CS259645B1 - Tricyclic 4-substituted 1-methyltetrahydrothiopyranium iodides - Google Patents

Abstract

The solution falls into the field of drug synthesis. Its subject is tricyclic 4-substituted 1-methyltetrahydrothiopyranium iodides of the general formula I in which —X— denotes —S~·, —CH2CH2—■ or —CH2S— and R denotes a hydrogen atom or methyl. The substances according to the solution are antihistamines devoid of centrally suppressive action, useful in the therapy of allergic diseases. They are accessible from the corresponding tricyclic ketones by reactions with 4-tetrahydrothiopyranylmagnesium bromide, subsequent acid-catalyzed dehydration and finally addition of methyl iodide.

Description

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

(I) wherein - X - is - S -, - CH 2 CH 2 - or - CH 2 S - and R is hydrogen or methyl.

The compounds according to the invention represent a new type of antihistaminic drugs useful in allergic diseases. The fact that they are sulphonium salts (belonging to a wider group of so-called onion salts) makes their inability to penetrate the heinatoencephalic barrier into the brain impeding central suppression, which is a common and unpleasant side effect of the vast majority of known and used antihistamine therapy. pharmaceuticals. In contrast, their peripheral antihistamine effects, evaluated in guinea pigs when administered orally, in particular by the bronchospasm protection test, induced by inhalation of a histamine aerosol (the PD 50 is the intermediate protective dose) are fully developed. Less typical is their effect on the total effect of histamine in guinea pigs. In part, they have marked peripheral anticholinergic activity in the prevention of total acetylcholine (240 mg / kg scj in guinea pigs. Their acute toxicity when administered orally in mice is very low since doses of 500 mg / kg did not act totally in either case; slight attenuation which, however, disappeared within 1 to 2 hours after administration Now, specifically for the individual substances according to the invention (mostly oral administration):

1-Methyl-4- (9-thioxanthylidene) tetrahydrothiopyranium iodide shows a PD 50 = 10 mg / kg in the histamine aerosol test. At the same dose, 25% of the animals protect against the total effect of histamine in the so-called detoxification test. In the prevention of total acetylcholine action, over 50% of animals protect at an oral dose of 10 mg / kg, which is assessed as a significant protective effect (anticholinergic).

4. (10,11-Dihydrodibenzo [a, d] cyclohepten-5-ylidene) -1-methyltetrahydrothiopyranium iodide is more effective in the histamine aerosol test than the previous compound; PD 50 = 1.8 mg / kg. Similar to the previous compound, at a dose of 10 mg / kg, 25% of the animals protect against total histamine exposure in a standard embodiment. It has a marked anticholinergic effect in preventing the total action of acetylcholine; an oral dose of 10 mg / kg protects more than 50% of the animals.

4- (6,11) -Dihydrodibenzo [b, e] thiepin-11-ylidene) -1-methyltetrahydrothiopyranium iodide is the most potent substance in the histamine aerosol test; PD 50 = 1.1 mg / / kg.

1-Methyl-4- (2-methyl-6,11-dihydrodibenzo [b, e] thiepine-11-ylidene) tetrahydropyranium iodide also showed antihlstaminic activity in a guinea pig histamine aerosol test; PD50 = 4.9 mg / kg.

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 known ketones of the general formula II

O (II) wherein X and R denote the same as in Formula I. References to the literature describing the preparation of these ketones are given in the examples. On the other hand, it is necessary to prepare Grignard's 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. of formula (II) with 4-tetrahydrothiopyranylmagnesium bromide prepared The products are secondary alcohols of formula (III)

(III) wherein X and R are again the same as in Formula I. The next step is the acid-catalyzed dehydration of these alcohols, for example by treatment with thionyl chloride. in dichloromethane in the presence of pyridine or treatment with acetyl chloride in boiling chloroform. The products of this second step are the unsaturated sulfides of formula IV

wherein X and R are again the same as in Formula I. The final step is the reaction of the compounds of formula IV with methyl iodide, usually 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 and IV are crystalline. It is often necessary 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 said possibilities.

