CS237487B1 - 2-aminoethyletheres derived from 2-substituted 6,11-dihydrodibenzo/b,e/thiepin-11-oles and salts of the same - Google Patents

Abstract

The invention is within the scope of synthetic drugs. Its subject is 2-aminoalkyl ethers derived from 2-substituted 6,11-dihydrodibenzo (b, e) thiepin-11-ol of formula (I) n fχ OCH2CH2 N___X (AND) wherein R is chlorine or methyl and X is a divalent radical of NH, NCH 3, NCH 2 CH 2 OH, NCOOC2H5 or OH / C-.___, In CF, Cl and their salts with organic acids, preferably maleic acid. These substances are antihistamines, antiarrhythmics and antimicrobials active ingredients, so they come for practical use in therapy allergic diseases, cardiac disorders rhythm and in the treatment of microbial infections. Basic by the method of preparing the compounds of the invention are the substitution reactions of the respective 11- (2-bromoethoxy) compounds with amines, i. piperazine and its corresponding derivatives a 4- (4-chloro-3-trifluoromethylphenyl) -4-piperidinol. Neutralization with organic base acids are obtained crystalline salts of which are preferred maleate

Description

The present invention relates to 2-aminoalkyl ethers derived from 2-substituted 6,11-dihydrodibenzo (b, e) thiepin-11-oles of the obeonic formula I

H OCH ₂ CH ₂ phi X (X) wherein R represents a chlorine atom or methyl and X is a divalent residue of NH, NCH ₃ , NCH ₂ CH ₂ OH, NCOOC ₃ H 6 or _QH

Cl and their salts with organic acids, preferably maleic acid.

The compounds of the invention of formula (I) are novel and possess some types of pharmacodynamic activity that are useful in therapy. First of all, it is the antihistaminic effect that makes them useful in allergic diseases. Furthermore, it is an anti-rhythmic effect useful in the treatment of cardiac rhythm disorders. Finally, it is the antimicrobial effect in in vitro assays that indicates the usefulness of the compounds of the invention in the chemotherapy of microbial infections. These effects have been found in tests in experimental animals and are listed below specifically for several typical compounds of the invention.

2-chloro-11- (2-piperazinoethoxy) -6,11-dihydrodibenzo (b, e) thiepine was tested in the form of bis (hydrogen maleate). Its acute toxicity in mice by intravenous administration, LD ^ g = 40 mg / / kg. At a dose of 8 mg / kg i.v. the compound exhibits an antiarrhythmic effect in rats against aconitine arrhythmias, which is comparable in intensity to that of quinidine. At the same dose, the compound produces short-term and relatively deep reductions in blood pressure in normotensive rats. In vitro inhibitory activity against the following microorganisms (minimum inhibitory concentrations in <µg / ml given): Streptococcus beta-haemolyticus 25, Streptococcus faecalis 50, Staphylococcus pyogenes aureus 50, Escherichia coli 100, Trichophyton mentagrophytes 50.

1- [2- (2-methyl-6,11-dihydrodibenzo (b, e) thiepin-11-yloxy) ethyl] -4- (2-hydroxyethyl) piperazine was also tested as bls (hydrogen maleate). Its acute toxicity in mice by oral administration is very low; LD 50 is greater than 2 g / kh. At an oral dose of 5 mg / kg, the compound showed an antihistamine effect in guinea pigs (protection of guinea pigs from the lethal effect of 5 mg / kg intrajugularly administered histamine); intensity, it is similar to p

mebrofenhydramine (Bromadryl). At a concentration of 100 µg / ml, it inhibits the growth of Staphylococcus pyogenes aureus.

1- / 2- (2-chloro-6,11-dihydrodibenzo (b, f) thiepin-11-yloxy) ethyl] -4- (4-chloro-3-trifluoromethylphenyl) piperidin-4-ol was tested It exhibited inhibitory activity in vitro against the following microorganisms (minimum inhibitory concentrations in µg / ml given): Staphylococcus beta-haemolyticus 12.5, Streptococcus faecalis 100, Staphylococcus pyogenes aureus 25, Saccharomyces pasterianus 50, Trichophyton mentagrophytes 50.

