CS262162B1 - 2-/6,11-dihydrodibenzo/b,e/thiepin-11-ylamino/alkanoic acids and ethylesters and amides them - Google Patents

Abstract

The solution lies in the field of synthetic drugs. Its subject is 2- (6,11-dihydrodibenzo / b, e / thiepin-11-ylamino) alkanoic acids, their ethyl esters and amides. Concerns 2 and 3 carbon alkanoic acid derivatives atoms. Substances according to solution show anti-inflammatory and anticonvulsant efficacy so they are suitable for use in therapy inflammatory conditions and in the treatment of epilepsy. Described the synthesis is based on 6,11-dihydrodibenzo / b, e / thipm-11-amine, which reactions with ethyl esters of the corresponding haloalkane acids give the ethyl esters according to the invention solution. These are both alkaline hydrolysis they provide acids according to the solution, on the other hand, by ammonolysis in an autoclave at 135 ° C giving the corresponding amides.

Description

The invention relates to 2- (6,11-dihydrodibenzo [b, e] thieipin-11-ylamino] alkanoic acids, their ethyl esters and amines of formula (I).

(/) in which,

R is hydrogen or methyl;

R ¹ represents OH, OC 2 H 5 or NH 2.

The compounds according to the invention are characterized by anti-inflammatory and anti-seizure activity, so that they are suitable for practical use in the treatment of inflammatory conditions and in the treatment of epilepsy. For the individual substances according to the invention, the following pharmacological data, obtained in animal experiments (mice and rats), can be given:

2- (6,11-dihydrodihenzo [b, e] thiepin-11-ylamimo) acetic acid (I, R = H, R ¹ = OH). Acute-Toxicity in mice, LD 50 is greater than 1000 mg / kg when administered orally (this dose does not yet cause death of the animals, so the substance is extremely toxic). In an assay that uses carrageenin inflammation in a rat as a model, an oral dose of 200 mg / kg inhibits inflammation by 14%, which is assessed as a mild anti-inflammatory effect.

2- (6, ll-dihydrO'dibenzo / b, e / thiepin-l-ylamino jpropion-oic acid (I, R - CH3, ^R1 = OH). The substance is similarly low toxic substance as the previous one: Oral dose-one 00-0 mg per kilogram does not induce death of mice at all (LD 50 > 1000 mg / kg b) Similarly to the previous compound, it has a mild anti-inflammatory effect in the rat carrageenin inflammation test (oral dose 200 mg / kg inhibits inflammation by 13 o / o).

2- (6,11-dihydro-dibenzo [b, e] thiepin-11-ylamine ethyl acetate (I, R = H, R ¹ = OC 2 H ⁵ ). Toxicity of the substance is very low; LD 50> 1000 mg / kg po ( In the carrageenin inflammation test, it shows a slight anti-inflammatory effect (an oral dose of 200 mg / kg inhibits inflammation in rats by 10%).

2- (6, ll-dihydro-dibenzo / b, e / thiepin-l-ylamino) -acetamide (I, R = H, R ¹ = -NH 2]. Acute toxicity in mice, LD> 1000 mg / kg (oral dose this does not at all The substance exhibits anti-inflammatory efficacy in rats in three model inflammations, in all cases an oral dose of 200 mg / kg was administered, which inhibits inflammation by 32% in the case of kaolin edema and 28% in the case of a-adjuvant edema. and in the case of carrageenin edema 11%.

Furthermore, the compound has anticonvulsant activity in 11 mice. At an oral dose of 100 mg / kg, the substance protects 100% of the animals from electroshock-induced seizures; PD 50 = 43 mg / kg p.o. In the pentetrazole seizure test, the mean protective dose PD 50 is 50 mg / kg p.o. Thus, the substance is more anticonvulsant than phenytoin.

2- (6, ll-dihydro-dibenzo / b, i: / -thiepine-ylaminojpropionamid (I, R - CH3, ^R1 = NH2). The acute toxicity in mice upon oral administration, LD = 940 mg / kg. Substances For a In an electroshock-induced convulsion test in mice, its median protective dose PD 50 equals 204 mg per kilogram after the substance further has a mild inducing effect in the mouse rotating rod test; ED 50 = 27-5 mg / kg after

The compounds of formula (I) may be prepared by a variety of general methods of organic synthesis. The examples describe a process using the known 6,11-dihydrodibenzo [b, e] thiepi-n-11-amine as the starting material (Valenta V. et al., Colltect. Czech. Chem. Commun. 45, 517, 1980). This compound provides ethyl esters of formula I, R ¹ = OC 2 H 5 by substitution reactions with ethyl esters of haloacetic-2-halopropionic acids. Ethyl chloroacetic acid, bromoacetic acid, 2-chloropropionic acid and 2-bromopropionic acid ethyl esters are preferably used. The substitution reactions take place, for example, in toluene at the boiling point of this solvent in the presence of anhydrous alkali carbonates and at a reaction time of several tens of hours. The ethyl ester can be converted to the free acid (I, R ¹ = OH) by hydrolysis with sodium hydroxide in refluxing aqueous methanol. The amides of formula I (R ¹ = NH 2) can be obtained, for example, by ammonolysis of ethyl esters carried out in practice by heating these substances with excess liquid ammonia in methanol at 135 ° C.

