CH636878A5 - 1-Substituted 8-iodo-6-phenyl-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepines, processes for their preparation and pharmaceutical preparations containing these compounds - Google Patents

Description

The invention relates to new 1-substituted 8-iodo-6-phenyl-4H-s-triazolo [3,4c] thieno [2,3e] l, 4-diazepines of formula I.

and their acid addition salts.

The acid addition salts are physiologically compatible.

In this formula:

R2 is a hydrogen, chlorine or bromine atom; and R3 is a chlorine or bromine atom, the methoxy group, a C3 to Ca cycloalkyl group, a 5- or 6-membered saturated or unsaturated ring containing an oxygen, sulfur or nitrogen atom, and, if R2 is a hydrogen * or a Bromoma means also a methyl group.

The new compounds of the formula I and their acid addition salts are obtained according to the invention by a) preparing compounds of the formula I in which R3 has the meanings given above with the exception of a chlorine or bromine atom,

a) a compound of formula II

636878

J

(II)

in which R2 has the meaning given and X is an HS,

NH2, a lower alkoxy or alkyl mercapto group or a halogen atom, with a compound of formula III

R3-CO-NH-NH2 (III),

in the

R3 has the meaning given under a), or ß) a compound of the formula IV

NH - NH0

J

in which R2 has the meaning given, with an acid of the formula V

R3-COOH (V),

in the

R3 has the meaning given under a) or converts a functional derivative of this acid.

A functional derivative of the acid of formula V is e.g. a connection of one of the formulas Va to Ve

R3-C (OR ') 3 (Va)

R3-C (= NH) -OR '(Vb)

R3-COOR "(Vc)

R3- (C0) 20 (Vd)

R3-COHal (Ve),

wherein

R3 has the meaning given above,

R 'is a lower alkyl group and

R "is the residue of an aliphatic, araliphatic or aromatic alcohol.

b) To prepare compounds of the formula I in which R3 is a chlorine or bromine atom or the methoxy group, a compound of the formula VI

5

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636878

6

(VI)

in the

R2 has the meaning given, chlorinate or brominate and, if desired, then replace the chlorine or bromine atom with a methoxy group.

c) According to the invention, the compounds of formula I are also prepared by using a 4,1-oxazepine of formula VII

(VII),

in which R2 and R3 have the meaning given, by treatment with a strong mineral acid at the oxygen atom, the hydrohalide which forms is mixed with a phosphorus or sulfur halide, the dihalide obtained in this way is reacted with ammonia or ammonia-providing substances and the thieno [2 , 3e] triazolo [3,4c] 5,6-dihydro-1,4-diazepine to an end product of formula I dehydrated.

A compound of the formula I obtained according to a), b) or c) is subsequently, if appropriate, converted into a physiologically acceptable acid addition salt.

The reaction a, a) can generally be carried out at temperatures 35 between 100 and 250 ° C both without solvent and in solvents, such as e.g. Methanol, ethanol, dioxane, chloroform, tetrahydrofuran, benzene, toluene, xylene or mixtures of these solvents, without or in the presence of an acidic catalyst (e.g. hydrochloric acid, sulfuric acid, 40 phosphoric acid, polyphosphoric acid, acetic acid, propionic acid, benzenesulfonic acid or toluenesulfonic acid); it is generally without isolation of the resulting intermediates of formula VIII

NH - NH - CO - R "

(VIII)

to the end product, but isolation of the intermediate product is possible without difficulty if the reaction conditions are milder (e.g. at room temperature).

The reaction a, β) generally takes place using a suitable functional derivative of acetic acid, for example an orthoester of the formula R3-C (OR ') 3, an imino ether of the formula R3-C (= NH) -OR', an ester of Formula R3-COOR "(e.g. a

60 methyl, ethyl or nitrophenyl ester), an acid anhydride of the formula (R3-C0) 20 or an acid halide of the formula R3-CO-Hal. R 'is a lower alkyl group and R "is the rest of an aliphatic, araliphatic or aromatic alcohol. The imino ethers are usually used in the form of their salts with mineral acids, for example as chlorohydrate.

