CS268630B1 - Process for the preparation of 6- (aminoalkoxy) dibenxo / b, f-thiepine-10 (11H) -ones and their hydrochlorides - Google Patents

Abstract

The solution falls into the field of drug synthesis. Its subject is a method for preparing 2-dimethylamino(or piperidino)ethyl ethers and 3-dimethylamino(or piperidino)propyl ethers derived from 6-hydroxydibenzo[b,f]thiepin-10(11H)-one and its 2-chloro derivative, as well as their hydrochlorides. The substances mentioned have antimicrobial activity in in vitro tests and are therefore potential chemotherapeutics. In addition, they exhibit some other pharmacodynamically advantageous properties. Their preparation according to the solution consists in the reactions of sodium salts of the named phenol ketones with 2-dimethylamino(or piperidino)ethyl chloride or 3-dimethylamino(or piperidino)propyl chloride in boiling ethanol in the presence of sodium ethoxide. The obtained bases are converted into hydrochlorides by neutralization with hydrochloric acid or hydrogen chloride.

Description

The invention ee relates to a process for the preparation of 6- (aminoalkoxy) dibenzo [b, f] thiepin-10 (11H) -ones of the general formula I

(I) in which R ¹ represents a hydrogen atom or a chlorine atom, NR 9 is a dimethylamine or piperidine residue and n is 2 or 3, and their hydrochlorides.

The compounds of the formula I, in particular in the form of the hydrochlorides, show antimicrobial antimicrobials in in vitro tests, so that they can be considered as potential chemotherapeutics. In addition, they exhibit still other useful pharmacodynamic properties, as discussed below, which make them potential drugs. The compounds of the formula I can also be used as intermediates in the preparation of other pharmacodynamic active ingredients.

Biological properties The following are listed for the following substances according to the invention:

(i) 6- (2-Dimethylaminoethoxy) dibenzo [b, f] thiepin-10 (11H) -one as hydrochlorides (B) 6- (2-Piperidino) ethoxy) dibenzo [b, f] thiepin-10 (11H) ) -one in the form of hydrochloride hemihydrate (c) 6- (3-Dimethylaminopropoxy) dibenzo [b, f] thiepin-10 (1H) -one in the form of hydrochlorides (D) 6- (3- (Piperidino) propoxy) dibenzo (b) f) thiepin-10 (11H) -one in the form of hydrochlorides (E) 2-Chloro-6- (2-dimethylaminoethoxy) dibenzo [b, f] thiepin-10 (11H) -one in the form of hydrochloride hemihydrate

Compound A: acute toxicity in mice, LD ^ _Q = 56 mg / kg IV; 257 mg / kg po Shows a mild ataxic effect in a rotating rod test in mice; ED ₅₀ = 18.4 mg / kg iv In the presence of histamine detoxification in guinea pigs at a subcutaneous dose of 10 mg / kg, it slightly prolongs the latenology of guinea pigs (indication of antihistamine effect). In vitro microbial activity (test organisms and minimum inhibitory concentrations in mg / l): Streptococcus / 3 haemclyticus, 100; Staphylococcus pyogenes aureus, 100; Proteus vulgaris, 100; Candida albicans, 50.

* Substance B: dumbbells in the test

Acute toxicity in mice, LD 50 = 33 mg / kg i.v. It shows mild ataxic eruption rods in mice / Εϋ $ θ = 10 mg / kg i.v. It has an antitussive effect in guinea pigs in which the cough is caused by an aerosol of a citric acid solution; at an oral dose of mg / kg suppresses cough attacks by approximately 50 tocoecus / 3-haemclyticus, 100; Streptococcus reus, 50; Trichophyton mentagrophytes, 50.

%. In vitro antimicrobial effects: Strep-faecalis, 100; Staphylococcus pyogenes au Substance C: Acute Toxicity in mice, ΙΌ ^ θ = 29.9 mg / kg iv; 324 mg / kg po Ataxic effect in the rotating rod test in mice, ED ₅₀ = 15.0 mg / kg iv. At the same dose, it slightly but statistically significantly reduced the incidence of gastric ulcers after reserpine in rats (thymole effect).

Mtka D: Acute toxicity in mice, LD ^ ₀ = 40 mg / kg iv, Ataxic effect in the rotating rod test in mice, ED ^ e 12.2 mg / kg iv, Antimicrobial effects in vitro: Streptococcus faecalis, 100; Staphylooooous pyogenes aureus, 50; Pseudomonas aeruginosa, 50; Trichophyton mentagrophytes, 12,5,

Substance E: Acute toxicity in mice, = 75 mg / kg i.v. At a concentration of 10 .mu.g / ml, it attenuates the contractions of isolated rat duodenum induced by acetylcholine to 50% (sposmolytic effect). It has an anorectic effect in mice; in oral doses of 25 to 75 mg / kg in

CS 268 630 Bl inhibits food intake by 50%. Antimicrobial effects in vitro: Streptooooous / J -haemolytioua, 50} Staphylococcus pyogenes aureus, 25, Trichophyton mentagrophytes, 50.

The compounds of formula I according to the invention are prepared by reactions of the sodium salts of phenol ketones of formula II

OH (ID, in which R ¹ denotes the same as in formula I, with aminoalkyl chlorides of general formula III οι (οη ₂ ) _Λ in which NR ₂ and n denotes the same as in formula I, Reactions are performed in boiling ethanol and to convert phenol ketones of formula Sodium ethoxide is used for the sodium salts and, if an appropriate excess is used, the aminoalkyl chlorides of the formula III can be used in the form of commercially available hydrochlorides. 6-hydroxydibenzo [b, f] thiepin-10 (11H) -one see Protiva M. et al., Collect, Czeoh.Chem.Commun., 40, 2667 (1975); 2-chloro-6-hydroxydibenzo [b, f]. / thiepin-10 (11H) -cn see Protiva M. et al., Collect.Czech.Chern.Commun. 46, 2245 (l98l).

