CS268632B1 - Process for the preparation of δ- (methylaminoalkoxy) -dibenzo / b, f / thiepine-10 (11 H) -ones and salts thereof - Google Patents

Abstract

The solution falls into the field of drug synthesis. Its subject is a method for preparing 6-(2-methylaminoethoxy and 3-methylaminopropoxy)dibenzo /b,f/thiepin-1O(1 1H)-ones, their 2-chloroderivatives and salts with pharmaceutically acceptable inorganic or organic acids. The substances according to the invention are intermediates in the preparation of biologically active compounds and partly exhibit some useful biological effects (antimicrobial, centrally depressant, spasmolytic, antiarrhythmic, antitussive). The preparation method consists in the reaction of 6-(2-dimethylaminoethoxy and 3-dimethylaminopropoxy)dibenzo- [b,f]thiepin-1O( 1 11I) -ones and their 2-chloro derivatives with ethyl chloroformate in boiling benzene and subsequent alkaline hydrolysis of the obtained esters of N-substituted carbamic acids. The obtained bases are converted into salts by neutralization reactions.

Description

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

(I), in which R represents a hydrogen atom or a chlorine atom and n is 2 or 3, and their salts with pharmaceutically acceptable inorganic or organic acids.

The compounds of the formula I are characterized by useful biological properties and can be used as intermediates in the synthesis of other biologically active substances. The compounds of the formula I have, for example, antimicrobial activity in in vitro tests, so that they can be considered as potential chemotherapeutics, and have also shown a moderate centrally suppressive and incoordinating, spasmolytic, antiarrhythmic and antitussive effect.

Substances for which specific biological data can be reported. They are identified as (a), (b) and (c), first their identity and then the activities found:

(a) 6- (2-methylaminoethoxy) dibexiso [b, f] thiepin-10 (11H) -one as hydrochloride, (B) 2-chloro-6- (2-methylaminoethoxy) dibenzo [b, f] thiepin-10 (11H) -one 10 (11H) -one in the form of the hydrochloride and (c) 6- (3-methylaminopropoxy) dibenzo [b, f] thiepin-10 (11H) -one in the form of the neutral oxalate hemihydrate. Substance (A): Acute toxicity in mice, = 63.8 mg / kg i.v. Ataxic efficacy in the rotating rod test in mice, = 23.2 mg / kg i, v, At an oral dose of 50 mg / kg, induces a statistically significant attenuation of the spontaneous motility of the mice (tranquilizing effect).

Substance (B): Acute toxicity in the mouse, ϋζ, θ = 88.4 mg / kg i, v. In vitro antimicrobial activity (test organisms listed and minimum inhibitory concentrations found in mg / l): Streptococcus / 5-haemolytious, 25j Streptococcus faecalls, 25j Staphylococcus pyogenes aureus, 25j Proteus vulgaris, 100.

Substance (c): Acute toxicity in mice, LD ₅₀ = 54.0 mg / kg iv j after oral administration of 877 mg / kg. At concentrations of 1 to 10 mg / l it suppresses acetylcholine-induced contractions of isolated rat duodenum at 5 °, similarly at 10 mg / 1 it suppresses similar contractions induced by barium chloride (spasmolytic effect). At an intravenous dose of 2.5 mg / kg it exhibits antiarrhythmic effect in rats against aconitine-induced arrhythmias. At an oral dose of $ 0 mg / kg, it is antitussive in guinea pigs (cough attacks were induced by aerosol of citric acid solution and the dose caused inhibition of cough attacks by 52% compared to 100% control), at a concentration of 100 mg / kg. 1 inhibits the growth of Streptococcus faecalis in vitro.

The process for the preparation of the compounds of the formula I according to the invention consists in the partial demethylation of the corresponding 6- (dimethylaminoalkoxy) dibenzo [b, f] thiepin-10 (1H) -ones of the formula H.

(ID>

CS 268 632 D1 in which Ran denotes the same as in formula I. These starting materials of formula II have not yet been described in the literature, and therefore Jojioh's preparation is described in the examples.

