CS250581B1 - Esters of tricyclic piperazinoethanol and rheir maleates - Google Patents

Description

The invention relates to esters of the tricyclic piperazinoethanol of the formula I

0 / in which

R is phenyl, methoxy, methylthio, phenoxy, 4-morpholinyl (= morphophino) and carboxymethyl, and their maleate.

Compounds of formula I are esters of 2-chloro-10- [4- (2-hydroxyethyl) piperazino] -10,11-dihydrodibenzoyl, thiepine of formula II

Cl

(li) which is known as a non-cataleptic neuroleptic ("dochloxythepin") (Dlabač A. et al., Activ. Nerv. Super. 17, 217, 1975; Valchář M "Dlabač A .: Cesk. Fysiol. 25, 277, 1978). Among its esters, acetate (Shindelář K. et al., Collect. Czech. Chem. Commun. 42, 3 605, 1977) and decanoate (Jílek JO, et al., Collect. Czech. Chem. Commun. 40) have been described in the literature. The esters of the present invention are highly potent centrally depressant, exhibit iantidopaminergic activity in biochemical assays (causing increased concentrations of dopamine metabolites in the rat brain striatum), while being non-cataleptic and They are useful as non-cataleptic neuroleptics in the treatment of schizophrenia while being free from the unpleasant side effects of conventional neuroleptics, they also exhibit antimicrobial activity in in vitro assays and are therefore potential chemotherapeutic agents. as found in bio All substances were tested as maleates and the doses indicated are mostly oral.

2-Chloro-10- [4- (2-phenylacetoxyethyl) piperazino] -10,11-dihydrodibenzo (b, f) thiepine. Acute toxicity in mice, LD 50 = 240 mg / kg. Incoordinating effect in rotating rod test in mice, ED 50 - 1.0 mg / kg. At a dose of 100 mg / kg it induces catalepsy in 10% of the rats (negligible effect) and at a dose of 50 mg / kg is ineffective against apomorphine stereotypes in rats. After administration of a dose of 80 mg / kg to rats, the haemovanilic acid level in the rat brain striatum is increased by 150 to 200% at 3 hour intervals. In an in vitro test, it is antimicrobially active against Trichophyton mentagrophytes at a concentration of 50 µg / ml.

2-Chloro-10- [4- (2-methoxyacetoxyethyl) piperazino-10,11-dihydrodibenzo (b, f) thiepine Acute toxicity in mice, LD 50 = 220 mg / kilogram. Rotating rod in mice, ED 50 - = 3 11 mg / kg The cataleptic effect in rats appears at a very high dose of 100 mg / kg (catalepsy in 30% of animals) At 50 mg / kg it is ineffective antiapomorphine in rats at the indicated concentrations (in μ%! (milliliter) acts antimicrobial in vitro against the following organisms:

Streptococcus fl-haemolyticus 50

Streptococcus faecalis 50

Staphylococcus pyogenes aureus 25, Escherichia coli 50

Mycobacterium tuberculosis 12,5, Trichophyton mentagrophytes 50.

2-Chloro-10- [4- [2-methylthioacetoxyethyl) piperazino] -10,11-dihydrodibenzo (b, f) thiepine. Rotating rod in mice, ED 50 = 3.0 mg / / kg. The cataleptic effect (in 30% of animals) in rats is seen at a very high dose of 100 mg / kg. At a dose of 50 mg / kg, it does not have antiapomorphine activity in rats. After administration of a dose of 40 milligrams per kilogram to rats, there was a significant increase in the level of homovanilic acid in the rat brain striatum at 3 hour intervals; after administration of 20 milligrams per kilogram, there is a significant increase in the level of 3,4-dihydroxyphenylacetic acid in the same brain.

In an in vitro test, it is antimicrobially active against Trichophyton mentagrophytes at a concentration of 50 Mg / ml.

2-Chloro-10- [4- (2-phenoxyacetoxyethyl) piperazino] -10,11-dihydrodibenzo (b, f J thiepine. Acute toxicity in mice, LD 50 = 326 mg / kg. Rotating rod in mice, ED 50 = 1 9 mg / kg.