The reaction conditions can be selected depending on the acid derivative used. In general, it can

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636878

Reaction both without and with solvents (e.g. in methanol, ethanol, chloroform, tetrahydrofuran, benzene, toluene or mixtures of these solvents without or in the presence of an acidic catalyst (e.g. hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, acetic acid, propionic acid, benzenesulfonic acid or toluenesulfonic acid) The presence of a base, for example 2-methylimidazole, is also useful as a catalyst, and the reaction temperature is generally between 0 ° C. and 300 ° C., preferably 20 ° and 180 ° C.

To produce such end products of the formula I, in which R3 is a chlorine or bromine atom or a methoxy group, according to process b), a compound of the formula VI is brominated or chlorinated. The halogenation is generally 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 by means of a halosuccinimide. The reaction temperature in this reaction is generally between room temperature and the reflux temperature of the reaction mixture, depending on the starting material used and the method used.

If desired, an 8-halogen compound thus obtained can be converted into the corresponding methoxy derivative.

In this case, the halogen compound is generally dissolved in sodium methylate and the solution is heated under reflux.

Starting from an 8-iodo-6-phenylthieno [2,3f] tri-i5 azolo [3,4a] 4, l-oxazepine of the formula VII, the end product of the formula I according to the invention is obtained in accordance with the following scheme

10th

(VII)

CH2-0H

(Vlla)

\ CH2-Hal2

CH-Hal

R

(Vllb)

(Vile)

636878

8th

Here, the oxazepine ring of the compound of formula VII is first treated by treatment with a strong mineral acid, e.g. split with strong hydrochloric acid or hydrobromic acid at the oxygen atom. To do this, it is generally sufficient to leave the compound in a solution strongly acidified with hydrochloric acid or hydrobromic acid for a few minutes to a few hours at room temperature. The hydrohalide of the compound of the formula VIIa which forms in this reaction is generally extracted from the reaction solution in the cold with a water-immiscible solvent, preferably a chlorinated hydrocarbon such as chloroform or methylene chloride, and - expediently after evaporation of the extraction solution - with a phosphorus or sulfur halide such as thionyl chloride or phosphorus tribromide. The reaction temperature here is generally between 0 and 40 - preferably about 20 ° C.

After the excess halide and any solvent still present have been distilled off, the residue, consisting of a dihalide of the formula VIIIb, is reacted with ammonia or ammonia-providing substances such as urotropin. Preferred solvents for the reaction with ammonia are lower alcohols, e.g. Methanol or ethanol, ethyl acetate, dioxane, tetrahydrofuran or inert hydrocarbons such as benzene and its homologues; but liquid ammonia can also be used for the reaction. The reaction temperature is generally between 0 ° C and the boiling point of the solvent used; however, the reaction is preferably carried out in an autoclave. The compounds of the formula Vile are obtained in excellent yield.

Instead of the compound of the formula VIIa, the reaction with a phosphorus or sulfur halide can also be carried out with the corresponding dihydroxy compound of the formula

J

1H-OH

carry out. They are obtained by heating the strongly acidic solution of the compound of the formula VII and can be extracted from the reaction solution in the same manner as described for the compound of the formula VIIa.

Dehydrogenation of the compound of formula Vile to the end product of formula I is carried out using suitable dehydrating agents such as e.g. of halogens or of compounds of the higher oxidation levels of chromium or manganese, for example a chromate, a bichromate or a permanganate. Examples of suitable solvents for the reaction with a halogen are chlorinated hydrocarbons such as chloroform or methylene chloride; In this reaction, a tertiary organic base, for example pyridine, is expediently added to scavenge the hydrohalic acid formed.

The oxidation with the mentioned compounds of

Chromium or manganese is generally carried out in solvents such as acetone, tetrahydrofuran or dioxane.

Depending on the type of oxidizing agent, the reaction temperature is generally between 0 ° C and the boiling point of the solvent used.

If desired, the end product of the formula I can be converted into a physiologically acceptable acid addition salt in the customary manner. Acids suitable for salt formation are, for example, hydrohalic acids, 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.