In the first step, the compounds of formula II are treated with ethyl chloroformate in boiling benzene to demethylase, resulting in carbamates of formula HI

in which Ran again denotes the same as in formula I. These carbamates are isolated from the reaction mixtures as neutral products and can be further processed in the crude state. However, some crystallize well, so they can be isolated in a homogeneous state and characterized analytically and spectrally, and then further processed. The second step consists in the alkaline hydrolysis of the carbamates of formula III, which is preferably carried out with a boiling solution of potassium hydroxide in ethanol. The final products are isolated as bases, which are mostly crystalline, and which are converted neutralised with pharmaceutically acceptable inorganic or organic acids to the corresponding salts. Purification of the final products can be performed by crystallization of these salts and the base liberated from the pure salts. They are homogeneous and can be used for spectral characterization. All substances described in the invention are novel and their identity has been established by analytical and spectral methods. The following examples are merely illustrative of the possibilities of the invention and are not intended to describe all of these possibilities in an exhaustive manner.

Example 1

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

To a stirred solution of 7.3 g of 6- (2-dimethylaminoethoxy) dibenzo [b, f] thiepin-1O (11H) -one in 50 ml of benzene was added dropwise a solution of 5.4 g of ethyl chloroformate in 20 ml of benzene, a mixture of ee stirred at 60-70 ° C for 30 min and then refluxed for 3 h. After cooling, the reaction mixture was filtered, the filtrate was washed with 3M HCl and water, dried over magnesium sulfate and evaporated. The neutral residue (7.4 g, 80%) is N-methyl-N- (2- (10-oxo-1H-dibenzo [b, f] thiepin-6-yloxy) ethyl) carbamic acid ethyl ester, crystallized from ethanol and melts in the pure state at 103-106 ° C.

A mixture of 3.7 g of this ester, 2.8 g of potassium hydroxide and 3.5 ml of ethanol is refluxed for 4 hours with stirring, the ethanol is evaporated off in vacuo, the residue is diluted with water and the product is extracted with benzene. Treatment of the ee extract gave 2.8 g (94 g of an oily product) which crystallized from a mixture of ether and petroleum ether and melted in pure form at 61-64 DEG C. Neutralized with hydrogen chloride in methanol in the presence of ether caught crystalline hydrochloride which crystallized from methanol and 208 to 212 ° C.

The required starting 6- (2-dimethylaminoethoxy) dibenzo [b, f] thiepin-10 (11H) -one is prepared from the known 6-hydroxydibenzo [b, f] thiepin-10 (11H) -one (Protiva M. et al. । Collect, Czech, Chem «Commun. 40, 2667 (1975 ((as a result; '

6-Rydroxydibenzo [b, f] thiepin-10 (11H) -one (12.12 g) and 10.8 g of 2-dimethylaminoethyl chloride hydrochloride are added to a solution of sodium ethoxide, which is previously prepared by dissolving 3.0 g of sodium in 350 ml of ethanol. The mixture was stirred and refluxed for 9 h. After standing through a pad, the precipitated sodium chloride is filtered off and the filtrate is filtered

The mixture is dissolved in water, the solution is washed with benzene and basified with aqueous ammonia. The liberated base is isolated by extraction with benzene. Evaporation of the extract gave 10.4 g (66%) of an oily yellow bass which was used for carbathate processing. It crystallizes from cyclohexone and melts in the pure state at 69-71 ° C. For characterization, Ji can be converted to the hydrochloride, m.p. 176-179 ° C (ethanol ether).