At a dose of 50 mg / kg, it is ineffective antiapomorphine in rats and induces catalepsy in only 10 percent of rats. In vitro antimicrobial activity against the following organisms (concentration in µg / ml:

Streptococcus β-haemolyticus 50

Streptococcus faecalis 50

Staphylococcus pyogenes aureus 25, Escherichia coli 12.5,

Proteus vulgaris 100,

Trichophyton mentagrophytes

2-Chloro-10- [4- (2-morpholinoacetoxyethyl) piperazino] -10,11-dihydrodibenzo (b, f) thiepine. Acute toxicity in mice, LD 50 - 170 mg / kg. Rotating rod in mice, ED 50 - - 2.0 mg / kg. At a dose of 50 mg / kg it is ineffective antiapomorphine in rats and induces catalepsy in only 30% of rats. In vitro antimicrobial action (concentration in g / ml):

Streptococcus / Miaemolyticus 2'5

Streptococcus faecalis 100

Staphylococcus pyogenes aureus 25, Escherichia coli 25

Proteus vulgaris 100,

Mycobacterium tuberculosis 12.5.

2-Chloro-10- [4- (2- / 3-carboxypropionoxy / ethyl] piperazino] -10,11-dihydrodibenzo (b, f) thiepine Acute toxicity in mice, LD 50 = 150 milligrams per kilogram. ED50 = 1.1 mg / kg, the incoordination effect is long-lasting because the developed maximal effect lasts for the entire observation period, ie 5 h. At 100 mg / kg the substance has a cataleptic effect in 30% of rats, at 50 mg / kg At 80 mg / kg, the substance induces an increase in the concentration of homovanilic acid in rat striatum of 150 to 200% at 100 (µg / ml) inhibits the growth of Staphylococcus pyogenes aureus and Escherichia coli in an in vitro test.

The compounds of the formula I according to the invention can be prepared by acylation of a compound of the formula II with the corresponding acids of the formula III

R = CH 2 COOFI (III) wherein

R denotes the same as in formula I, or their reactive derivatives (chlorides, anhydrides, esters).

The acylation of the alcohol of formula II with free acids in dichloromethane in the presence of N, N‘-carbonyldiimidazole proceeds smoothly at room temperature. The esterification of the alcohol of formula (II) by the action of acid anhydrides in boiling benzene also proceeds smoothly, a method particularly suitable for the use of succinic anhydride. The details of the preparation of the substances according to the invention are illustrated by the examples, which are not intended to limit the invention to the conditions set forth in the examples. The esters of formula I prepared are basic in nature and are generally oily. Acid neutralization affords salts of which the maleates are part of the invention and are preferred for their good crystallinity; Maleic acid is pharmacodynamically safe and therefore suitable for the preparation of salts useful as pharmaceuticals. All esters of formula I are novel. Their identity was ensured by analyzes and spectral methods.

230381

Example 1

2-Chloro- 10- (4- (2-phenylacetoxyethyl) piperazino) -10,11-dihydrodibenzo (b, phthiepin.

2.45 g of phenylacetic acid are added to a stirred solution of 3.20 g of 90% N, N dichl-carbonyldilimidazole in 40 ml of dichloromethane under a nitrogen atmosphere. After 10 min. 6.0 g of 2-chloro-10- [4- (2-hydroxyethyl) piperazino] -10,11-dihydrodibenzo [b, f] thiepine (II; Jílek JO et al., Coll. Czech. Chem. Commun. 40, 2887 (1975)], stirred for a further 2 hours at room temperature, allowed to stand for 48 hours and evaporated in vacuo, the residue was dissolved in 50 ml of benzene, the precipitated imidazole was filtered off after 2 hours and washed with benzene. re-evaporate under reduced pressure, the glassy residue is dissolved in 20 ml of acetone and a solution of 1.80 g of maleic acid in 10 ml of acetone is added to the solution, and 0.80 g of imidazole hydrogen maleate (m.p. 136-137 ° C dec.) The mother liquor is partially evaporated under reduced pressure and standing for 3 hours to precipitate the maleate of the desired product, 5.20 g (54%), mp 154-155 ° C (acetone), its analysis is consistent with C32H33CIN2O6S ( mass spectrum shows the basis (C28H29ClN2O2S).

Example 2

2-Chloro-10- [4- (2-methoxyacetoxyethyl) piperazino) -10,11-dihydrodibenzo (b, phthiepin.

