CS209929B2 - Method of making the new substituted 4h-s-triazolo/3,4c/-thieno/2,3e/-1,4 diazepins - Google Patents

Abstract

Compounds of general formula (I> <IMAGE> (wherein R2 is hydrogen, fluorine, chlorine or bromine; R3 is chlorine, bromine or alkyl; and R4 and R5 independently are hydrogen, alkyl, or hydroxyalkyl, or, together with the nitrogen atom to which they are attached, form a 5- or 6-membered saturated heterocyclic ring optionally substituted by one or two methyl groups and when a 6-membered ring, optionally containing an oxygen atom) exhibit neuroleptic activity and show tranquilizing, anxiolytic and/or tensiolytic properties.

Description

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

optionally substituted with one methyl group, and the resulting six membered ring may optionally contain an oxygen atom as another heteroatom.

The present invention provides a process for the preparation of these novel compounds of the general formula

I. Further, the invention describes the use of said compounds as active ingredients in medicine.

According to the invention, the novel compounds of the formula I can be obtained by reacting a compound of the formula II

in which

R @ 2 represents a hydrogen, chlorine or bromine atom,

R 3 represents a chlorine atom, a bromine atom or an alkyl group having 1 to 3 carbon atoms;

R 4 and R 5 are either the same or different and in each case represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or a hydroxyalkyl group having 2 to 3 carbon atoms, or both together form a four or five membered group. an alkylene chain in which

R 2 and R 3 have the above meanings and

Hal represents a halogen atom, reacted with an amine of the general formula

III <

(III) wherein

R4 and R5 are as defined above.

The reaction of the compound of formula II with an amine of formula III is carried out either without a solvent or in a solvent such as benzene, toluene, dioxane, tetrahydrofuran or chlorinated hydrocarbons such as tetraichloromethane or methylene chloride, preferably boiling the solvent used. The reaction with lower amines (dimethylamine, diethylamine and the like) is preferably carried out in an autoclave.

The reaction time depends on the starting materials used and can range from a few minutes to several hours.

The 1-amino compounds (Rd and R5 are hydrogen) are obtained by reacting 2-hydrazino-thieno [2,3e] -1,4-diazepine with cyanogen bromide, according to the following reaction scheme:

i \

[see К. T. Potis and C, Hirsch, J. Org. Chem. 33, 143 (1968)].

Suitable solvents in this case are alcohols, benzene, toluene and halogenated hydrocarbons.

These compounds may optionally be alkylated in the conventional manner. The alkylating agents used are preferably alkyl halides, dialkyl sulfates or toluenesulfonic acid esters. Solvents such as tetrahydrofuran, dimethylformamide or lower alcohols may be used in the present case, but the alkylation may be carried out without the addition of a solvent. In the case of introduction of a hydroxyalkyl radical, reaction with alkylene oxide is recommended.

For example, the following compounds can be obtained as described above:

8-bromo-6- (o-chlorophenyl) -1-amine ^; n-4H-s-triazolo [3,4c] thieno [2,3e] -1,4-diazepine

8-bromo-6- (o-chlorophenyl) -1-methylamino-4H-s-triazolo [3,4c] thieno [2,3e] -1,4-diazepine

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

8-bromo-6- (o-chlorophenyl) -1-dimethylamino-4H-s-triazolo [3,4c] thieno [2,3e] -1,4-diazepine,

8-Bromo-6- (o-chlorophenyl) -1-diethylamino-4H-s-triazoio [3,4c] thieno [2,3e] -1,4-diazepine

8-Bromo-6- (o-chlorophenyl) -1- (N-methyl-N-ε-1-α-α-α) -4-N-5-α-γ-α-ω [3,4-s] β-α [2,3e] -1,4-diazepine

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

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

8-Bromo-6- (o-chlorophenyl) -1-di-n-butylamino-4H-s-triazolo [3,4c] thieno [2,3e] -1,4-diazepine

8-bromo-6- (o-chlorophenyl) -1-N-methyl-N- (β-hydroxyethyl) amino-4H-s-triazolo [3,4c] thienof 2,3e] -1,4-diazepine