The compounds of the formula I according to the invention are accessible by various methods, the basic one being the substitution reaction of 2-bromoethyl ethers of the formula II

H OCH ₂ CH ₂ Bi in which R denotes the same as in formula I, with the corresponding amines, i.e. piperazine, its Ν-methyl-, N- (2-hydroxyethyl) - and N- (ethoxycarbonyl) derivative and further with 4 - (4-chloro-3-fluoromethyl) phenylpiperidin-4-ol. These substitution reactions can advantageously be carried out in most cases in an excess of said amines, which then serve not only as the reaction component but also as hydrogen bromide scavengers and finally as reaction media. The reactions are carried out at elevated temperatures, i.e. at 80 to 120 ° C, with the upper limit being the most advantageous in terms of reaction speed and yield.

The substitution reactions can also be carried out using an equivalent or only a small excess of amines in the presence of potassium carbonate in a boiling suitable solvent, e.g. ethanol. The starting bromoethyl ethers of formula (II) are novel, the preparation of which is described in the examples. Secondary amines of formula I in which X = NH may also be prepared by alkaline hydrolysis of carbamates of formula I in which X = NCOC = Hg. Neutralization of the crude bases with organic acids, preferably maleic acid, yields crystalline salts and crystallizes them to purify the desired substances. By alkalization, these pure salts can be decomposed and extracted with organic solvents to obtain a homogeneous base of formula I.

All of the novel compounds described in the present invention, both the end products of Formula I and intermediates, were assured not only by analysis but also by all conventional spectral methods in terms of chemical identity. The following examples are intended to illustrate the preparation possibilities of the compounds of the present invention, but are not intended to describe all possible methods of preparation.

Example 1

2-chloro-11- [2- (4-methylpiperazino) ethoxy] -6,11-dihydrodibenzo (b, e) thiepine

A mixture of 5.0 g of 11- (2-bromoethoxy) -2-chloro-6,11-dihydrodibenzo (b, e) thiepine and 5.0 g of 1-methylpiperazine was stirred for 5.5 h under reflux in a 120 ° C bath. Deň: 32 ° C. After cooling, the mixture was diluted with 30 ml of 4% sodium hydroxide solution and extracted with chloroform. The extract was washed with water, dried over potassium carbonate and evaporated under reduced pressure. The residue was dissolved in 25 ml of ethanol and neutralized with a solution of 3.5 g of raaleic acid in 10 ml of ethanol. Standing overnight and filtration gave 7.5 g (89%) of the bis (hydrogen maleate) desired base melting at 175-177 ° C. Recrystallization from aqueous methanol gave the pure product, m.p. Mp 179-181 ° C.

The starting 11- (2-bromoethoxy) -2-chloro-6,11-dihydrodibenzo (b, e) thiepine is a new and hitherto unwritten substance obtained, for example, by the following procedure: Mixture 25.0 g 2-chloro-6, 1l-dihydrodibenzo (b, e) thiepine-11-ol (Malen Ch. Et al., U.S. Pat. No. 2,065,636), 250 ml benzene,

18.0 g of 2-bromoethanol and 1.75 ml of sulfuric acid are stirred and refluxed for 1 hour. After cooling, the mixture was washed with water, 5% sodium bicarbonate solution and again with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in hot benzene, the solution was filtered, petroleum ether was added to the filtrate and the mixture was left to crystallize in the cold. On standing for 24 h, 31.1 g (88%) of the desired pure product melted at 90-92 ° C.

