CS249499B1 - 4-piperidyl-and 4 perhydroazepinylethers derived from 6,11-dihydrodibenzo(b,e)thiepin-11-ols,their maleates and quaternary salts - Google Patents

Abstract

The solution lies in the field of drug synthesis. Its subject matter is 1-methyl-4-piperidyl 1-methylperhydro-4-azepinylethers derived from 6,11-dihydrodibenzo / b, e-thiepin-11-ol and its 2-methyl derivative, as well as their maleates and quaternary salts. These substances in pharmacological tests have properties potential antidepressants and antihistamines. They are therefore applicable in mental therapy depression and allergic diseases whereas this duality of their effects is not on failure to use them in one or the other indication. They are permissible by substitution reactions the corresponding 11-chloro-6,11-dihydrodibenzo / b, e / thiepine or methanesulfonates 6,11-dihydrodibenzo [b, e] thiepin-11-ol with 1-methylpiperidin-4-ol, respectively. 1 with methylperhydroazepin-4-ol. The base of the finite products are oily racemates or mixtures two racemates; however, they provide usable crystalline hydrogen maleate and quaternary salts, in particular methoiodides.

Description

The present invention relates to 4-piperidyl and 4-perhydroazepinyl ethers derived from 6,11-dihydrodibenzo [b, e] thiepin-11-oles of Formula I

wherein R is hydrogen or methyl and n is 2 or 3, their maleate and quaternary salts.

Literature / Protiva íl. et al. , Collect. Czech. Chem. Commun. 29, 2161, 1964;

Metyšová J. et al., Arzeneim-Forsch. 15, 524 (1965); čs. U.S. Pat. 113,624) discloses several 2- (tert-amino) -ethyl ethers derived from 6,11-dihydrodibenzo [b, e] thiepin-11-ol. They were found to be significantly antlhistamine active, while their antireserpine / i. potential antidepressant / activity was negligible. For quaternary salts of these substances / Rajšner clay. et al., Collect. Czech. Chem. Commun. 34, 1278, 1969 / the character of peripheral parasympatholytics with a mild peripheral antiserotonin component predominated. Tropin ethers derived from 6,11-dihydrodibenzo [b, e] thepine Cs have also been described. U.S. Pat. 140 825; Svýc. U.S. Pat.

482,719], which are also parasympatholytics; their quartz salt / Belg. U.S. Pat. No. 812,799] are bronchospasmolytics useful in the treatment of asthma.

The compounds of the invention of formula I and their salts are surprisingly typical thymoleptics, i.e. potential antidepressants. They are also moderately effective antihistamines. Thus, they can be used both in the treatment of mental depression and in the treatment of allergic diseases. At the same time, they are only moderately buffering, which is their advantage. The duality of their effect does not interfere with their use in one or another indication. The antihistamine effect does not interfere with their use in the treatment of depression and, on the other hand, the antidepressant effect is in no way manifested in allergic patients using their antihistamine and antiallergic effects.

In particular, the results of testing the individual compounds according to the invention on experimental animals are given, in particular, when administered orally.

11- (1-methyl-4-piperidyloxy) -6,11-dihydrodibenzo [b, e] thiepine (1, R 5, n 5) 2) was tested as hydrogen maleatate. Its acute toxicity in mice (LD ₁₀ ) is 221 mg / kg; toxic symptoms after higher doses are tremor and clonic seizures. At a dose of 10 mg / kg, it increases the spontaneous locomotor activity of the mice in the Dews test; however, at a dose of 50 mg / kg, it strongly suppressed locomotor activity. In the rotating rod test in mice, it has a slight discoordination effect with a maximum at 45 min after administration; median effective dose causing ataxia mice with 50 S / ED _5Q / 62 mg / kg. In rats at doses of 20 and 50 mg / kg, the ulcerogenic effect of reserpine significantly antagonizes. It suppresses reserpine ptosis in mice at up to a relatively high dose of 100 mg / kg.

