CS223428B1 - 3-Amino-M-phenyl-3-dihydrodibeuzo (b, e) thiepymes and their salts - Google Patents

Abstract

Invent. with. relates to new 3-amino-11-phenyl-6,11-dihydrodibenzo(b,e)thiepines, optionally substituted in position 2 by a methyl group, in which the amino group is a residue of piperidine, N-methylpiperazine or N-(2-hydroxyethyl)piperazine. The invention also relates to salts of these substances. The substances according to the invention and their salts exhibit antimicrobial and anthelmintic effects, so they can be considered as potential chemotherapeutics and antiparasitics; at the same time they are practically non-toxic. They are accessible either by anomalous substitution reaction of 11-phenyl-11-chloro-6,11-dihydrodibenzo(b,e)thiepine and its 2-methyl derivative with the aforementioned amines, or by a clearly occurring reduction of 3-amino-11-phenyl-6,11-dihydrodibenzo(b,e)thiepines. )thiepin-ll-ols with hydroiodic acid.

Description

Invention. se. refers to novel 3-amino-11-phenyl-6,11-dihydr, Qdihenzo (b, e) thiepines optionally substituted in the 2-position with a methyl group wherein the amino group is a residue, piperidine, N-methylplperazine or N- ( The compounds of the invention and their salts exhibit antimicrobial and anthemimetic effects, so that they can be considered as potential chemotherapeutic and antipanasitic agents, and at the same time are practically non-toxic.

They are accessible either by an anomalous substitution reaction, by reaction of 11-phenyl-11-chloro-6,11-dihydrodibenzyl (b, e) thiepine and its 2-methyl derivative with the named amines, or by a clear reduction of 3-amino-11-phenyl- 6,11-dihydrodihenzoj b, e) thiepin-11-ol with hydroiodic acid.

This invention relates to novel 3-amino-11-phenyl-6,11-dihydrodibenzo (b, e) thiepines of formula I,

wherein R is hydrogen or methyl and X is CH 2, a residue of NCH 3 or NCH 3 CH 2 OH, and salts thereof with pharmaceutically acceptable inorganic or organic acids.

The compounds of the formula I and their salts show intensive antimicrobial effects in in vitro tests, in particular against Gram-positive microorganisms. They also show anthelmintic effects and anorectic activity has been identified from pharmacodynamic effects. At the same time, they are practically non-toxic, so that they are suitable as antimicrobial drugs. As an illustration of the properties of the substances according to the invention, the effects of the following two substances are described in more detail. Antimicrobial activity is reported as · minimum inhibitory concentration in µg / ml:

11-Phenyl-3- (4-methylpiperazino) -6,11-dihydrodibenzo (b, e jthiepine was tested as maleate-momohydrate. Antimicrobial effects: Streptococcus β-haemolyticus, 6.2; Streptococcus faecalis, 12.5; Staphylococcus pyogenes aureus, 12.5; Escherichia coli, 25; Saccharomyces pasterianus, 50; Trichophyton mentagrophytes, 50; Aspergillus niger, 50. Intense activity against staphylococci was confirmed by study on 20 strains of Staphylococcus pyogenes aureus, with a minimum inhibitory concentration ranging from 6; When administered orally, the acute toxicity test in mice appears to be practically non-toxic, with an LD 50 greater than 2.5 g / kg, and even at this high dose, the mice did not die within 5 days of follow-up. at high doses, mice exhibit long-term decreased activity and ptosis (central depressant effect).

11-Phenyl-3- [4- (3-hydroxypropyl) piperazino] -6,11-dihydrodibenzo (b, e thiepine was tested in the form of bis (hydrogen maleate) solvated with 2.5 mol of water. Antimicrobial effects: Streptococcus / 3-haemolyticus , 12.5; Streptococcus faecalis, 100; Staphylococcus pyogenes aureus, 25; Escherichia c.o11, 50; Mycobacterium tuberculosis, 100; Trichophyton mentagrophytes, 50. Also, the compound is practically non-toxic when administered orally in mice; / kg did not cause any mortality of mice for 5 days of observation At 300 mg / kg, the compound showed anorectic effect in mice (food consumption was 83% lower than that of control animals) and showed significant anthelmintic activity against Nippostrongylus brasiliensis worm.

The compounds of the invention can be prepared in two ways. One is the substitution reaction of 11-phenyl-11-chloro-6,11-dihydrodihenzo (b, ejthiepines of formula II,

wherein R is hydrogen or methyl, with amines of formula III,

H

(III) in which X denotes the same as in formula I. As can be seen, it is an anomalous substitution reaction in which the incoming group does not arrive at the site of the eliminated group, i.e. the chlorine atom. The reaction must be explained by a rearrangement of the primary cation, which results from the removal of the chloride anion from position 11.

The rearrangement consists in shifting the double bonds and the positive charge to the 3 position, allowing the amino group to enter this position. In the final stage, the whole | molecules by rearomatization, ie by returning the double bonds to their original positions. These anomalous substitution reactions, which are obviously due to the strong spherical inhibition of the eliminated group, usually proceed only as a side reaction and the preparation of the compounds of formula I is associated with more or less laborious separation from the products of the normal substitution reaction. Crystallization or chromatography are particularly suitable for these separations. The starting chloro derivatives of formula II are known and the literature is cited in the examples.