All the substances described in the invention are novel, their identity being ensured by the usual analytical and spectral methods. The compounds of the formula I are basic in nature and, by neutralization with hydrochloric acid or hydrogen chloride, give hydrochlorides which crystallize well, are soluble in water and the process for their preparation by the neutralization reaction just mentioned is part of the invention.

The preparation of the individual compounds according to the invention is described in the following examples, which, however, are merely illustrative of one variant of the process according to the invention and are not intended to describe all possible variants.

Example 1

6- (2-Dimethylaminoethoxy) dibenzo [b, f] thiepin-10 (11H) -one

To a stirred solution of sodium ethoxide, which is prepared by dissolving 3.0 g of sodium in 350 ml of ethanol, is added, with stirring, 12.12 g of 6-hydroxybenzo [b, f] thiepin-10 (11H) -one and, after stirring for 10 minutes. 10.6 g of 2-dimethylaminoethyl chloride hydrochlorides. The mixture was refluxed with stirring for 9 h. After standing overnight, the precipitated sodium chloride was removed by filtration, the filtrate was weakly acidified with hydrochloric acid and evaporated to dryness in vacuo. The residue is dissolved in water, the solution is washed with benzene, basified with aqueous ammonia and the liberated base is isolated by extraction with benzene. Work-up of the extract gave 10.4 g (66%) of an oily base which crystallized from cyclohexane and melted in pure form at 69-71 DEG C. Neutralization with hydrogen chloride in a mixture of ethanol and ether gave the hydrochloride, which crystallized from the same mixture and in pure form. melts at 176-179 ° C.

Example 2

6- (2- (Piperidino) ethoxy) dibenzo [b, f] thlepin-10 (11H) -one

In a similar reaction, 12.1 g of 6-hydroxydibenzo [b, f] thiepLn-10 (11H) -one with 12.9 g of 2- (piperidino) ethyl chloride hydrochloride in sodium ethoxide solution (from 3.0 g of sodium and 250 ml of ethanol) ) (reflux for 7 h) gave 14.6 g (83%) of practically homo

CS 268 630 B1 gennl of an oily base which crystallizes from a mixture of cyclohexane and hexane and melts at 55-58 ° C. C.

Example 3

6- (3-Dimethylaminopropoxy) dibenzo [b, f] thiepin-10 (11H) -one

In a similar reaction, 6.7 g of 6-hydroxydibenzo [b, f] thiopin-10 (11H) -one with 6.6 g of 3-dimethylanxinopropylohloride hydrochloride in sodium ethoxide solution (from 1.73 g of sodium and 200 ml of ethanol) (boiling for 10 h under reflux) 6.4 g (71%) of an almost homogeneous oily base are obtained, which is converted into the hydrochloride by treatment with hydrogen chloride in a mixture of ethanol and ether, m.p. 181 DEG-183 DEG C. (ethanol ether). A completely pure base is liberated from the purified hydrochloride by aqueous amene, which is isolated by extraction with ether. However, it is still oily, so it can be used to measure spectra.

Example 4

6- (3- (Piperidine) propoxy) dibenzo [b, f '/ thiepine-10 (11H) -one

In a similar reaction, 10.9 g of 6-hydroxydibenzo [b, f] thiepin-10 (11H) -one with 12.5 g of 3- (piperidine) propyl chloride hydrochloride in a solution of sodium ethoxide from 2.5 g of sodium and 200 ml of ethanol (var. under reflux for 8.5 h) 14.0 g (85%) of a crystalline base melting at 78-80 ° C (cyclohexane) are obtained. Neutralization with hydrogen chloride affords the hydrochloride, which crystallizes from acetone and melts at 166-169 ° C.

Example 5

2-Chloro-6- (2-dimethylaminoethyloxy) dibenzo [b, f] thie pln-10 (11H) -one

In a similar reaction, 3.1 g of 2-chloro-6-hydroxydibenzo [b, f] thiepin-10 (11H) -one with 2.6 g of 2-dimethylaminoethyl hydrochloride hydrochloride in sodium ethoxide solution (reflux for 11.5 h) ) 2.5 g (64 g of crystalline base are obtained, which is purified by crystallisole from cyclohexane, m.p. 101 DEG-103 DEG C. Neutralization with hydrochloric acid in ethanol and addition of ether gives the hydrochloride hemihydrate, m.p. 197 DEG-199 DEG C. (ethanol).

Claims (1)

OBJECT OF THE INVENTION Process for the preparation of 6- (aminoalkoxy) dlbenzo [b, f] thien-10 (11H) -ones of the general formula I (I) _; In which R ¹ represents a din atom and n is 2 or 3, and tons of the general formula II vnd-fku or a chlorine atom, NR 1 is a residue of dimethylamine or of its hydrochloric hydrochlorides, characterized in that the sodium salts of phenolecene (Π) _? wherein R ¹ is the same as in formula I, ee is reacted with aminoalkyl chlorides of formula III ^{C1 (} ^ ^{) n NR} 2 (III), in which NR ₂ and n are the same as in formula I, in boiling ethanol in the presence of sodium ethoxide and the bases of formula I obtained are converted into the hydrochlorides by neutralization with hydrochloric acid or hydrogen chloride.