CS209899B2 - Method of making the new substituted 1-piperazinyl-4h-s-triazolo /3,4c/ thieno/2,3e/ -1,4-diazepines - Google Patents

Description

CZECHOSLOVAK SOCIALIST REPUBLIC (19) DESCRIPTION OF THE PATENT 209899 (11) (B2) É (22) Registered 19 07 78 (21) (PV 1312-80) (32) (31) (33) Priority from 21 07 77 ( P 27 32 921.1) Federal Republic of Germany (40) Published · 31 03 81 (51) Int. Cl.3 C 07 D 495/14 OFTAD FOR INVENTIONS AND DISCOVERIES (45) Published 15 06 84 WEBER KARL-HEINZ dr., LANGBEIN ADOLF dr., GAU-ALGESHEIM, (72) SCHNEIDER CLAUS dr., INGELHEIM / R., LEHR ERICH dr.

The inventor of WALDALGESHEIM, BOKE KARIN dr., INGELHEIM / R. and KUHN FRANZ JOSEF dr., BINGEN (NSR) 173)

Patent of C. H. BOEHRINGER SOHN, INGELHEIM / R. (NSR) (54) Method for the production of new substituted 1-piperazinyl-4H-s-triazolo- [3,4c1 thieno (2,3e] -1,4-diazepines 1)

The present invention provides novel substituted 1-piperazinyl-4H-s-triazolo [3,4-c] thieno [2,3e] -1,4 diazepines of formula I

2 of them as active ingredients in medicines. Of the straight or branched alkyl groups having 1 to 17 carbon atoms, in the meaning of R4, the preferred groups are 1 to 6 carbon atoms. The term "halogen" refers to fluorine, chlorine, bromine and iodine atoms.

The substituent on the phenyl ring may include the o-, m-, or p- radius.

The pyridyloid residue may be attached to the piperazine core of the piperazine core at position 2, 3 or 4.

According to the invention, the novel compounds can be prepared by salifying a compound of formula (II)

Wherein R 1 is a radical of formula R 4 -CO 2, R 2 is fluoro, chloro or bromo, R 3 is chloro, bromo or alkyl having 1 or 2 carbon atoms and R 4 is hydrogen, alkyl of 1 C 1 -C 17 alkoxy, phenyl group, MO 2 phenyl group or pyridyl group, a process for the preparation thereof, and is 209899 wherein R 2 and R 3 are as defined above for halide; or an anhydride derived from a carboxylic acid of formula R 4 COOH, wherein R 4 is as defined above.

The acylation of the compounds of formula (II) with a carboxylic acid halide or anhydride can be carried out using an excess of the acylating agent or also in a suitable inert solvent such as dioxane, tetrahydrofuran, benzene, toluene or xylene. In many cases, it has been found useful to add an inorganic or organic base such as pyridine, triethylamine, potassium carbonate or sodium bicarbonate to bind the acid. Depending on the starting materials used, the reaction temperature and reaction time can be varied within wide limits. Thus, the reaction temperature can be varied between room temperature and the boiling point of the solvent used and the reaction time can be from a few minutes to several hours.

