CS268626B1 - Process for the preparation of basic 2-chloro-10,11-dihydrodibenzo / b, f / thiepin-10-yl sulfides and their salts - Google Patents

Abstract

The invention relates to the field of drug synthesis. It relates to a method for preparing 2-chloro-10- (S-substituted thio)-10, 11-dihydrodibenzo[b,f] thiepines, where the S-substituent is the group -CH(R) (Ct-L) NR R, where R represents a hydrogen atom or tenyl, n is 2 or 3 and NR R is a residue of dimethylamine, diethylamine, cyclohexylamine, 1-benzylpiperazine or 1-(ethoxycarbonyl)piperazine, and their salts. The preparation method according to the solution consists in S-alkylation of 2-chloro-10,11-dihydrodibenzo /b,f/thiepin-10-thiol with chlorides of the formula (C1CH(R) (CH2)nNR R , where the general symbols have the same validity as above and in the subsequent conversion of the obtained bases into salts by neutralization reactions. The substances according to the solution are potential chemotherapeutics (antimicrobial activity in vitro) and also have some features of the activity of antidepressants, anorectics, antitussives, antiarrhythmics and spasmolytics.

Description

The invention relates to a process for the preparation of basic 2-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-yl sulfides of the general formula I.

^S / ¾¾.

Γ ň Ύ i (υ.

SCFT (CH _O) NR ¹ R | 2 Π

R

2 in which R represents a hydrogen atom or renyl, n represents 1 or 2 and NR R is a residue of dimethylamine, diethylamine, cyclohexylamine, 1-benzylpiperazine or 1- (ethoxycarbonyl) piperazine, and their salts with pharmacologically acceptable inorganic or organic acids.

The compounds of the formula I in the form of salts show in the tests ir. in vitro significant antimicrobial activity, so that they can be considered as potential chemotherapeutics. In addition, some of them show mild ataxic activity, anti-serpin activity in hypothermia and ptosis tests in mice, potentiate the toxicity of yohimbine, reduce blood pressure in normotensive rats for a short time, and have anorectic, antitussive and antiarrhythmic effects. They show spasmolytic effects on acetylcholine and barium chloride on the isolated intestine. I therefore suggest applicability in other areas as antidepressants, anorectics, antitussives, antiarrhythmics and antispasmodics.

The following specific biological data can be mentioned for the individual substances according to the invention:

N, N-Dimethyl-2- (2-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-ylthio) ethylamine was tested as hydrogen maleate. It acts slightly ataxically in the rotating rod test in mice; ED 50 = 126 mg / kg po In the reserpine hypothermia test in mice, the substance has a significant antireserpine effect at an oral dose of 25 mg / kg. At a dose of 100 mg / kg, it potentiates the toxicity of yohimbine in 10% of mice. Minimum inhibitory concentration (in pg / ml) against some microorganisms. ^- .: Streptococcus β-haemolyticus 50, Streptococcus faecalis 25, Staphylococcus pyogenes aureus 3,1, Escherichia coll 25, Proteus vulgaris 50, Saccharomyces pasterianus 50, Trichophyton mentagrophytes 25.

N, N-O-methyl-3- (2-chloro-10,11-dihydrodibenzo [b, f] thiepin-1C-ylthio) propylamine was tested as hydrogen maleate. Acute toxicity in mice even when administered LD ^ ₀ = 60 mg / kg. Ataxic effect in mice, ΕΟ ^ θ = 145 mg / kg po At a dose of 50 mg / kg po potentiates the toxicity of yohimbine in 40% of mice. At iv doses of 5 to 12 mg / kg, it antagonizes aconitine arrhythmias in the rat heart. At concentrations of 1 to 10 pg / ml, it suppresses the contraction of the isolated rat duodenum by 50%. At an iv dose of 12 mg / kg, it induces short-term profound decreases in blood pressure in anesthetized normotensive rats. Minimum inhibitory concentrations (in pg / ml) for antimicrobial action in vitro: Streptococcus β-haemolyticus 50, Streptococcus faecalis 25, Staphylococcus pyogenes aureus 6,2, Pseudomonas aeruginosa 100, Escherichia coli 50, Proteus vulgaris 100aster Saccharomy 50, Saccharomyces 25..

N, N-Diethyl-2- (2-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-ylthio) ethylamine was tested as hydrogen oxalate. Ataxic effect in a rotating rod test in mice, ΕΟ ^ θ 129 mg / kg p.o. at an oral dose of 100 mg / kg potentiates the toxicity of yohimbine in 30% of mice. Minimum inhibitory concentrations (in pg / ml) for in vitro antimicrobial activity: Streptococcus β-haemolyticus 50, Streptococcus faecalis 50, Staphylococcus pyogenes aureus

6.25, Pseudomonas aeruginosa 100, Saccharomyices pasterianus 50, Trichophython mentathon mentagrophytes 25.

