CS225894B1 - Method of preparing 3-/4-methylpiperazino-dibenzo-/b,f/-1,2,4-triazolo/4,3-d/-1,4-thiazepines and methansulphonates thereof - Google Patents

Description

The compounds of formula (I) are intermediates in the synthesis of pharmacodynamically active drugs, and their methanesulfonates are themselves highly fermacologically active. Even low doses have effects similar to those of pentetrazole or tryptamine (seizure effect). When administered intravenously, they have both a short-term hypotensive effect and a hypertensive effect in normotensive rats. In the in vitro test they show a spasmolytic effect, predominantly anticholinergic, which in one case is also confirmed by a mydriatic effect.

In one case, a hypoglycaemic effect was reported, in one case a positive inotropic (cardiostimulatory) effect. The individual substances according to the invention tested in the form of dimethanesulfonates can be mentioned as follows:

3- (4-Methylpiperazino) dibenzo (b, R) -1,2,4-triazolo (4,3-d) -1,4-thiazepine (I, R ^{* 1 * * * V} = R ^ = = H Acute oral toxicity in mice, between 50 and 100 mg / kg (100 mg / kg dose) induces 100 mort mortality, 50 mg / l g g induces mortality in some animals). Acute IV toxicity in mice, LD ^ q is 1.4 mg / kg (female); when administered iv to rat females, the LD ₅₀ is 1.35 mg / kg. In both animal species, the substance induces tonicextensor convulsions similar to those observed with pentetrazole.

6-Chloro-3- (4-methylpiperazino) dibenz (b, f) -1,2,4-tria pyrazolo (4,3-d) -1, 4-thia-benzodiazepine (X, R ¹ = Cl, R ² = H): Acute toxicity in female mice by intravenous administration, LDjq = 0.4 mg / kg; in LLjq rats is 0.26 mg / kg given iv administration. Accompanying effects of toxic doses are tonic-extensor convulsions of a similar type to pentetrazole. At an oral dose of 60 mg / kg to mice, similar convulsions were observed and 60% of the animals died. The iv dose caused short-term, deep reductions in blood pressure in normotensive rats. In in vitro assays (on isolated rat duodenum), the compound inhibits smooth muscle contractions induced by both acetylcholine and barium chloride at concentrations of 1 to 10 µg / ml. On an isolated rabbit atrial atrium preparation, the compound at a concentration of 10 to 25µg / ml has a positive inotropic, ie, cardiostimulatory effect. Following an oral dose of 0.4 mg / kg in rats, blood sugar levels are reduced by 15 to 22% after 2 h (results of two experiments); already an oral dose of 0.2 mg / kg po causes a decrease in blood glucose of 18%.

12-Chloro-3- (4-methylpiperazino) dibenzo (b, f) -1,2,4-triazolo- (4,3-d) -1,4-thiazepine (1 ', r' = H, R ² = Cl): Acute toxicity in rats by iv administration, LD ^ q = 7.8 mg / kg; concomitant effects of toxic doses are convulsions of a similar type to those after tryptamine (clonic to rolling).

In mice, LD 50 is 12.5 mg / kg v. At an oral dose of 40 mg / kg, the substance inhibits the locomotor activity of the mice in a Dews beam test to less than 50% compared to the control. At doses of 20 and 40 mg / kg p.o. the substance induces ataxia in 20 resp. 30% of mice in the rotating rod test.

At a dose of 2.5 mg / kg i.v. it induces abrupt and short-term increases in blood pressure in normotensive rats. At concentrations of 0.1 to 1.0 µg / ml, the substance has a spasmolytic effect on isolated rat duodenum against acetyloholin contractions which is specific (anticholinergic) because the same concentration does not affect barium chloride contractions. The anti-allergic nature of the effects of the substance is also confirmed by the mydriatic effect on the mouse pupil, which is manifested in intraperitoneal doses of 1.0 to 2.5 mg / kg.

