NL7905483A - NEW SUBSTITUTED 4H-S-TRIAZOLO / 3,4C / THIE-NO / 2,3E / 1,4-DIAZEPINES, METHOD OF PREPARATION THEREOF, AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS. - Google Patents

Description

t “* * * C.H. Boehringer Sohn, Ingelheim am Rhein, Federal Republic of Germany.

Burma under German law

Novel substituted 4H-s-triazolo / 3,4c / thieno / 2,3e / -1,4-diazepines, method of preparation thereof, as well as pharmaceutical preparations containing these compounds.

The invention relates to compounds of the general formula I, wherein hydrogen, fluorine, chlorine or bromine, R 1 represents chlorine or bromine or an alkyl radical having 1 to 3 carbon atoms and R 1 and R 1, which are the same or different, hydrogen, an alkyl radical of 1-4 carbon atoms or a hydroxyalkyl radical of 2-3 carbon atoms or R, and Rc together form a 4- or 5-membered alkylene chain, which may optionally be substituted by one or two methyl groups, and wherein the 6-ring, optionally if further heteroatom can contain an oxygen atom.

The invention further relates to a method of preparing the new compounds of the general formula 1 as well as to their use as active substances in medicaments.

The new compounds of the general formula I can be obtained (a) by reacting a compound of the general formula 2, in which and have the meanings indicated above, with an amine of the general formula 3, wherein R 1 and R have the meanings indicated above, or 0 (b) by dehydration of a compound of general formula 4, wherein R 1, R 1, R 1, and R 1. have the meanings indicated above, in a manner known per se.

7905483 i \ * - 2 -

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The reaction of the compounds of the general formula II with an amine of the formula III takes place either without a solvent or in a solvent, such as benzene, toluene, dioxane, tetrahydrofuran, a chlorohydrocarbon, such as tetrachloro-carbon or methylene chloride, preferably at the boiling temperature of the respective solvent used. In the reaction with lower amines (dimethylamine, diethylamine, etc.), the reaction is preferably carried out in an autoclave.

The reaction time depends on the starting material used and can vary between a few minutes and several hours.

Dehydration of the compounds of the general formula IV is effected using suitable dehydrating agents, for example halogens or also compounds of the higher oxidation steps of chromium or manganese, for example a chromate, a dichromate or a permanganate. Chlorocarbons, such as chloroform or methylene chloride, can be mentioned as suitable solvents for the reaction with a halogen. The oxidation with the said compounds of chromium or manganese takes place in solvents such as acetone, tetrahydrofuran or dioxane, if desired with the addition of phase transport catalysts. Depending on the nature of the oxidizing agent, the reaction temperature is generally between 0 ° C and the boiling temperature of the solvent used.

The 1-amino compounds (R @ en = hydrogen) are obtained by reacting a 2-hydrazino-thieno / 2,3e / 1,4-diazepine with cyanogen bromide according to the reaction scheme indicated on the formula sheet (see KT Potts and C Hirsch, J. Org. Chem. 33, 143 (1 * 968)).

Alcohols, benzene, toluene and halohydrocarbons are suitable as solvents.

These compounds can be alkylated if desired. Preferred alkylating agents are alkyl halides, dialkyl sulfates or esters of toluene sulfonic acid; solvents such as tetrahydrofuran, dimethylformamide or lower alcohols are used, but the alkylation can also be carried out without adding a solvent. In the case of the introduction of a hydroxyalkyl radical, it is recommended to carry out the reaction with an alkylene oxide.

