IE46501B1 - Triazolothienodiazepines - Google Patents

Abstract

The 1-substituted 8-iodo-6-phenyl-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepines of the formula I, as well as their physiologically tolerated acid addition salts, are prepared by cleaving a 4,1-oxazepine of the formula VII at the oxygen atom by treatment with a strong mineral acid, adding a phosphorus or sulphur halide to the hydro halide which forms, reacting the dihalide thus obtained with ammonia or substances giving rise to ammonia, and dehydrogenating the product. The substituents in the formulae I and VII have the meanings given in Patent Claim 1. Further preparation processes are given in Patent Claims 7 to 11 and 13. The compounds exhibit valuable therapeutic properties, in particular tranquillising, tension-releasing and sedative activity, as well as an intensive anticonvulsive effect, in association with extraordinarily low toxicity. In addition, they can be employed for improving feed uptake in mammals.

Description

This invention is concerned with novel 1-substituted 8-iodo-6-phenyl-4H-s-triazolo[3,4c]thieno[2,3e] 1,4-diazepines having interesting pharmacological properties.

According to the present invention, there are provided compounds of general formula (wherein R2 represents a hydrogen, chlorine or bromine atom; and 10 represents a chlorine or bromine atom, a methoxy group, a G^-Gg-cycloalkyl group, a 5- or 6-membered oxygen- , sulfur- or nitrogen atom-containing saturated or unsaturated ring or, where R^ represents a hydrogen or bromine atom, a methyl group) and acid addition salts thereof It will be appreciated that salts of the compounds of general formula I for use in medicine should be physiologically acceptable. Other salts may however be useful in the preparation of the compounds of general formula I or physiologically acceptable salts thereof.

As stated above, the compounds of general formula I and their acid addition salts possess interesting pharmacological properties. Thus pharmacological tests which we have carried out have indicated anxiolytic, tension-relieving and sedative actions, a strong anticonvulsive action, and also the property of substantially increasing the uptake of food in warm-blooded animals.

The compounds according to the invention have furthermore been demonstrated to have very low toxicity.

Preferred compounds according to the invention by virtue of their particularly interesting pharmacological properties include compounds of formula I in which represents a cyclohexyl or tetrahydropyranyl group. Particularly preferred compounds according to the invention by virtue of their especially interesting pharmacological properties aie the following:8-iodo-6-(o-chlorophenyl)-l-cyclohexyl-4H-s-triazolo [3,4cj-thieno[2,3e]l,4-diazepine and its physiologically acceptable acid addition salts. 8-iodo-6-(o-chlorophenyl)-l-tetrahydropyranyl-(4)-4Hs-triazolo[3,4c]thieno[2,3e]l,4-diazepine and its physiologically acceptable acid addition salts. 8-iodo-6-(o-bromophenyl)-l-methyl-4H-s-triazolo[3,4c]thieno[2,3e]l,4-diazepine and its physiologically acceptable acid addition salts, 8-iodo-6-(o-chlorophenyl)-l— bromo-4H-s-triazolo[3,4c]thieno-[2,3e]l,4-diazepine and its physiologically acceptable acid addition salts;and 8-iodo-6-(o-chlorophenyl)-l-methoxy-4H-s-triazolo [3,4c]thieno[2,3e]l,4-diazepine and its physiologically acceptable acid addition salts.

The novel compounds of general formula I and their acid addition salts may be prepared by the following - 3 d@SOi processes, which processes form further features of the present invention!a) for the preparation of compounds of general formula I where R^ is as defined above other than a chlorine or bromine atom, either a) reacting a compound of formula (wherein R2 is as hereinbefore defined and X represents “SH,“NH2s a C-j-Cg alkoxy- or alkylmercapto group or a halogen atom) with a compound of formula r3-co-nh-nh2 (III) (wherein R'^ is as hereinbefore defined other than a chlorine or bromine atom),or β) reacting a compound of formula (wherein R2 is as hereinbefore defined) with an acid of formula , 46S01 Rg - COOH (V) (wherein Rg is as hereinbefore defined other than a chlorine or bromine atom) or with a functional derivative of the said acid; b) for the preparation of compounds of formula I where R3 represents a chlorine or bromine atom or a methoxy group, chlorinating or brominating a compound of formula (wherein Rg is as hereinbefore defined), and if desired converting the compound of formula I in which Rg represents a chlorine or bromine atom thus formed into a further compound of formula I in which Rg represents a methoxy group; or c) dehydrogenating a compound of formula '/ - 5 >46501 (wherein and Rg are as hereinbefore defined) , the compound of formula VIIc preferably being first prepared from a compound of formula VII (VII) The compounds of formula I obtained by processes a) , b)or c) may then if desired be converted into physiologically acceptable or other acid addition salts thereof.