8-bromo-6- (o-chlorophenyl) -1-di- (3-hydroxyethyl) amino-4H-s-triazolo [3,4c] thieno [2,3e] -1,4-diazepine

8-Ethyl-6- (o-chlorophenyl) -1-dimethylamino-4H-s-triazolo [3,4c] thieno [2,3e] -1,4-diazepine

8-Chloro-6- (o-Chlorophenyl-1-dimethylamino-4H-s-triazolo [3,4c] thienof 2,3e] -1,4-diazepine

8-bromo-6-phenyl-1-dimethylamino-4H-s-triazolo [3,4c] thieno [2,3e] -1,4-diazepine 8-bromo-6- (o-bromophenyl) -1-dimethylamino- 4H-s-triazolo [3,4c] thieno [2,3e] -1,4-diazepine

8-Bromo-6- (o-chlorophenyl) -1-piperidino-4H-s-triazolo [3,4c] thienof 2,3e-1,4-diazepine

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

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

8-bromo-6- (o-chlorophenyl) -1- (2'-methylmorpholino) -4H-s-triazolo [3,4c] thieno [2,3e] -1,4-diazepiin

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

8-bromo-6- (o-chlorophenyl) -1-pyrrolidino-4H-s-triazolo [3,4c] thieno [2,3-c] -1,4-diazepine.

The starting materials of the formula II are known from the literature.

The resulting products of formula (I) have valuable therapeutic properties. In various pharmacological tests, the compounds exhibit buffering, anxiolytic and tension-releasing effects. 'During training. experiments · ^m: moto showed that the novel compounds exhibit a significant neuroleptic effect. This effect was found in a modified test described by Dobrin and Rhyne in Arch. Int. Pharmacodyn. 178, 351-355 (1969), in which animals actively resist against pre-signaled unpleasant stimuli (discrlmlnated actlve)

In particular, this test showed that the new compounds only suppressed the timely behavior of the animals to avoid animals having unpleasant stimuli (electric shocks), but the response of the animals to the immediately following shock remains completely unchanged. Such a selective effect in commercial neuroleptics, such as chlorpromazine, is evaluated as a distinct indicator of neuroleptic properties (Cook, L., Sepinwall, J., Proceedings of the Sixth International Congress of Pharmacology, Volume 3 - Central Nervous System) and behavioral Oxford: Pergamon 1976 (b).

It is further remarkable that this selectivity is particularly pronounced in this case and greatly exceeds the selectivity of commercial preparations.

Thus, the novel compounds of the invention are particularly useful for suppressing psychomotor states of irritation and anxiety, such as those found in schizophrenia, but this soothing and relaxing effect does not cause any wakefulness disturbances.

Particularly active compounds have been found to be those products of the formula I in which R2 represents a chlorine atom, R3 represents a bromine atom and each of R4 and R5 represents a C1-C4 alkyl group or a hydroxyethyl group.

The following table compares the efficacy of a representative compound of the invention with the known commercial formulation "diazepam" in five different assays, which are commonly used in testing psychopharmaceuticals. It is clear from the data in this table that the novel compound of the invention is considerably more effective than diazepam in individual tests. In particular, much lower toxicity of the compound of the invention should be pointed out.

T abu 1 lk a. v ^; ”? * ·. * test compound according to diazepam of the invention autagomising the effect of pentetrazole (mouse; oral administration) 0.23

Geller, (rat; oral · administration) 2.2 audiogenic convulsions (mouse; · oral administration) 2.4 physical activity (mouse; oral administration) 0.08 explorations (mouse; oral administration) 4.6

LD 50/48 hours (mouse; oral) .1800

Legend:

Substance of the Invention: 1'-Dimethyl-4'-dimethoxy-4- (5'-b ') - (O-chlorophenyl) -4H-s-triazolo [3, 4c] thieno [2,3e] 1,4- ^ 261 ^ autagonizing the effects of pentetrazole:

Μ. I. Gluckmann, Curr. Ther. Res., 7, 721 (1965).

Geller:

J. Geller, Arch. Int. Pharmacodyn. 149, 243 (1964).

The unit dose of the compounds of the invention is, when administered orally, from 0.05 to 50 mg, preferably from 0.1 to 25 mg, daily dose from 5 to 150 mg.