For example, according to the above-mentioned processes, the following end products can be obtained, namely 8-bromo-6- (o-chlorophenyl) -1-amino-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, 10 8-bromo-6- (o-chlorophenyl 1-ethylamino-4H-s-triazolo / 3,4c / thieno / 2,3e / - 1,4-diazepine, 8-bromo-6- (o-chloropheny1) -1-dimethylamino-4H-s-triazolo / 3 4c / thieno / 2,3e / 1,4-diazepine, 8-bromo-6- (o-chlorophenyl) -1-diethylamino-4H-s-triazolo / 3,4c7thieno-15 / 2,3e71.4-diazepine, 8-Bromo-6- (o-chlorophenyl) -1- (N-methyl-N-ethylamino) -4H-s-triazolo / 3,4c7-thieno / 2,3e71,4-diazepine, 8-bromo-6- (o-chloropheny1) -1-n-propylamino-4H-s-triazolo / 3,4c7thieno / 2,3e7l.4-diazepine, 20 8-bromo-6- (o-chlorophenyl) -1-di-isopropylamino- 4H-s-triazolo / 3,4c7thieno- / 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-chloropheny 1) -1 -N-methyl-N- (β-hydroxyethy 1) -amino-4H-s-25 triazolo / 3,4c / thieno / 2,3e / 1,4-diazepine, 8-bromo-6- (o-chloropheny1) -1-di- (β-hydroxyethy1) -amino-4H- s-triazolo- / 3,4c / thieno / 2,3e71 · 4-diazepine, * 8-ethy1-6- (o-chloropheny1) -1-dimethylamino-4H-s-triazolo / 3,4c7thieno- / 2,3e 1.4-diazepine, 8-chloro-6- (o-chlorophenyl) -1-dimethylamino-4H-s-triazolo / 3,4-thieno-2,3e-1,4-diazepine, 8-bromo-6-phenyl-1 -dimethylamino-4H-s-triazolo / 3,4c7thieno / 2,3e71,4-diazepine, 8-bromo-6- (o-bromophenyl) -1-dimethylamino-4H-s-triazolo / 3,4c7thieno-55/2 , 3rd / I.4-diazepine, 790 5 483 - 4 ..........

Λ * t 8-bromo-6- (o-chloropheny1) -1-piperidino-4H-s-triazolo / 3,4c / thieno- / 2,3e / l.4-diazepine, 8-bromo-6- (o - chlorophenyl) -1- (2'4'-dimethylpiperidino) -4H-s-triazolo- / 3,4c / thieno / 2,3e / 1,4-diazepine, 5-8-bromo-6- (o-chloropheny ' l) -1-morpholino-4H-s-triazolo / 3,4c / thieno / 2,3e / - 1,4-diazepine, 8-bromo-6- (o-chlorophenyl) -1- (Z-methylmorpholino) -4H- s-triazolo / 3,4c / -thieno / 2,3e / 1,4-diazepine, 8-bromo-6- (o-chlorophenyl) -1- (4 '. -methylpiperidino) -4H-s-triazolo / 3,4c7 10 thieno / 2,3e / 1,4-diazepine, and 8-bromo-6- (o-chlorophenyl) -1-pyrrolidino-4H-s-triazolo / 3,4c / thieno / 2,3e / l. 4-diazepine.

The starting compounds of the general formula II are known from the literature. The starting compounds of the general formula IV are obtained by reacting a compound of the formula 5, in which R 1 and the above meanings and Hal represents a halogen atom, with an amine of the general formula 3 under the conditions indicated in (a) and then subsequent exchange of the ring oxygen atom by a nitrogen atom, such as is described, for example, in German patent application P 2,531,678.

The final products of the general formula 1 have valuable therapeutic properties. For example, when performing various pharmacological test methods, they exhibit calming, anxiolytic and stress relieving properties. In addition, 25 dressage tests showed that the new compounds have a pronounced neuroleptic effect. This activity was determined by the reported discriminated active avoidance behavior according to a modified test by Dobrin, P.B., Rhyne, Arch. Int. Pharmacodyn. 178, 351-356 (1969).

In particular, it was found that the new compounds only suppress the timely avoidance actions, but on the contrary leave the reaction to the direct shock completely intact. Such selective activity is valued as a strong indication of neuroleptic properties in commercially available neuroleptics, such as chlorpromazine (L. Cook, 7905483 t .. 5 J. Sepinwall, Proceedings of the sixth international congress of pharmacology. , Vol. 3 - Central Nervous system and behavioral pharmacology, Oxford, Pergamon 1976 b).

It should further be noted that this selection 5 is particularly pronounced in the present case and is clearly superior to that of the commercially available products.

The new compounds according to the invention are therefore particularly suitable for the elimination of psychomotor arousal and anxiety states, such as they occur, for example, in schizophrenia, but this calming and relaxation effect does not cause a disturbance in the degree of alertness.

Particularly effective have been found the end products of the general formula I, wherein chlorine, R 1 bromine and and R 1 represent lower alkyl groups or a β-hydroxyethyl radical.

The individual dose of the compounds according to the invention is 0.05 - 50 and preferably 0.1 - 25 mg when administered orally, while the daily dose is 5 - 150 mg.