At a dose of 10 mg / kg, it also antagonizes the hypothermic effect of reserpine in mice (at 73% compared to control). In the rat perfenazine catalepsy test, the substance has an anti-cataleptic effect in most animals in the experiment at doses of 40-50 rag / kg; even at a dose of 20 mg / kg the effect is significant. The lethal effect of yohimbine in mice is inhibited at relatively high doses (ED 50 * 62 mg / kg). The substance acts antihistamine in guinea pig tests. In the histamine aerosol test, the median effective dose is Ρϋ ^ θ / 0.47 rag / kg. In the histamine detoxification test, a dose of 2 mg / kg protects more than 50% of the animals in the experiment.

2-methyl-11- (1-methyl-4-piperidyloxy) -6,11-dihydrodibenzo [b, e] thiepine (1, Ra'CH.j) at 2) was also tested as hydrogen maleate (reported results are in all recalculations based on. Acute Toxicity in Mice, LD ^-375 375 mg / kg. At sublethal doses, the substance acts as a depressant, at higher doses it causes toxic symptoms of convulsion.

*

Discoordination effect in rotating rod test in mice, ED _5q - 54 mg / kg. At a dose of 150 mg / kg, it increases the hypnotic effect of thiopental to twice the control value. Using chemical stimulation (intraperitoneal administration of acetic acid), it shows an analgesic effect in mice; ED50 ₌ 50 mg / kg. In the ulcerogenic effect of reserpine in rats, it has a mild antireserpine effect at 20 mg / kg. It shows antihistamine effect in guinea pig tests.

In the histamine aerosol test, it is 0.32 mg / kg and in the histamine detoxification test, 2 animals in Group 8 protect the 2 mg / kg dose.

11- (1-methylperhydroazepin-4-yloxy) -6,11-dihydrodibenzo (b, e) thiepine (1, R * Η, n »3) was tested as hydrogen maleate. Acute toxicity in mice, LD ^ g s = .188 mg / kg. At sublethal doses it acts as a depressant, then causes toxic symptoms of convulsive character.

In the rotating rod test in mice, it acts slightly discoordination (Εϋ ^ θss 33 mg / kg, maximum 45 min after administration). At a dose of 20 mg / kg it has a statistically significant antagonist effect on the ulcerogenic action of reserpine in rats; at a dose of 50 mg / kg, this effect is very pronounced.

It has a marked anticataleptic effect in rats in the perfenazine catalepsy assay; the mg / kg dose is anticataleptic in virtually all animals in the group.

It is a moderate antihistamine: in a histamine aerosol test in guinea pigs, its PD _{5q is} 0.34 mg / kg; in the guinea pig histamine detoxification test, a dose of 2 mg / kg provides full protection in 50 * animals.

2-methyl-11- (1-methylperhydroazepin-4-yloxy) -6,11-dihydrodibenzo [b, e] thiepine (R, CH2) n-3] was also tested as hydrogen maleate. Acute Toxicity in Mice, LD 50 g-260 mg / kg. The toxic effects of sublethal doses are similar to those of the foregoing. Antireserpine effect: a dose of 50 mg / kg inhibits the slightly ulcerogenic effect of reserpine in rats. Antihistamine effects: in a guinea pig histamine aerosol test, PD ₅₀ e 0.41 mg / kg; in the guinea pig histamine detoxification test, 4 animals of Group 7 protect the 10 mg / kg dose.

The compounds of formula (I) of the invention are amenable to nucleophilic substitution by 11-chloro-6,11-dihydrodibenzo [b, e] thiepine substitution reactions. Seidl V. et al., Monatsh. Chem.

96, 650 (1965) or in-situ 6,11-di-dihydrodibenzo [b, e] -thiepin-11-ol methanesulfone esters prepared by Rajsner M., Protiva M., Cesk. Parm. 11, 404 (1962) and 2-methyl-6,11-dihydrodobenzo [b, e] thiepin-11-ol (Rajsner M. et al., Collect. Czech. Chem. Commun. ’

34, 1015, 1969 (with the corresponding aminoalcohols, i.e. 1-methylpiperidin-4-ol) (commercial product) and 1-methylperhydroazepin-4-ol (Ebiiother A., Jucker E., Hely. Chim. Acta 47, 745 (1964)].