Of the compounds of the invention, acid-NY (I, R ¹ - = OH) are -amfoterní nature and well crystallized like- such; esters (R ¹ = OC 2 H 5) are basic in nature and crystallize in the form of salts, eg, hydrochlorides; amides (I, R ¹ = NH 2) are also b-azic in nature and can be obtained in the form of crystalline bases. All of the compounds of the invention are novel; their identity was confirmed by analytical and spectral methods. The examples below are merely illustrative of the possibilities of synthetic methods in this class of substances. No, its purpose is to describe all possible synthetic methods.

Example 1

2- (6,11-Dihydr-0'-dibenzo [b, e] thiepin-11-ylamino-ethyl acetate)

A mixture of 7.04 g of 6,11-dihydrodibenzo [b, e] thiepine-11-amine, 70 ml of toluene, 20 g of anhydrous potassium carbonate and 20.2 g of chloroethyl acetate is stirred and boiled for 32 h under reflux condenser. After cooling, the mixture was diluted with toluene, the solid was removed by filtration and washed with toluene, the filtrate was washed with water, filtered with charcoal, dried with magnesium sulfate and evaporated under reduced pressure on a rotary evaporator. The residue crystallized from 13 ml of ethanol to give 6.7 g (69%) of the desired product, which melts at 95-99 [deg.] C. Further crystallization from ethanol yields an analytically pure substance, mp 99-101 [deg.] C. Ethanol and addition of ether gave crystalline hydrochloride which crystallized from ethanol / ether and melted at 145-146 ° C with decomposition.

Example 1 a d 2

Ethyl 2- (6,11-dihydrodibenzo [b, e] thiepin-11-ylamino) propionate

A stirred mixture of 4.54 g of 6,11-dihydrodihenzo [b, e] thiepine-11-amine, 60 ml of toluene, 10.1 g of anhydrous sodium carbonate and 10.85 g of ethyl 2-bromoproipionate is refluxed for 46 h. and processed similarly to · in Example 1. 6.5 g (99 percent) of a crude oil are obtained which, by neutralization with hydrogen chloride in ethanol and addition of ether, gives a crystalline hydrochloride which crystallizes from a mixture of ethanol and ether and melts at 148.5 to 150.5 degrees Celsius.

Example 3

2- (6,1 l-dihydrobenzene / b, e / thiepin-11-ylamino) acetic acid

A mixture of 5.3 g of 2- (6,11-dibydro-dibenzo [b, e] thiepin-11-ylamino) -acetate (see Example 1j), 17.5 ml of 10% sodium hydroxide and 17.5 ml of methanol is stirred and boiled. The methanol is evaporated off under reduced pressure, the residue is diluted with 25 ml of water, the solution is filtered with charcoal and the filtrate is washed with ether At 40 DEG C. the sodium salt solution is neutralized with 2.5M-CH. After cooling, the precipitated product is filtered, washed with water and dried to give 2.9 g (60%) of the crude amino acid, which is recrystallized from aqueous ethanol and melts at 105-106 ° C. C.

Example 4

2- (6,11-dlhydrodibenzo [b, e] thiepin-11-yl) amino] propionic acid

Similar to the previous example, 5.45 g of 2- (6,11-dihydrodilbenzo [b, e] thiepine-11-ylamino) propionate (see Example 2) is reacted with 17.5 ml of 5M-NaOH in 17.5 ml. methanol to give 4.1 g (91%) of the crude product, which crystallized from • ethanol as a 2: 1 solvate with ethanol, mp 192.5 ° C.

Example 5

2- (6,11-dihydrodibenzo [b, e] thiepin-11-ylamino) acetamide

A mixture of 6.7 g of 2- (6,11-dihydrobenzo [b, e] thiepin-11-ylamino) ethyl acetate (see Example 1), 40 ml of liquid ammonia and 30 ml of methanol is heated in an autoclave for 4 hours. Deň: 32 ° C. It is then diluted with 50 ml of methanol, filtered with charcoal and the filtrate is evaporated. 5.7 g (94%) of the desired amide are obtained, which crystallizes from benzene and melts at 99-103 ° C.

Example 6

2- (6,11-dihydrodiibenzo [b, e] thiepin-11-ylainino] propionamide

As in the previous case, 3.6 g of 2- (6,11-dlhydrobenzo [b, e] thiepin-1'-ylamino) propionate hydrochloride (see Example 2) are reacted with 50 ml of liquid ammonia in 20 ml of methanol. 2.3 g (78%) of crude product is obtained, which crystallizes from a mixture of benzene, ethanol and petroleum ether and melts at 102-105 ° C. This material is a 3: 1 solvate with benzene. mp to 80-82 ^and C and this product is the unsolvated desired amide.

Claims (1)

2- (6,11-idihydrodiobenzo [b, e] thie, pin-11-ylamino) alkanoic acids, their ethyl esters and amides of formula I I INVENT in which R is hydrogen or methyl and R ¹ is OH, OC 2 H 5 or NH 2.