The compounds of formula I have been incorporated into Upjohn Co. patents and applications. (Belg. 795,790, West German Publication No. 2,306,762, U.S. 3,850,942 and U.S. 3,886,175; Chem. Abstr. £ 2, 126 553, 1973) and from the point of view of the patent literature thus find new substances. However, in more detail, we find that none of the 3-piperazinodibenzo (b, f) -1,2,4-triazolo (4,3-d) -1,4-thiazepine-type substances are present in the above-mentioned publications. described, it is not characterized by melting point, ie it must be considered that neither of them was prepared and that the majority of the cited writings are of a fictitious nature. From the point of view of the practice in the scientific chemical literature, such substances have to be seen as not yet described, ie new. Regardless of this concept, the method of preparation of the substances according to the cited publications is different from the method we now describe. We have also confirmed the fictitious nature of the cited writings by finding the way of preparation described therein unrepeatable.

The process for the preparation of the compounds of the formula I according to the invention consists of a four-step process starting from the thiolactams of the formula II

R

(II)

The thiolactams are first treated with hydrazine hydrate in boiling ethanol or 1-butanol to give the new hydrazones of formula III,

R

R ¹ (III) in which R 1 and R ^{2 are} again the same as in formula I. These compounds can also be formulated as tautomeric hydrazines with endocyclic double bond and exocyclic residue -NHNHg (the spectral methods used did not allow a clear distinction between these structures). Some of the starting thiolactams are known (West German Patent Publication 2,301,399; US 3,853,882; Chem.

Abstr. 22, 105308 (1973). partly new and in this case the description of their preparation is included in the examples.

A further step of the invention is the reaction of the hydrazine derivatives III with ethyl orthoformate in ethanol in the presence of sulfuric acid; the reaction results in cyclization to the dibenzo (b, f) -1,2,4-triazolo (4,3-d) -1,4-thiazepines of formula IV,

(IV)

2 in which R and R denote again the same as in formula I.

A third stage of the process of the invention is the bromination of compounds of formula dine and chloroform. Bromination is clearly the most reactive

IV with bromine in a 3-position skeleton pyripole position resulting in 3-bromodibenzo (b, f) -1,2,4-triazolo (4,3 "d) -1,4-thiazepines of formula V,

wherein R ¹ and R ^{2 are} again the same as in the preceding formulas. The final step is the substitution reaction of these bromo derivatives (V) with excess boiling 1-methylpiperazine to obtain crystalline compounds of formula I and their neutralization with methanesulfonic acid crystalline dimethanesulfonates which are water-soluble and suitable for pharmacological testing and for the possible manufacture of dosage forms. All of the novel compounds and novel intermediates are crystalline, samples of which were purified by crystallization to a constant melting point and are given in the examples. To determine the identity of the products, all these substances were analyzed and studied by conventional spectral methods. In all cases, the identity of the substances was confirmed.

Example 1

2

3- (4-Methylpiperazino) dibenzo (b, f) -1,2,4-triazolo (4,3-d) -1,4-thiazepine (I, R = R = H) Mix 4.95 g 3- bromo dibenzo (b, f) -1,2,4-triazolo (4,3-d) -1,4-thiazepine and 12 g of 1-methylpiperazine are boiled under stirring at 160-170 ° C for 8 h. After standing overnight at room temperature, the reaction mixture was diluted with 120 mL of water, basified with 5 mL of aqueous ammonia and extracted with dichloromethane. The extract is washed with water and then shaken with 60 ml of 5% hydrochloric acid to separate the neutral and basic substances. Treatment of a dichloromethane solution of 1.7 g was recovered unchanged starting bromo derivatives V (fi '= R ² · H). The acidic aqueous solution was basified with conc. aqueous ammonia and the basic product isolated by extraction with dichloromethane. The extract was dried over potassium carbonate and evaporated in vacuo. The residue was crystallized from 30 ml of ethanol. 2.25 g of the desired base are obtained, melting at 240 DEG-241 DEG. Further recrystallization from ethanol gave an analytically pure material, m.p. 242-243 ° C. Neutralization of 0.4 g of base with 0.23 g of methanesulfonic acid afforded 0.45 g of dimethanesulfonate, which melted pure at 242-244 ° C (ethanol with a small amount of water).

