CS220189B1 - 11-amino-11-phenyl-6,11-dihydrodibenzo/b,e/thiepines and salts thereof - Google Patents

Abstract

The present invention relates to novel 11-amino-11-phenyl-6,11-dihydrodibenzo (b, ejthiopines, substituted optionally in position 2 or v position 3 with a methyl group, wherein the amino group it consists of the rest of the pyrrolidine, piperidine, morpholine, ethylenediamine, N, N- -methylethylenediamine, N, N-diethylethylenedlamine or N- (3-aminopropyl) rnorpholine. It further relates to salts of these compounds with pharmaceutically acceptable salts harmful acids. Substances by of the invention exhibit antimicrobial effects in vitro tests, anti-inflammatory effects, antitussive, centrally depressant and anthelmintic. On that basis they come in consideration for use as a medicament. Their preparation is performed by substitution reactions 11- -phenyl-11-chloro-6,11-dihydriodibenzo (b, e) - thiepine and its 2-methyl- or 3-methyl derivative with said amines. The salts are being prepared neutralizing bases with acids, wherein it is preferable to use weak organic acids (preferably maleic acid), because of the strong mineral acid products cleavage to form salts of the starting amines.

Description

The present invention relates to novel 11-amino-11-phenyl-6,11-dihydrodibenzo [b, e) thiepines of the formula I

in which

R ¹ denotes the radical of a pyrrolidino, piperidino, morpholino, 2-aminoethylamino-, 2-dimethylaminoethyl lamino-, 2-diethylamino-ethylamino or 3-m | orfolinioprlopylam, Inio group,

R ² denotes an atom, hydrogen or methyl as well as R ³ denotes a hydrogen or methyl atom, and their salts with pharmaceutically acceptable inorganic or organic acids.

The compounds of formula (I) and their salts show antimicrobial effects in in vitro tests, and are generally very toxic and devoid of other pharmacodynamic effects. Occasionally, they have an anti-inflammatory, anti-tussive or centrally depressant effect at higher doses, which would not hinder their use in chemotherapy. Anthelmintic effect was found with one of the substances. In the following, the concentration in µg / ml is selected for the selected substances, which have an inhibitory effect on individual species of microorganisms. The results of acute toxicity tests and pharmacodynamic effects are presented.

11-Phenyl-11-piperidino-6,11-dihydrodibenzo: (b, jthiepine was tested as base. Antimicrobial activity: Streptococcus / 3-haemolyticus, 12.5; Staphylococcus pyogenes aureus, 25. Acute oral toxicity in mice, is very low, LD 50 is higher than 2500 mg / kg At an oral dose of 300 mg / kg, the substance showed an antitussive effect in guinea pigs in the citric acid aerosol test.

11-Phenyl-11-morpholino-6,11-dihydnodibenzo [b, e] thiepine has also been tested as a base. Antimicrobial activity: Trichophyton mentagrophytes, 50. Acute oral toxicity in mice is again very low; mg / kg.

11- (2-Aminoethylamino) -11-phenyl-6,11-dihydrodibenzo (b, e thiepine was tested as maleate (hemihydrate). Antimicrobial activity: Streptococcus / J-haemolyticus, 25; Streptococcus faecalis, 50; Staphylococus pyogenes 50; Escherichia coli, 50; Trichophyton mentagrophytes, 50. Acute oral toxicity in mice is again very low, with an LD 50 greater than 2500 milligrams per kilogram, and has shown anthelmiintic activity against the tapeworm Hymenolepis nana.

11-Phenyl-11- (2-dimethylaminoetbylamino) -6,11-dihydrodibenzo (b, e) thiepine was tested in the form of a maleate Antimicrobial activity: Streptococcus / 5-haemolyticus, 25; Streptococcus faecalis, 50; Staphylococcus pyogenes aureus, 50 Escherichia coli, 50. Acute oral toxicity in mice is very low, LD 50 is greater than 2500 mg / kg At an oral dose of 300 mg / kg, it exhibits an anti-inflammatory effect in the kaolin arthritis test in rats.

11-Phenyl-11- (2-diethylaminoethylamino) -6,11-dihydrodibenzo (b, ejthiepine was tested as a maleate. Antimicrobial activity: Strteptococcus / 5-haemolyticus, 25; Streptococcus faecalis, 50; Staphylococcus ¹ pyogenes aureus, 25; Escherichia coli, 25; Mycobacterium tuberculosis, 50. Acute toxicity in mice by intravenous administration, LD 50 = 50 mg / kg, LD 50 greater than 2500 mg / kg in oral fetus The subcutaneous dose of 10 mg / kg induces slight central depression in mice showing with reduced motility in a known environment.

