CS266761B1 - Tricyclic 3-quinuclidinylethers,their hydrogenmaleates and methods of their preparation - Google Patents

Abstract

The solution lies in the field of synthetic drugs. The subject matter of the present invention is the antimicrobial and tolymoleptically active 3- [6,11-dihydrodiobenzo [b] thiophen-1-yloxy / quinuclididines, optionally substituted at the 2-position of the skeleton with a halogen atom or methyl, as well as their hydrogenation and final processes for their preparation. . These consist in reacting the reactive esters of 6,1-dihydrodlbenzo [b, e] -lephenyl-1-ol, i.e. the pure 11-chloro-llaves used or the 11-methanesulphonyloxy derivatives used in the presence of alkali. reagents, i.e., alkali or pyridine carbonates at temperatures of 100 DEG to 120 DEG C. The materials obtained are mixtures of two racemates which can be partially or completely purified by crystallization of bases or hydrogen maleate.

Description

The invention relates to tricyclic 3-chlorocynyl ethers of the formula I

in which R represents a hydrogen atom, a halogen atom or a methyl group, their hydrogen maleates and processes for their preparation.

The compounds of the formula I according to the invention and their hydrogen maleates show marked antihedral and antireserpine effects in animal tests, so that they can be characterized as antihistamines and thymoleptics. Because their toxicity is mild and their central depressant action is weak, the compounds according to the invention are suitable for practical use in the treatment of allergic diseases and in mental depressive conditions.

The compounds according to the invention have been tested pharmacologically in the form of salts (predominantly hydrogen maleate) and have been administered generally orally. The following are the significant effects of the individual compounds of the formula I (stated doses in mg / kg. They are converted to bases).

3- (5,11-Dihydro-dibenzo [b, e) thlepin-11-yloxy] quinuclidine (1, R = H). Acute toxicity in mice, LD 50 = 165 mg / kg. In a histamine aerosol test in guinea pigs, a dose of 1 mg / kg has a protective effect in more than 50% of the animals. In a gustamine detoxification test in guinea pigs, 10 mg / kg protects 3% of animals from the lethal effect of hlstamine. In the rat test for the ulcerogenic effect of reserpine, a dose of 2D mg / kg has a marked antireserpine and protective effect. Dissociation effect in the rotating rod test in mice is only low; ED 2 = 3θ, θ mg / kg (60 min after administration).

3- [2-phlethyl-10,11-dihydro-benzo [b, e] thiepin-11-yloxy] -quinuclidine (1, R = CH 2).

Acute toxicity in mice, LD50 = 225 mg / kg. In a histamine aerosol test in guinea pigs, the mean protective dose of PD ^ g is 0.32 mg / kg. In a test in guinea pigs detoxlkace hlstaminu Intense has a protective effect of the PD-G = 33 mg / kg ⁱⁿ Test ulcerogenic effects of reserpine in rats is 20 mg / kg significantly and protektlvní antireserpine effect.

3- (2-Chloro-10,11-dihydrodibenzo [b, e] thieplin-11-yloxy) -quinuclidine (1, R = Cl). Acute Toxicity in mice, LD ^ g = 166 mg / kg. Antifungal activity It is weaker than the previous substances (in the histamine aerosol test in guinea pigs, a dose of 1 mg / kg protects only 25% of the animals), but the overall profile of the substance as a potential antidepressant is more pronounced. In the test for the ulcerogenic effect of reserpine in rats, a dose of 5 mg / kg already has a marked antireserpine and protective effect. In the mouse reserpine ptosis test, a dose of 30 mg / kg has a significant antireserpine effect. In the perphenazine catalepla test in rats, the substance was anticataleptic in 90% of animals at an oral dose of 50 mg / kg. In the test rotating! rods in mice has only a low long-acting effect (ED? At 10 mg / kg, it significantly blocks tremor and other oxotremorine-induced cholinomimetic manifestations in mice.

3- (2-Bromo-10,11-dihydro-benzo [b, e] thiepin-11-yloxy] -quinuclidine), R = Br]. Acute toxicity in mice, LDLg = 221 mg / kg. In a histamine aerosol test in guinea pigs, a dose of 1 mg / kg has a protective effect in more than 50% of the animals. In a pharyngeal detoxification test in guinea pigs

266761.

a dose of 10 mg / kg protects 25% of the animals from lethal exposure to hlstamln. In the rat ulcerogenicity test, a dose of 20 mg / kg has a significant anniererep effect. The dissociating effect in the rotating rod test in mice is weak, the ED 50 is 49.7 mg / kg.