Reaction a,a) may conveniently be effected at temperatures between 100 and 250°C either in the absence of a solvent or in the presence of a solvent which may for example comprise methanol, ethanol, dioxan, chloroform, tetrahydrofuran, benzene, toluene, xylene or mixtures of these solvents. The reaction is with advantage carried out in the presence of an acid catalyst (for example hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, acetic acid, propionic acid, benzenesulfonic acid or toluenesulfonic acid). The final product can in general be obtained without isolating the intermediate compound of formula -64U3U1 NH - NH - COR N-X r (VIII) The isolation of the intermediate compound of formula VIII is, however, practicable without difficulty if desired by the use of mild reaction conditions (for example by carrying out the reaction at room temperature).

Where the intermediate compound of formula VIII is isolated, the step of cyclising this compound to form a compound of formula I constitutes a further feature of the present invention.

Reaction a, β) is effected by using an appropriate functional derivative of the acid of formula V, for example an orthoester of formula Rg C(OR')g, an iminoether of formula Rg-C(=NH)-OR', an ester of formula RgCOOR (for example a methyl, ethyl or nitrophenyl ester), an acid anhydride or an acid halide of formula Rg-CO-Hal where Hal represents a halogen atom. In the above formulae, R ’ represents a C1 or C2 alkyl group and R represents the residue of an aliphatic or araliphatic alcohol or a phenol. The iminoethers are as usual con20 veniently used in the form of their salts with mineral acids, for example as the chlorohydrate.

The reaction conditions may be selected according to the functional derivative used. The reaction may in general be carried out either in the absence of a solvent or in the presence of a solvent which may for example comprise methanol, ethanol, chloroform, tetra7 46501 hydrofuran, benzene, toluene or mixtures of these solvents. The reaction is with advantage carried out in the presence of an acid catalyst (for example hydrochloric acid, sulfuric acid, phosphoric acid, poly5 phosphoric acid, acetic acid, propionic acid, benzenesulfonic acid or toluenesulfonic acid ) or in the presence of a base catalyst such as for example 2methylimidazole. The reaction temperature is conveniently between 0° and 300°C, preferably between 20° and 180°C.

The chlorination or bromination of a compound of formula (VI) according to Reaction b) is conveniently effected in solvents such as for example carbon tetrachloride, chloroform, methylene chloride, dioxan, tetrahydrofuran, dimethylformamide or a suitable hydrocarbon, optionally in the presence of a tertiary organic base such as for example pyridine. Alternatively Reaction b) may be effected by means of an appropriate halogenosuccinimide. The reaction temperature is conveniently between room temperature and the reflux temperature of the reaction mixture, the preferred temperature depending upon the starting materials and precise method used. If desired, the 8- halo compound prepared in accordance with Reaction b) may then be converted into the corresponding 8-methoxy compound, conveniently by refluxing with sodium methoxyl ate.

Using Reaction c) according to the invention and starting from a compound of formula VII, the compound of formula Vile may be obtained according to the following reaction scheme: 46S0 i (Vila) (Vllb) 46301 In doing so, the first step involves splitting at the oxygen atom of the oxazepine ring of the compound of formula VII by treatment with strong hydrochloric acid or hydrobromic acid. For this purpose, it suffices in general to treat the compound of formula VII with strong hydrochloric or hydrobromic acid solution for a period of from several minutes to several hours at room, temperature. The hydrohalide of the compound of formula Vila formed during this reaction can be extracted from the reaction solution in the cold by means of a water-immiscible solvent, preferably a chlorinated hydrocarbon such as chloroform or methylene chloride and, conveniently .after evaporating off the extraction solvent, is admixed with a phosphorus or sulfur halide such as thionyl chloride or phosphorus tribromide. The reaction temperature is conveniently between 0 and 40°C, preferably about 20°C.