Compounds made by Causan; according to the invention, they can be used either alone or in combination with other active substances of 1.2.

1,2

1.4

15.5

99D according to the invention, and optionally in combination with other pharmacologically active agents, such as spasmolytics or β-receptor blocking agents. Suitable dosage forms are, for example, tablets, capsules, suppositories, solutions, syrups, emulsions or dispersible powders. Suitable tablets may be obtained, for example, by admixing the active ingredient (s) with known excipients, for example, inert diluents such as calcium carbonate, calcium phosphate or lactose, 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 effecting agent such as carboxymethyl cellulose, carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets may also consist of several layers.

In an analogous manner, dragees can be obtained by coating dragee cores prepared in a manner similar to tablets with agents commonly used to coat dragees, such as collidone, shellac, gum arabic, talc, titanium dioxide or sugar, to achieve a depot effect or to prevent incompatibility. dragee cores may also consist of several layers. Similarly, the dragee coatings may consist of several layers in order to achieve a depot effect, with the aid of the excipients mentioned above for the tablet formulation in all of these dosage forms.

The syrups containing the active ingredient according to the invention or the active ingredient combinations may further comprise a sweetening agent, such as saccharin, cyclamate, glycerin or sugar, as well as a flavoring agent, for example a flavoring agent such as vanillin or orange extract. These syrups may additionally contain a suspending aid or thickening agent such as sodium carboxymethylcellulose, a wetting agent, for example, a condensation product of a fatty alcohol with ethylene oxide, or a preservative such as p-hydroxybenzoate.

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

Capsules containing one or more active compounds or combinations of active compounds can be prepared, for example, by mixing the active compounds with inert carriers such as milk sugar or sorbitol and filling the mixture with gelatin capsules.

Suitable suppositories may be obtained, for example, by mixing the appropriate carrier materials, such as neutral fats or polyethylene glycol or derivatives thereof, with the active ingredients or the active ingredient combination.

The invention is illustrated by the following non-limiting examples.

Example 1 1-dimethylamino-8-bromo-6- (o-chlorophenyl) -4H-s-trlazolo [3,4c] thieno [2,3e] -1,4-diazepine

4.5 g (0.01 mol) of 1,8-dibromo-6- (o-chlorophenyl) -4H-s-triazolo [3,4c] thleno [2,3e] -1,4-diazepine are added together with 50 ml of dimethylamine in 150 ml of dioxane was heated in an autoclave at 100 ° C for 1 hour. The solvent is distilled off, the residue is partitioned between water and methylene chloride, the imethylene chloride phase is separated, washed with water and dried over magnesium sulphate. The residue was applied to a silica gel column and the product was eluted with methylene chloride / methanol (98: 2). After distilling off the solvent and crystallizing from ethyl acetate, 2.2 g (52% of theory) of the title compound melting at 106 DEG-168 DEG C. is obtained.

Example 2 1-Amino-8-bromo-6- (o-chlorophenyl) -4H-s-triazolo [3,4c] thlenof 2,3e] -1,4-diazepine

A mixture of 5 g (0.013 mol) of 2-hydrazino-5- (o-chlorophenyl) -7-bromothieno [2,3e] -1,4-diazepine in 100 ml of ethanol, 1.4 g of cyanogen bromide and 1.4 g of sodium carbonate was heated to 60 ° C for 30 minutes. The reaction mixture was evaporated, the residue was taken up in methylene chloride and chromatographed on silica gel. 1.5 g (29% of theory) of the desired product melting after crystallization from ethanol at 251 DEG-252 DEG C. is obtained.

Example 3 1-d'methylamino-8-bromo-6- (o-chlorophenyl) -4H-s-triazolo [3,4c] thieno [2,3e] -1,4-diazepine

395 mg of 1-amino-8-bromo-6- (o-chlorophenyl) -4H-s-triazolo (3,4c] thienof 2,3e] -1,4-palzepine together with 5 mml of 85% formic acid and 2 The reaction product was shaken with methylene chloride, the organic phase was evaporated and the residue was chromatographed on silica gel to give 250 mg (60% of theory) of the title compound, m.p. m.p. 164-166 ° C.

