CS260087B1 - Thienotricyclic 4-substituted 1-methyltetrahydrothiopyranium iodides - Google Patents

Description

The present invention relates to thienotricyclic 4-substituted 1-methyltetrahydrothiopyranium iodides of formula I

(I »in which X represents -S-, -CH 3 or -CO-.

The compounds according to the invention represent a new type of antihistaminic drugs useful in allergic diseases. The fact that they are sulfonium salts (belonging to a wider group of so-called onium salts) determines their inability to penetrate the blood-brain barrier into the brain, which impedes the central suppressive effect, a common and unpleasant side effect of the vast majority of known and antihistaminic therapies. pharmaceuticals. In contrast, their peripheral anthistamine effects, evaluated in guinea pigs when administered orally, in particular by the bronchospasm protection test induced by inhalation of the histamine aerosol (medium protective dose indicated), are fully developed. Their effects on the lethal effect of histamine in guinea pigs and their peripheral antiserotonion activity are also partially proven. In part, they have a pronounced peripheral anti-alcoholergic activity manifesting in the prevention of lethal acetylcholine (240 mg / kg s.c) in guinea pigs.

Their acute oral toxicity in mice is very low; doses of 500 mg / kg are not yet lethal. The only toxic symptom is a slight attenuation, which usually disappears within 1 to 2 hours after administration. The compounds according to the invention have also been shown to have an antimlrobial effect in in vitro tests which could be used as a basis for their usefulness in the chemotherapy of infectious diseases. In particular, for the individual substances according to the invention (mostly oral administration):

4- (4,9-dihydrothieno (2,3-c) -2-benzothiepin-4-ylidene (-1-methyltetrahydrothiopyranium iodide (I, X = S)) results in mild depression of mice following doses of 100 and 500 mg / kg, The compound shows an antihistamine effect in the histamine aerosol test of 5.3 mg / kg and also has a protective effect in the guinea pig histamine detoxification test: a 10 mg / kg dose protects 37.5% At 10 mg / kg, the substance has a protective effect against the toxicity of acetylcholine in guinea pigs (protects 40 S. animals) at a concentration of 50 µg / ml and has an inhibitory effect on the growth of Trichophyton mentagrophytes in an in vitro test.

4- (9,10.dihydro-4H-benzo (4,5) cyclohepta) 1,2-b) thiophen-4-ylidene) -1-metyltetrahydrothiopyraniumjodid (I, X = CH ₂₎ having in the experiment of acute toxicity in mice at doses of 100 to 500 mg / kg similar properties to the previous substance. The IDjq is approximately 2500 mg / kg (after this dose, 50% of the animals are killed between 72 and 96 hours after administration). The substance exhibits an antihistamine effect in a guinea pig histamine aerosol test, with an LD 50 of somewhat greater than 10 mg / kg.

At concentrations ranging from 25 to 50 µg / ml, the compound has an inhibitory effect on the growth of Staphylococcus pyogenes aureus and Trichophyton mentagrophytes in in vitro tests.

1-methyl-4- (10-oxo-9,10-dihydro-4H-benzo) 4,5) cyclohepta-1,2-bthiophen-4-ylidene) tetrahydrothiopyranium iodide I, X = Co). In mice, administration of doses of 100 and 500 mg / kg rarely causes death; in the dose range of 400 to 500 mg / kg, a short-term cushioning effect occurs. It shows an antihistamine effect in a guinea pig histamine aerosol test, Ρϋ ^ θ = 10 mg / kg. The same dose protects 1/8 of the animals from the lethal action of histamine in the guinea pig histamine detoxification test. At a dose of 10 mg / kg, it slightly suppressed serotonin-induced rat paw edema.