Example 2

2-chloro-11- [2- (4-methylpiperazino) ethoxy] -6,11-dihydrodibenzo (b, e) thiepine

A mixture of 5.0 g of 11- (2-bromoethoxy) -2-chloro-6,11-dihydrodibenzo (b, e) thiepine (see Example 1), 1.5 g of 1-methylpiperazine, 2.0 g of potassium carbonate, and 4 g. ml of ethanol was refluxed for 3 h. After cooling, it is diluted with water and extracted with chloroform. The extract is shaken with 25 ml of ice-cold and 1: 4 dilute hydrochloric acid, the precipitated solid is filtered off and the filtrate is separated. The acidic aqueous layer was basified with aqueous ammonia and the liberated base was isolated by extraction with ether. The oil was obtained in a yield of 2.4 g (46%). Neutralization with 1.5 g of maleic acid in ethanol gave 2.7 g of bis (hydrogen maleate) which, after crystallization from aqueous methanol, melts at 179-181 ° C and is identical to the product obtained in Example 1.

Example 3

2-methyl-11- [2- (4-methylpiperazino) ethoxy] -6,11-dihydrodibenzo (b, e) thiepine

A mixture of 7.0 g of 11- (2-bromoethoxy) -2-methyl-6,11-dihydrodibenzo (b, e) thiepine and 7.0 g of 1-methylpiperazine is stirred and heated at 120 to 125 ° C for 4, After standing overnight, the mixture was partitioned between chloroform and 1: 4 dilute aqueous ammonia, the chloroform layer was washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in 70 mL of warm ethanol and neutralized with 5 g of maleic acid in 20 ml of ethanol.

9.5 g (79%) of crystalline bis (hydrogen maleate) precipitate, melting at 166-169 ° C. The pure material was obtained by recrystallization from a mixture of aqueous methanol and acetone, m.p. Mp 174-175 ° C.

The starting 11- (2-bromoethoxy) -2-methyl-6,11-dihydrodibenzo (b, e) thiepine used has not been described in the literature. It can be obtained as follows: A mixture of 30.0 g of 2-methyl-6,11-dihydrodibenzo (b, e) thiepine-11-ol (Rajsner M. et al., Collect. Czech. Chem. Commun. 34, 1). 015 (1969), 330 ml of benzene, 23.2 g of 2-bromoethanol and 3.2 ml of sulfuric acid are treated in a similar manner to that described in Example 1. 38.4 g (86%) of the desired compound are obtained, which crystallizes from benzene as a 6: 1 benzene solvate and melts at 108-110 ° C (benzene-hexane).

Example 4

1- [2- (2-chloro-6,11-dihydrodibenzo (b, e) thiepin-11-yloxy) ethyl] -4- (2-hydroxyethyl) piperazine

A mixture of 5.0 g of 11- (2-bromoethoxy) -2-chloro-6,11-dihydrodibenzo (b, e) thiepine (see Example 1) and 5.5 g of 1- (2-hydroxyethyl) piperazine is stirred and heated 5.5 h at 120 ° C. Work up similar to Example 1. 8.0 g (91%) of bis (hydrogen maleate) melting at 149-151 ° C were obtained. An analytical sample was obtained by recrystallization from a mixture of methanol and ether, m.p. Mp 154-156 ° C.

Example 5

1- [2- (2-methyl-6,11-dihydrodibenzo (b, e) thiepin-11-yloxy) ethyl] -4- (2-hydroxyethyl) piperazine

Reaction of 7.0 g of 11- (2-bromoethoxy) -2-methyl-6,11-dihydrodibenzo (b, e) thiepine (see Example 3) with 7.0 g of 1- (2-hydroxyethyl) piperazine at 120-125 ° C for 4.5 h and similar treatment as in the previous example gave 11.4 g (90%) of bis (hydrogen maleate), m.p. 153-154 ° C (aqueous methanol).

Example 6

2-chloro-11- [2- (4-ethoxycarbonylpiperazino) ethoxy] -6,11-dihydrodibenzo (b, e) thiepine

A mixture of 10.0 g of 11- (2-bromoethoxy) -2-chloro-6,11-dihydrodibenzo (b, e) thiepine (see Example 1) and 13.0 g of 1- (ethoxycarbonyl) piperazine was heated for 5.5 h. at 120 ° C. After cooling, partition between water and chloroform, wash the chloroform layer with water and shake with cold dilute hydrochloric acid. The separated aqueous layer was immediately basified with 20% sodium hydroxide solution and the product was extracted with chloroform. The extract was dried over potassium carbonate and evaporated under reduced pressure to give 11.2 g (93%) of the desired oil base. Neutralization with oxalic acid gives the hydrogen oxalate, which crystallizes from ethanol / ether mixtures and melts at 172-173 ° C.