In the first case, the reaction is carried out, for example, in boiling toluene and in the presence of anhydrous potassium carbonate. In the latter case, the above-mentioned amino alcohols are converted by reaction with methanesulfonyl chloride in pyridine into methanesulfone esters which are not isolated and treated by directly adding said amino alcohols to the reaction mixture and heating to 70-80 ° C.

In both cases, crude oily bases of formula I are obtained, which can be purified by chromatography. The molecules of perhydroazepine derivatives of formula X (n → 3) contain two centers of asymmetry and the products are therefore mixtures of two racemates. All bases provide crystalline maleates which are suitable for pharmacological testing and for the manufacture of dosage forms by neutralization with maleic acid. Reactions with alkyl halides, especially methyl iodide, give base I the corresponding quaternary salts, especially the methiodides. The ether bond in the compounds of formula I is highly labile, which is manifested by instability and cleavage under the action of stronger acids. All of the compounds of the invention are novel; their identity was assured by analyzes and spectra.

The following examples are merely illustrative of the methods of preparation of the compounds of the invention, but are not intended to exhaust all of the possibilities of these methods.

EXAMPLE 1 11- (1-methyl-4-piperidyloxy) -6,11-dihydrodibenzo [b, e] thiepine (1, Re H, na2)

To a solution of 2.1 g of 1-methylpiperidin-4-ol in 10 ml of xylene was added 1.8 g of anhydrous sodium carbonate with stirring, followed by a solution of 4.1 g of 11-chloro-6,11-dihydrodibenzo [b, e] thiepine. in 25 ml xylene. The mixture was heated under reflux for 7 h. After standing overnight, it is washed with 50 ml of water and the bases are removed from the organic phase by shaking with a solution of 3.5 g of (+) - tartaric acid in 50 ml of water.

The aqueous tartrate solution was separated, basified with aqueous ammonia, and the liberated bases were isolated by extraction with dichloromethane. The extract was washed with water, dried over potassium carbonate and evaporated under reduced pressure. The residue was dissolved in chloroform containing 5% methanol and applied to a 10 g silica gel column. The column is washed with a total of 350 ml of said solvent mixture. Evaporation of the filtrate gave 3.95 g (73%) of a chromatographically uniform oil base.

Dissolve in 5 ml of ethanol and neutralize with a solution of 1.90 g of maleic acid in an additional 5 ml of ethanol. After addition of 40 ml of ether, crystallization of the hydrogen maleate occurs, which is completed by standing overnight. 4.5 g of hydrogen maleate melting at 179-182 ° C are obtained by suction. Recrystallization from ethanol / ether gave an analytically pure salt, m.p. 180-182 ° C.

Example 2

2-methyl-11- (1-methyl-4-piperidyloxy) -6,11-dihydrodibenzo (b, e) thiepin (X, R 5 · CH 3, n 2)

To a solution of 11.7 g of 2-methyl-6,11-dihydrodibenzo [b, e] thiepine-11-ol in 30 ml of pyridine was added dropwise 6.3 g of methanesulfonyl chloride dropwise over 10 minutes, the temperature spontaneously rising to about 65 °. C. The mixture was stirred without heating for 4 h and left to stand overnight. Then 11.5 g of 1-methylpiperidin-4-ol are added, heated to 75-80 ° C and stirred at this temperature for 6 hours. After standing overnight, the mixture is partitioned by shaking between 100 ml of dichloromethane and 100 ml of water. The aqueous phase is extracted three more times with 25 ml of dichloromethane, the organic phases are combined, washed with 50 ml of saturated sodium chloride solution, dried over potassium carbonate and evaporated under reduced pressure. The residue is chromatographed on a column of 110 g of silica gel (Merck). By eluting with benzene, 2.2 g of less polar impurities were separated and then chloroform, to which 3% methanol was added later, eluted with 12.1 g (71%) of a chromatographically homogeneous oily base. This was dissolved with heating, together with 4.2 g of maleic acid in 15 ml of ethanol and addition of 30 ml of ether and cooling, to give the resulting hydrogen maleate to crystallize 14.2 g, m.p. 184 DEG-186 DEG C. (ethanol-ether).

Example 3 11- (1-methylperhydroazepin-4-yloxy) -6,11-dihydrodibenzo [b, e] thiepin (X, RaH, n = 3).