1 - (- 2- (2-Chloro-10,11-dihydrodibenzo [b, f] thiepin-10-ylthio) ethyl) -4- (ethoxycarbonyl) piperazine was tested as the hydrochloride. It potentiates the toxicity of yohimbine in mice at an oral dose of 500 mg / kg p.p. (ΕΟ ^ θ). At a dose of 1 g / kg p.p. significantly antagonizes reserpine

CS 268626 Bl millet in mouse. Acute toxicity in mice (LD ₅₀ ) is greater than 2.5 g / kg orally. At an oral dose of 300 mg / kg, it slightly reduces the locomotor activity of mice.

N, N-dimethyl-3-phenyl-3- (2-chloro-10 _| ll-dihydro-dibenzo / b f _l / thiepin-10-ylthio) propylamine was tested as the hydrogen oxalate. Acute toxicity, L0 ₅₀ = 1,500 mg / kg po in mice. Ataxic effect in the rotating rod test in mice, E0 ₅₀ = 204 mg / kg po At a dose of 100 mg / kg po potentiates the toxicity of yohimbine in 40% of mice. At oral doses of 50 to 100 mg / kg, it reduces food intake in mice by 50% (anorectic effect). Minimum inhibitory concentrations (in pg / ml) for antimicrobial action in vitro: Streptococcus - heemolyticus 100, Streptococcus faecalis 100, Staphylococcus pyogenes aureus 3.1, Pseudomonas aeruginosa 100, Saccharomyces pasterianus 25, Trichophyton mentagrophyillus 25, .

Racemates and N-cyclohexyl-2- (2-chloro-10 ₁ l-dihydro-dibenzo / b, f / thiepin-10-ylthio) -2-phenylethylamine was tested as the hydrogen oxalate monohydrate. Ataxic effect in the rotating rod test in mice, Ε0 ₅ θ = 562 mg / kg po At a dose of 250 mg / kg po potentiates the toxicity of yohimbine in 40% of mice.

Racemat b N-cyclohexyl-2- (2-chloro-10,11-dihydrodibenzo [b, r] thiepin-10-ylthio-2-phenylethylamine) was tested as hydrogen oxalate. q = 500 mg / kg po

1-Benzyl-4- (3- (2-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-ylthio) -3-phenylpropyl) piperazine was tested as bis (hydrogen oxalate). The acute toxicity of LD 50 in mice is greater than 2,500 mg / kg p.o. In the test in guinea pigs, in which an aerosol of citric acid solution was induced by coughing, it has an antitussive effect; an oral dose of 300 mg / kg suppresses cough attacks to 18% of control. .

The compounds of the formula I are prepared according to the invention by alkylation of 2-chloro-10,11-dihydrodibenzo [b, f] thiepine-10-thiol with chlorides of the formula II.

CÍCH (CH _) „NR ¹ R ² । 2 n

R (II)

12 in which R, n and NR R are the same as in formula I. The starting thiol is a novel substance, the preparation of which is described in Example 1. The chlorides of formula II are partly commercially available, partly they must be prepared according to the literature; the relevant literature is cited in the relevant examples. The alkylation can be performed in various ways. Advantageously, the hydrochlorides of the starting aminoalkyl chlorides of the formula II can be used instead of the free and unstable bases. It is necessary to work in the presence of alkaline reagents, preferably sodium ethoxide or potassium carbonate, the purpose of which is (1) to convert the starting thiol to an alkali salt, (2) to liberate the free base of formula II from the hydrochlorides used and (3) to bind the hydrogen chloride molecule. Ethanol (in which case sodium ethoxide serves as a base), 2-propanol, acetone, butan-2-one, dimethylformamide, etc. can be used as solvents. C, i.e. using ethanol and acetone at the boiling points of these solvents. Basic fractions representing viscous oils are isolated from the reaction mixture, which are converted into crystalline salts by neutralization with pharmaceutically acceptable inorganic or organic acids. These are purified by crystallization. Homogeneous bases can be released from pure salts and used to measure spectra. When R is phenyl, the molecules of the respective compounds of the formula I contain two centers of chirality and the products formed are mixtures of two racemates which can optionally be separated by base chromatography or salt crystallization. All substances according to the invention are new and their identity has been ensured by analytical and spectral methods. Further details of the process for the preparation of the compounds of the formula X according to the invention follow from the examples, which, however, are merely illustrative of the possibilities of the invention.

Example 1 ', N, N-Dimethyl-2- (2-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-ylthio) ethylamine To a solution of sodium ethoxide prepared from 0.35 g of eodic acid and 30 ml of ethanol. 4.2 g of 2-chloro-10,11-dihydrodibenzo [b, f] thiepine-10-thiol are added, and the solution is stirred for 10 minutes.

