CS197191B1 - 8-chlor-10-/n up 4-alkylpiperazino/-10,11-dihydrodibenzo/b,f/thiepines having oxygen containing fuction groups in position 3 and in n-alkyl - Google Patents

Description

The invention relates to 8-chloro-10- (N- ^4- alkylpiperazino) -10,11-dihydrodibenzo (b, f) thiepines having 3-cyano-acid functions in the N-alkyl of formula I,

where S ¹ represents a hydrogen atom, methyl or methane sulfonyl, B? denotes n and is 2 or 3, as well as their pharmaceutically acceptable salts with organic acids.

hydrogen or ethyl with inorganic or

197 191

The compounds of the formula I and their salts are mild tranquilizers with a negligible cataleptic component. They also exhibit antimicrobial effects so that they are useful as medicaments. For example, the compound of formula X and " H and H " Z, which has been tested in the form of crystalline dihydrochloride monohydrate, is very toxic. Its mean lethal dose of LDjq is greater than 1 g / kg when administered orally; said dose induces death of 40% of the mice in the experiment. The substance acts centrally in mice as shown by the incoordinating action in the rotating rod test; mean effective dose that induces staxia, ED 50 * 69 mg / kg. The substance is not cataleptic in the rat test at an oral dose of 50 mg / kg. The higher homogeneity of this compound, i.e. the compound of formula I, wherein R ^ «R R «Han = 3, was also tested in the form of dihydrochloride monohydrate when administered orally in mice and rats. It is again very toxic; LD40 ^with 940 mg / kg. It also acts centrally damping, which is manifested by an incoordinating action; ΕΙϊ ^ θ “32 mg / kg (mice, po).

The substance is slightly active cataleptiocyte in rats; median effective dose = 67 mg / kg.

It has also been shown to have antimicrobial activity in in vitro assays; appropriate microorganisms and minimum inhibitory concentrations in g / ml are given: Streptococcus / 3-haemolyticue 3.12; Streptocoocue faecalis 100; Staphylococcus pyogenes aureus 50; Escherichia eoli 50; Mycobacterium tuberculoeie 25; Saccharomycee pasterianus 12.5; Trichophyton methegropytee? 5; Candida albicana 50. Remarkable is the efficacy against hemolytic streptococcus.

The compounds of the invention may be prepared by various methods as described in the Examples. For example, compounds of formula I wherein H ^{1 is} methyl, B 2? H and Z or 3 can be prepared from the known 8,10-dichloro-3-methoxy-10,11-dihydrodibenzo (b, f) thiepine of formula II

(ID, (K. Shindelar et al., Collect.Czech.Chem.Commun. 39. 3548, 1974)) by substitution reactions and 1- (2-hydroxyethyl) - and 1- (3-hydroxypropyl) piperazine. Their demethylation with bromide with boric borohydride results in a low yield of compounds of formula I where R @ 1 = B @ 2 = Han @ 2 or 3, but when the reaction mixture is decomposed with ethanol, solvolysis of the boronic ester formed to the branched chain oxygen function results in compounds of formula I where R ^ = H, -C CHH, n «2.. For the preparation of compounds of formula I wherein R ^» lřř = Han ³ 2 or 3, it is preferable to start from the known 8-chloro-3-methoxydibenzo (b, f) thiepine- 10 (11H) -one of formula III (III),

(K. Shindelar et al., Cited), which is demethylated to 8-chloro-3-hydroxydibenzo (b, f) thiepin-10 (11H) -one of formula IV by preheating with pyridine hydrochloride at 200 ° C.

(IV),

This hydroxyketone is further reduced with sodium borohydride to 8-chloro-10,11-dihydrodibenzo (b, f) thiepine-3,10-diol of formula V,

which is esterified by reaction with methanesulfonyl chloride in the presence of triethylamine on both hydroxyl functions to form an unstable di (methanesulfone) ester. This ester is subjected to aminolysis without isolation by treatment with excess 1- (2-hydroxyethyl) - or 1- (3-hydroxypropyl) piperazine. Primary branching of aminolysis occurs, allowing the isolation of compounds of formula 1 wherein R ' ^{L 3} methane sulfonyl, R = H and ³ 2 or 3. These compounds are also subject to aminolysis under the action of the above piperazine derivatives so that the end products are compounds I, wherein R ^1, S ^{2 3} H and n 2 or 3. All the compounds of formula X according to the invention are basic in nature, so that they can be converted to the corresponding salts by neutralization with pharmaceutically acceptable acids as described in the examples.