Example 7

2-chloro-11- [2- (4-ethoxycarbonylpiperazino) ethoxy] -6,11-dihydrodibenzo (b, e) thiepine

A mixture of 5.0 g of 2-chloro-6,11-dihydrodibenzo (b, e) thiepine-11-ol (literature cited) and 50 ml of benzene is saturated with hydrogen chloride gas for 1 hour. The benzene is then evaporated in vacuo, replaced with 50 ml of xylene, 4.0 g of 1-ethoxycarbonyl-4- (2-hydroxyethyl) piperazine (Moore TS et al., J. Chem. Soc. 1929, 39) is added and the mixture was refluxed for 5 h. After cooling, it is washed with water, dried over potassium carbonate and evaporated. 5.7 g (67%) of a crude oily base are obtained, which is neutralized with oxalic acid in aqueous ethanol to give the hydrogen oxalate, which also crystallizes as the monohydrate, m.p. Mp 167-168 ° C (96% ethanol). Thin layer chromatography on silica gel showed the identity of the products obtained according to Examples 6 and 7.

Example 8

2-chloro-11- (2-piperazinoethoxy) -6,11-dihydrodibenzo (b, e) thiepine

A mixture of 9.0 g of oily base 2-chloro-11- [2- (4-ethoxycarbonylpiperazino) ethoxy] -6,11-dihydrodibenzo (b, e) thiepine (see Examples 6 and 7), 15 ml of ethanol and 10.0 g of potassium hydroxide was stirred and refluxed for 1 h in a bath heated to 120 ° C. After cooling, the mixture was partitioned between water and benzene, the base was extracted from the benzene layer into 100 ml of ice-cold 5% hydrochloric acid, the separated aqueous layer was basified with 20% sodium hydroxide solution and the base was extracted with benzene. The extract was dried over potassium carbonate and evaporated in vacuo. 5.2 g (69%) of the desired oily base are obtained which, by neutralization with 3.3 g of maleic acid in 40 ml of ethanol, yields 5.9 g of crystalline bis (hydrogen maleate), m.p. 147 DEG-149 DEG C. (ethanol).

Example 9

1- [2- (2-chloro-6,11-dihydrodibenzo (b, e) thiepin-11-yloxy) ethyl] -4- (4-chloro-3-trifluoromethyl) piperidin-4-ol

A mixture of 4.5 g of 11- (2-bromoethoxy) -2-chloro-6,11-dihydrodibenzo (b, e) thiepine (see Example 1), 3.0 g of 4- (4-chloro-3-trifluoromethylphenyl) - 4-piperidinol (Shindelar K. et al., Collect. Czech. Chem. Commun. 38, 3879, 1973), 1.7 g of potassium carbonate and 6 ml of ethanol are stirred and refluxed for 5 hours. After diluting with 15 ml of water, the mixture is extracted with dichloromethane, the extract is dried over potassium carbonate, filtered with charcoal, and the filtrate is evaporated in vacuo. The residue is dissolved in 15 ml of ethanol and neutralized with a solution of 1.0 g of maleic acid in 10 ml of ethanol. 5.5 g (75%) of hydrogen maleate are obtained, which crystallizes from a mixture of acetone and ether and melts at 201-203 ° C.

Claims (2)

SUBJECT OF THE INVENTION 2-aminoethyl ether derived from 2-substituted 6,11-dihydro-dibenzo (b, e) thiepin-ll-ol of formula X in which R represents chlorine or methyl and X is dvojmooný radical NH, NCH ^, NCHjCHjOH, NCOOC ₂ H ₅ or and salts thereof with organic acids, preferably maleic acid. Corrections in printed descriptions of the invention In the printed description of the invention for author's certificate No. 237 487 (FV 1496-84), the chemical formula (I) was misprinted in the annotation, formula (i) and (II) on page 2 and formula (I) in the subject matter of the invention .