect at an oral dose of 50 mg / kg. In the rat reserpine ulcer test, the test substance is markedly antireserpine active at an oral dose of 100 me / kg.

N-methyl-3- (11-methyl-6,11-dlhydrodibenzo [b, e] thiepin-6-yl] propylamine (I, R = H) was also tested in the form of hydrogen maleate In an acute toxicity test in female mice by intravenous administration is the mean lethal dose LD 50 = 47.4 mg / kg, the toxic symptoms of lower doses are ataxia and limb paresis In a rotating rod test in mice, the substance induces a co-ordination disorder with intravenous administration starting at 10 mg / kg, at 30 mg / kg the short-term incontinence present in most mice, and half of them are corrected within 30 min ip after administration In the reserpine hypothermia test, the substance antagonizes the oral dose of 10 mg / kg and statistically significantly antagonizes the ulcerogenic effect of reserpine kg.

For the preparation of the compounds of the formula I according to the invention, one can start from 11-methyl-6,11-dihydrodibenzo [b, e] thiepine, which has not been described so far, the preparation of which is known from 11-methyl-6,11-dihydrodibenzo [b, e] thiepine-11. -ol (Umio S., Ueda I .: Japanese. 72 33 358 (Chem. Ahstr. 77, 164 540, 1972); Hori M. et al .: Yakugaku Zasshi 98, 1333, 1978) is described in U.S. Pat. example.

From the 11-methyl-6,11-dihydrodibenzo [b, e] thiepine, an anion is formed on carbon C-6 by treatment with n-butyllithium in ether / hexane, followed by treatment with 3-dimethylaminopropyl chloride to form a compound of formula (I, R - CH3). The base is oily and is isolated as a crystalline hydro-chloride which corresponds analytically to the assumption. The oily base liberated from the hydrochloride is a mixture of the stereoisomers, the minority of which can be eliminated by chromatography.

Using the ¹ H NMR spectrum, it can be unequivocally confirmed that the branch chain is indeed at the 6-position and that, at this position, the reaction with butyllithium produced a carbanion. The crude base of formula I (R = CH 3) can then be converted to the compound of formula I (R = H) by partial demethylation by reaction with ethyl chloroformate in boiling benzene and alkaline hydrolysis of the resulting and uncharacterized carbamate. This base is also oily and the ¹ H NMR spectrum determines its components as 35% of equatorial stereoisomers A. H-6 and 65% of stereoisomers B with axial H-6. The base again provides crystalline hydrogen maleate which can be used for pharmacological tests and for the preparation of dosage forms. Further details of the preparation of the compounds of the formula I according to the invention are given by way of example, which are merely illustrative of the possibilities for synthesizing the compounds of the formula I.

Example 1

N, N-dimethyl-3- (11-methyl-6,11-dihydrodibenzo [b, e] thiepin-6-yl) propylamine (I, R = CH 3)

To a stirred solution of 3.4 g of 11-methyl-6,11-dihydrodibenzo [b, e] thiepine in 35 mL of ether was added over 45 min. 8.5 g of a 15% solution of n-butyllithium in hexane are added dropwise at 14 to 18 ° C. The resulting red mixture was stirred at room temperature for 1.5 h. The mixture was stirred for 3.5 h and allowed to stand overnight. After diluting with 50 ml of ether, the stirred and cooled mixture is quenched by the slow addition of 15 ml of water, the organic layer is separated and washed with water, and the bases are shaken to 75 ml of 1M HCl (three times) by shaking.

3.6 g (100% conversion) of the hydrochloride monohydrate of the desired compound precipitated from the acidic aqueous solution for 1 h, which crystallized from 2-propanol and melted at 116-120 [deg.] C. Evaporation of the organic phase from which the bases were extracted 1.2 g of the starting 11-methyl-6,11-dihydrodibenzo [b] e / thiepine were recovered.

The hydrochloride (2.6 g) was suspended in 20 ml of water, 1.5 ml of 2.5 Μ-NaOH was added, and the liberated bases were extracted with ether. Evaporation of the extract gave 1.9 g of an inhomogeneous base (R = CH3) which, according to thin-layer chromatography, was a mixture of the predominant amount of isomer with R _F 0.6 and a minor amount of isomer with R _F 0.7. This base is chromatographed on a column of 100 g of silica gel. Elution with a mixture of 97% chloroform and 3% methanol gives 1.7 g of a practically homogeneous oily base whose ¹ H NMR spectrum does not show split signals and confirms the presence of one proton on C-6 and C-11 carbons, simultaneously confirming structure I (R = -CH 3). The base provides maleic acid neutralization with crystalline hydromaleinate, which crystallizes from a mixture of ethanol and ether and melts at 115-116.5 ° C.

The 11-methyl-6,11-dihydrodibenzo (b, e) thiepine starting material used is not yet described in the literature and can be obtained as follows:

A mixture of 25 ml of 55% hydroiodic acid and 0.4 g of sodium hypophosphite monohydrate is stirred for 15 min at 80 ^and C, then diluted with 25 ml of acetic acid, 3.1 g of red phosphorus and 7.25 g of 11-methyl are added. -6,11-dihydrodibenzo (b, e) thiepine-11 ol (literature cited). The mixture was refluxed for 3 hours under nitrogen, cooled to 50 ° C, diluted with 50 ml of benzene, filtered with charcoal and the filtrate evaporated in vacuo. The residue was extracted with benzene, the extract was washed with 5% sodium bisulfite solution and water, dried and evaporated. Crystallization of the residue from 80 ml of ethanol yielded 6.3 g (93%) of the desired compound, melting at 66-67.5 ° C (ethanol).

Example 2

N-methyl-3- (11-methyl-6,11-dihydrodibenzo [b, e, thiepin-6-yl) propylamine (I, R = H)

To a stirred solution of 1.9 g of ethyl chloroformate in 6 ml of benzene is added dropwise a solution of 3.1 g of Ν, Ν-dimethyl-3- (11-methyl-6,11-dihydrodibenzo [b, e] thiepin-6-yl) over 30 min. of propylamine (Example 1) in 10 ml of benzene and refluxed for 2.5 h. After standing overnight, it is diluted with 50 ml of benzene, washed with 25 ml of 1M-HCl and water, dried and evaporated under reduced pressure. The residue (3.5 g of oily carbamate) was dissolved in 10 ml of ethanol, 8.0 g of potassium hydroxide was added, and the mixture was stirred and refluxed in a 115 ° C bath for 2 h. After standing overnight, it is diluted with 30 ml of water and extracted with benzene. Workup of the extract yielded 2.7 g (71%) of an oily inhomogeneous base which was converted by neutralization with 1.2 g of maleic acid in 25 ml of ethanol and addition of 30 ml of ether to 3.1 g of hydrogen maleate. This crystallizes from a mixture of ethanol and ether and melts at 160-162 ° C. A sample of the purified hydrogen maleate is quenched with 1M-NaOH and the base isolated by extraction with ether. It is an oil which identifies ¹ H NMR as a mixture of 35% of Isomer A with equatorial H-6 and 65% of Isomer B with axial H-6.

Claims (2)

OBJECT OF INVENTION 3- (11-methyl-6,11-dihydrodibenzo [b, e] thiepin-6-yl) propylamines of formula I wherein R is methyl or hydrogen, and their hydrogen maleates.