Examples

EXAMPLE 1 8-Chloro-10 ~ / 4- (2-hydroxyethyl) piperazin / 3-methoxy-10, ll-dihydro-dibenzo (b, f) thiepin (I, R₁ = ghj ^R2 = Η, n = 2 )

A mixture of 19 g of 1- (2-hydroxysthyl) piperazine, 20 ml of absolute chloroform and 15 g of 8,10-dichloro-3-methoxy-10,11-dihydrodibenzo (b, f) thiepine (II) was refluxed for 6 hours. . The chloroform was then distilled off, the residue was quenched with 50 ml of water and extracted with benzene. The extract was washed with 5% sodium hydroxide solution and water, and then shaken with excess 2, 1H-H 2 SO 4. The acidic solution containing the sulfate of the desired product is separated, basified with aqueous ammonia and the base isolated by extraction with benzene. The extract was washed with water, dried over magnesium sulfate and filtered with charcoal. Evaporation of the filtrate gave 14.0 g (72%) of an oily base, suitable for further work. For characterization, neutralization of this base with maleic acid in ethanol can produce crystalline di (hydrogen maleate), which after recrystallization from ethanol is completely pure and melts at 138-141 ° C.

Example 2 8-Chloro-10- [4- (3-hydroxypropyl) piperazino] -3-methoxy-10,11-dihydrodibenzo (b, f) thiepine (I, R 2 -CH ² , R ² - Η, n = 3 )

A mixture of 20 ml of chloroform, 20.7 g of 1- (3-hydroxypropyl) piperazine and 15.0 g of 8,10-dichloro-3-methoxy-10,11-dihydrodibenzo (b, f) thiepine (II) is refluxed for 6 hours. and the reaction mixture is worked up analogously to the previous case. 14.0 g (70%) of an oily base are obtained which, by neutralization with maleic acid, gives a crystalline di (hydrogen maleate) of m.p. 132 DEG-134 DEG C. (ethanol).

Example 3 8-Chloro-10- / 4- (3-ethoxypropyl) piperazino / -3-hydroxy-10, ll-dihydro-dibenzo (b, f) thiepin (I, R ¹ = H, R ² = C ^ n = 3)

To a solution of 9.3 base of 8-chloro-10- [4- (3-hydroxypropyl) piperazino] -3-methoxy-10,11-dihydro-dibenzo (b, f) thiepine in 30 ml of dichloromethane was stirred at 10-20 for 15 minutes with stirring. A solution of 22 g of boron tribromide in 20 ml of dichloromethane is added dropwise, the mixture is stirred for 5 hours at room temperature, after standing overnight 30 ml of ethanol are added under external cooling and stirred for 8 hours. The oethanol is then evaporated, the residue is dissolved in 100 ml of pure ethanol, 15 ml of 20% sodium hydroxide solution are added and refluxed for 6 hours. After evaporating the ethanol in vacuo, the residue is diluted with water, the insoluble matter is removed by filtration, the filtrate is acidified with hydrochloric acid, the hydrochloride solution obtained is washed with benzene and then basified with 20% sodium carbonate solution. The precipitated product is isolated by extraction with dichloromethane, after which the amorphous base obtained is converted to neutral fumarate with m.p. 117 DEG-120 DEG C. (acetone). The identity of the substance was ensured by means of a mass spectrum which showed a molecular ion of m / e 432.1640, which corresponds to the total composition of the base C ^ HggCIN ^ OgS

EXAMPLE 4 8-Chloro-10- / 4- (3-hydroxypropyl) piperazin / -3- (methanesulfonyloxy) -10, ll-dihydro-dibenzo (b, thiepin (I, R₁ = SO2CH} R ² - Η n = 3)

To a solution of 8.36 g of 8-chloro-10,11-dihydrodibenzo (b, f) thiepine-3,1-diol (V) in 150 ml of dichloromethane is added 10 g of triethylamine, and then at -10 to 10 DEG C. over 10 minutes. ^g 0 C added dropwise 7.6 g of methanesulfonyl chloride. The mixture was stirred for 1 hour at 0 ° C, then washed with ice water, ice-cold 10% hydrochloric acid and 5% sodium hydrogen carbonate solution, dried over sodium sulfate and evaporated. The residue is the theoretical (13.0 g) obtained starting material V di (methanesulfonic) ester. It is dissolved in 30 ml of chloroform, 17.3 g of 1- (3-hydroxypropyl) piperazine are added and the mixture is refluxed for 1 hour. cooler. After cooling, it is quenched with water and extracted with benzene. The extract was washed with water and the basic product was shaken with 5% hydrochloric acid into the aqueous phase as a hydrochloride solution. After filtration, the aqueous solution was basified with sodium carbonate and the product was extracted again with benzene. Treatment of the extract ae yields an oily base which is converted to crystalline di (hydrogen maleate) by melting with maleic acid in a mixture of acetone and ether, mp 131-132 ° C (acetone-ether). The identity of the substance is ensured both by analysis and by mass spectrum, which shows a molecular ion of m / e 482, which corresponds to the total composition of the base

The starting 8-chloro-10,11-dihydrodibenzo (b, f) thiepine-3,10-diol (V) is a novel compound which can be prepared from the known 8-chloro-3-methoxydibenzo (b, f) thiepine-10 ( 11H) -one (III) as follows:

To a solution of pyridine (130 ml) in ethanol (130 ml) was slowly added hydrochloric acid (155 ml) and the solution was evaporated to dryness in vacuo. To the remaining pyridine hydrochloride was added 23 g of 8-chloro-3-methoxydibenzo (b, f) thiepin-10 (11H) -one and the mixture was heated with stirring until the internal temperature reached 200 ° C; it is maintained at this temperature for 80 minutes. After cooling to 80 [deg.] C., 400 ml of water are added and allowed to stand overnight after mixing. The precipitated crystalline product is suction filtered, washed with water and dried in vacuo. Crude 8-chloro-3-hydroxydibenzo (b, f) thiepin-10 (11H) -one is obtained, which is recrystallized from 70 ml of ethanol. 15.8 g of pure product (73%) with m.p. Mp 200-203 ° C.

15.8 g of the preceding hydroxyketone are dissolved in 240 ml of ethanol at 72 DEG C. with stirring, and a solution of 2.15 g of borohydride is added dropwise with stirring over 15 minutes. of sodium hydroxide in 20 ml of water containing 0.5 ml of a 20% sodium hydroxide solution. The mixture is refluxed for 6 hours, the ethanol is evaporated, the residue is quenched with 130 ml of water and the product is extracted with benzene. Evaporation of the extract gave 14.3 g (90%) of crystalline 8-chloro-10,11-dihydrodibenzo (b, f) hiepine-3,1-diol, which crystallized from benzene and melted at 146-148 ° in pure state. C.

Example 5 8-Chloro-10 / 4- (2-hydroxyethyl) piperazino / -3-hydroxy-10,11-dihydrodibenzo (bf) thiepine (I, R ¹ = R ² = Η, n = 2)

To a solution of 6.9 g of 8-chloro-10,11-dihydrodibenzo (b, f) thiepine-3,10-diol and 8.4 g of triethylamine in 130 ml of dichloromethane at -10 to 0 ° C was added dropwise 6.4 methane sulfonyl chloride ; the mixture was stirred at 0 ° C for 1 h, then washed with ice water, ice cold

5% hydrochloric acid and 5% sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and the dichloromethane is evaporated. 16.5 g of 1- (2-hydroxyethyl) piperazine are added to the residue and the mixture is heated in a 140 ° C bath for 6 hours. After cooling, it is diluted with water and extracted with dichloromethane. The extract is thoroughly washed with water and then the product is transferred to the aqueous phase by shaking with excess 5% hydrochloric acid. The acidic hydrochloride solution was separated, the acidity was partially dulled with 20% sodium hydroxide solution and finally basified with excess sodium hydrogen carbonate. The liberated phenolic base is extracted with chloroform and the extract is chromatographed over a column of 600 g of neutral alumina activity II. A small portion of the less polar impurities is eluted with chloroform, and then 2.91 g of the desired base is eluted with a mixture of chloroform and ethanol, which crystallizes from benzene as a half-benzene solvate and melts at 111-113 ° C. Neutralization with the appropriate acids yields a neutral fumarate with m.p. 211 DEG-212 DEG C. with decomposition (acetone); on the other hand, dihydrochloride monohydrate melting at 169 DEG-174 DEG C. (95 DEG ethanol-ether).

Example 6 8-Chloro-11- [4- (3-hydroxypropyl) piperazino] -3-hydroxy-10,11-dihydrodibenzo (b, f) thiepine (I, H ¹ = trans = n, 3)

To a solution of 6.9 g of 8-chloro-10,11-dihydrodibenzo (b, f) thiepine-3,10-diol and 8.4 g of triethylamine in 130 ml of dichloromethane was stirred at -10 to 0 ° C for 10 min. 6.4 g of methanesulfonyl chloride were added dropwise. The mixture was stirred at 0 ° C for 1 h, then washed with ice water, ice-cold 5 N hydrochloric acid, and 5 N sodium chloride solution. hydrogen carbonate. It is dried over sodium sulphate and the dichloromethane is evaporated. 15.2 g of 1- (3-hydroxypropyl) piperazine are added to the residue and the mixture is heated in a 140 ° C bath for 6 hours. Then ee processes as in the previous case. 5.8 g of crude phenolic base are obtained, which crystallizes from a mixture of benzene and cyclohexane as a solvate in half the molecule of bepzene and melts in the pure state at 108 to 110 ° C. Neutralization with hydrogen chloride in ethanol gives the dihydrochloride, which crystallizes from 95% ethanol and melts at 172-175 ° C.

Claims (1)

8-Chloro-10- (N, 4-alkylpiperazino) -10,11-dihydrodibenzo (b, phthiazepines with β-oxygen functions at the 3-position and in the N-alkyl of formula I wherein R ⁴ is hydrogen, methyl or methanesulfonyl; hydrogen or ethyl; and n is 2 or 3, as well as their pharmaceutically acceptable salts with inorganic or organic acids.