FI60016B - PROCEDURE FOR THE FRAMEWORK OF THERAPEUTIC SUBSTITUTES SUBSTITUTES 6-PHENYL-4H-S-TRIAZOLO- (3,4C) -THIENO (2,3E) -1,4-DIAZEPINE - Google Patents

Description

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Patant- och registerttyralaan Ansakin uthgd och utl.sk rtftin pubikired 31.07.81 (32) (33) (31) Requested atuolkau * —Bafird priority 02 .O3.7I + 20.07.7! +, 2i + .09.7 ^, 21.12.7 * * Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) P 21 + 10030.9, P 21 + 3501 + 1.2, P 21 + 1 + 5 ^ 30.6, p 21 + 60776.9 (Tl) CH Boehringer Sohn, D-6507 Ingelheim am Rhein, Federal Republic of Germany (DE) (72) Karl-Heinz Weber, Gau-Algesheim, Adolf Bauer, Ingelheim am Rhein,

Peter Danneberg, Ockenheim, Franz Josef Kuhn, Bingen, Federal Republic of Germany-Förbundsrepubliken fysklahd (DE) (7IO Leitzinger Oy (5I +) Method for the treatment of therapeutically valuable substituted 6-phenyl-1 + Hs - triazolo- for the preparation of thieno / 2,3e7-1,1-diazepines -For the preparation of therapeutic derivatives of 6-phenyl-1 + Hs-triazolo [3, Uo7-thieno] 2,3e7-1,1'-diazepiner (62) Divided by application 750592 (patent 59099) _

Avdelad frän trap 750592 (patent 59099)

The invention relates to a process for the preparation of substituted 6-phenyl-4H-s-triazolo [3,4-c] thieno [2,3e] -1,4-diazepines of the general formula I.

, NV

R3 -42 ΗιΊί? 9Τ,> (I) -5 / j and their physiologically acceptable acid addition salts.

2 6001 6 In this formula, the bromine atom R2 is a hydrogen, fluorine, chlorine or bromine atom, and R3 is a chlorine or bromine atom.

The novel compounds of the general formula I and their acid addition salts can be obtained by chlorinating or brominating a compound of the formula II (R 1) and R 2 in which R 1 and R 2 have the same meaning as above, and that any The compound of the formula I is converted into a physiologically acceptable acid addition salt.

To prepare the final products of general formula I, a compound of formula II is brominated or chlorinated. The halogenation takes place in a solvent 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 halosuccinimide. The reaction temperature in this reaction depends on the starting material and process used and is between room temperature and the reflux temperature of the reaction mixture.

If desired, the final products of the general formula I can be converted into their physiologically acceptable acid addition salts in the customary manner. Suitable acids for salt formation include, for example, hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid, cyclohexylsulfamic acid, citric acid, tartaric acid, ascorbic acid, maleic acid, formic acid, salicylic acid and menthulonic acid and menthanic acid or toluene.

The preparation of the compounds of general formula II can be carried out according to said information.

The compounds of general formula I or their acid addition salts have valuable therapeutic properties. Using a variety of pharmacological testing methods, they have been shown to be effective as anxiolytic, stress-relieving, and muscle relaxant agents, and in addition, they have potent anticonvulsant activity. In mammals, they also significantly increase food intake. Of note is also their very low toxicity. They are superior to the known thieno-1,4-diazepines without other triazole rings and are known, for example, from DT-OS 2,155,403 and 2,221,623, in particular for their very pronounced anticonvulsant activity in the so-called pentetrazole test. ; and although they resemble the 8-alkyl-6-aryl-thieno [2,3e] -4H-s-triazolo [3,4-c] -1,4-diazepines known from DT-OS 2,229,845, the magnitude of their effect is more than about ten times. Compounds or their acid addition salts in which R1 represents a bromine atom, R2 represents a chlorine or bromine atom and R1 represents a bromine atom have proved to be particularly valuable in this case.

The compounds prepared according to the invention have been compared with compounds known from the prior art. The following methods have been used in the comparative experiments: 1. Pentetrazole antagonism (M. I. Gluckmann, Curr. Ther. Res.

2, 721 (1965)). The mean effective dose (ED, -q) of the test compounds that canceled out pentylenetetrazole. lethal dose of 125 mg / kg in 50% of experimental animals. Pentylenetetrazole was injected one hour after administration of the test compound.