An oral dose of 300 mg / kg produces an anti-inflammatory effect in the kaolin arthritis test in rats.

11-Phenyl-11- (3-morpholinopropoxy) -6,11-dihydrodibenzo (b, e) thiepine was tested as a maleate. The acute toxicity in mice by oral administration is very low; LD 50 = 2500 mg / kg. showed an anthelmintic effect against Nippostrongylus brasiliensis worm.

Compounds of formula (I) may be prepared by substitution reactions of chloro derivatives of formula (II)

in which

R ² and R ³ have the same meaning as in formula I, with amines of general formula III ·

HR ¹ (III) in which

R @ ¹ is also the same as in formula I. Such substitution reactions are performed using at least 100% excess of the amine III in a suitable inert solvents at temperatures of 50-100 ° C. Chloroform and dichloromethane have proven to be particularly advantageous solvents and the reactions are then carried out at the boiling point of the reaction mixtures. In most cases, these normal substitution reactions are accompanied by rearrangement reactions whose products are required from the desired substances

S separated by crystallization or chromatography. The starting chlorides of formula (II) are either known compounds and the literature is cited in the Examples section, or they are novel compounds whose preparation is described in the Examples section.

The compounds of formula I are quite generally unstable in the presence of strong mineral acids. In aqueous media, solvolysis occurs to give the corresponding 11-hydroxy derivatives and salts of the starting amines III. Solvolysis also takes place in the ethanolic environment, the products of which are the corresponding 11-ethoxy derivatives and salts of the starting amines of formula III. Thus, weaker inorganic acids are particularly suitable for the preparation of salts of the compounds of formula (I), and in particular organic acids, and in particular diamines of formula (I), provide well-crystallizing salts, e.g. with maleic acid. These. maleatees are preferable to free bases for carrying out biological assays and preparing dosage forms. Salts are included within the scope of this invention. Examples

1. 11-Phenyl-11-pyrrolidino-6,11-dihydrodibenzo (b, e) thiepine

A mixture of 4.85 g of 11-phenyl-11-chloro-6,11-dlhydrodibenzoyb, e) thlepin (M. Hori et al., Yakugaku Zasshi 98, 1195, 1978), 10 ml of chloroform and 17.4 g of pyrrolidine is boiled. 5 hours under reflux. After. cooling is diluted with 60 ml of chloroform, filtered with carboraffin and the filtrate is evaporated under reduced pressure. The residue is diluted with 120 ml of benzene and the solution is washed several times with water. The benzene solution is then dried with carbonate; Potassium and evaporate again. The residue crystallized upon dissolution in 15 ml of benzene and 15 ml of petroleum ether. 2.3 g (43%) of the desired base are obtained, m.p. 234-238 ° C. Recrystallization from the same solvent mixture gave the pure product, mp 243-244 ° C.

2. 11-Phenyl-11-piperidino-6,11-dihydrodibenzo (b, e) thiepine

A mixture of 25.5 g of 11-phenyl-11-chloro-6,11-dihydrodibenzo [b, e] thepine (literature cited), 55 ml of chloroform and 30 g of piperidine was heated under reflux for 8 hours. Dilute with 250 ml of benzene and 100 ml of ether and wash repeatedly with water. The organic phase was dried over potassium carbonate and evaporated under reduced pressure. The residue is dissolved in a mixture of 50 ml of benzene and 50 ml of petroleum ether and the solution is chromatographed on a column of 500 grams of neutral ¹ alumina (activity III). After separating a minor amount of the less polar material, 14.15 g of the base mixture is eluted, successively boiled with 50 ml portions of ethanol, and the individual solutions obtained are left to crystallize. The first three fractions contain predominantly the undesired positional isomer of the product. From other fractions, 5.3 g of homogeneous base, mp 192-195 ° C, is obtained by crystallization, which is the desired substance by analysis and by 1 H-NMR spectrum.

3. 11-Phenyl-11-morpholino-6,11-dihydrodibenzo [b, e] thlepin

A mixture of 4.85 g of 11-phenyl-11-chloro-6,11-dihydrodibenzio (b, e) thiepine (literature cited), 10 ml of chloroform and 15 ml of morpholine was refluxed for 13 hours. It is then evaporated under reduced pressure, the residue is dissolved in benzene and the solution is washed thoroughly with water. Dried over potassium carbonate and filtered with carboraffin. The filtrate was evaporated under reduced pressure. The semi-solid residue gave 3.1 g (55%) of the crude product, m.p. 200 DEG-204 DEG C., by crystallization from 15 ml of benzene. Recrystallization from benzene gave pure substance melting at 211-212 degrees Celsius.