The processes for the preparation of the compounds of the formula I, which are also the subject of the invention, use in particular two methods. The first is based on 11-chloro-10,11-dihydrodibenzo [b, e] thiepines of the general formula II in which R is the same as in the formula I. The compounds of the general formula II are known in some cases (see, for example, Seidlová V. et al. . (Flonatsh.Chem. 96, 650, 1965 /. As long as their preparation have been described, it is mentioned in the Examples. These react with chlorinated 3-chlnuklidíndlem / LH Stembach ^first Kaiser, S. J. Am. 74, 2215, 1952 (in the presence of anhydrous alkali carbonates in suitable inert solvents at elevated temperatures. It is preferred to work, for example, in dioxane at the boiling point of this solvent.

The second method is based on 10,11-dihydrodibenzo [b, e] -thleplin-11-ol of the general formula III

GCaXr ^{mi /} ·

OH in which R denotes the same as in formula I. These alcohols are also known in part (see, for example, Bartl V. et al., Collect. Czech.Chem.Commun. £ 9, 1S16, 19B4 /; if not already described, their preparation is included in the examples. The alcohols of formula III are previously converted to methanesulfonates in pyridine by treatment with methanesulfonyl chloride in pyridine and treated in situ with 3-quinuclidinol. The reactions take place in pyridine, which binds the resulting methanesulfonic acid; operating at temperatures of 100 to 120 ° C, preferably at the boiling point of pyridine.

In both methods, inhomogeneous products are obtained which are mixtures of basic and neutral substances. These can either be separated by extracting from solutions in hydrophobic solvents bases into aqueous solutions of weak organic acids. Preferably, a solution of tartaric acid is used, since the aqueous solutions of the waves of the compounds of the formula I are relatively stable. Aqueous solutions of strong mineral or strong organic acids cannot be used because they cleave the ether bond of the compounds of formula I. From aqueous solutions of tartrates, the bases of formula I are liberated with aqueous ammonia and purified by chromatography on silica gel. It is also possible to chromatograph crude mixtures of neutral and basic products, the less polar neutral components being eluted first.

The substances of formula I are basic in nature and neutralized. acids provide the corresponding salts. Of these, the hydrogen maleates which form part of the invention are particularly preferred. (The base molecules of formula I contain two centers of chirality and accordingly the crude products are mixtures of two racemates. Crystallization of bases or salts can strongly enrich these mixtures on one component or even prepare homogeneous comoonents; The compounds of the formula I are new and their identity has been established by analyzes and spectra, and further details of the process for their preparation are given by way of example, which, however, is merely illustrative of the possibilities of the invention.

266761 Example 1

3- (6,11-D-dihydro-dibenzo [b, e) thiazol-11-yloxy] -quinuclidine [1, R = H]

To a solution of 4.5 g of 3-chlouclidinol in 65 ml of dioxane was added 4.9 g of anhydrous potassium carbonate, followed slowly by stirring 8.7 g of 11-chloro-10,11-dihydrodibenzo [b, e] thlepin (literature cited). /. The mixture was refluxed for 1 h, part of the dioxane was evaporated in vacuo and the residue partitioned between water and benzene. The benzene solution is washed with water and the bases are extracted by shaking into a solution of 10 g of tartaric acid in 100 ml of water. The separated aqueous solution was basified with aqueous ammonia and the liberated bases were extracted with dichloromethane. The extract was worked up to give 6.8 g of inhomogeneous product, which was chromatographed on a 60 g silica gel column. Elution with a mixture of 90% chloroform, 5% chloroform saturated with aqueous ammonia and 5% methanol gives 6.1 g (51%) of a homogeneous desired base which crystallizes from ethanol and melts constantly at 151-153 ° C. For characterization, it is neutralized with 2,4,6-trinitrobenzoic acid in a mixture of ethanol and ether to give 2,4,6-trinitrobenzoate, which melts at 101-103 ° C.

Example 2 '

3- (2-methyl-6,11-dihydrohydrobenzo [b, e) thlepin-11-yloxy] quinuclidine [1, R = CH3]

In a manner similar to Example 1, 7.9 g of 3-chlorocidinol are reacted with 14.8 g of 11-chloro-2-methyl-6,11-dihydrodibenzo [b, e] -thiepine and 7.85 g of potassium carbonate in 120 ml of dioxane at 90 ° C (reaction time 2h). Similar work-up gave the crude basic product (8.9 g), which was chromatographed on 45 g of silica gel. 7.4 g (37%) of the homogeneous desired base are obtained, which crystallizes from 2-propanol or from ethanol and has a constant m.p. of 176 DEG-178 DEG. Neutralization with maleic acid in a mixture of 95% ethanol and ether gives the hydrogen maleate hemihydrate, mp 193-196 ° C (ethanol ether).