After distilling off excess halide and, if required, any solvent still present, the residue consists of a dihalide of formula Vllb which can be reacted with ammonia or an ammonia-producing substance such as *Urotropine. Lower alcohols such as for example methanol or ethyl acetate, dioxan, tetrahydrofuran or inert hydrocarbons such as benzene and its homologues are conveniently used as solvents for the reaction with ammonia. Liquid ammonia may also be used for this reaction. The reaction temperature is conveniently between 0°C and the boiling point of the solvent used.

The reaction is preferably carried out in an autoclave.

*Urotropine is a trade mark • 10 46801 We have suceeded by this method in preparing the compound of formula Vile in excellent yield.

Instead of the compound of formula Vila, there may be used for the reaction with a phosphorus or sulfur halide also the corresponding dihydroxy compound of formula This compound can be obtained by heating a strongly acid solution of the compound of formula VII and may be extracted from the reaction solution in the same manner as described above for the compound of formula Vila.

Dehydrogenation of the compound of formula Vile to the final product of formula I is conveniently effected using dehydrogenation agents such as, for example, halogens and chromium- or magnesium- containing oxidising agents, e.g. chromates, dichromates and permanganates.

Suitable solvents for the reaction with a halogen include chlorinated hydrocarbons such as for example chloroform or methylene chloride. This reaction is preferably carried out in the presence of a tertiary organic base, for example pyridine, which reacts with the hydrohalic acid released during the reaction.

Suitable solvents for the reaction with chromiumor magnesium- containing oxidising agents include - 11 46501 acetone, tetrahydrofuran and dioxan. The reaction temperature is conveniently between 0°C and the boiling temperature of the solvent, the temperature which is advantageously used depending upon the particular oxidising agent which is utilised for the reaction.

The compounds of formula I according to the invention prepared by the processes according to the invention can if desired be subsequently converted to acid addition salts thereof. Acids suitable for the preparation of physiologically acceptable acid addition salts are, for example, hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid, cyclohexylsulfaminic acid, citric acid, tartaric acid, ascorbic acid, maleic acid, formic acid, salicylic acid, methanesulfonic acid and toluenesulfonic acid. Compounds of formula II used as starting materials can be produced analogous to the compounds described in German Offenlegungsschrift 2 217 157 by iodizing the thieno-diazepine-3-one of formula in conventional manner and reacting the iodine compound thus obtained with phosphorus pentasulfide in a solvent such as pyridine, dimethylformamide or tetrahydrofuran or a mixture of such solvents. The temperatures used are 46801 conveniently between room temperature and the reflux temperature of the reaction mixture. The corresponding 3-mercapto compound is obtained which, after formation of corresponding salts with the aid of a metallization agent such as sodium methylate or sodamide, may be converted without previous separation into the corresponding methylmercapto compound in the usual way by treatment with alkylating agents such as for example methyl iodide.

The hydrazine derivatives of formula IV may be produced by reacting a compound of formula II with hydrazine.

This reaction is conveniently carried out in one of the above-mentioned solvents and one of the previously mentioned acid catalysts may if desired be present. The temperature for the reaction is conveniently between room temperature and the reflux temperature of the reaction mixture.

The starting compounds of formula VII have been described in our Patent Specification No. 43694 and may be obtained, for example, by reacting 7-iodo-5-phenyl-thieno[2,3f]-oxazepine-2thione with hydrazine hydrate and an orthoacetate in a manner known per se.

According to a further feature of the present invention, there are provided pharmaceutical compositions comprising as active ingredient a compound of formula I as hereinbefore defined or a physiologically acceptable acid addition salt thereof in association with a pharmaceutical carrier or excipient.

The compositions may for example be presented in a form suitable for oral, rectal or parenteral administraticn and are conveniently formulated as dosage units. - 13 46501 The pharmaceutical compositions in dosage unit form preferably contain from 0.05 to 50mg of active ingredient according to the invention per dosage unit, such compositions for oral administration advantageously containing from 0.1 to 25 mg of active ingredient according to the invention per dosage unit with a preferred daily dose of 5 to 150 mg of the said active ingredient.