The compounds according to the invention can be used alone or in combination with other active substances according to the invention, optionally also in combination with further pharmacologically active substances, such as antispasmodics or β-receptor blocking agents. Suitable dosage forms are, for example, tablets, capsules, suppositories, solutions, juices, emulsions or dispersible powders. Suitable tablets can, for example, by mixing the active substance or the active substances with known auxiliary substances, for example inert diluents, such as calcium carbonate, calcium phosphate or milk sugar, wetting agents, such as corn starch or alginic acid, binders, such as starch or gelatin, lubricants, such as magnesium stearate or talc, and / or means for obtaining a depo effect, such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also consist of several layers.

Likewise, dragees can be prepared by coating cores analogous to the tablets obtained with agents commonly used in dragee coatings 790 54 83 * 6 .....

for example, kollidone or shellack, gum arabic, talc, titanium dioxide or sugar. The core may also consist of several layers to obtain a depot effect or to avoid an incompatibility.

Likewise, the dragee coating may also be multilayered to provide a depot effect, using the excipients listed above for the tablets.

Juices of the active substances according to the invention, for example combinations of active substances, may additionally also contain a sweetener, such as saccharine, cyclamate, glycerol or sugar, as well as a flavor-enhancing agent, for example flavoring substances, such as vanillin or orange extract. They may additionally contain suspending aids or thickeners, such as sodium carboxymethyl cellulose, wetting agents, such as condensation products of fatty alcohols with ethylene oxide, or preservatives, such as p-hydroxybenzoates.

Injection solutions are prepared in the usual manner, for example with the addition of preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediamine tetraacetic acid, and filled into injection vials or 20 ampoules.

The one or more active substances or combinations of capsules containing active substances can for instance be prepared by mixing the active substances with inert carriers, such as milk sugar or sorbite, and encapsulating them in gelatin capsules.

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

The invention is further illustrated but not limited by the following examples.

Example I

1-Dimethylamino-8-bromo-6- (o-chlorophenyl) -4H-s-triazolo / 3,4c / thieno / 2,3e / 1,4-diazepine.

35 0.01 Mol (= 4.5g) 1,8-dibromo-6- (o-chlorophenyl) -4H-s-triazolo / 3,4c7 “790 5483 • Β Ψ **» 7 thieno / 2,3e / 1,4-diazepine are heated in an autoclave with 50 ml of dime thylamine in 150 ml of dioxane for 1 hour at 100 ° C. The solvent is distilled off, the residue is partitioned between water and methylene chloride, the methylene chloride phase is separated, washed with water and dried over magnesium sulfate. The residue is placed on a SiO 2 column and the substance is eluted with methylene chloride-methanol (98: 2).

After distilling off the solvent, 2.2 g (52% of theory) of the title compound are obtained from vinegar ester; melting point = 166-168 ° C. Example II

10 l-Dimethylamino-8-bromo-6- (o-chlorophenyl) -4H-s-triazolo / 3,4c / thieno / 2,3e / 1,4-diazepine.

4.2g (= 0.01 mol) 1-dimethylamino-8-bromo-6- (o-chlorophenyl) -4H-s-triazolo / 3,4c / thieno / 2,3e / 5.6-dihydro-1,4- Diazepine is dissolved in 50 ml of methylene chloride and after adding 0.2 grams of triethyl-N-15 benzylanmonium chloride at 0-5 ° C with a solution of 2 grams of potassium permanganate in 20 ml of acetone. After 15 minutes, Na bisul cycling solution is added and the reaction mixture is acidified with dilute sulfuric acid. The title compound is obtained from the organic phase.

The yield is 3.1 grams (75% of the theory); mp 165-167 ° C.

The 5.6 dihydro compound was obtained in the following manner.

(a) 53 mmol (= 20 g) 7-broonr-5- (o-chlorophenyl) -thieno / 2,3e / 4,1-oxazepine-2-thione (prepared as described in Belgian Patent 844,170) are made in 600 ml of methylene chloride with 12 g of formylhydrazide 25 and 80 ml of pyridine stirred at room temperature for 45 minutes.

Then 10 grams of POGl2 in 50 ml of methylene chloride are added dropwise at a maximum of 35 ° C and the mixture is stirred under reflux for 5 hours. After cooling, the organic phase is shaken with 200 ml of 2N hydrochloric acid and washed with water. After drying, the organic phase is evaporated and the residue is taken up in hot vinegar ester.

On cooling, 15 grams (75% of theory) of 8-bromo-6- (o-chlorophenyl) -4H-s-triazolo / 3,4c / thieno / 2,3e / 4,1-oxazepine are obtained; melting point = 176-178 ° C.