. '6001 6 4 2. Conflict situation (induction of passive avoidance) (J. Geller, Arch. Int. Pharmacodyn. 149, 243 (1964)).

3. Combat experiment (suppression of aggression due to isolation) (Wirth et ali Arch. Int. Pharmacodyn. 115, 1-31 (1958)).

4. Toxicity (Litchfield and Wilcoxon, J. Pharmacol.

Exp. Therap. 96, 99 (1949)) ·. The mean lethal dose (LD ^ q) was determined.

Albino mice (NMRI) weighing 20-25 g and albino rats (FW-49) weighing 140-200 g were used as experimental animals, and the test compounds were administered orally as a suspension in olive oil by means of an esophageal tube.

The compounds used in the experiments and the results obtained are as follows. Test compounds * A. 1,8-dibromo-6- (o-chlorophenyl) -4H-s-triazolo [3,4-c] thieno [2,3e] -1,4-diazepine (Example 1).

δ · 8-chloro-6- (o-chloro-phenyl) -1-methyl-4H-s-triazolo [3,4-c] thieno [2,3e] -1,4-diazepine ).

c. 8-ethyl-6- (o-chloro-phenyl) -1-methyl-4H-.s-triazolo [3,4-c] thieno [2,3e] -1,4-diazepine (DOS 2,229,845) .

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The following Table I shows the experimental results obtained.

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JC 0 3 X EH x \ 6 60016 Preparation of starting material; 8-bromo-6- (O-chlorophenyl) -4H-s-triazolo [3,4-c] thieno [2,3-e] -1,4-diazepine 27 g of 7-bromo-5- (o-chlorophenyl) -2-hydrazine -3H- / 2,3e7-thieno-1,4-diazepine, melting point about 300 ° C (decomposes), is boiled for 30 minutes at reflux in a mixture of 23 ml of orthomuric acid and 300 ml of ethanol. The solvent is evaporated and the residue is triturated with ether.

Yield: 26 g, melting point 214-216 ° C.

Example 1 1,8-Dibromo-6- (o-chlorophenyl) -4H-s-triazolo [3,4-c] thieno [2,3-b] 1,4-diazepine 10 g of 8-bromo-6- (o-chlorophenyl) -4H-s-Triazolo - [3,4-c] thieno [2,3,3] -1,4-diazepine is dissolved in a mixture of 20 ml of pyridine and 100 ml of methylene chloride and heated for 7 hours. 6.3 g of bromine dissolved in 25 ml of methylene chloride are then added over a period of 5 minutes and the mixture is further heated at reflux for 3 hours.

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

7.0 g = 60% of the title compound are obtained, melting point 210-211 ° C.

Example 2 8-Bromo-6- (o-chlorophenyl) -1-chloro-4H-s-triazolo [3,4-c] thieno [2,3-e] -1,4-diazepine.

6.6 g of 8-bromo-6- (o-chlorophenyl) -4H-s-triazolo [3,4-c] thieno [2,3e] -1,4-diazepine were dissolved in 60 ml of chloroform to which 2, 7 ml of pyridine at room temperature. Chlorine was bubbled into this solution for 5 minutes, and finally the solution was refluxed for 30 minutes. After boiling, the mixture was shaken with chloroform and water, the solution was dried, evaporated and the residue was filtered through silica gel. After recrystallization from ethanol, the title compound was obtained at 4.8 g = 67% of theory and had a melting point of 161-162 ° C.

Claims (1)

6001 6 7 A process for the preparation of therapeutically valuable substituted 6-phenyl-4H-s-triazolo-C3,4cJ-thieno-12,3eJ-1,4-diazepines of the formula I> 1 \ r, - <r 3N 'tT } li1-R2 in which R1 is a bromine atom R2 is a hydrogen, fluorine, chlorine or boron atom, and R3 is a chlorine or bromine atom, and their physiologically acceptable acid addition salts, characterized in that the compound of the formula II yN \ R is chlorinated or brominated. f 'N1 ^ X = .N (ID riTR2 wherein R1 and R2 have the same meaning as above, and that optionally the compound of the formula I is converted into a physiologically acceptable acid addition salt.