For example, the following final products can be produced by the method described above: 8-bromo-6- (o-chlorophenyl-1-N-orylpiperazino-4H-s-itriazolo- [3,4c] thieno) 2,3e] -1 , 4-diazepine, 1- (N-acetylpiperazino) -8-bromo-6- (o-chlorophenyl) -4H-s-triazolo- [3,4c] thieno] 2,3e] -1,4-diazepine, 1 - (N-acetylpiperazino) -8-ethyl-6- (o-chlorophenyl) -4H-s-triazolo [3,4-d] thieno] 2,3e] -1,4-diazepine, 1- (N-acetylpiperazino) -8-chloro-6- (o-chlorophenyl) -4H-s-triazolo [3,4-thieno [2,3e] -1,4-diazepine, 1- (N-acetylpiperazino) -8-bromo- 6 - (fluorophenyl) -4H-s-triazolo [3,4c] thieno] 2,3e] -1,4-diazepine, 1- (N-acetylpiperazino) -8-bromo-6- ( o-bromophenyl] -4H-s-triazolo- [3,4c] thieno] 2,3e] -1,4-diazepine, 8-bromo-6- (o-chlorophenyl) -1- (N-s-arylpiperazino) -4H-s-triazolo- [3,4c] thieno] 2,3e] -1,4-diazepine, 8-bromo-1- (N-caproylpiperazino-6 - (o-chlorophenyl) -4H-s -triazolo- [3,4c] thiophene 2,3e] -1,4-diazepine, 8-bromo-6- (o-chlorophenyl) -1- (N-benzoylpiperazine j -4H-s-triazolo [3,4c] thieno] 2,3e-1,4-diazepine, 8-bromo-6- (o-chlorophenyl) -1- [N- (p-fluorobenzoylpiperazinoj-4H -s-triazolo- [3,4c] thieno [2,3-d] -1,4-diazepine, 8-bromo-6- (o-chlorophenyl) -1- [N- (o-chlorobenzoyl) piiper azino] - 4H-s-triazolo [3,4c] thieno] 2,3e] -1,4-diazoline, 8-bromo-6- (o-chlorophenyl) -1- (N-nicotinoylpiperazin-4H) -s-triazolo- [3,4c] thieno] 2,3e] -1,4-diazinine, 8-bromo-6- (o-chlorophenyl) -1- (N-pi-colinoylpiperazin-4H-s-triazolo) - [3,4c] thieno] 2,3e] -1,4-diazepine, 1- (N-ethoxycarbonylpiperazino) -8-bromo-6- (o-chlorophenyl) -411-s-triazolo- [3,4c] thieno] 2,3e] -1,4-diazepine The starting materials of the formula II can be obtained, for example, by reaction of appropriately substituted 1-halo-4H-s-triazolo [3,4-c] thieno] 2,3e 1,4-diazepine with piperazine or 1-piperazinyl-4H-s-triazol-1-yl] 3,4-thieno] -2,3e-5,6-dihydro-1,4-diazepine with piperazine . The resulting compounds of formula (I) have valuable therapeutic properties and can be used as anxiolytics, tranquilizers, sedatives and neuroleptics. The main effect may be different for individual substances, so that some of these compounds are they use predominantly as neuroleptics, others predominantly as sleepers and the like.

These compounds, in addition to the pronetrancquilizing and anxiolytic components of the curicus, have a good effect on the rat test, in which the animals are actively avoiding unpleasant stimuli, both of which have time-shifted peaks. First, the neuroleptic effect only appears later on the anxiolytic effect. Neuroleptic properties of acylpiperazinyl derivatives can also be deduced from biochemical tests.

The novel compounds are therefore particularly suitable for the removal of psychomotor disturbances and anxiety such as occur in schizophrenia and for the treatment of pain and sleep disorders of various origins. The following methods were used to test the anticonvulsant efficacy, tranquilization activity and toxicity of the compounds of the invention. 1. Antagonizing the effect of pentetrazoles; [Μ. I. Gluckmann, Curr. Ther. Res. 7, 721 (1965).

The mean effective dose (ED 50) of the test compound is determined, which abolishes a lethal effect of 125 µg / kg of pontylentotrazole in 50% of the test animals. Pentyltotrazole is administered intraperitoneally 1 hour after the test compound is administered. 2. Inhibition of Passive Avoidance Test [J. Geller, Arch. Int. Pharmacodyn. 149, 243 (1964)]. 3. Discriminative Active Avoidance [P. B. Dobrin, Arch. Int. Pharmacodyn. 178,351—356 (1969)]

This test demonstrates the possible neuroleptic efficacy of the test compounds.

The rats are trained to press a button on the warning signal. If the button is not depressed, a short painful electric shock will get into the paws. When a certain dose of neuroleptic agent is administered, the animals do not feel the need to press a button even if they know that there will be a painful stimulus. The following table shows the dosed compound in mg / kg, after which the keystroke rate is reduced by 50%. 4. Toxicity [Litchfield and Wilcoxon,]. Pharmacol.Exp. Therap. 96, 99 (1949)].

The median lethal dose (LD 50) is determined.