Used starting 3-bromdibenzo (b, f) -1, 2,4-ttiazolo (4,3-d) -1,4-thiazepine (V, R ¹ = R ² = H) has not yet been described in literature. It can be prepared as follows from the known dibenzo (b, f) -1,4-thiazepine-11 (10H) -thione (West German Publication 2,301,399; US 3,853,882; Chem. Abstr. 22, 105, 308, 1973):

A mixture of 15.8 g of dibenzo (b, f) -1,4-thiazepine-11 (10H) -thione, 11.4 g of 100% hydrazine hydrate and 450 ml of 1-butanol was heated to reflux for 30 minutes with stirring. After cooling, the solution was filtered and the filtrate was evaporated under reduced pressure. The residue was diluted with 200 mL of water and extracted with dichloromethane. The extract was washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is dissolved in 40 ml of dichloromethane, the solution is filtered and the filtrate is crystallized by addition of 150 ml of hexane. Upon standing overnight, a precipitate 10.1 g (64%) of substantially pure dibenzo (b, f) -1,4-thiazepine-I1 (10H) -hydrezonu III, R = R ² = H). Recrystallization of the sample from hexane / chloroform gave an analytically pure material, m.p. 121-123 ° C.

22.3 ml of sulfuric acid are added dropwise over 5 minutes to the stirred mixture of 47.3 g of the previous resonate, 2100 ml of ethanol and 116.2 g of ethyl orthoformate. The mixture was stirred at room temperature for 2 h and then heated at 70 ° C for 1 h. After cooling, it is neutralized with stirring by slowly adding a solution of 72.5 g of sodium hydrogen carbonate in 790 ml of water, the mixture is evaporated under reduced pressure to 1/3 of the original volume, the residue is diluted with 400 ml of water and extracted with dichloromethane. The extract was washed with water, dried over potassium carbonate and evaporated under reduced pressure. The inhomogeneous residue is chromatographed on a column of 300 g of silica gel (Lachema 100/160). The dichloromethane eluates were discarded and the combined chloroform eluates were evaporated. The residue was crystallized from 550 ml of ethanol. Suction and treatment of the mother liquor yielded a total of 26.5 g (54%) of dibenzo (b, f) -1,2,4-triazolo (4,3-d) -1,4-thiazepine (IV, R1 ^). = R ² = H), melting at 213.5 to 215 ° C. Crystallization of the sample from ethanol yields an analytically pure product, melting at 215-216 ° C.

To a solution of 5.2 g of the above triazolo derivative in 50 ml of chloroform was added 3.2 g of pyridine and a solution of 3.36 g of bromine in 20 ml of chloroform was added dropwise with stirring over 15 minutes. The mixture is boiled for a further 30 min, while stirring another 3.2 ml of pyridine and _; 1.1 ml of bromine and boiled under stirring for an additional 30 min. It is left to stand at room temperature for 48 hours and the chloroform solution is washed with 50 ml of 5% sodium thiosulphate solution and water. It is dried over sodium sulphate and evaporated to dryness under reduced pressure. The residue was dissolved in chloroform and chromatographed over a column of 65 g of silica gel (Merck 60). Already the first fraction eluted with chloroform 7.6 g of crude desired 3-bromdibenzo (b, f) -1, 2,4-triazolo (4,3-d) -1,4-thiazepine (V, R '= ^R2 = H ). Crystallization from ethanol / chloroform and treatment of the mother liquors gave 4.9 g (74%) of the product melting at 192-194 ° C. Recrystallization from chloroform-ethanol no longer raises this melting point.

Example 2

6-Chloro-3- (4-methylpiperazino) dibenz (b, f) -1, 2,4-triazolo (4,3-d) -1,4-thiazepine (I, R = Cl, R ² = H). 15.0 g of 3-bromo-6-chlorodibenzo (b, f) -1,2,4-triazolo (4,3-d) -1,41 2

-thiazepine (V, R = Cl, R = H) and 40 g of 1-methylpiperazine were refluxed for 7.5 h. Work up analogously to Example 1 gave 12.7 g (81%) of the desired product melting at 202-205 ° C. Crystallization of the sample from ethanol gave an analytically pure material, melting at 203.5-205.5 ° C. Neutralization with methanesulfonic acid in ethanol gives the dimethanesulfonate melting pure at 231.5-233 ° C.