The active ingredients according to the invention may be used singly, in combination with other active ingredients according to the invention or, if required, in combination with pharmacologically active substances such as spasmolytics or β-receptor blocking agents as further active ingredients.

Examples of convenient forms of pharmaceutical compositions according tothe invention are tablets, coated tablets, capsules, suppositories, solutions, suspensions, syrups, emulsions and dispersible powders. Tablets may be obtained, for example, by admixing the active ingredient(s) with known excipients, e.g. inert diluants such as calcium carbonate, calcium phosphate or lactose, disintegrants such as com starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talcum and/or sustained release agents such as carboxypolymethylene, carboxymethyl· cellulose, cellulose acetatephthalate or polyvinyl acetate.

The tablets may if desired be made up of several layers.

Coated tablets may be obtained by coating cores produced analogous to the tablets with tablet-coating substances such as, for example, polyvinylpyrrolidone, shellac, gum arabic, talcum, titanium dioxide or sugar. - 14 46501 In order to obtain sustained release or to avoid incompatibilities the core may if desired consist of several layers. The tablet coating may also if desired consist of several layers for providing sustained release and the excipients mentioned above for the tablets may be used.

Syrups of the active ingredient or active ingredient combinations may contain a sweetener such as for example saccharin, cyclamate, glycerin or sugar as well as a taste improving agent such as, for example, vanilla or orange extract flavouring. In addition they may contain suspending agents or thickeners such as sodium carboxymethyl cellulose, wetting agents such as the condensation products of fatty alcohols with ethylene oxide and protection agents such as p-hydroxybenzoates.

Injectible solutions can be produced in conventional manner, for example with the addition of preserving agents such as p-hydroxybenzoates or stabilizers such as alkali metal salts of ethylenediamine tetraacetic acid, and filled into injection vials or ampoules.

Capsules containing one or more active ingredients or active ingredient combinations may be produced, for example, by admixing the active ingredients with inert carriers, such as lactose or sorbitol, and filling into gelatin capsules.

Suitable suppositories may be produced, for example, by admixing with conventional carriers therefor, such as neutral fats or polyethyleneglycol or its derivatives.

The following examples illustrate the invention:15 46501 Example 1 8-Iodo-l-cyclohexyl-6-o-chlorophenyl-4H-s-triazolo[3,4c] thieno[2,3e]1,4-diazepine .1 g = 10 mmol of 8-iodo-6-(o~chlorophenyl)-l-cyclohexyl5 thieno[2,3f]triazolo[3,4a]4,l-oxazepine of m.p. 217 to 219°C are dissolved while stirring for 30 minutes in 200 ml of concentrated hydrobromic acid at room temperature. The solution is poured into 400 ml of ice-water, neutralized with ammonia, shaken with methylenechloride and afterwards washed with water. 5.2 g = 88% of theory of [l-iodo-2(5-cyclohexyl-3-hydroxymethyl-triazplyl-4-)-3-thenyl] o-chlorophenyl-bromomethane are obtained, which are dissolved without further purification in 200 ml of methylenechloride and refluxed with 10 ml of SOC^ for 30 minutes. Subsequently, the reaction mixture is washed with ice-water and dilute ammonia. After drying and evaporating, the residue is triturated with isopropylether and the crude product is separated by suction filtration. The latter is dissolved in 200 ml of methanol and admixed with gaseous ammonia until a constant pressure of 5 atmospheres is achieved.

This is followed hy heating to 40°C for 30 minutes, and the solution is then suction filtered over kieselguhr and evaporated. The product is purified by column-chromatography. 3.9g = 87% of theory of 8-iodo-5,6-dihydro-6-o-chlorophenyl25 l-cyclohexyl-thieno[2,3e]triazolo[3,4c]l,4-diazepine are obtained, which are dissolved in 200 ml of acetone and stirred with 1 g of pulverized KMnO^ for 20 hours at room temperature. The manganese dioxide is suction filtered off, the solution is evaporated and the residue is brought to crystallization with ether. Yields 3..5 g = 92% of theory of m.p. 233 to 235°C.