White mice (NMRI) weighing 20-25 g or white rats (FW-49) weighing 140-200 g are used as experimental animals. The test compound is administered orally in suspension in olive oil under the esophageal probes. The results of the above described tests (graphically determined) are shown in the following table. Geller antagonist tested Dobrin LD 50 effect (rat) (rat) (mouse) pentetrazole mg / kg (mouse) mg / kg mg / kg mg / kg 1- (N-acetylpiperazino) -8-bromo-6- (o- chlorophenyl) -4H-s-triazolo [3,4-c] thieno [2,3e] -1,4-diazepine 0.5 5.1 <30 1280 ° -1.

Legend: * 'This value is approximate because no animal died at a given dose

The unit dose of the compounds of the invention is 0.05 to 50 mg, preferably 0.1 to 25 milligrams (by oral administration), and the daily dose is then from 5 to 150 mg.

The invention is illustrated by the following non-limiting Examples. Example 1 1- (N-acetylpiperazino) -8-bromo-6- (o-chlorophenyl) -H-triazolo [3,4-c] thiophene 2,3e] -1,4-diazepine 4.6 g (0, 01 mol of 8-bromo-6- (o-chlorophenyl) -1-piperazino-4H-s-triazolo [3,4-b] thieno [2,3e] -diazepine was stirred in 100 ml of acetic anhydride for 20 minutes. The reaction mixture is poured onto ice and made alkaline with ammonia. The acetyl derivative is taken up in methylene chloride, the methylene chloride phase is dried and the residue is brought to crystallization by addition of ether. The yield of the title compound melting at 247-249 ° C was 3.8 g (76% of theory). Example 2 8-bromo-6- (o-chlorophenyl) -1- (N-ethoxycarbonylpiperazineHH-s-triazolo- [3,4-c] thiophene 2,3e) -1,4-diazepine 4.6 g (0, 01 mol) 8-bromo-6- (o-chlorophenyl-1-piperazino-4H-s-thiazolo [3,4-c] thieno [2,3e] -1,4-diazepine in 100 ml tetrahydrofuran The mixture is stirred for 30 minutes at room temperature with 2 ml of ethyl chloroformate, cooled, water and methylene chloride are added, the mixture is basified with ammonia, the methylene chloride phase is dried, evaporated and the residue is chromatographed. m.p. 216 DEG-218 DEG C., 4.8 g (91% of theory). EXAMPLE 3 1- (N-methylpiperazino) -8-bromo-6- (o-chlorophenyl) -H-triazolo [3,4-c] thienoic acid 2,3e] -1,4-diazepine 4.6 g (0.01 mol) 8-bromo-6- (o-chlorophenyl-1-piperazino-4H-s-triazolo [3,4-d] thieno [2,3-d] -1,4-diazepine; 3e] -1,4-diazepine is refluxed in 100 ml of formic acid for 3 hours, poured into ice, made alkaline with 2 N sodium hydroxide solution. The resulting formate is taken up in methylene chloride and worked up in an analogous manner to Example 1.

The yield of the product melting at 203-215 ° C is 3.9 g (80% of theory).

The following compounds of formula (I) are also prepared by the procedures described above

AND

Claims (1)

7 209899 8 Example No. R2 R3 Ri Melting point (° C) 4 Cl Br 294 5 Cl Br 311-312 6 Cl Br Oc ° 247-248 7 Cl O2H5 CH3 - 220-224 8 Cl Cl CH3 Cl-CH 3 - (CH 2) 16 -CO-126 to 128 10 Cl Cl CH 3 - (CH 2) 4 -CO- 173 to 175 11 Cl Cl CH 3 - (CH 2) 15 -CO-126 to K-SUBJECT OF THE INVENTION Process for the preparation of new substituted 1-piperazinyl-4H-s-triazolo [3,4-c] thieno- [2,3e] -1,4-diazepines of the formula I group, halophenyl group or pyridyl group characterized in that it catalyzes the compound of formula (II) wherein R 1 is a radical of formula R 4 -CO 2, R 2 is fluoro, chloro or bromo, R 3 is chloro, bromo or alkyl having 1 or 2 carbons and R 4 is hydrogen, alkyl of 1 to 1 C 17 alkyl, C 1 -C 2 alkoxy, phenyl in which R 2 and R 3 are as defined above, by the action of a halide or anhydride derived from a carboxylic acid of formula R 4 COOH, wherein R 4 is as defined above . seveiogralia, n. p., plant 7, Most