Example 1

1-Methyl-4- (9-thioxanthylidene) tetrahydrothiopyranium iodide

By reacting 46.8 g of 4-bromototrahydrothiopyran with 19.1 g of magnesium in a mixture of 90 ml of ether and 35 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 major portion of the bromo derivative is added dropwise over 1 hour. The mixture was stirred without heating for 20 minutes and then refluxed for 1 hour to complete reagent formation. It is then diluted with 250 ml of tetrahydrofuran, cooled to 8 [deg.] C and a total of 27.7 g of thioxanthon is added in portions with stirring over a period of 20 minutes (5-10 [deg.] C) (Ziegler JH: Ber. Dtsch. Chem. , 2469, 1890). The mixture is mixed with

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 100 g of ammonium chloride, 250 ml of water, 400 g of ice and 250 ml of benzene. Unreacted magnesium was filtered off and the filtrate was extracted with benzene. The extract is washed with 100 ml of saturated sodium chloride solution, dried over magnesium sulphate and evaporated under reduced pressure. The residue is heated with 40 ml of boiling benzene and the mixture is left to crystallize for two days. 24 g of an inhomogeneous product are obtained by suction and dissolved in 300 ml of boiling benzene. The insoluble matter was removed by filtration, the filtrate was evaporated to a volume of 150 ml and left to crystallize overnight. Filtration gave the first 7.5 g of practically pure 9- (4-tet, rahydrothiopyranyl) thioxanthen-9-ol, mp 157-161 ° C. The combined mother liquors were evaporated and the residue was chromatographed on a column of 250 g of silica gel. Elution with a mixture of benzene and petroleum ether removes less polar contaminants and regenerates 7.8 g of the starting thioxanthone. Elution with benzene alone gave an additional 14.0 g of the desired tertiary alcohol; the total yield is thus 21.5 grams (73% per conversion). Crystallization of the crude product from benzene yields a pure substance melting at 185-187 ° C. Crystallization from benzene can also give a 3: 1 solvate with benzene, which melts at 166-168 ^° C.

A mixture of 13.6 g of the preceding compound, 85 ml of chloroform and 10.2 g of acetyl chloride was stirred and refluxed for 2.5 hours. It is then evaporated under reduced pressure. The residue was quenched with 10 mL of water, basified with 50 mL of 20% sodium hydroxide solution and extracted with dichloromethane. Work-up of the extract yielded 13.2 g of crude 4- (9-thioxanthylidene) tetrahydrothiopyran, which was dissolved in 100 ml of benzene and filtered through a column of 60 g of silica gel, washed with 200 ml of benzene and the filtrate evaporated under reduced pressure; 6 g (66%) of a 6: 1 solvate of the title compound with benzene, mp 170-171 ^° C (benzene).

A mixture of 4.7 g of the preceding compound, 3 ml of benzene, 56 ml of nitromethane and 22.5 g of methyl iodide is left to stand at room temperature for 3 days. The precipitated crystalline 1-methyl-4- (9-thioxanthylidene) tetrahydrothiopyranium iodide is filtered off with suction, washed with benzene and dried in vacuo, 5.7 g (82%), m.p. 175-178 ° C.

Example 2

4- (10,11-Dihydrodibenzo (a, d) cyclohepten-5-yildene) -1-methyltetrahydrothiopyranium iodide

The Grignard reagent is prepared from 10.9 g of magnesium and 26.7 g of bromotetrahydrothiopyran in 50 ml of ether and 30 ml of tetrahydrofuran a.

Dilute with 100 mL of tetrahydrofuran. A solution of 17.3 g of 10,11-dlhydrodibenzo [a, d] cyclohepten-5-one (Mychajlyszyn V., Protiva M .: Coll. Czech. Chem. Commun. 24, 3 955 (1959) in 80 ml of tetrahydrofuran. The mixture was worked up in a similar manner to Example 1. The crude product (29.8 g) was chromatographed on 400 g of silica gel. The less polar component was eluted with a mixture of benzene and petroleum ether and 17.6 g (68% of 5- (4-tetrahydrothiopyranyl) -10,11-dihydrodibenzo [a, d] cyclohepten-5-ol) eluted with benzene. by rechromatography of the sample on neutral alumina (activity II) and then crystallization from a mixture of benzene and hexane, mp 169-170 ° C.

A solution of 8.5 g of the preceding compound and 14.6 g of pyridine in 130 ml of dichloromethane was added dropwise over 80 minutes to a stirred solution of 7.3 g of thionyl chloride in 40 ml of dichloromethane at -10 to -5 ° C. The mixture was stirred at 0 ° C for 1 hour and quenched with 30 g of tartaric acid in 150 ml of water with stirring and cooling over 10 minutes. 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 (9.4 g) was chromatographed on a 130 g silica gel column. Elution with a mixture of 20% benzene and 80% petroleum ether gave 4.2 g (53%) of the desired 4- (10,11-dihydrodibenzo [a, d) cyclohepten-5-ylidene) tetrahydrothiopyran, mp 129-131 ^° C, in the first fractions (hexane).