The 8-iodo~6(o-chlorophenyl)-l-cyclohexyl-thieno[2,3f] triazolo[3,4a]4,l-oxazepine used as starting compound may be produced as follows: a) 7-Iodo-5-(o-chlorophenyl)-thieno[2,3f]oxazepine-2-one 13.5 g = 48 mmol of 5-(o-chlorophenyl)-thieno[2,3f] oxazepine-2-one are dissolved in 500 ml of chloroform and admixed with 13 g of iodine and 8.8 g of HgO(red) while stirring at room temperature (10 to 15 minutes). After stirring has been continued for 80 minutes, the reaction mixture is suction filtered over kieselguhr and washed with sodium bicarbonate solution and then with sodium thiosulfate solution. The dried chloroform phase is evaporated and the residue is brought to crystallization. The crystals that are freed from the solvent are washed with a little methylene chloride. g = 77% of theory of the title compound are obtained. M.p.230 to 232°C. b) 7-Iodo-5-(o-chlorophenyl)-thieno[2,3f]oxazepine-2-thione g « 37 mmol of the oxazepine-2-one are suspended in 80 ml of diglyme and after addition of 6. 6 g of and 6 g of NaHCOj are heated for 5 minutes to 55°C. Afterwards, the reaction mixture is poured into 200 ml of water, the precipitate is separated hy suction filtration, washed neutral with water and dried at 50°C in vacuo. Yield: 14 g = 90% of theory of the tide compound of m.p. 145°C (decomp.). -.17 46501 c) 8-Iodo-6-(o-chlorophenyl)-l-cyclohexyl-thieno[2,3f]triazolo[3,4a]4,l-oxazepine 2,1 g = 5 mmol of the thione are dissolved in 40 ml of tetrahydrofuran and admixed with 0.5 ml of hydrazine hydrate. After a few minutes the reaction is finished and the solvent is evaporated 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 with 20 mi of ethanol and 20 ml of ethyl cyclohexane carboxylate for 30 minutes. After suction filtration, the solution is evaporated and the ether is brought to crystallization.

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

Example 2 8-Iodo-l-cyclohexyl-6-o-chlorophenyl-4H-s-triazolo[3,4c] thieno[2,3e]1,4-diazepine .5 g of 7-iodo-5-(o-chlorophenyl)-3H[2,3e]thieno-l, 4-diazepine-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 suction filtered off in vacuo and recrystailized from ether. 4.8 g = 96% of theory of 7-iodo-5-(o-chlorophenyl)-2hydrazino-3H[2,3e]thieno-1,4—diazepine of m.p. 145°C (decomp.) are obtained. 4.8 g of the hydrazino compound are refluxed with 50 ml of absolute alcohol and 30 ml of ethyl cyclohexane carboxylate for 2 hours while stirring, the reaction mixture is evaporated in vacuo, the residue is eluted over silica gel comprising 5% of methanol and recrystallized from acetonitrile. .3 g = 91.3% of theory of the title compound of m.p. 233 to 235°C are obtained.

The starting compound was obtained as follows: a) 5 g of 5-(o-chlorophenyl)-3H[2,3e]thieno-l,4—diazepine-2-one are suspended in 200 ml of chloroform and a total of 3.3 g of HgO and 4.9 g of iodine are added alternatively. After stirring for 15 minutes at room temperature, the precipitated crystals are suction filtered off and these are washed with sodium bicarbonate and sodium thiosulfate up to a neutral reaction. After evaporation and recrystallization of the residue from alcohol, the 7-iodo5-(o-chlorophenyl)-3H[2,3e]thieno-l,4-diazepine-2-one is obtained, m.p. 222 to 224°C, yield: 6.4g = 87.7% of theory. b) 6.4 g of the 7-iodo compound are stirred in 100 ml of pyridine and 6.2 g of ϊ*£^5 lor U hours at t0 80°c· Subsequently, the reaction mixture is decomposed in 200 ml of sodium chloride solution and ice. The resulting crystals are washed with ether. 6.1 g = 92.4% of theory of 7-iodo-5-(o-chloroohenyl)3H[2,3e]thieno-l,4-diazepine-2-thione of m.p. 202°C are obtained.