Starting 3-bromo-6-chlorodibenzo (b, f) -1,2,4-triazolo (4,3-d) -1,4-thiazepine (V, R ¹ = Cl, o

R = H) has not been described in the literature yet and can be prepared as follows from the known 8-chlorodibenzo (b, f) -1,4-thiazepin-11 (10H) -one (Protiva M., Rach V .: Collect. Chem. Commun. 24, 207 (1959) i

A mixture of 65.4 g of 8-chlorodibenzo (b, f) -1,4-thiazepin-11 (10H) -one, 900 ml of pyridine and 44.4 g of phosphorus pentasulphide is stirred and refluxed for 4 to 5 hours under nitrogen. . After cooling, the mixture was poured into a solution of 1325 g of sodium chloride in 5 l of water. The precipitated product is filtered off with suction and washed thoroughly with water and dried in vacuo. The crude product was crystallized from a mixture of 160 ml of dimethylformamide and 150 ml of ethanol. 50 g (72%) are obtained. 8-chlorodibenzo (b, f) -1,4-thiazpein-11 (10H) -thione melting at 267-270 ° C. Crystallization of the sample from the same solvent mixture gave an analytically pure material, melting at 272-272.5 ° C.

Reaction of a mixture of 38 g of 8-chlorodibenzo (b, f) -1,4-thiazepine-11 (10H) thione, 27.5 g of 100% hydrazine hydrate in 570 ml of ethanol at reflux for 5 hours and a similar treatment as in Example 1 32.7 g (87%) of 6-chlorodibenzo (b, f) -1,4-thiazepine-11 (1OH) -hydrazone, m.p. 134 DEG-136 DEG C., are obtained. mp 136.5-138 ° C.

To a solution of 30.9 g of the preceding hydrazone in 1200 ml of ethanol was added 58.2 g of ethyl orthoformate, and then 12.7 ml of sulfuric acid was added dropwise with stirring over 15 minutes.

The mixture was stirred at room temperature for 1.5 h and then worked up in a similar manner as described in Example 1 for the analogous compound. There were obtained 28.6 g (89%) of almost pure 6-chlorodibenzo (b, f) -1, 2,4-triazolo (4,3-d) -1, 4-thiazepine (IV, R ¹ = Cl, R ² = H) melting at 239-241 ° C. Crystallization of the sample from chloroform / hexane gave an analytically pure material, mp 242-244 ° C.

In the next step, 25.2 g of the preceding triazolo derivative is brominated in a mixture of 220 ml of chloroform and 28 g of pyridine using 28.2 g of bromine similar to that described in Example 1. The crude product obtained in this way is chromatographed on a 150 g silica gel column. Already the first chloroform eluates represent the desired 3-bromo-8-chlorodibenzo (b, f) -1,2,4-triazolo (4,3-d) -1, 41 2

-thiazepine (V, R = Cl, R = H). Crystallization from chloroform / hexane gave 26.7 g (83%) of almost pure product melting at 195-200 ° C. Crystallization of the sample from ethanol gave an analytically pure product, m.p. 199-200 ° C.

Example 3

12-Chloro-3- (4-methylpiperazino) dibenz (b, f) -1,2,4-triazolo (4,3-d) -1, 4-thiazepine (I, R = H, R ² = Cl ). The substitution reaction of 14.6 g of 3-bromo-1 2-chlorodibenzo (b, f) -1,2,4-triazolo (4,3-d) -1,4-thiazepine with 32 g of boiling 1-methylpiperazine is carried out analogously as in Examples 1 and 2. Workup afforded 11.0 g of crude base melting at 233-235 ° C. Crystallization of the sample gave an analytically pure product, melting at 235-236.5 ° C (ethanol). Neutralization with methanesulfonic acid in ethanol gave the dimethanesulfonate melting pure at 262-263.5 ° C (aqueous ethanol).