(b) 28 Grams of this compound are distributed in 280 ml of methylene chloride and 8.9 ml of pyridine with 5.4 ml of bromine. The mixture is refluxed for 3 hours, refluxed with water after cooling, the organic phase is dried with magnesium sulfate, evaporated and the residue is passed over SiO4. 19.2 grams (57% of theory) of 1,8-dibromo-6- (o-chlorophenyl) -4H-s-triazolo / 3,4c / thieno / 2,3e / 4,1-oxa-5 are obtained from methanol zepine; melting point = 138 ° C.

(c) 9.2 Grams (0.02 mol) of the dibromo compound are heated in an autoclave with 300 ml of dioxane and 100 ml of dimethylamine for 1 hour at 100 ° C. After the solvent has been distilled off, the residue is taken up in methylene chloride, washed with water, the organic phase is dried over magnesium sulphate and 1-dimethylamino-8-bromo-6- (o-chlorophenyl) -4H-s is obtained as the residue. -triazolo / 3,4c / thieno / 2,3e / 4,1-oxazepine as an oil (7.0 grams = 82% of theory).

(d) 8.5 Grams (0.02 mol) of the oxazepine obtained according to (c) are stirred with 50 ml of concentrated hydrobromic acid for 1 hour at room temperature. It is diluted with 200 ml of water, made alkaline with ammonia and shaken with 100 ml of methylene chloride. The methylene chloride solution is stirred with 4 ml of thionyl chloride for 1 hour. The excess thionyl chloride is decomposed carefully with water and dilute ammonia, the organic phase is separated off and, after evaporation and addition of ether, 20 grams are obtained (92% of theory) 3-dimethylamino-4- / 3- (o-chlorph eny 1-bromomethyl) -5-bromothieny 1- (2) / -5-chloromethyl-1,2,4-triazole melting point = 203 ° C.

. (e) 5.3 Grams (0.01 mol) of the triazole are heated in an autoclave with 100 ml of ammonia-saturated methanol for 30 minutes at 60 ° C. The product is evaporated and the product is worked up. The yield is 2.8 grams (66% of theory) 1-dimethylamino-8-bromo-6- (o-chlorophenyl) -4H-s-triazolo / 3,4c / thieno / 2,3e / 5,6- dihydro-1,4-diazepine; melting point = 155-157 ° C.

Example III

30 l-Amino-8-bromo-6- (o-chlorophenyl) -4H-s-triazolo / 3,4c / thieno / 2,3e / 1,4-diazepine.

0.013 mol (= »5 g) 2-hydrazino-5- (o-chlorophenyl) -7-bromo-thieno / 2,3e / - 1,4-diazepine with 100 ml of ethanol, 1.4 g of cyanogen bromide and 1 .4 grams of sodium carbonate are heated to 60 ° C for 30 minutes. It is evaporated, the residue is taken up in methylene chloride and chromatographed on SiOg 790 54 83. The yield is 1.5 grams (29% of theory) with a melting point of 251-252 ° C (from ethanol).

Example IV

1-Dimethylaraino-8-bromo-6- (o-chlorophenyl) -kH-s-triazolo / 3, UcTthieno-5 / 2,3e7l-U-diazepine.

395 mg of 1-Amino-8-bromo-6- (o-chlorophenyl) -kis-triazolo / 3,4-thieno / 2,3e7-1-k-diazepine together with 5 ml of 85 lb-formic acid and 2 ml of 30J6 * s formalin solution refluxed for 15 hours.

After cooling, the reaction product is shaken with methylene chloride.

The organic phase is evaporated and the residue is chromatographed on a silica gel column. 250 mg of the title compound having a melting point of 16U-166 [deg.] C. (theoretical) are obtained from the eluates.

Analogous to Examples I-IV, the following final products were prepared.

15 7905483 - 10 .....

* * v ft

Example B -N Bp R- Mp. (° cj _i____ V -m-CH3 Cl Br 166-168 5 VI -HU-CgHj Cl Br 22U-22 6 VII -N (C2H5) 2 Cl Br 11 + 3-11 + 5 VIII o Cl Br 22 ^ -226 1Q IX 3 Cl Br 205-207 X -lT ^ CE3 ^ CHg-CHg-OH Cl Br 175-176 XI -N VcEL Cl Br 180 15 W 3 XII -hG Cl Br 209-210 xiii -n (ch3) 2 ci c2h5 130-132 20 XIV -N (CH3) 2 Cl Cl 15 ^ -155 XV -R (CH3) 2 H Br 216-217 XVI -N (CH3) 2 Br Br 171 25 XVII -NH- (CH2) 2- CH3 Cl Br 11 + 8-150