The following compounds of formula I have been prepared by methods analogous to those described in Examples 1 and 2.

Example *2 *3 m.p.°C 3 ’ ’Cl Q 228 to 230 4 Cl H 218 to 220 5 Cl Br 225 to 226 6 Cl Cl 222 to 224 7 Cl 220 to 222 8 Cl ύ 223 to 225 9 Cl -OCHj 201 to 203 10 Cl Q 160 (decomp.) 11 Br CH3 231 to 233 12 H ch3 250 to 251 - 20 46501 Formulation Examples Example A Coated Tablets tablet core is composed of: active ingredient according to the invention 1.0 mg lactose 28.5 mg corn starch 19.0 mg gelatin 1.0 mg magnesium stearate 0.5 mg 50.0 mg Production: A mixture of the active ingredient with lactose and com starch is granulated with a 10% aqueous gelatin solution through a screen of 1 mm mesh-size, dried at 40°C and passed once more through the screen. The granulate thus obtained is admixed with magnesium stearate and pressed. The cores thus obtained are coated in the conventional way, the coat being applied with the aid of an aqueous suspension of sugar, titanium dioxide, talcum and gum arabic. The finished coated tablets are polished with beeswax.

Final weight of coated tablet: 100 mg Example B Tablets Active ingredient according to the invention 0.5 mg lactose com starch soluble starch magnesium stearate 50.0 mg 43.5 mg .0 mg 1.0 mg 100.0 mg Production: The active ingredient and magnesium stearate are granulated with an aqueous solution of the soluble starch, the granulate is dried and admixed thoroughly with lactose and com starch. The mixture is pressed into tablets of 100 mg weight, each tablet comprising 0.5 mg of active ingredient.

Example C Suppositories suppository is composed of: active ingredient according to the invention 5.0 mg suppository' mass 1,695.0 mg Production: The finely pulverized substance is stirred into the molten suppository mass cooled to 40°C with the aid of an immersion homogenizer. The mass is poured at 35°C into slightly precooled moulds.

Having regard to the provisions of Section 14 of the Patents Act, 1964, attention is directed to Claims 1 to 4 of Patent Specification No. 38,883.

Claims (10)

1. Compounds of general formula (wherein

2. Compounds as claimed in claim 1 in the form of physiologically acceptable acid addition salts,

3. Compounds as claimed in claim 1 or claim 2 wherein Rj represents a cyclohexyl group, 15

4. , Compounds as claimed in claim 1. or claim 2 wherein Rj represents a tetrahydropyranyl group.