Compounds of the formula II are expediently prepared analogously to the compounds described in DE-OS 2217 157 by iodination of the thienodiazepin-3-one of the formula IX

by iodinating them in the usual way and reacting the iodine compound obtained in a solvent such as pyridine, dimethylformamide or tetrahydrofuran or their mixtures with phosphorus pentasulfide. The temperatures used here can e.g. lie between the room temperature and the reflux temperature of the reaction mixture. This gives the corresponding 3-mer capto compound which, after it has been reacted with the aid of a metalating agent such as sodium methylate or sodium amide in a solvent to give the corresponding salts, without prior separation in the usual way with alkylating agents, e.g. Methyl iodide, can be converted into the corresponding methyl mercapto compound.

The hydrazine derivatives of formula IV can be prepared by reacting a compound of formula II with hydrazine. This can be done in one of the solvents mentioned above, if desired one of the aforementioned acidic catalysts can be present. The temperature is conveniently between the room temperature and the reflux temperature of the reaction mixture.

The starting compound of formula VII is described in DE-OS 25 31 679; it can be obtained, for example, by reacting a 7-iodo-5-phenylthieno [2,3f] oxazepine-2-thione using hydrazine hydrate and an orthoacetic acid ester in a manner known per se.

The compound of formula I or its physiologically tolerated acid addition salts has valuable therapeutic properties. It has been shown to be anxiolytic, tension-relieving and sedative in the application of various pharmacological test methods and has also shown an intensive anticonvulsant effect. It also has the property of significantly increasing feed intake in mammals. Their exceptionally low toxicity is remarkable. The single dose is in everything

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generally at 0.05 to 50, preferably 0.1 to 25 mg (oral) and 5 to 150 mg as a daily dose.

The compound obtainable 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 blockers. Suitable forms of use are, for example, tablets, capsules, suppositories, solutions, juices, emulsions or dispersible powders. Corresponding tablets can be obtained, for example, by mixing the active ingredient (s) with known auxiliaries, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or agents to achieve the depot effect, such as carboxypolymethylene, carboxymethylcellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets can also consist of several layers.

Correspondingly, coated tablets can be produced by coating cores produced analogously to the tablets with agents conventionally used in coated tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. The core can also consist of several layers to achieve a deposit effect or to avoid incompatibilities. Likewise, the coated tablet shell can also consist of several layers in order to achieve a depot effect, it being possible to use the auxiliaries mentioned above for the tablets.

Juices of the active substances or combinations of active substances according to the invention can additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar as well as a taste-improving agent, e.g. Flavorings, such as vanillin or orange extract, contain. They can also contain suspending agents or thickening agents, such as sodium carboxymethyl cellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.

Injection solutions are made in the usual way, e.g. with the addition of preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, and filled into injection bottles or ampoules.

The capsules containing one or more active ingredients or combinations of active ingredients can be produced, for example, by mixing the active ingredients with inert carriers, such as milk sugar or sorbitol, and encapsulating them in gelatin capsules.

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

example 1

8-iodo-1-cyclohexyl-6-o-chlorophenyl-4H-s-tri-azolo [3,4c] thieno [2,3e] 1,4-diazepine

5.1 g = 10mMol8-iodo-6- (o-chlorophenyl) -l-cyclohexyl-thieno [2,3f | triazolo [3,4a] 4, l-oxazepine of melting point 217 to 219 ° C by stirring for 30 minutes dissolved in 200 ml of concentrated hydrobromic acid at room temperature. The solution is poured into 400 ml of ice water, neutralized with ammonia, shaken out with methylene chloride and washed with water. 5.2 g = 88% of theory [1-iodo-2- (5-cyclohexyl-3-hydroxymethyl-triazolyl-4) -thenyljo-chlorophenyl-bromomethane are obtained, which are dissolved in 200 ml of methylene chloride without further purification and mixed with 10 ml SOCh

Be refluxed for 30 minutes. The reaction mixture is then washed with ice water and dilute ammonia. After drying and evaporation, the residue is triturated with isopropyl ether and the crude product is filtered off with suction. This is dissolved in 200 ml of methanol and gaseous ammonia is added until a pressure of 5 atm remains constant. The mixture is then heated to 40 ° C. for 30 minutes, then the solution is suctioned off through diatomaceous earth and evaporated. The product is purified by column chromatography. 3.9 g = 87% of theory 8-iodo-5,6-dihydro-6-o-chlorophenyl-1-cyclohexyl-thieno [2,3e] tria-zolo [3,4c] 1,4-diazepine are obtained , which are dissolved in 200 ml of acetone and stirred with 1 g of powdered KMn04 for 20 hours at room temperature. The manganese dioxide is suctioned off, the solution is evaporated and the residue is crystallized using ether.