4. 11- (2-Amino-ethylamino) -11-phenyl-6,11-dihydrodibenzio (b, e) thiepine

A mixture of 3.35 g of 11-phenyl-11-chloro-6,11-dihydrodibenzo (b, e) thiepine (literature cited), 9.0 g of ethylenediamine and 25 ml of chloroform was refluxed for 3.5 hours. It is then evaporated off with approximately 20 ml of chloroform, the residue is diluted with toluene, the solution is washed with water, dried over potassium carbonate and evaporated under reduced pressure. The residue was crystallized from 6 ml of benzene to give 3.2 g of crude base (62%) melting at 105-112 ° C. Neutralization of this base with maleic acid in ethanol gives a crystalline maleate which is purified by recrystallization from 95% ethanol, m.p. 172-172.5 ° C.

5. 11-Phenyl-11- (2-dimethylaininoethylamine) -6,11-dihydrodibenzo (b, e) thiepine

A mixture of 4.85 g of 11-phenyl-11-chloro-6,11-dihydrodibenzo (b, e) thiepine (literature cited), 8 ml of chloroform and 4.9 g of 2-dimethylaminoethylamine is refluxed for 6.5 hours. The volatiles were then evaporated under reduced pressure, the residual oily base (5.7 g, 100%) was dissolved in 15 ml of ethanol and neutralized with 3.5 g of maleic acid in 8 ml of ethanol. Addition of 40 ml of ether precipitated 4.7 g of crystalline maleate, which was purified by crystallization from a mixture of ethanol and ether, m.p. 190-191 ° C.

6. 11- (2-Diethylaminoethylamino) -11-phenyl-6,11-dihydrodibenzo (b, e) thiepine

To a solution of 4.85 g of 11-phenyl-11-chloro-6,11-dihydrodibenzo (b, e) thiepine (literature cited) in 12 ml of chloroform is added 17.5 g of 2-diethylaminoethylamine and the mixture is refluxed for 6 hours. cooler. The chloroform is then evaporated, the residue is dissolved in 100 ml of toluene and the solution is washed thoroughly with water. The basic product is then shaken into 150 ml of 1M HCl. The acidic aqueous solution was separated and basified immediately with 50 ml of 5M-NaOH. The liberated base is extracted with ether, the extract is dried over potassium carbonate and evaporated. The residual oily base (5.0 g 83%) was dissolved in 15 ml ethanol and the solution was neutralized by the addition of a solution of 2.9 g maleic acid in 10 ml ethanol. Addition of ether precipitates crystalline maleate which is purified by crystallization from ethanol; mp 167-169 ° C.

7. 11-Phenyl-11- (3-morpholinopropylamino) -6,11-dihydro-dibenzio (b, e-thiepine)

To a solution of 4.85 g of 11-phenyl-11-chloro-6,11-dihydrodibenzo- (b, e-thiepine (literature cited) in 10 ml of chloroform) was added 14.4 g of N- (3-aminopropyl) -morpholine and the mixture was After refluxing for 6 hours, the chloroform is evaporated, the residue is diluted with 100 ml of toluene and the solution is washed thoroughly with water, and then the basic product is extracted by shaking into 150 ml of 1M HCl. After drying the extract with potassium carbonate, the ether is evaporated and the remaining base (4.3 g, 67%) crystallizes on standing, mp 160-170 ° C. The pure base is obtained by recrystallization from the mixture. benzene, cyclohexane and petroleum ether, mp 171.5-174.4 ° C. Neutralization with maleic acid in a mixture of ethanol and ether gives a neutral maleate that crystallizes from ethanol and melts in the pure state at 166.5-167.5 ° C.

8. 11-F-enyl-2-methyl-11-piperidino-6,11-dihydro-dibenzophobe, thiepin

To a solution of 5.05 g of 11-phenyl-11-chloro-2-methyl-6,11-dihydrodibenzoyl (b, e) thiepine (K. Onogi and M. Nagakura, Jpn. Kokai Tokkyo Koho 79/125 662 (Chem. Abstr. 92, 198, 397, 1980) in 10 ml of chloroform, 18 ml of piperidine are added and the mixture is refluxed for 18 hours. It is then dissolved in 300 ml of benzene and the solution is washed thoroughly with water. It is dried over potassium carbonate and evaporated. The residue is dissolved in a mixture of 30 ml of benzene and 30 ml of petroleum ether and the solution is chromatographed on a column of 300 grams of neutral alumina (activity II). The solvent mixture eluted with a fraction of 4.68 g of a non-faint crystalline base which was purified by repeated crystallization from ethanol and melted at 215-218 ° C.