A second method of preparing compounds of formula I is to reduce the alcohols of formula IV,

in which R1 and X are the same as in formula I, hydroiodic acid, for example in boiling acetic acid, can be advantageously used for the reduction. In this way, the compounds of formula I are the only products, which is an advantage of the method. A disadvantage is that the starting compounds of formula IV have not yet been described and need to be prepared by multi-step syntheses, as described in the examples.

Compounds of formula I, when X = CH 2, are weak bases which yield salts hydrolyzing in the presence of water. For this reason, it is necessary to test these substances and possibly use them as bases. In contrast, when X is a methylamine or 2-hydroxyethylamine residue, the corresponding compounds I are strong bases which, by neutralization, provide well-crystallizing salts. Particularly preferred are maleates suitable for carrying out bioassays and for preparing dosage forms.

Examples

EXAMPLE 1 11-phenyl-3-piperidino-6,11-dihydrodibenzo (b, thiepin

A mixture of 4.85 g of 11-phenyl-11-chloro-6,11-dihydrodibenzo [b, e] thiepine (M. Hori et al., Yakugaku Zasshi 88, 1195, 1978), 10 ml of chloroform, and 11.1 g of piperidine are treated with The chloroform is evaporated, the residue is dissolved in 120 ml of benzene, the solution is washed thoroughly with water, dried over potassium carbonate and evaporated, the oily residue is dissolved in 12 ml of cyclohexane and the solution is left in the refrigerator for 12 hours. 2.2 g (43%) of the crude desired product (the normal product of substitution being in the mother liquor) melting at 180 DEG-190 DEG C. Recrystallization from a mixture of benzene and petroleum ether gave the pure product, mp 191 DEG-194 DEG. identity is ensured by (a) a ¹ H-NMR spectrum which shows a signal at 5.20 ppm corresponding to a proton on a trityl carbon, (b) a ¹³ C-NMR spectrum, (c) identity with the product of Example 2, using a unique synthetic procedure.

Example 2 11-Pheinyl-3-piperidino-6,11-dihydrodibenzo (b, e) thiepine

To a solution of 10 mL of 57% hydroiodic acid in 10 mL of acetic acid was added 1.0 g of 11-phenyl-3-piperidino-6,11-dihydrodibenzo (b, e) thiepine-11-ol and the mixture was refluxed for 4 hours. cooler in a bath at 120 ° C. After cooling, it is diluted with water, basified with 50% sodium hydroxide solution and the product isolated by extraction with chloroform. After drying and evaporation, the extract is obtained

1.05 g of crude product, mp 189-193 ° C, which, after a single recrystallization from a mixture of benzene and ethanol, is pure and melts at 192-194 ° C. When compared with a product prepared according to the foregoing embodiment, an identity by all criteria (analysis, spectrum, mixed melting point, R _f in TLC).

The starting 11-phenyl-3-piperidino-6,11-dihydrodibenzo (b, e) thiepine-11-ol is a novel compound which can be prepared, for example, by the following procedure:

A mixture of 143.8 g of 3-bromoaniline, 77 g of pentamethylenedibromide and 500 ml of ethanol is refluxed for 23 hours. Then the ethanol was evaporated, the residue was treated with 10% sodium hydroxide solution and extracted with benzene. The extract was dried with potassium carbonate and worked up by distillation. 55.5 g (70%) of N- (3-bromophenyl) piperidine boiling at 157-163 [deg.] C./15 mm Hg are obtained.

To 3.5 g of lithium wire in 250 ml of ether was added dropwise 53.8 g of N- (3-bromophenyl) piperidine and the mixture was boiled under nitrogen for 30 hours. Then, with stirring for 15 min. 4.8 g of sulfur flower are added and the mixture is refluxed for 1 hour. After cooling, the mixture is quenched by the dropwise addition of a mixture of 20 ml of hydrochloric acid and 40 ml of water, the addition of a further 10 ml of hydrochloric acid resulting in a slightly acidic reaction which is dulled with sodium bicarbonate. The ether phase is then separated and shaken with 300 ml of 10% sodium hydroxide solution. The alkaline solution was separated, acidified with 50 ml of hydrochloric acid and 20 ml of acetic acid and the product was extracted with benzene. Treatment of the extract by distillation gives the desired 3-piperidinothiophenol boiling at 135-137 ° C / 70 Pa.

Dissolve 0.7 g of sodium in 15 ml of ethanol to prepare a solution of sodium ethoxide, add 5.75 g of 3-piperidinothiophenol in 5 ml of ethanol and 4.0 g of phthalide, and reflux for 3.5 hours. The ethanol is evaporated, the residue is dissolved in water and the solution is acidified with 2.5 ml of acetic acid. The precipitated semi-solid product was extracted with benzene, and the extract was evaporated. The residue was recrystallized from a mixture of benzene and petroleum ether. 5.85 g of 2- (3-piperidinophenylthiomethyl) benzoic acid melting at 126 DEG-129 DEG C. is obtained.