5. ' ing acetone, tetrahydrofuran or dioxan. 45. A process as claimed in any of claims 37 to 44 wherein the compound of formula Vile is first prepared by conversion of a compound of formula Ν· (VII) 10 )6. A process as claimed in claim 45 wherein the said conversion is effected via compounds of formula I (Vila) and - 30 46501 (Vllb) 47. A process as claimed in claim 45 wherein the said conversion is effected via compounds of formula (Vllb) A process as claimed in any of claims 12 to 47 - 31 48 wherein the compound of formula I thus formed is subsequently converted 1 to an acid addition salt thereof. 49 A process.as claimed in claim 48 wherein the compound of formula I thus formed is converted to a physiologically acceptable acid addition salt. 50. A process'as claimed in any of claims 12 to 49 substantially as herein described. 51. A process as claimed in any of claims 12 to 49 substantially as herein described in any of Examples 1 to 12. 52. Compounds of formula I as defined in claim 1 when prepared by a process as claimed in any of claims 12 to 47, 50 and 51. 53. Acid addition salts of compounds of general formula I as defined in claim 1 when prepared by a process as claimed in claim 48 or claim 49. 54. Pharmaceutical compositions comprising as active ingredient a compound of formula I as defined in claim 1 or a physiologically acceptable acid addition salt thereof in association with a pharmaceutical carrier or excipient. 55. Compositions as claimed in claim 54 in a form suitable for oral, rectal or parenteral administration. 56. Compositions as claimed in claim 54 or claim 55 in the form of tablets, coated tablets, capsules, suppositories, solutions, suspensions, syrups, emulsions or dispersible powders. 57. Compositions as claimed in any of claims 54 to 56 in the form of dosage units, 58. Compositions as claimed in claim 57 containing from 0.05 to 50 mg of active ingredient per dosage unit. 59. Compositions as claimed in claim 58 for oral 32 46501 administration containing from 0.1 to 25 mg of active ingredient per dosage unit. 60. Compositions as claimed in any of claims 54 to 59 which contain a further pharmacologically active ingredient. 5 61. Compositions as claimed in claim 60 wherein the said further active ingredient comprises a spasmolytic or β-receptor blocking agent. 62. Pharmaceutical compositions as claimed in claim 54 substantially as herein described. 5 formula I as defined in claim 1 which comprises dehydrogenating a compound of formula 38. A process as claimed in claim 37 wherein the reaction is effected in the presence of a halogen as dehydrogenation 10 agent. 39. A process as claimed in claim 38 wherein the reaction is effected in the presence of a solvent comprising a chlorinated hydrocarbon. 40. A process as claimed in claim 39 wherein the 15 chlorinated hydrocarbon comprises chloroform or methylene chloride. 41. A process as claimed in any of claims 38 to 40 wherein the reaction is effected in the presence of a tertiary organic base. 20 42. A process as claimed in claim 41 wherein the tertiary organic base comprises pyridine. 43. A process as claimed in claim 37 wherein the - 29 46501 reaction is effected in the presence of a chromate, dichromate or permanganate as dehydrogenation agent. 44, A process as claimed in claim 43 wherein the reaction is effected in the presence of a solvent compris 5 phosphoric acid, polyphosphoric acid, acetic acid, propionic acid, benzenesulfonic acid or toluenesulfonic acid. 32. A process as claimed in any of claims 20 to 29 wherein the reaction is effected in the presence of a base 10 catalyst. 33. A process as claimed in claim 32 wherein the base catalyst comprises 2-methylimidazole. 34. A process as claimed in any of claims 20 to 33 wherein the reaction is effected at a temperature of from 15 0 to 300‘C. 35. A process as claimed in claim 34 wherein the said temperature is from 20 to 180°C. 36. A process for the preparation of compounds of general formula I ns defined in claim 1 (where Rg represents a 20 chlorine or bromine atom or a methoxy group) which comprises chlorinating or brominating a compound of formula H_Z \ N (wherein Rg is as defined in claim 1), and if desired - 28 (VI) converting the compound of formula I in which Rg represents a chlorine or bromine atom thus formed into a further compound of formula I in which Rg represents a methoxy group. 37. A process for the preparation of compounds of general 5' 5, 8-Iodo- 5 Rj represents a hydrogen, chlorine or bromine atom; and Rj represents a chlorine or bromine atom, a methoxy group, a Cj-Cg-cycloalkyl group, a 5- or 6-membered oxygen-, sulfur- or nitrogen atom- containing saturated or unsaturated ring or, where Rj represents a hydrogen or bromine 10 atom, a methyl group) and acid addition salts thereof.

6. -(o-chlorophenyl)-l-cyclohexyl-4H-s-triazolo[3 4c]-thieno[2,3e]l,4-diazepine and its physiologically acceptable acid addition salts. 20 6. 8-Iodo-6-(o-chlorophenyl)-l-tetrahydropyranyl-(4)4H-s-triazolo[3,4c]thieno[2,3ejl,4-diazepine and its physiologically acceptable acid addition salts. - 23 46501

7. 8-Iodo-6-(o-bromophenyl)-l-methyl-4H-s-triazolo[3,4c]thieno[2,3e]l,4-diazepine and its physiologically acceptable acid addition salts .

8. 8-Iodo-6-(o-chlorophenyl)-l-bromo-4H-s-triazolo[3,4c]thieno[2,3e]l,4-diazepine and its physiologically acceptable acid addition salts.