A) A mixture of 6.2 g of 11-chloro-6,11-dihydrodibenzo [b, e] thiepine, 50 ml of xylene, 3.88 g of 1-methylperhydroazepin-4-ol and 2.76 g of anhydrous potassium carbonate is boiled with stirring 10 hours under reflux. After cooling, it is washed with 120 ml of water and the base is taken from a xylene solution into a solution of 10 g of (+) - tartaric acid in 150 ml of water. From the separated aqueous solution, the bases are liberated with excess aqueous ammonia and isolated by extraction with dichloromethane.

The extract was dried over potassium carbonate and evaporated. The residue was dissolved in benzene and the solution was applied to a column of 25 g silica gel (Merck). Elution with benzene yields 0.7 g of low polar impurities and then elutes 1.5 g of the desired, chromatographically uniform, oily base with a mixture of 90% chloroform, 5% ammonia saturated chlorine and 5% methanol. Neutralization with malannic acid in ethanol and addition of ether gives a crystalline hydrogen maleate, mp 129-132 ° C.

Β / Κ of a solution of 8.0 g of 6,11-dihydrodibenzo [b, e] thiepin-11-ol in 25 ml of pyridine was added with stirring over 10 min 4.6 g of methanesulfonyl chloride. The mixture was self-heated to 50 ° C, stirred without heating for 4 h and then left to stand overnight. While stirring, 6.8 g of 1-methylperhydroazepin-4-ol is added and heated at 75-80 ° C for 6 hours. After standing overnight, it is partitioned between 100 ml of dichloromethane and 100 ml of water by shaking.

The aqueous phase is extracted twice more with a small amount of dichloromethane and the combined dichloromethane phases are washed with 50 ml of saturated sodium chloride solution, dried over potassium carbonate and evaporated. The residue is chromatographed on a 70 g silica gel column. As in the previous examples, 5.5 g (35%) of a homogeneous oil base is obtained. Neutralization with maleic acid gives crystalline hydrogen maleate / t. 128-131 ° C), identical to the substance prepared according to A.

In order to prepare the quaternary salt, 1.7 g of base are dissolved in 10 ml of ethanol, 1.4 g of methyl iodide are added, left at room temperature for 1 hour, then briefly refluxed and allowed to stand overnight. By suctioning, 2.2 g of the methiodide, i.e. 4- (6,11-dihydrodibenzo [b, e] thiepin-11-yloxy) -1,1-dimethylperhydroazepinium iodide, m.p.

Example 4

2-methyl-11- (1-methylperhydroazepin-4-yloxy) -6,11-dihydrodibenzo [b, e] thienyl (1, R5 with CH3, n-3)

To a solution of 8.5 g of 2-methyl-6,11-dihydrodibenzo [b, e] thiepin-11-ol in 25 ml of pyridine was added dropwise 4.6 g of methanesulfonyl chloride dropwise over 15 minutes, stirred for 4 hours without heating and allowed to stand. at rest overnight. 6.8 g of 1-methylperhydroazepin-4-ol are then added and heated at 80 ° C for 6 hours with stirring. After cooling, it is diluted with 100 ml of dichloromethane and washed with 100 ml of water.

The aqueous phase is extracted twice more with dichloromethane, the organic phase is combined, dried and evaporated. The residue is chromatographed on a column of 70 g of silica gel (Merck). 4.9 g of low polar fractions were eluted from the column with benzene and then with chloroform. Then, a mixture of 93% chloroform, 2% methanol and 5% ammonia saturated chloroform eluted with 3.5 g (28%) of a homogeneous oily base. Neutralizing it with 1.47 g of malelic acid in 10 ml of ethanol and diluting the resulting solution with 12 ml of ether slowly crystallizes 2.2 g of hydrogen maleate, m.p. 158-161 ° C.

Claims (1)

SUBJECT OF THE INVENTION 4-Plperidyl and 4-perhydroazepinyl ethers derived from 6,11-dihydrodibenzo [b, e] thiepin-11-oles of formula (I) (1) in which R is hydrogen or methyl and n is 2 or 3, their maleate and quaternary salts.