CS203085B2

CS203085B2 - Method of producing novel substituted 6-aryl-4h-s-triazolo/3,4-c/thieno/2,3-e/-1,4-diazepines

Info

Publication number: CS203085B2
Application number: CS785955A
Authority: CS
Inventors: Karl-Heinz Weber; Adolf Bauer; Peter Danneberg; Franz J Kuhn
Original assignee: Boehringer Sohn Ingelheim
Priority date: 1974-07-20
Filing date: 1978-09-14
Publication date: 1981-02-27

Description

The present invention relates to a process for the preparation of novel substituted 16-aryl-4H-s-triazolo [3,4-c] thieno [2,3-e] -1,4-diazepines of the formula (I) -1,4-diazepines

The novel compounds of the formula I and their acid addition salts can be obtained according to the invention by the compound of the formula VI

where

R1 represents a hydrogen, chlorine or bromine atom, or a C1-4 alkyl group,

R @ 2 represents a hydrogen, chlorine or bromine atti, a nitro group or a trifluoromethyl group, and

R @ 3 denotes a chlorine or bromine atom, an alkoxy group or an alkyl mercapto group in each case having from 1 to 3 carbon atoms, as well as their physiologically acceptable acid addition salts.

where

R1 and R2 are as defined above, chlorine or bromine, whereupon, if desired, the chlorine or bromine atom in the compound is replaced by an alkoxy or alkylmercapto group and the optionally obtained compound of formula I is converted into a physiologically acceptable acid addition salt.

For the preparation of the final compounds of the formula I, a compound of the formula VI is used

203083 brominates or chlorinates. The halogenation is carried out in solvents such as carbon tetrachloride, chloroform, methylene chloride, dioxane, tetrahydrofuran, dimethylformamide or a suitable hydrocarbon, optionally with the addition of a tertiary organic base such as pyridine or halo succinimide. The reaction temperature in this reaction varies between room temperature and the reflux temperature of the reaction mixture, depending on the starting material used and the procedure used.

The 8-halogenated compound thus obtained can be converted, if desired, into the corresponding alkoxy- or alkyl-mercapto compound.

If an alkoxy group is introduced, the halogenated compound is dissolved in an alkali metal alcoholate and the solution is heated to reflux.

To prepare alkylmercapto compounds, the halogenated compound is dissolved in an aprotic solvent such as dioxane, tetrahydrofuran, dimethylformamide or hexamethylphosphoric triamide (HMPT) or in an alcohol and reacted with an alkali metal mercaptide; The alkali metal mercaptide can be produced in situ in this reaction, for example by introducing mercaptan into an alkali metal alcoholate solution containing the dissolved halogenated compound.

The final compounds of the formula I can be converted into physiologically harmless acid addition compounds, as required, in the customary manner. Suitable acids for preparing salts are, for example, hydrohalic acid, sulfuric acid, phosphoric acid, nitric acid, cyclohexylsulfamic acid, citric acid, tartaric acid, ascorbic acid, maleic acid, formic acid, salicylic acid or methane- or toluenesulfonic acid and the like.

The preparation of the compounds of the general formula VI is described in German Offenlegungsschrift No. 2,410,030 and is carried out by the compound of the general formula II

where

X is SH, NH2, lower alkoxy or alkylmercapto;

R1 and R2 are as defined above, reacted with formic acid orthoester,

The compounds of the formula I or their acid addition compounds have valuable therapeutic properties. They have been shown to be effective anxiolytically, relieve tension and have a muscular relaxant effect, and an intense anticoinvulsive effect, using various pharmacological test methods. They also have the property of substantially increasing food intake in mammals. Their remarkably low toxicity is also noteworthy. The known thieno-1,4-diazepines without an additional triazole ring, which are known, for example, from DOS 2155 403 and 2 (2) 1623, in particular their very strong anticonvulsant effect in the so-called pentetrazole test, surpasses resemble the known 8-alkyl-6-arylthieno [2,3-e] -4H-s-1 ^; The triazolo [3,4-c] -1,4-diazepines of DOS 2,229,845, but have a potency of more than ten times higher due to their efficacy. Particularly valuable have been those compounds and, where appropriate, acid addition salts thereof, in which R1 is a bromine atom, R2 is a chlorine or bromine atom and R3 is a bromine atom or a methoxy group, especially