The starting 11-chloro-2-methyl-6,11-dihydrohydrobenzo [b, e] thlepin, which has not yet been described in the literature, is prepared by the following procedure from the known 2-methyl-6,11-dihydrohydrobenzo [b, e] thlepin. / thiepin-ll-olu / Rajšner ΓΠ. et al., Collect.Czech.Chern.Commun. 34, 1015.1969 /:

To a solution of 36.3 g of 2-methyl-6,11-dihydrodibenzo [b, e] thlepin-11-ol in 450 ml of benzene was added 20 g of anhydrous calcium chloride, and the suspension was saturated with anhydrous hydrogen chloride for 2.5 h. After standing overnight: the calcium chloride is filtered off, the filtrate is evaporated under reduced pressure and the residue is crystallized from 65 ml of cyclohexane. 37.4 g (96%) of the desired substance melting at 117 DEG-118 DEG C. are obtained.

Example 3

3- (2-Chloro-6,11-dihydro-dibenzo [b, e) thieprop-11-yloxy] -quinuclidine [1, R = Cl]

To a stirred solution of 12.5 g of 2-chloro-6,11-dihydrodibenzo [b, e] -thiepyridin-11-ol (cited above) in 75 ml of pyridine was added dropwise 6.3 g of methanesulfonyl chloride, and the mixture was stirred for 1 hour at room temperature. 70 ° C and 2 h at room temperature. After standing overnight, 8.8 g of 3-quinuclidinol are added and the mixture is heated under reflux at 110 DEG-115 DEG C. for 5 hours with stirring. After cooling, the mixture was diluted with 100 ml of water and extracted with chloroform. The extract was washed with water, dried and evaporated under reduced pressure. The residue is chromatographed on a 180 g silica gel column. The neutral components of the mixture were removed by elution with benzene, and then a mixture of 93% chloroform, 5% chloroform saturated with aqueous ammonia and 2% methanol eluted 8.2 g (46%) of the desired base, which crystallized from ethanol, m.p. 150-152 ° C. It gives hydrogen maleate melting at 177-180 ° C (ethanol ether).

Example 4

3 ^- / 2-Bromo-6,11-dihydrodibenzo / b, e / thlepln-l-yloxy / -quinuclidin / 1, R = Br /

Similarly to the previous example, 15.4 g of 2-bromo-6,11-dihydrodibenzo [b, e] thiepin-11-ol were reacted with 6.3 g of methanesulfonyl chloride in 50 ml of pyridine, and 6.9 ml of the reaction mixture was added to the reaction mixture. g of 3-quinuclidinol. A similar work-up gives 20.1 g of a mixture of basic and neutral products, which is chromatographed on 150 g of silica gel. Chromatography procedure It is similar to the previous example. 13.6 g of crude desired product (65%) are obtained, which is extracted with 30 ml of boiling toluene, the insoluble matter is removed by filtration and the filtrate is cooled to give 8.3 g of crystalline product, which can be further recrystallized from ethanol and which then melts at 157-160 ° C. It gives hydrogen maleate melting at 166-190 ° C (ethanol ether).

The starting 2-bromo-6,11-dihydrodibenzo [b, e] thiepin-11-ol can be prepared from the known 2-bromodibenzo [b, e] thiepin-11 (6H) -one / Rajšner ΙΪ1. et al..Czech.Farm. 11, 451, 1962 / as follows:

To a solution of 50.0 g of 2-bromodebenzo [b, e] thiepin-11 (6H) -one vil of warm ethanol was added a solution of 5.0 g of sodium borohydride in 20 ml of water containing 2 drops of 20% hydroxide solution with stirring over 20 minutes. sodium. The mixture was refluxed for 2 hours, the ethanol was evaporated under reduced pressure and the residue partitioned between water and chloroform. Treatment of the organic phase together with the undissolved crystalline substance gives 50.3 g (theoretical yield) on the desired substance, m.p. 166.5-167 ° C (benzene).

Claims (3)

OBJECT OF THE INVENTION Tricyclic 3-quinuclidinyl ethers of the general formula I OaZAAr (i) in which R represents a hydrogen atom, a halogen atom or a methyl group and their hydrogen maleates. 2. A process for the preparation of the compounds according to claim 1 of the formula I, characterized in that 11-chloro-10,11-dihydrohydibenzo [b, e] thtepines of the formula II (11) in which R is the same as in the formula I are introduced for reaction with 3-chlorocidinol in the presence of anhydrous alkali carbonates in inert solvents, preferably in boiling dioxane. 3. A process for the preparation of the compounds according to claim 1 of the formula I, characterized in that 10,11-dihydrodibenzo [b, e] thiepin-11-ols of the formula III are used. in which R is the same as in formula I, are converted by treatment with methanesulfonyl chloride in pyridine to methanesulfonates which are treated in situ with 3-quinuclidinol at temperatures of 100 to 120 ° C.