The compounds of the formula I according to the invention are accessible, for example, by the synthetic procedure described in the examples. It is based on the known ketones of the general formula XX in which Y is -CH3S12

OCH, (Rajener M. et al., Collect. Czech. Chem. Commun. 32, 2854, 1967), 9,10-dihydrobenzo (4,5) -cyclohepta (1,2-) thiophen-4-one (Bastian JM Ebnther A., Helv. Chim. Acta 49, 214 (1966)) and 10-methoxybenzo (4,5) cyclohepta (1,2-b) thiophen-4-one (Waldvogel E. et al., Helv. Chim Acta 59: 866 (1976)). On the other hand, it is necessary to prepare Grignard reagent from 4-bromotetrahydrothiopyran (Fehnel EA, Lackey PA, J. Am. Chem. Soc. 73, 2 473, 1951) by reacting with magnesium in a mixture of tetrahydrofuran and ether. ketones of formula IX with 4-tetrahydrothiopyranylmagnesium bromide prepared The products are secondary alcohols of formula III

(III),

wherein Y denotes the same as in formula II. The next step is acid-catalyzed dehydration of these alcohols, for example by treatment with thionyl chloride in dichloromethane in the presence of pyridine or with hydrochloric acid in boiling dioxane. In the case of a compound of the formula III in which Y ' -CH " alcohol to break down

OCH, enol ether, so that in the other cases the products of this second stage are unsaturated sulfides of the general formula IV

in which X denotes the same as in formula I. The final step is the reaction of the compounds of formula IV with methyl iodide, for example carried out in a mixture of benzene and nitromethane at room temperature using a large excess of methyl iodide. This reaction results in crystalline sulfonium iodides of the formula I.

All compounds of formulas I to IV are crystalline. It is usually expedient to use silica gel chromatography to isolate them and obtain them in a pure state. All substances described in the invention are novel; their identity was assured by analytical and spectral methods. Further details of the preparation thereof are given in the examples, which are merely illustrative of the possibilities of the invention and are not intended to limit the scope of the invention to the possibilities described.

he added

4- (4,9-dihydrothieno (2,3-c) -2-benzothiepin-4-ylidene) -1-methyltetrahydrothiopyranium iodide (I, X-S,

By reacting 34.7 g of 4-bromotetrahydrothiopyran with 14.1 g of magnesium in a mixture of 60 ml of ether and 25 ml of tetrahydrofuran, a Grignard reagent is prepared. Magnesium is activated by washing with chloroform and then with an iodine bean. The reaction is started with about 10% of the bromo derivative initiated with a few drops of 1,2-dibromoethane. The reaction then proceeds without heating (reflux) and the bulk of the bromo derivative is added dropwise over 1 h.

The mixture was stirred without heating for 20 minutes and then refluxed for 1 hour to complete reagent formation. It is then diluted with 100 ml of tetrahydrofuran, cooled to 5 ° C, and a solution of 22.5 g of thieno (2,3-c) -2-benzothiepin-4 (9H) is added dropwise with stirring over 20 min (5-10 ° C). -one in 85 ml of tetrahydrofuran. The mixture is kept at 5-10 ° C for a further 2 hours, left overnight at room temperature and finally refluxed for 15 minutes.

After cooling, it is poured into a mixture of 75 g of ammonium chloride, 200 ml of water, 300 g of ice and 200 ml of benzene. The unreacted magnesium was filtered off and the aqueous phase of the filtrate was extracted with benzene. The benzene phases are combined, washed with 100 ml of saturated sodium chloride solution, dried over magnesium sulphate and evaporated under reduced pressure. The residue (46.3 g of the mixture) is chromatographed on a column of 550 g of silica gel. Elution with a mixture of benzene and petroleum ether and the first fractions of benzene alone removes less polar by-products.

Continued elution with benzene gave 9.6 g (30%) of the desired 4- (4-tetrahydrothiopyranyl) -4,9-dihydrothieno (2,3-c) -2-benzothiepin-4-ol, which crystallized from toluene and melts at 201-202 ° C in pure state.