9. 8-Iodo-6-(o-chlorophenyl)-l-methoxy-4H-s-triazolo[3,4c]thieno[2,3e]l,4-diazepine and its physiologically acceptable acid addition salts. 10. Compounds as claimed in claim 1, with the exception of compounds as claimed in any of claims 5 to 9, as herein specifically disclosed. 11. Compounds as claimed in any of the preceding claims in the form of their addition salts with hydrohalic acids, sulphuric acid, phosphoric acid, nitric acid, cyclohexylsulfaminic acid, citric acid, tartaric acid, ascorbic acid, maleic acid, formic acid, salicylic acid, methanesulfonic acid or toluenesulfonic acid. 12. A process for the preparation of compounds of general formula I as defined in claim 1 (where is other than a chlorine or bromine atom) which comprises reacting a compound of formula (II) 24 4 6 5 01 (wherein is as defined in claim 1 and X represents -SH,-NH 2 , a or C 2 alkoxy or alkyl-mercaptogroup or a halogen atom) with a compound of formula R 3 - CO - NH - NH 2 (III) (wherein R^ is as defined in claim 1 other than a chlorine or bromine atom). 13. A process as claimed in claim 12 wherein the reaction is effected at a temperature of from 100 to 250°C. 14. A process as claimed in claim 12 or claim 13 wherein the reaction is effected in the absence of a solvent. 15. A process as claimed in claim 12 or claim 13 wherein the reaction is effected in the presence of a solvent comprising methanol, ethanol, dioxan, chloroform, tetrahydrofuran, benzene, toluene or xylene. 16. A process as claimed in any of claims 12 to 15 wherein the reaction is effected in the presence of an acid catalyst. 17. A process as claimed in claim 16 wherein the acid catalyst comprises hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, acetic acid, propionic acid, benzenesulfonic acid or toluenesulfonic acid. 18. A process as claimed in any of claims 12 to 17 wherein an intermediate compound of formula 25 46901 (wherein R 2 ^d ^3 are as defined in claim 12) is isolated during the course of· the reaction. 19. A process for the preparation of compounds of general formula I as defined in claim 1 (where R^ other than a chlorine or bromine atom) which comprises cyclising a compound of formula (VIII) (wherein R 2 and R^ are as defined in claim 12), ; 20. A process for the preparation of compounds of general formula I as defined in claim 1 (where R^ is other than a chlorine or bromine atom) which comprises reacting a com- (wherein R 2 is as defined in claim 1) with an acid of formula R 3 - COOH (V) (wherein R^ is as defined in claim 1 other than a chlorine or bromine atom) or with a functional derivative of the said acid. 21. A process as claimed in claim 20 wherein the functional derivative is an orthoester of formula R 3 -C(OR') 3 - 26 46501 in which R' represents a or Cg alkyl group and R^ is as defined in claim 20. 22, A process as claimed in claim 20 wherein the functional derivative is an iminoether of formula R 3 -C(~NH)-OR' in which R' represents a (η or Cg alkyl group and R^ is as defi/ned in claim 20. 23, A process as claimed in claim 22 wherein the iminoether is used in the form of a salt thereof with a mineral acid . 24, A process as claimed in claim 20 wherein the functional derivative is an ester of formula R^-COOR in which R represents the residue of an aliphatic or araliphatic alcohol or a phenol and R 3 is as defined in claim 20. 25, A process as claimed in claim 24 wherein the functional derivative is a methyl, ethyl or nitrophenyl ester. 26, A process as claimed in claim 20 wherein the functional derivative is an acid anhydride of formula R 3 -(C0) 2 0 in which R^ is as defined in claim 20. 27, A process as claimed in claim 20 wherein the functional derivative is an acid halide of formula R^- COHal which Hal represents a halogen atom and R^ is as defined in claim 20. 28, A process as claimed in any of claims 20 to 27 wherein the reaction is effected in the absence of a solvent . 29, A process as claimed in any of claims 20 to 27 wherein the reaction is effected in the presence of a solvent comprising methanol, ethanol, chloroform, tetrahydrofuran, benzene or toluene, 30, A process as claimed in any of claims 20 to 29 - 27 46501 wherein the reaction is effected in the presence of an acid catalyst. 31. A process as claimed in claim 30 wherein the acid catalyst comprises hydrochloric acid, sulphuric acid,

10. 63. Pharmaceutical compositions substantially as herein described in any of Examples A to C.