9. 11-Phenyl-3-methyl-11-piperidino-6,11-dihydrodibenzo (b, e) thiepine

To a solution of 3.0 g of 11-phenyl-11-chloro-3-methyl-6,11-dihydrodibenzo (b, e-thiepine in 10 ml of dichloromethane) was added dropwise a solution of 2.6 g of piperidine in ml of dichloromethane at 20 ° C with stirring. The mixture was stirred at 20-23 ° C for 20 hours, then 1.0 g of piperidine was added and the mixture was refluxed for 1 hour, volatiles were evaporated under reduced pressure, the residue diluted with 100 mL of benzene, and the solution was washed thoroughly. It is dried over potassium carbonate and evaporated under reduced pressure, the oily residue is dissolved in 10 ml of cyclohexane and the solution is left to crystallize in a refrigerator. After 3 days of standing, 1.1 g (32%) of crystalline base are precipitated. Purified by crystallization from cyclohexane, mp 182-185 ° C.

The 11-phenyl-11-chloro-3-methyl-6,11-dihydrodibenzo (b, e-thiepine starting material used) is a novel compound and is prepared as follows;

Dissolve 5.15 g of sodium in 75 ml of absolute ethanol to prepare a solution of sodium ethoxide, add 27.8 g of m-thiocresol and then 30 g of phthalide, and stir the mixture under reflux for 3 hours. It is then diluted with 100 ml of hot water, the ethanol is evaporated off, diluted with an additional 100 ml of hot water and the solution is filtered hot with carboraffin. The filtrate was cooled and slowly acidified with the addition of 45 ml of 5M-HCl. After standing the next day, the precipitated 2- (3-methylphenylthiomethyl) benzoic acid was suction filtered, washed with water and dried in vacuo to give 51.1 g (88%) of the crude product, mp 90-94 ° C. aqueous ethanol to give the pure product, mp 97-99 ° C.

Polyphosphoric acid is prepared by mixing 110 ml of 85% phosphoric acid with 180 g of phosphorus pentoxide and heating the mixture at 125 ° C for 1.5 hours. 50.0 g of the preceding acid are added in portions with stirring, and the mixture is stirred at 110 to 120 ° C for 1.5 hours. After cooling to 30 DEG C., 600 ml of ice-water are quenched and extracted with benzene. The extract was washed with water, 1M-NaOH and again with water, dried over sodium sulfate and evaporated. The solid residue is crystallized from 180 ml of ethanol. 34.1 g (73%) of 3-methyldibenzo (b, -e) thiepin-11 (6H) -one, m.p. 67-68 ° C, are obtained.

By reacting 4.15 g of magnesium with 29.5 g of bromobenzene in 130 ml of ether, a Grigard reagent is prepared in the usual manner, to which is added dropwise with stirring at 25 to 29 ° C over 40 minutes. solution of 20.4 g of the preceding ketone in 90 ml of benzene. The mixture was then refluxed for 3.5 hours, quenched by the dropwise addition of 140 ml of 20% ammonium chloride solution and extracted with benzene. The extract was dried (MgSO4) and evaporated. The crude product was recrystallized from 90 ml of toluene. 21.9 g (81%) of 11-phenyl-3-methyl-6,11-dihydrodibenzo (b, e) thiepin-11-ol, m.p. 183-186 ° C, are obtained. The pure product, m.p. 184.5-186 ° C, is obtained by further crystallization from toluene.

A solution of 1.78 g of thionyl chloride in 10 ml of dichloromethane is added dropwise over 3 hours to a solution of 4.8 g of the preceding alcohol in 50 ml of dichloromethane with stirring at up to 20 ° C. The mixture was stirred for an additional 3 hours at this temperature and the overnight was evaporated in vacuo at a maximum temperature of 22 ° C. The solid residue (4.9 g, 97%) was stirred at 50C with 50 ml of petroleum ether and after 30 min. the undissolved product is aspirated. This operation is repeated once more to give 3.9 g (77%) of the desired 11-phenyl-11-chloro-3-methyl-6,11-dihydrodibenzo (b, thiepine melting at 111-113 °). C.

Claims (1)

11-Amino-11-phenyl-6,11-dihydrodibenzo (b, e) thiepines of formula I OF THE INVENTION in which R ¹ represents a radical pyrrolidino, piperidino, morpholino, 2-aminoethylamino-, 2-dimethylaminoiethylamino-, 2-or 3-diethylaminoethylamino- morfoIintoprtopyIaminnskupinu, R ² is hydrogen or methyl and R ³ also represents a hydrogen atom or methyl, and their salts with pharmaceutically acceptable inorganic or 'organic acids.