CS 268626 81 3>

3.5 g of anhydrous potassium carbonate, 2.16 g of 2-dimethylaminoethyl chloride hydrochloride and 35 ml of ethanol are added. The mixture was stirred at 60 ° C for 1 h and then refluxed for 1 h. The ethanol was evaporated under reduced pressure and the residue was partitioned between benzene and water. The base is extracted from the benzene solution into 20 ml of 2.5M-HCl, the acidic aqueous solution is basified with aqueous ammonia and the crude base is isolated by extraction with benzene. Report- <

The extract was obtained to give 4.9 g (93%) of an oily yellow base. Neutralised help 1.8 g of acid-:

4.6 g of crystalline hydrogen maleate are prepared in 15 ml of ethanol with the addition of 30 ml of ether, which crystallizes from ethanol and melts in pure form at 108-110 ° C.

The starting 2-chloro-10,11-dihydrodibenzo [b, f] thiepine-10-thiol, which has not yet been described in the literature, is prepared from the known 2,10-dichloro-10,11-dihydrodibenzo [b, f]. / thiepine (Plez K. et al., Collect, Czech.Chem.Commun. 33, 1852 (1968) as described below: j

A mixture of 4.2 g of 2,10-dichloro-10,11-dihydrodibenzo [b, f] thiepine, 1.3 g of thiourea and ml of dimethylformamide was stirred at 80 DEG C. for 3.5 hours and the solvent was evaporated in vacuo.

The residue is crystallized from a mixture of ethanol and acetone and purified by crystallization from 2-propanol. Yield 5.0 g (94%) of S- (2-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-yl) isothiuronium chloride melting at 137 DEG-140 DEG C. are obtained by crystallization from a mixture.

of ethanol and ether, Form B is obtained, melting at 183.5-184 ° C.

A mixture of 4.4 g of the preceding substance (form A or B) and 6 ml of 6M-NaOH is stirred and boiled under.

reflux for 2 h in a nitrogen atmosphere. Dilute with 15 ml of water and acidify with 5M-H 2 SO 4.

to pH 2 and the product is isolated by extraction with benzene. Work-up of the extract gave 3.3 g (99%) of crude thiol melting at 90-110 ° C. Crystallization from cyclohexane gave the pure material, m.p. 100-102 ° C.

Example 2

N, N-Dimethyl-3- (2-chloro-10,11-dihydrobenzo [b, f] 1H-pin-10-ylthio) propylamine

Similar reaction (as in Example 1) 4.2 g of 2-chloro-10,11-dihydrodibenzo [b, f] thiepine-10-thiol, sodium ethoxide (0.35 g of sodium and 30 ml of ethanol), 3.5 g of potassium carbonates and 2.4 g of 3-dimethylaminopropyl chloride hydrochloride (var. 3 h) give 5.1 g (94%) of crude oily base, which is converted in a similar manner to crystalline hydrogen maleate, m.p. 73.5-76 ° C (ethanol ether).

Example 3

N, N-Diethyl-2- (2-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-ylthio) ethylamine

To a stirred solution of 4.2 g of 2-chloro-10,11-dihydrodibenzo [b, f] -thiepine-10-thiol:

4.5 g of potassium carbonate and then 2.8 g of hydrochloride are added in 70 ml of acetone:

2-diethylaminoethyl chloride. The acetone was evaporated and replaced with 10 ml of dimethylformamide .:

The mixture was stirred at 60 ° C for 2 h and at 100 ° C for 40 min. It is diluted with 60 ml of benzene, washed with water and extracted with 30 ml of 2.5M-HCl. The hydrochloride solution was basified with aqueous ammonia and the base was isolated by extraction with benzene. An oak thick oil was obtained in a yield of 4.6 g (81%). Neutralization with oxalic acid dihydrate in aqueous ethanol gives crystalline hydrogen oxalate, m.p. 162-165 ° C (aqueous ethanol).

Example 4:

N, N-O-methyl-3-phenyl-3- (2-chloro-11,11-dihydrodibenzo [b, f] -thiepin-10-ylthio) propylamine.