Preparation Examples (a) Dragees 1 Dragêkern contains: Active substance of the invention 1.0 mg

Milk sugar 28.5 mg

Corn starch 19.0 mg

Gelatin 1.0 mg

Magnesium stearate 0.5 35 50.0 mg 7905483. 11

Preparation

The mixture of the active substance with milk sugar and corn starch is granulated with a 10% aqueous latin solution through a sieve with a mesh width of 1 mm * at 0 ° C and dried again through a sieve. The granulate thus obtained is mixed with magnesium stearate and pressed. The cores thus obtained are conventionally provided with a coating which is applied with an aqueous suspension of sugar, titanium dioxide, talc and gum arabic. The finished dragees are polished with beeswax 10. The dragee - final weight is 100 mg.

(b) Tablets

Active substance according to the invention 0.5 mg

Milk sugar 50.0 mg

Starch 1 * 3.5 mg 15 Soluble starch 5.0 mg

Magnesium stearate 1.0 mg 100.0 mg

Preparation

The active substance and magnesium stearate are granulated with an aqueous solution of the soluble starch, the granulate is dried and intimately mixed with milk sugar and corn starch. The mixture is then pressed into tablets weighing 100 mg, each containing 0.5 mg of the active ingredient.

(c) Suppositories 25 1 suppository contains: active substance according to the invention 5.0 mg suppository mass 1695.0 mg

Preparation

The finely powdered substance is stirred into the melted suppository mass with the aid of an immersion homogenizer. The mass is poured into slightly pre-cooled molds at 35 ° C.

35 7905483

Claims (10)

15 CONCLUSIONS 1. New substituted 4H-s-triazolo / 3,4c/thieno/2,3e/1,4-diazepines of the general formula 1, wherein hydrogen, fluorine, chlorine or bromine, R1 represents chlorine or bromine or an alkyl radical having 1-3 carbon atoms and and R 1, which are equal to or different, represent hydrogen, an alkyl radical of 1-4 carbon atoms or a hydroxyalkyl radical of 2-3 carbon atoms or R 1 and R 8. together form a 4- or 5-membered alkylene chain, which may optionally be substituted by one or two methyl groups, and wherein the 6-ring may optionally contain an oxygen atom as further heteroatom. 2. New substituted 4'-s-triazolo / 3,4c / thieno / 2,3e / 1,4-diazepines of the general formula 1, wherein R 2 is a chlorine atom, R 1 a bromine atom and R 1 and R 1 alkyl groups of 1-3 carbon atoms or ones of the radicals represent a β-hydroxyethyl group. 3. 1-Dimethylamino-8-bromo-6- (o-chlorophenyl) -4H-s-triazolo / 3,4c / thieno / 2,3e / 1,4-diazepine. 4. 1-Diethylamino-8-bromo-6- (o-chloro-phenyl) -4H-2-triazolo / 3,4c / thieno / 2,3e / 1,4-diazepine. 5.1 / N-methy1-N- (8-hydroxyethy1) -amino / -8-bromo-6- 790 54 83 w-13 (o-chlorophenyl) -1 * Hs-triazolo / 3, Uc7thieno / S , 3e71.U-diazepine. 6. Process for the preparation of a new substituted 1 * Hs-triazolo / 3, Uc7thieno / 2,3e7l-dizepines, characterized in that compounds of the general formula 1, wherein Rg, Rl, Rl and R ^ 5 have the meanings indicated in claim 1, prepared by using (a) a compound of the general formula II, wherein Rg and R ^ have the meanings indicated above and Hal represents a halogen atom, with amines of the general formula III, wherein R ^ and R ^ 10 have the above-mentioned meanings, dehydrate or (b) dehydrate compounds of the general formula U, in which Rg, R ^, R ^ and R ^ have the meanings indicated above, in a manner known per se. 7 * Pharmaceutical preparations containing, as active substance, one or more compounds of the general formula 1 as defined in claim 1, optionally in combination with conventional auxiliary and / or carrier substances, Method for the treatment of psychomotor arousal and anxiety states and diseases of a schizophrenic nature, characterized in that use is made of a pharmaceutical preparation as defined in claim 7 * Pharmaceutical preparations according to claim 7 in the form of pharmaceutical articles, such as tablets or the like. 10. Compounds, methods and pharmaceutical preparations as described in the description and / or examples. 30 35 ';! ; 7905483