1,8-dibromo-6-o-chlorophenyl-4H-s-triazolo [3,4-c] thienol [2,3-e] -1,4-diazepine (R 1 = Br, R 2 = Cl, R 3 = Br J and

BRIO-8-ol-6-chlorophenyl-l-dimethoxy-4H-s-triazole [3,4-c thienoj 2,3-e] -1,4-diazepine (R = Br, R ₂ = Cl, R 3 = OCH3] and their acid addition salts.

White mice weighing 20-25 g or white FW 49 rats weighing 140-200 g were used for the tests. Except for the Geller conflict test, 10 animals were used for each dose. Geller's conflict test was performed with 4 animals for each dose. The test substances were suspended in olive oil and in all cases introduced into the stomach by a pharynx probe.

1. Pentetrazole antagonism:

Dose that abolishes the lethal effect of 125 mg / kg of pentylentetrazole in 50% of animals administered intraperitoneally 1 hour after the dose of test substance [Μ. I. Gluckmann,

Curr. Ther. Res., 7, 721 (1965)].

2. Geller test:

A dose at which animals in conflict are pressing a round object ten times to obtain a food pill, although a signal on at the same time announces that together with the food pill they will be punished in the form of an electrical wound (J. Geller, Arch. Int. Pharmacodyn) 149, 243 (1964)].

3. Mice Boijoivity Test:

Dose at which aggressiveness ceases in 50% of animals. It is determined in adult males who were kept in the dark during 3-4 weeks of Isolation against young male mice. [Wirth, Gosswald, Horlein, Risse and Kreiskott, Arch. Int. Pharmacodym. 115: 1-31 (19S8)].

4, LD50:

Dose that survives 50% of the animals. [Lichfield and Wilcoxon, J. Pharmacol, Exptl. Therap. 96, 99 (1949)].

The values were determined graphically in all tests. The test results are shown in the following table:

20308S

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A single dose of the compounds of the invention is 0.05 to 50 ', preferably 0.1 to 25 m, g (orally) and 5 to 150 mg as a daily dose.

The compounds obtainable according to the invention can be used alone or in admixture with other compounds of the invention or also in combination with other pharmacologically active substances, such as spasmolytics or β-receptor blocking agents. Suitable dosage forms are, for example, tablets, capsules, suppositories, solutions, juices, emulsions or dispersible powders. The tablets may, for example, be prepared by mixing the active ingredient (s) with known excipients, for example inert excipients. diluents such as calcium carbonate, calcium phosphate or milk sugar, tablet disintegrating agents such as corn starch or alginic acid, binders such as starch or gelatin, glidants such as magnesium stearate or talc, and / or a depot effect, such as carboxypolymethylene, carboxymethylcellulose, acetylcellulose phthalate, or polyvinyl acetate. Tablets may consist of multiple layers.

Dragees can optionally be obtained by coating cores obtained analogously to tablets, by conventional means for the purpose used, for example, collidone or shellac, Arabian gum, talc, titanium dioxide or sugar. To achieve a depot effect or to prevent incompatibilities, the core may also consist of multiple layers. Likewise, the dragee coating may consist of several layers, with the aid of the substances already mentioned in the preparation of tablets.

The juices of the compounds of the invention, or combinations thereof, may also additionally contain sweetening agents such as saccharin, cyclamate, glycerin or sugar, as well as flavorings, for example flavoring agents such as vanillin or orange extract. In addition, they may contain suspending aids or thickening agents, such as. sodium carboxymethylcellulose, wetting agents, for example the condensation products of higher aliphatic alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.

Injectable solutions are prepared by conventional means, for example, with the addition of preservatives, such as p-hydroxybenzoates, or stabilizers, such as the alkali salts of ethylenediaminetetraacetic acid, and are then filled into vials or ampoules.

For example, one or more active ingredients, or active ingredient combinations comprising capsules, may be prepared by mixing the active ingredients with inert carriers such as milk sugar or sorbent and filling them in gelatin capsules.