A solution of 3.7 g of the preceding compound and 5.9 g of pyridine in 90 ml of dichloromethane was added dropwise over 80 minutes to a stirred solution of 2.9 g of thionyl chloride in 20 ml of dichloromethane at -10 to -5 ° C.

The mixture was stirred at 0 ° C for 1 h and quenched with stirring with a solution of 15 g of tartaric acid in 75 ml of water, which was added over 10 min. The mixture was extracted with dichloromethane, the extract was washed with 2% potassium hydroxide solution and water, dried over magnesium sulfate and evaporated.

The residue (4.2 g) is chromatographed on a 50 g silica gel column. Elution with a mixture of 25% benzene and 75% petroleum ether removes a small amount of by-product and then washes with benzene alone 2.9 g (83%) of the desired 4- (4,9-dihydrothieno (2,3-c) -2-benzothiepine). 4-ylidene) tetrahydrothiopyran, which crystallizes from benzene and melts in the pure state at 175-177 ° C.

A mixture of 2.1 g of this material, 20 ml of benzene, 15 ml of acetone and 10 g of methyl iodide is allowed to stand at room temperature for 4 days. The precipitated crystalline end product (I, X → S) is filtered off with suction, washed with benzene and dried in vacuo. It was obtained as a 6: 1 solvate with benzene in a yield of 2.8 g (87%), m.p. 173 DEG-174.5 DEG (acetone-benzene).

Example 2

4- (9,10-dihydro-4H-benzo (4,5) cyclohepta (1,2-b) thiophen-4-ylidene) -1-methyltetrahydrothiopyranium iodide (X, X = CH 3) ·

The Grignard reagent solution is prepared as in Example 1 by reacting 35.8 g of 4-bromotetrahydrothiopyran with 14.6 g of magnesium in a mixture of 70 ml of ether and 30 ml of tetrahydrofuran, diluted with 200 ml of tetrahydrofuran and added dropwise over 60 min. with stirring, a solution of 21.4 g of 9,10-dihydrobenzo (4,5) cyclohepta (1,2-b) thiophen-4-one in 65 ml of tetrahydrofuran. The temperature is maintained at 3 to 5 ° C. The mixture was then stirred at room temperature for 30 min and left in the refrigerator overnight. On the second day, 75 g of ammonium chloride are poured into a stirred mixture,

200 ml water, 300 g ice and 200 ml benzene. The unreacted magnesium was filtered off with suction and the aqueous layer of the filtrate was extracted with benzene. The combined benzene phases are washed with 100 ml of saturated sodium chloride solution, dried over a mixture of sodium sulphate and magnesium sulphate and evaporated under reduced pressure.

The residue (38.4 g of the mixture) is chromatographed on a column of 500 g of silica gel. Benzene-petroleum ether mixtures with increasing benzene content eluted less polar by-products and then benzene was eluted with 11.9 g (38%) of the desired 4- (4-tetrahydrothiopyranyl) -S, 10-dihydro-4H-benzo (4,5). 1-cyclohepta (1,2-b) thiophen-4-ol, which crystallizes from benzene and melts in the pure state at 189-191 ° C.

A solution of 8.6 g of the preceding compound and 14.6 g of pyridine in 130 ml of dichloromethane is added dropwise with stirring to a solution of 7.3 g of thionyl chloride in 40 ml of dichloromethane at -10 to -3 ° C over 50 minutes.