Yield: 3.5 g = 92% of theory from F. 233 to 235 ° C.

The 8-iodo-6- (o-chlorophenyl) -1 -cyclohexyl-thieno [2,3f] triazolo [3,4a] 4,1-oxazepine used as the starting compound can be prepared as follows:

a) 7-iodo-5- (o-chlorophenyl) thieno [2,3f] oxazepin-2-one

13.5 g = 48 mmol 5- (o-chlorophenyl) thieno [2,3f] oxazepine

2-one are dissolved in 500 ml of chloroform and 13 g of iodine and 8.8 g of HgO (red) are added with stirring at room temperature (10 to 15 minutes). After stirring for 80 minutes, the reaction mixture is filtered off with kieselguhr and washed with sodium carbonate solution and then with sodium thiosulfate solution. The dried chloroform phase is evaporated and the residue is crystallized. The crystals freed from the solvent are washed with a little methylene chloride.

15 g = 77% of the theory of the title compound of melting point 230 to 232 ° C. are obtained.

b) 7-iodo-5- (o-chlorophenyl) thieno [2,3f] oxazepine-2-thione

15 g = 37 mmol of the oxazepin-2-one are in 80 ml

Suspended diglyme and heated to 55 ° C for about 5 minutes after adding 6.6 g P2S5 and 6 g NaHCÛ3. The reaction mixture is then poured into 200 ml of water, the precipitate is filtered off with suction, washed neutral with water and dried at 50 ° C. in vacuo.

Yield: 14 g = 90% of the theory of the title compound of F. 145 ° C (decomposition).

c) 8-iodo-6- (o-chlorophenyl) -1 -cyclohexyl-thieno [2,3f] tri-azolo [3,4a] 4,1-oxazepine

2.1 g = 5 mmol of the thione are dissolved in 40 ml of tetrahydrofuran and mixed with 0.5 ml of hydrazine hydrate. The reaction is complete after a few minutes and the solvent is evaporated off in vacuo. The residue is taken up in methylene chloride, washed with water, the dried solution is evaporated again and the reaction mixture is refluxed for 30 minutes with 20 ml of ethanol and 20 ml of ethyl cyclohexane carboxylate. It is suctioned off, the solution is evaporated and the mixture is crystallized with ether.

Yield: 2.0 g = 77% of theory of the title compound of mp 217 to 219 ° C.

Example 2

8-iodo-1-cyclohexyl-6-o-chlorophenyl-4H-s-tri-azolo [3,4c] thieno [2,3e] 1,4-diazepine

5.5 g of 7-iodo-5- (o-chlorophenyl) -3H [2,3e] thieno-1,4-diazepin-2-thione are stirred with 120 ml of tetrahydrofuran and 2.3 g of hydrazine hydrate for 1 hour at room temperature. The precipitated crystals are then suctioned off in vacuo and recrystallized from ether.

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636878

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4.8 g = 96% of theory 7-iodo-5- (o-chlorophenyl) -2-hydrazino-3H [2,3e] thieno-1,4-diazepine of melting point 145 ° C. (decomposition ).

4.8 g of the hydrazino compound are stirred with 50 ml of absolute alcohol and 30 ml of ethyl cyclohexanecarboxylate under reflux for 2 hours, the reaction mixture is evaporated in vacuo, the residue is eluted over silica gel with methylene chloride containing 5% methanol and recrystallized from acetonitrile.

5.3 g = 91.3% of the theory of title compound from F. 233 to 235 ° C. are obtained.