Suitable suppositories can be prepared, for example, by mixing suitable carriers such as neutral fats or polyethylene glycol or derivatives thereof.

Example 1, 8-Dibro®-6- (o-chlorophenyl) -4H-s-triazolo [3,4-c] thiene-2,3-e] -1,4-diazepine

(a) 10 g of 8-bromo-6 - <(o-chlorophenyl) -4H-s-triazolo [3,4-c] thienof 2,3-e] -1,4-diazepine are dissolved in a mixture consisting of 20 ml pyridine and 10 ml of methylene chloride and heated for 7 hours. Then 6.3 g of bromine dissolved in

The reaction mixture was cooled, diluted with imethylene chloride, and the solution was shaken twice with 1 N hydrochloric acid and once with water. After drying, the methylene chloride was evaporated and the residue was recrystallized from ethanol.

7.0 g of the title compound (i.e. 60 proc.), M.p. 210 DEG-211 DEG C. are obtained.

(b) The starting compound is obtained as follows:

g of 7-bromo-5- (o-chlorophenyl) -2-hydrazino-3H- [2,3-e] thieno-1,4-diazepine, melting at about 300 ° C (decomposition), is heated at reflux for a period of time. 30 minutes in a mixture consisting of 23 ml of orthoformic acid and 300 ml of ethanol, the solvent was evaporated and the residue was triturated with ether.

Yield 20 g, m.p. 214-216 ° C.

Example 2

8-Bromo-6- (o-chlorophenyl) -1-methoxy-3H-s-triazo, loi [3,4-c] thieno [2,3-e] -1,4-diazepine.

gl, 8-dibromo-6- (o-chlorophenyl) -4H-s-triazolo [3,4-c] thieno [2,3-e] -1,4-diaazepiin was heated at reflux for 2 hours in solution of 0.6 g of sodium in 70 ml of methanol. The reaction mixture was evaporated, diluted with water and then shaken with methylene chloride. The methylene chloride phase was dried and the methylene chloride was evaporated. From the residue after recrystallization with ethanol to give 7 g (i.e. 76%] of the title compound, mp 198-200 ° C ^Q

Example 3

8-bromo-6- (o-chlorophenyl) -1-methylmercapto-4HHS-trlazo [3,4-cthieno [2,3-e] -1,4-diazepine

Dissolve 0.15 g of sodium in 40 ml of absolute methanol and introduce into the solution

34.0 mg of methylmeercaptan. Then 2.5 gl, 8-diibromo-6- (o-chlorophenyl203085 nyl) -4H-s-triazololo [3,4-c] thleno [2,3-e] -1,4- diazepine and heated to a temperature between 40 to 50 ° C. After about 30 minutes, no dibromo compound can be detected by thin layer chromatography. The solution is then evaporated, the residue is dissolved in methylene chloride, the methylene chloride is shaken several times with water, the organic base is dried, the solvent is evaporated and the residue is chromatographed on a column of silica.

920 mg (40%) of the title compound of melting point 158-160 ° C is obtained.

Further, the end products listed in the following examples included in the table were obtained according to the above procedure.

Table

Example number R1 R2 R3 Temperature

Claims

A process for the preparation of novel substituted 6-aryl-4H-s-triazolo [3,4-cthienoyl 2,3-e] -1,4-diazepiines of the formula I with an acid salt, characterized in that the compound of the formula VI where

R1 represents a hydrogen, chlorine or bromine atom or an alkyl group of 1 to 4 carbon atoms,

R2 represents a hydrogen, chlorine or bromine atom, a nitro group or a trifluoromethyl group; and

R 3 represents a chlorine or bromine atom, an alkoxy group or an alkylimercapto group having from 1 to 3 carbon atoms each, but also their physiologically harmless additions

R1 and R2 are as defined above, chlorine or bromine, whereupon, if desired, the chlorine or bromine atom of the compound is replaced by an alkoxy or C1 -C3 alkylmercapto group by reaction with an alkali metal alkoxide or an alkali metal mercaptide and the thus obtained the compound of formula (I) is converted into a physiologically acceptable acid addition salt.