The mixture is stirred for a further 2 hours at 0-5 ° C and a solution of 30 g of tartaric acid in 150 ml of water is added with stirring. The organic layer was separated, the aqueous was extracted with dichloromethane, the combined dichloromethane phases were washed with water, 2% sodium hydroxide solution and dried over a mixture of sodium sulfate and magnesium sulfate. The residue (9.9 g) is evaporated under reduced pressure and chromatographed on a column of 150 g of silica gel. 6.3 g (78%) of the desired 4- (10,11-dihydrobenzo (4,5) cyclohepta (1,2-b) thiophen-4-ylidene) tetrahydrothiopyran, which crystallizes from a mixture of benzene and hexane and melted at 139-141 ° C in pure state

To a solution of 3.6 g of this material in a mixture of 18 ml of benzene and 50 ml of nitromethane was added 17 g of roethyl iodide and the mixture was left at room temperature for 5 hours. The precipitated crystalline product is then filtered off with suction, washed with benzene and dried in vacuo. 4.8 g (90%) of the desired end product of formula (X, X → Cl 2) are obtained, which melts at 167.5-170 ° C.

Example 3 1-methyl-4- (10-oxo-9,10-dihydro-4H-benzo (4,5) cyclohepta (1,2-b) thiophen-4-ylidene) tetrahydrothiopyranium iodide (I, X-CO).

As in the previous examples, the Grignard reagent was prepared by reacting 41.9 g of 4-bromotetrahydrothiopyran with 17.1 g of magnesium in a mixture of 85 ml of ether and 110 ml of tetrahydrofuran, diluted with 200 ml of tetrahydrofuran and cooled to 5 ° C with stirring for 30 min. 24.2 g of 10-methoxybenzo (4,5) cyclohepta (1,2-b) thiophen-4-one is added portionwise; the temperature is maintained between 5 and 10 ° C. The reaction mixture was then allowed to stand for 1h without cooling and left in the refrigerator overnight. It is decomposed by pouring into a mixture of 80 g of ammonium chloride, 200 ml of water and 300 g of ice.

300 ml of benzene are added with stirring. The unreacted magnesium was removed by suction, the benzene layer was separated from the filtrate, the aqueous was extracted with benzene, the benzene phases were combined, washed with 100 ml of water, dried over sodium sulphate and magnesium sulphate and evaporated under reduced pressure. The residue (44.1 g of the mixture) is chromatographed on a column of 500 g of silica gel. Elution with a mixture of benzene and petroleum ether removes the less polar by-products and washes with benzene 28.4 g of crude product which is recrystallized from 70 ml of benzene. 21.8 g (27%) of pure desired 4- (4-tetrahydrothiopyranyl, -10-methoxy-4H-benzo (4,5) cyclohepta (1,2-b) thiophen-4-ol) melting at 208 was obtained. to 210 ° C.

A mixture of 80 ml of hydrochloric acid, 200 ml of dioxane and 21.8 g of the previous substance is stirred and refluxed for 1.5 hours and then poured into 800 ml of water. The product was extracted with chloroform, the extract was washed with saturated sodium bicarbonate solution, dried over a mixture of sodium sulfate and magnesium sulfate, and evaporated under reduced pressure. The residue was dissolved in 150 ml of benzene, 40 g of silica gel was added and the mixture was evaporated to dryness in vacuo. The solid which constitutes the anchored mixture on silica gel is applied to a column of 280 g of silica gel. The column was eluted first with a mixture of benzene and petroleum ether, resulting in the removal of a small amount of less polar impurities, and eluting with Bamboo benzene was 10.1 g (51%) of almost pure 4- (10-oxo-9,10-dihydro-4H-benzo ( 4,5) cyclohepta (1,2-b) thiophen-4-ylidene) tetrahydrothiopyran, which melts at 196-199 ° C after recrystallization from benzene / hexane.

The above product (5.5 g) was dissolved in 55 ml of benzene with heat, after cooling 40 ml of methanol and 12.5 g of methyl iodide were added. The mixture is allowed to stand at room temperature for 4 days. Aspiration, washing with benzene and drying in vacuo afforded 5.1 g of the desired end product of formula (I, X → Co), m.p. Mp 195-199 ° C.

Claims (1)

OBJECT OF THE INVENTION A thienotricyclic 4-substituted 1-methyltetrahydrothiopyranium iodide of the formula I wherein X is -S-, -GH- or -CO-.