5.7 g of the preceding acid are added to 50 g of polyphosphoric acid at 130 DEG C. and the mixture is stirred at that temperature for 30 min. Quench by pouring onto ice, basify with 50% sodium hydroxide solution and extract with chloroform. The extract was dried over potassium carbonate and evaporated. The residue was dissolved in benzene and chromatographed on a column of 200 g silica gel. Benzene eluted with 3.18 g of the desired 3-piperidinodibenzo (b, e) thiepin-11 (6H) -one, which crystallized from a mixture of benzene and cyclohexane and melted at 138-138.5 ° C.

A solution is prepared in a conventional manner

Τ;

Grignard reagents by reaction 0) 73 g ·; of magnesium with 4.71 g of bromobenzene in 30 ml of ether. At room temperature; a solution of 2.9 g of the previous ketone in 20 ml of benzene was added dropwise with stirring, and the mixture was refluxed for 4 hours. After cooling, decompose by slow addition, 25 ml of a 2 ^Ο / ο ammonium chloride solution and shake with benzene. Work-up of the benzene extract yields crude 11-phenyl-O-piperithino-η 11 -dihydradibenzo (b, e) thiepih-11-ol, which is the only one? crystallization from a mixture of benzene and petroleum ether; (2.26 g) is completely pure and melts at 218-221 ° C. with decomposition; Workup of the mother liquor gave a second product so that the overall yield was 2.70 g (74%).

EXAMPLE 3 11-Phenyl-2-methyl-3-piperidino-6,11-dihydro-benzo (b) e) thiepime

To a solution of 5.05 g of 11-phenyl-11-chloro-2-methyl-6,11-dihydrodibenzo (b, e) thiepine, (K. Onogi and M. Nagakuram Jpn. Kokai Tokkyo Koho; 79/125 662; Ghem) (1980, 92, 198 397) 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 washed thoroughly with water. Dry with carbonate; potassium evaporate. The residue is dissolved in; a mixture of 30 ml of benzene, and 30 ml of petroleum ether, and the solution is; Chromatography on a column - 300 g · neutral alumina (activity - II). Said mixture of solvents is; eluting with a 4.68 g of a mixture of bases from which a normal substitution product was obtained by crystallization from ethanol. After separation, the mother liquors were rechromatographed on a 200 g silica gel column. 1.74 g of the crude material is eluted with benzene which, by repeated crystallization from ethanol, provides the desired base: mp 176-178 [deg.] C. Its identity is ensured both by analysis and by spectra (IC and 1 H-NMR).

Example 4 '

11-Phenyl-3- (4-methylpiperazino) -6- ₍ 11-dihydnodibenzor (b; e) thiepine)

Síněs 4,85. g 11-phenyl-11-ghloro-1 H -dihydrododibenzyl (h, e) tftiepine ^; (literature cited), 12 ml of chloroform and 15.3 g of 1-methylpiperazine were heated under reflux for 5.5 hours. It is then diluted with 100 ml of benzene, washed thoroughly with water, and the hand product is shaken out with 100 ml of 1 M-MGi Clarified solid hydrochloride. The filtrate was added to the aqueous phase and the suspension was quenched with 30 ml of 5 M NaOH. Excluded; the base is extracted with benzene), the extract is dried over potassium carbonate and evaporated. The crystalline residue (base) is purified by crystallization from a mixture of benzene; 3.1 g (54% of product melting at 20 DEG -207 ^DEG C.). An analytically pure product is obtained by further crystallization from the above mixture and melts at 207.5 ^DEG C. (petroleum ether).

209.5 ° C. Neutralizing the base with acid; with maleic acid in acetone / ethanol, after addition of ether, crystalline maleate monohydrate is obtained in a pure state, melting at 169.5-171.5 ° C (ethanol ether).

Example 5

1,1-phenyl-3- [4- (2-hydroxy-ethyl) -piperazino] -6,11-dihydrodibenzo (: b, e) thiepine

Similar to the foregoing, the reaction is carried out with 4.85 g of 11-phenyl-11-chloro-6,11-dihydradadiene (b, e), hiepine (literature cited), 22 g. 1-G-hydroxyethylpiperidine in 12 ml of boiling chloroform. Analogous treatments yield 2.8. g. (.45%.). The base, which is crystalline and in the pure state, melts at -156 ° C to 160 ° C (ethanol). Its identity is again ensured by analysis and spectra. Neutralization with maleic acid, in a mixture, wet aGetone, and ether crystalline bis (hydrogen maleate; solvated with 2.5 moles of water, mp 10.2-104 ° C),

Claims (2)

SUBJECT V 3-Amino-11-phenyl-6,11-dihydrodibenzo (b, e) thiepines of formula Γ, Y N E L E.Z.U. wherein R is hydrogen or methyl and X is CH 2; the residue NGH 3 or NCH 2 CH 2 OH, and their salts with pharmaceutically acceptable inorganic or organic acids. Severography, n. P., Plant 7, Most Oefia- 2,40 Kčs-