In a nitrogen atmosphere, to a stirred solution of 3.25 g of 90% N, N'-carbonyldiimidazole in 30 ml of dichloromethane was added a solution of 1.80 g of methoxyacetic acid (Fridman SG, W. Ob. Chim. 24, 642, 1954) in 4 ml. dichloromethane. The mixture is stirred for 10 minutes, a solution of 6.0 g of compound II (lit. quoted) in 10 ml of dichloromethane is added, stirred for a further 2 hours at room temperature, left to stand for 48 hours and evaporated in vacuo. The residue is dissolved in 50 ml of benzene, crystalline Imidazole precipitates from the solution, which is removed by filtration, the filtrate is again evaporated and the residue is left to crystallize on standing. 5.78 g (81%) of the desired crystalline base are obtained, mp 103-104 degrees Celsius (acetone). Neutralization with maleic acid in acetone gives the maleate C27H31CIN2O7S, mp 153-154 ^{° C,} (acetone).

Example 3

2-Chloro-10- [4- (2-methylthioacetoxyethyl) piperazino] -10,11-dihydrodibenzo (b, phthiepin)

Similar reaction of 3.25 g of 93% N, N'-carbonyldiimidazole with 1.7 g of methylthioacetic acid (Challenger F., Hollingsworth HD, J. Chem. Soc. 1959, 61) in 70 ml of dichloromethane, followed by treatment with 6.0 g. II (lit. quoted) in 15 ml of dichloromethane and a similar treatment as in the previous examples, yielded 6.1 g of an oily product which still contained a minor amount of imidazole. Chromatograph on a 90 g neutral alumina column (activity II), eluting with benzene to give 5.5 g (74%) of the desired homogeneous oily base, neutralizing maleic acid in acetone and adding ether to give crystalline C27H31CIN2O6S2 maleate, mp 137-137 1.5 degrees Celsius (acetone) (mass spectrum points to C23H27ClN2O2S2).

Example 4

2-Chloro-10- [4- (2-phenoxyacetoxyethyl) piperazino) -10,11-dihydrodibenzophenyl] thiepin

As in Example 1, 3.2 g of N, N'-carbodiimidazole were first treated with 2.75 g of phenoxyacetic acid and then 6.0 g of compound II (lit. quoted) in 40 ml of dichloromethane. A similar treatment, including imidazole removal, yielded 8.0 g of crude oil which was neutralized with 1.90 g of maleic acid in 40 ml of acetone. A small amount of the imidazole (hydrogen maleate) precipitated is filtered off and the filtrate crystallizes to give 7.30 g (72%) of the maleate hemihydrate of the title compound, mp 150-152 ^° C (acetone). Analysis of the substance corresponds to the following composition C32H33ClN2O7S + 0.5 H2O.

Example 5

2-Chloro-10- [4- (2-morpholinoacetoxyethyl) piperazino] -10,11-dihydrodibenzo (b, f) thiepine

As in the previous examples, 3.25 g of 93% N, N'-carbonyldiimidazole was treated with 2.32 g of morpholinoacetic acid (Remizov AL, Zh. Ob. Chim. 34, 3,187, 1964) in 70 ml of dichloromethane and after 15 minutes stirring with a solution of 6.0 g of compound II (lit. quoted) in 15 ml of dichloromethane. The mixture was stirred at room temperature for 2 hours, allowed to stand for 20 hours and evaporated. The residue was dissolved in 50 ml of benzene and the solution was allowed to stand overnight. The crystallized imidazole is filtered off and the filtrate is evaporated in vacuo. The residue was dissolved in 70 ml of acetone and the solution was neutralized with solution. 3.8 g of maleic acid in 12 ml of acetone. The resulting solution was partially evaporated and diluted with ether; 8.20 g (69 percent) of the dimaleinate hemihydrate of the desired compound of the formula C34H40ClN3O11S + 0.5 H2O are precipitated, m.p.

133.5 degrees Celsius (acetone-ether) (mass spectrum indicates C26H32ClN3O3S base).

Example 6

2-Chloro-10- [4- (2- / 3-carboxypropionoxy / ethyl) piperazino] -10,11-dihydrodibenzo (b, phthiepin)

To a solution of 6.0 g of compound II (lit. quoted) in 75 ml of benzene was added 1.6 g of succinic anhydride and the mixture was refluxed for 5 hours with stirring. After evaporation of the benzene under reduced pressure, the residue is overlaid with a mixture of 20 ml of petroleum ether and 20 ml of acetone and left to stand overnight. 6.6 g (87%) of the desired ester crystallized, m.p. 149 DEG C. (acetone). Treatment with maleic acid in a mixture of acetone and ether gives the maleate C28H31CIN2O8S melting at 141.5-142 ° C.

Claims (1)

Esters of a tricyclic piperazinoethanol of the general formula I in which: R is phenyl, methoxy, methylthio, phenoxy, 4-morpholinyl or carboxymethyl, and their maleates.