Example 2

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

Similarly, in the previous example, 6.96 g of 2-chloro-6- (2-dimethylaminoethoxy) dibenzo [b, f] thiepin-10 (11II) -one were reacted with 4.6 g of ethyl chloroformate in 60 ml of boiling benzene and 5.1 g (63%) of crude N- (2- (2-chloro-10-O10-1H-dibenzo [b, f] thien-6-yloxy) ethyl) -N-methylcarbamic acid ethyl ester are obtained, which crystallizes from ethanol and melts at 152-154 ° C,

As in the previous example, 3.3 g of this carbamate are hydrolyzed with a solution of 2.5 g of potassium hydroxide in 5 ml of ethanol at reflux for 10 hours. Similar work-up gives 1.9 g (70%) of a homogeneous desired base which crystallizes from a mixture of benzene and hexane and melts at 101-103 ° C. Neutralization with hydrogen chloride in a mixture of ethanol and ether gives the crystalline hydrochloride, m.p. 193-195 ° C (ethanol).

The required starting 2-chloro-6- (2-dimethylaminoethoxy) dibenzo [b, f] thiepin-10 (11H) -one is prepared in a manner similar to that described in the previous example by reacting 3.1 with 2-chloro-6-hydroxydibenzo (b, f) thiopin-10 (11H) -one (Protiva M. et al., Collect.Czech.Chem, Comun. 46, 2245 (1981)) with 2.6 g of 2-dimethylaminoethyl dichloride hydrochloride boiling in sodium ethoxide solution , prepared from 0.7 g of sodium and 40 ml of ethanol (boiling 11.5 h), 2.5 g (64%) of the crystalline desired substance are obtained, m.p. 101-103 ° C. For characterization, it can be converted to crystalline hydrochloride hemihydrate, m.p. 197-199 ° C (ethanol). Example 3

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

To a stirred solution of 5.2 g of ethyl chloroformate in 20 ml of benzene was added dropwise a solution of 7.9 g of 6- (3-dimethylaminopropoxy) dibenzo [b, f] thiepin-10 (11H) -one in 42 ml of benzene and the mixture was boiled. h under reflux. Work-up As in the previous examples, 7.2 g (77%) of practically homogeneous oily ethyl ester of N-methyl-N- (3- (10-oxo-1H-dibenzo [b, f] thiepin-6-yloxy) propyl are obtained. ) carbamic, which is used for the next reaction without further purification.

As in the previous examples, 2.0 g of this ester are hydrolyzed with a solution of 1.5 g of potassium hydroxide in 2 ml of ethanol (reflux for alcohol). Workup gave 1.4 g (86 of the desired oily yellow base, which was neutralized with oxalic acid dihydrate in 2 ml of boiling ethanol to give neutral oxalate hemihydrate, mp 198-201 ° C (80% ethanol-ether).

The required starting 6- (3-dimethylaminopropoxy) dibenzo [b, f] thiepine-10 (11H) -one is prepared in a manner similar to the analogous substances in the previous examples by reacting 6.7 g of 6-hydroxydibenzo [b, f] thiepine-1θ ( 11H) -one with 6.6 g of 3-dimethylaminopropyl chloride hydrochloride in a solution of sodium ethoxide from 1.73 β sodium and 200 ml of ethanol (b.p. 10 h at reflux). Analogous work-up gave 6.4 g (71%) of an almost homogeneous, oily, yellow base, which was used for the next reaction in this state. For characterization, it can be converted to the hydrochloride, which crystallizes from a mixture of ethanol and ether and melts at 181-183 ° C.

Claims (1)

Process for the preparation of 6- (methylaminoalkoxy) dibonzo [b, f] thliiopin-10 (11H) -ones of eyebrow formula I 0 CH. Z Π J (I), in which R represents a hydrogen atom or a chlorine atom and n is 2 or 3 »and their salts β with pharmaceutically acceptable inorganic or organic acids, characterized in that ae 6- (dimethylaminoalkoxy) dibenzo [b, f] thiepine -10 (11H) -ones of general formula II O (CH-) N (CH.). from n 3 from (II), subjected to the action of ethyl chloroformate in boiling benzene, the carbamates obtained (III), in which Ran again denotes the same as in formula I, are hydrolyzed with a boiling solution of potassium hydroxide in ethanol, after which the bases of formula I obtained are converted into neutralises! pharmaceutically acceptable inorganic or organic acids to the corresponding salts.