Reaction of the preceding compound with excess methyl iodide in benzene / nitromethane, similar to Example 1, affords the desired 4- (10,11-dihydrodibenzo [a, d] cyclohepten-5-ylidene) -1-methyltetrahydrothiopyr in 90% yield. anium iodide, mp 158-161 ° C (benzene-nitromethane).

Example 3

4- (6,11-Dihydrodibenzo [b, e] thiepin-11-ylidene) -1-methyltetrahydrothiopyranium iodide

The Grignard reagent was prepared from 3.65 g magnesium and 9.0 g 4-bromotetrahydrothiopyran in a mixture of 25 ml ether and 25 ml tetrahydrofuran; is reacted with a solution of 5.65 g of dibenzo (b, e) thiepin-11 (6H) -one (Rajsner R., Protiva M .: Cesk. Farm. 11, 404, 1962) in 25 ml of tetrahydrofuran and worked up. as in the previous examples. Chromatography of the crude product (11 g) on 200 g of silica gel eluting with benzene removed the less polar fractions in the first fractions and then gave 5.0 g (61%) of crude 11- (4-tetrahydrothiopyranyl) -6,11-dihydrodibenzo [b] e) thiepine-11-ol, which in this state is usable for the next reaction. The sample can be purified by repeated crystallization from a mixture of benzene and hexane, m.p. 150-155 ° C.

A solution of 5.3 g of the crude title compound and 8.7 g of pyridine in 70 ml of dichloromethane was stirred for 30 min. dropwise to a stirred solution of 4.3 g of thionyl chloride in 25 ml of dichloromethane at -5 to 0 ° C. The mixture is then stirred at this temperature for 2 hours, quenched with slow addition of 75 ml of 3% hydrochloric acid while cooling, the aqueous layer is separated, the organic phase is washed with 2% sodium hydroxide solution and water, dried over magnesium sulphate and evaporated. The residue (6.5 g) is chromatographed on a column of 80 g of silica gel. A mixture of 75% benzene and 25% petroleum ether eluted in the first fractions with 4.2 g (84%) of 4- (6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) tetrahydrothiopyran, which melted at 194-196 ° neat. C (cyclohexane).

As in the previous examples, the desired 4- (6,11-dihydrodibenzo (b, e) thiepin-11-ylidene) -1-methyltetrahydrothiopyranium iodide, mp 194, was obtained in 93% yield by reaction of the above sulfide with excess methyl iodide in benzene / nitromethane. to 196 ° C with decomposition.

Example 4 1-Methyl-4- (2-methyl-6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) tetrahydrothiopyranium iodide

As in the previous examples, the Grignard reagent was prepared from 15.5 g of magnesium and 38.0 g of 4-bromotetrahydrothiopyran in a mixture of 70 ml of ether and 30 ml of tetrahydrofuran, diluted with 160 ml of tetrahydrofuran and treated with 25.5 g of 2-methyldibenzoate. [b, e] thiepin-11 (6H) -one (Rajsner M. et al .: Cesk. Farm. 11, 451, 1962) in 100 ml of tetrahydrofuran. Workup gives 50 g of a mixture which is chromatographed on 500 g of silica gel. The less polar admixture was removed by the benzene / petroleum ether mixture and 13.8 g (38 percent) of the desired 11- (4-tetrahydrothiopyranyl) -2-methyl-6,11-dihydrodibenzo [b, e thiepin-11-ol] was eluted with benzene alone. , which was used in the next reaction without further purification. The sample can be purified by repeated crystallization from benzene, m.p. 182-183 ° C.

The previous crude product (11.1 g) was dehydrated similarly as above with 8.7 g of thionyl chloride in 200 ml of dichloromethane in the presence of 17.3 g of pyridine. Similar work-up gave 12.2 g of crude product which was chromatographed on a 110 g silica gel column. Benzene was eluted in the first fractions of 8.4 g (80%) of the desired 4- (2-methyl-6,11-dihydrodibenzo [b, e] - (11-ylidene) tetrahydrothiopyran), which melted at 128 DEG-128 DEG C. after crystallization from benzene / hexane. 131 ^C C.

Analogous to previous cases

259 was obtained by reacting the preceding sulfide with excess methyl iodide in a mixture of benzene and nitromethane in 97% yield of 1-methyl-4- (2-methyl-6,11-dihydrodibenzo [b, e] 45 thiepine-11-ylidene) tetrahydrothiopyranium iodide which crystallizes from a mixture of aqueous ethanol and ether as the monohydrate melting at 140-142 ° C.

Claims (1)

SUBJECT The tricyclic 4-substituted 1-methyltetrahydrothiopyranium iodides of formula I OF THE INVENTION in which —X— is —S—, —CH2CH2—, or —CH2S— and R is hydrogen or methyl.