The starting compound was obtained as follows:

a) 5g5- (o-chlorophenyl) -3H [2,3e] thieno-l, 4-diazepin-2-one are suspended in 200 ml chloroform and alternately a total of 3.3 g HgO and 4.9 g iodine are added. To

15 minutes of stirring at room temperature is suctioned off from the precipitated crystals and these are washed until neutral with sodium bicarbonate and sodium thiosulfate. After evaporation and recrystallization of the residue from alcohol, 7-iodo-5- (o-chlorophenyl) -3H [2,3e] thieno-1,4-diazepin-2-one of mp 222 to 224 ° C. is obtained in a yield of 6.4 g = 87.7% of theory.

b) 6.4 g of the 7-iodine compound are stirred in 100 ml of pyridine and 6.2 g of P2S5 at 70 to 80 ° C. for 4 hours. The reaction mixture is then decomposed in 200 ml of sodium chloride solution and ice. The resulting crystals are washed with ether.

6.1 g = 92.4% of theory 7-iodo-5- (o-chlorophenyl) -3H [2,3e] thieno-1,4-diazepin-2-thione of mp 202 ° C. are obtained .

The following end products were produced analogously to Examples 1 and 2:

example

R2

R3

F. ° C

r0vi

3rd

Cl

V

228 to 230

4th

Cl

1

H

218 to 220

5

Cl

Br

225 to 226

6

Cl

Cl

222 to 224

7

Cl

220 to 222

8th

Cl

Q

223 to 225

9

Cl

-0CH3

201 to 203

10th

Cl ii 1

160 (dec.)

example

R-

R3

F. ° C

11

Br

CHJ

231 to 233

12

H

CHs

250 to 251

5

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15

Formulation examples a) coated tablets 1 coated tablet core contains:

Active ingredient according to the invention

Milk sugar

Cornstarch

gelatin

Magnesium stearate

1.0 mg 28.5 mg 19.0 mg 1.0 mg 0.5 mg 50.0 mg

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30th

Manufacturing:

The mixture of the active substance with milk sugar and corn starch is granulated with a 10% aqueous gelatin solution through a sieve with a mesh size of 1 mm, dried at 40 ° C. and passed through a sieve again. The granules obtained in this way are mixed with magnesium stearate and pressed. The cores obtained in this way are coated in a conventional manner with a casing which is applied with the aid of an aqueous suspension of sugar, titanium dioxide, talc and gum arabic. The finished coated tablets are polished with beeswax.

Dragee final weight: 100 mg b) tablets

Active ingredient according to the invention 35 milk sugar corn starch soluble starch magnesium stearate

40

0.5 mg 50.0 mg 43.5 mg 5.0 mg 1.0 mg 100.0 mg

Manufacturing:

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

c) Suppositories 1 suppository contains:

Active substance according to the invention suppository mass

5.0 mg 1,695.0 mg

Manufacturing:

55 The finely powdered substance is stirred into the molten suppository mass, cooled to 40 ° C, using an immersion homogenizer. The mass is poured into slightly pre-cooled molds at 35 ° C.

B

Claims (14)