A solution of sodium ethoxide was prepared by dissolving 0.92 g of sodium in 25 ml of ethanol;

5.6 g of 2-chloro-10,11-dihydrodibenzo [b] f / thiepine-10-thiol are added, to the solution are added:

warm solution 4.7 g of 3- (dimethylamino) -1-phenylpropyl chloride hydrochloride (U.S. 4,018;

895; Ger.Offen. 2,500,100) in 50 ml of ethanol and the mixture is refluxed for 4 h

After standing overnight, the precipitated sodium chloride is filtered off, washed with ethanol and the filtrate is evaporated. The residue (8.8 g), which is a mixture of two racemic bases, is neutralized by pornting 2.8 g of oxalic acid dihydrate in 60 ml of ethyl acetate at 70 ° C. Crystallization of st-;

7.6 g (72%) of inhomogeneous hydrogen oxalate are obtained at room temperature, which:

melts at 107-108 ° C. >

"in

CS 268626 Bl

Example 5

N-Cyclohexyl-2- (2-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-ylthio) -2-phenylethylamine

To a solution of sodium ethoxide (from 20 ml of ethanol and 0.7 g of sodium) was added 4.5 g of 2-chloro-10,11-dihydrodibenzo [b, f] thiepine-10-thiol, after stirring for 10 minutes 0.6 g potassium carbonate and a warm solution, 4.1 g of 2- (cyclohexalamino) -1-phenylethyl chloride hydrochloride (Chapman NB, Triglie D.3., J. Chem. Soc. 1963, 1385) in 20 ml of ethanol. The mixture was refluxed for 6 h and then allowed to stand overnight. The precipitated sodium chloride is filtered off with suction, the solution is filtered with activated charcoal and the filtrate is evaporated in vacuo. The residue is dissolved in 50 ml of benzene, the solution is washed with water, dried over magnesium sulphate and evaporated. The residual oily mixture of racemic bases is neutralized with 1.9 g of oxalic acid dihydrate in 55 ml of ethyl acetate. On standing, 6.05 g (70%) of a mixture of hydrogen oxalates, melting at 96-99 ° C, precipitate out. Decompose with aqueous ammonia, isolate the base with benzene extraction and chromatograph on 120 g of silica gel. Elution with benzene and then chloroform gave 3.3 g of a homogeneous racemic base A which gave the hydrogonoxalate crystallizing from wet ethyl acetate as the monohydrate, m.p. 110.5-112 ° C.

Continuation of the elution with chloroform containing 5% ethanol gave 1.2 g of a homogeneous racemic base B, different from isomer A (as shown by thin layer chromatography on silica gel). This gives a hydrogen oxalate, crystallizing from a mixture of acetone and ether and melting at 99-102 ° C.

Example 6 · 1-Benzyl-4- (3-phenyl-3- (2-chloro-10,11-dihydrodibonzo [b, f] -thopin-10-ylthio) propyl) piperazine

2-Chloro-10,11-dihydrodibenzo [b, f] thiepine-1H-thiol (4.2 g), sodium ethoxide solution (1.1 g sodium, 25 ml ethanol), 6.0 g hydrochloride 3- (4 -benzyl-1-piperazinyl) -1-phenylpropyl chloride (Valenta V. et al., Collect. Czech. Chem. Commun. 46, 1280 (1981)) and 60 ml of ethanol were treated similarly to Example 4 (reflux). 10.5 h). The inhomogeneous base was converted to crystalline bis (hydrogen oxalate) (9.5 g, 83%), which was purified by crystallization from a mixture of dimethylformamide, ethanol and acetone, m.p. 214-214.5 ° C.

Example 7. 1- (Ethoxycarbonyl) -4- (2- (2-chloro-10,11-dihydrodibenzo [b, f] thiepin-10-ylthio) ethyl) piperazine.

To a solution of sodium ethoxide (0.95 g of sodium, 40 ml of ethanol) was added 5.6 g of 2-chloro-10,11-dihydrodibenzo [b, f] thiepine-10-thiol and, after stirring for 10 minutes, a solution of 5.14 g of hydrochloride 1. - (ethoxycarbonyl) -4- (2-chloroethyl) piperazine (Harfenist M., O.Am.Chem.Soc. 76, 4991 (1954) in 40 ml of ethanol. The mixture was stirred and refluxed for 3.5 hours. The ethanol was evaporated, the residue was diluted with water and extracted with benzene, and the extract was worked up to give 9.26 g of a crude oily base, which was converted into the hydrochloride mixture in ethanol, acetone and ether (8.3 g, 83%). from 95% ethanol leads to a pure substance, mp 202-203.5 ° C.

Claims (1)

OBJECT OF THE INVENTION Process for the preparation of basic 2-chloro-10,11-dihydro-dibenzo [b, f] thiepin-10-yl sulfides of the general formula I. * '; (AND) CS 268626 Bl Wherein R is hydrogen or phenyl, n is 1 or 2 and NR R is a residue of dimethylamine, diethylamine, cyclohexylamine, 1-benzylpiperazine or 1- (ethoxycarbonyl) piperazine, and their salts with pharmaceutically acceptable inorganic or organic acids, characterized by by reacting 2-chloro-XO, 11-dihydrodibenzo [b, f] thiepine-10-thiol with chlorides of the formula II. (II) in which R, n and NR R denote the same as in formula I, after which the bases obtained of formula They convert to neutral salts by neutralization with pharmaceutically acceptable inorganic or organic acids.