Default. 3-Bromo-1,2-chlorodibenzo (b, f) -1,2,4-triazolo (4,3-d) -1,4-thiazepine has not been described in the literature yet. It is prepared, for example, by the following procedure of the known 2-chlorodibenzo (b, f) -1,4-thiazepin-11 (10H) -one (Jaques R. et al., Helv. Chim. Acta 42, 1 265, 1959). ):

Said lactam (65.4 g) was reacted with 44.4 g of phosphorus pentasulfide in 800 ml of pyridine (reflux for 4.5 h). Analogous work-up as described for the analog of Example 2 afforded 56.7 g (85%) of 2-ehordibenzo (b, f) -1,4-thiazepine-11 (10H) -thione (II, R). ¹ = H, R ² = Cl) melting at 263-267 ° C. Crystallization from chloroform gave an analytically pure material, melting at 265-267 ° C.

Reaction of a mixture of 33.3 g of the above thiolactam with 24 g of 100% hydrazine hydrate in 500 ml of boiling ethanol (5 h) gives, as in the previous cases, 32.8 g (98%) of crude 2-chlorodibenzo (b, f) -1, 4-thiazepine-10 (11H) hydrazone (III. R ¹ = H, R ² = Cl), m.p.

Mp 135-140 ° C. Crystallization of the sample from chloroform / hexane gave an analytically pure product, m.p. 142-144 ° C.

12.5 ml of sulfuric acid are added dropwise with stirring to a mixture of 30.3 g of the preceding hydrazine derivative, 1170 ml of ethanol and 57.1 g of ethyl orthoformate, and the mixture is stirred at room temperature for 1 hour. A similar treatment as in Examples 1 and 2 gave 25.6 g (81%) of 12-chlorodibenzo (b, f) -1,2,4-triazolo- (4,3-d) -1,4-thiazepine (IV). R ¹ = H, R ² = Cl) melting at 239 DEG-240.5 DEG C. Recrystallization of a sample from ethanol-chloroform to afford analytically pure product melting at 240-241 ° C.

Bromine 24) 3 g of the preceding triazole derivative in a mixture of 300 ml of chloroform and 27 g of pyridine with 27.2 g of bromine, carried out analogously to Examples 1 and 2, is obtained by chromatography of the crude product 24.3 g (78%) of crude 3-bromo- 12-chlorodibenzo (b, f) -1,2,4-triazolo (4,3-d) -1,4-thiazepine (¢, R ¹ = H, R ² = Cl), m.p. 221-225 ° C. Crystallization of the sample from chloroform-hexane gave an analytically pure material, m.p. 225-227 ° C.

Claims (2)

SUBJECT OF THE INVENTION Process for preparing pins of the general formula 3- (4-methylpiperazino) dibenzo (b, f) -1,2,4-triazolo (4,3-d) -1,4-thiazole. (AND) Wherein R and R are the same or different and are hydrogen or chlorine, and their methanesulfonates, characterized in that the dibenzo (b, f) -1,4-thiazepine-10 (11H) -thiones of formula II , R (II) Wherein R and R are the same as in Formula I, treated with hydrazine hydrate in boiling ethanol or 1-butanol, obtained with the hydrazones of formula III, (III) In which R and R denote the same as in the preceding samples, they are cyclized by reaction with ethyl orthoformate in ethanol in the presence of sulfuric acid to dibenzo (b, f) -1,2,4-triazolo (4,3-d) -1 4-thiazepines of formula IV, R XIV) In which R and R are the same as in the preceding formulas, these are brominated in the next step with bromine in a mixture of chloroform and pyridine to give 3-bromodibenzo (b, f) -1,2,4-triazolo (4,3-d) ) -1,4-thiazepines of the formula I, Wherein R and R are the same as in the preceding formulas and are subjected to the following substitution reaction with boiling excess 1-methylpiperazine, whereupon the obtained bases of formula I are converted to methanesulfonic acid by neutralization to dimethanesulfonates.