636878 2. 8-iodo-6- (o-chlorophenyl) -1 -cyclohexyl-4H-s-tri-azolo [3,4c] thieno [2,3e] l, 4-diazepine and its physiologically compatible acid addition salts as compounds according to claim 1. 2nd PATENT CLAIMS 1,1-substituted 8-iodo-6-phenyl-4H-s-triazolo [3,4c] -thieno [2,3e] l, 4-diazepines of formula I. = N in the R2 is a hydrogen, chlorine or bromine atom; R3 is a chlorine or bromine atom, the methoxy group, a C3 to Cs cycloalkyl group, a 5- or 6-membered ring containing a saturated or unsaturated ring containing an oxygen, a sulfur or a nitrogen atom, and, if R2, a hydrogen atom or a Bromine means also mean a methyl group, as well as their physiologically tolerable acid addition salts. 3rd N (Vllb) dehydrated to give an end product of the formula I, and if appropriate converting such a compound of the formula I into a 65 physiologically acceptable acid addition salt. 3rd 636878 in which R3 has the meaning given above or converts a functional derivative of this acid and, if appropriate, converts a compound of the formula I obtained into a physiologically acceptable acid addition salt. 3. 8-iodo-6- (o-chlorophenyl) -l-tetrahydropyranyl- (4) -4H-s-triazolo [3,4c] thieno [2,3e] l, 4-diazepine and its physiologically tolerable acid addition salts as compounds according to claim 1. 4th CH2-0H (Vlla) (I), wherein R2 and R3 have the meanings given in claim 1, characterized in that a strongly mixed with a phosphorus or sulfur halide, the acidic solution of a 4,1-oxazepine of the formula VII obtained dihalide of the formula VIIb \ CH2-Hal2 CH-Hal R (Vllb) (VII), in which R2 and R3 have the meaning given above, heated, reacting the dihydroxy compound of the formula 35 VIII forming with ammonia or ammonia-providing substances and the thieno [2,3e] triazolo [3,4c] 5,6-dihydro- 1,4-diazepine of the formula Vile 45 50 CH2-0H (Vlld) > _ v mixed with a phosphorus or sulfur halide, the dihalide of the formula VIIIb thus obtained 4. 8-iodo-6- (o-bromophenyl) -l-methyl-4H-s-tri-azolo [3,4c] thieno [2,3ejl, 4-diazepine and its physiologically tolerable acid addition salts as compounds according to claim 1. 5 5. 8-iodo-6- (o-chlorophenyl) -1-bromo-4H-s-tri-azolo [3,4c] thieno [2,3e] l, 4-diazepine and its physiologically acceptable acid addition salts as compounds according to claim 1. 6. 8-iodo-6- (o-chlorophenyl) -1-methoxy-4H-s-triazolo- [3,4c] thieno [2,3e] 1,4-diazepine and its physiologically tolerable acid addition salts as compounds according to claim 1 . 7. Process for the preparation of compounds of formula I. = N wherein R2 and R3 have the meanings given in claim 1, with the exception of a chlorine or bromine atom for R3, characterized in that a compound of formula II J (II) in which R2 has the meaning given above and X has one HS, NH2, a lower alkoxy or alkyl mercapto group or a halogen atom, with a compound of formula III R3-CO-NH-NH2 (III), in which R3 has the meaning given above, and optionally converting a compound of the formula I obtained into a physiologically acceptable acid addition salt. 8. Process for the preparation of compounds of formula I. wherein R2 and R3 have the meanings given in claim 1, with the exception of a chlorine or bromine atom for R3, characterized in that a compound of formula IV J in which R2 has the meaning given above, with an acid of the formula V R3-COOH (V), 9. The method according to claim 8, characterized in that as a functional derivative of the acid of formula V, a compound of formula R3-C (OR ') 3 R3-C (= NH) -OR ' R3-COOR " R3- (C0) 20 R3-COHal (Va) (Vb) (Vc) (Vd) or (Ve), wherein R3 has the meaning given in claim 8, R 'is a lower alkyl group and R "mean the residue of an aliphatic, araliphatic or aromatic alcohol. 10. Process for the preparation of compounds of formula I. io 15 (I), wherein R2 has the meaning given in claim 1 and R3 is the methoxy group, characterized in that 20 a compound of the formula I is prepared by the process according to claim 10, in which R3 is a chlorine or bromine atom, then the chlorine or bromine atom against the methoxy group is exchanged and, if appropriate, a compound of the formula I obtained is converted into a physiologically acceptable acid addition salt. 10th 15 20th 25th 30th 35 40 45 50 55 60 65 11. Process for the preparation of compounds which atom splits, the hydrohalide which forms Formula I Formula Vlla 636878 12. Process for the preparation of compounds of formula I. (I), 30th 35 40 wherein R2 has the meaning given in claim 1 and R3 is a chlorine or bromine atom, characterized in that a compound of formula VI (i), 45 wherein R2 and R3 have the meanings given in claim 1, characterized in that a 4,1-oxazepine of the formula VII (VI), (VII), in which R2 has the meaning given above, chlorinated or brominated and, if appropriate, converted a compound of the formula I obtained into a physiologically acceptable acid addi- 65 in which R2 and R3 have the meaning given, by ion salt. Treatment with a strong mineral acid on oxygen 13. Process for the preparation of compounds of formula I. CH-Hal. R with ammonia or ammonia-providing substances and the resulting thieno [2,3e] triazolo [3,4c] 5,6-dihydro-1,4-diazepine of the formula Vile J dehydrated to give an end product of the formula I, and if appropriate converting such a compound of the formula I into a physiologically acceptable acid addition salt. 14. Pharmaceutical preparations containing, as active ingredient, compounds of the formula I in combination with auxiliaries and / or carriers.