The following products are obtained in an analogous manner to Examples 1 to 4:

Rd /

example - N Rž R5 melting point (° i number \ Rs 4 - -HN-CH 3 Cl Br 166 to 168 5 - HN-C2H5 Cl Br 224 to 226 6 - -N (C 2 H 5) 2 Cl Br 143 to 145 7 -kz> Cl Br 224 to 226 8 Cl Br 205 to 207 CH3 / 9 - -N Cl Br 175 to 176 \ CH2-CH2-OH 10 - _n Q-ch ₃ Cl Br 180 11 Cl Br 209 to 210 12 - -N (CH 3) 2 Cl C2H5 130 to 132 13 - -N (CH 3) 2 Cl Cl 154 to 155 14 - -N (CH 3) 2 H Br 216 to 217 15 - -N (CH 3) 2 Br Br 171 16 - -NH- (CH 2) 2 -CH 3 Cl Br 148 to 150 The following is an example of the composition and preparation of dosage forms containing: (b) Tablets effective substances according to the invention. Ingredients:

(a) Dragees

One dragee core contains the following components:

active ingredient according to the invention 1,0mg milk sugar 28,5mg corn starch 19,0mg gelatin 1,0mg magnesium stearate 0,5mg

50.0 mg

Preparation:

The mixture of the active ingredient with milk sugar and corn starch is granulated through a 1 mm mesh screen using a 10% aqueous gelatin solution, dried at 40 ° C and passed through a sieve again. The granules so obtained are mixed with magnesium stearate and dragee cores are pressed. The cores thus obtained are conventionally coated with an aqueous suspension of sugar, titanium dioxide, talc and gum arabic. The finished dragee is polished with beeswax. The resulting dragee weight is 100 milligrams.

active ingredient according to the invention 0.5mg milk sugar 50.0mg corn starch 43.5mg soluble starch 5.0mg magnesium stearate 1.0mg

100.0 mg

Preparation:

The active ingredient and the magnesium stearate are granulated using an aqueous solution of soluble starch, the granulate is dried and thoroughly mixed with milk sugar and corn starch. Tablets weighing 100 mg each containing 0.5 mg of active ingredient are then compressed from the mixture.

c) Suppositories The suppository contains the following components: active ingredient according to the invention 5.0 · mg suppository mass 1695.0 mg

Preparation:

The finely-powdered active ingredient is mixed into the molten suppository to 40 ° C after the immersion homogenizer is allowed. The resulting mass is then cast at 35 ° C in slightly cooled molds.

(d) Ampoules (solution for injection)

Ingredients:

active substance according to invention 0.5 wt. part sodium pyrosulfite 1.0 wt. part disodium ethylenediamine- tetraacetic acids 0.5 wt part

SUBJECT

Claims (1)

OBJECTS sodium chloride 8.5 parts by weight, distilled water up to 1000.0 parts by weight Preparation: The active ingredient and excipients are dissolved in sufficient water and the solution is adjusted to the desired concentration with additional water. The resulting solution is filtered and filled under aseptic conditions with 1 ml ampoules, which are then sterilized and sealed. Each ampoule contains 0.5 mg of active substance. VYNALEZU From production and production 4H-s-'triazolo [3,4- c] thieno: nO '[2,3e] -l, 4-dia ₁ benzodiazepine of formula I may optionally contain a further heteroatom such as oxygen atom. characterized in that the compound of formula (II): wherein: R2 represents a hydrogen, chlorine or bromine atom, R 3 represents chlorine, bromine or C 1 -C 3 alkyl; R 4 and R 5 are either the same or different and are each a hydrogen atom, a C 1 -C 4 alkyl group or a C 2 -C 3 hydroxyalkyl group, or both together form a four or five membered alkylene chain, optionally substituted one methyl group, the resulting six-membered ring in which R2 and R3 are as defined above and Hal represents a halogen atom, reacted with an amine of formula III Rt / HN (III) \ R5 in which Rd and R5 are as defined above.