EP0000479A1 - Substituted 1-piperazinyl-4H-s-triazolo (3,4-c)thieno(2,3-e)1,4-diazepines, process for their preparation and medicaments containing them - Google Patents

Substituted 1-piperazinyl-4H-s-triazolo (3,4-c)thieno(2,3-e)1,4-diazepines, process for their preparation and medicaments containing them Download PDF

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EP0000479A1
EP0000479A1 EP78100263A EP78100263A EP0000479A1 EP 0000479 A1 EP0000479 A1 EP 0000479A1 EP 78100263 A EP78100263 A EP 78100263A EP 78100263 A EP78100263 A EP 78100263A EP 0000479 A1 EP0000479 A1 EP 0000479A1
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Prior art keywords
triazolo
thieno
piperazinyl
radical
general formula
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German (de)
French (fr)
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EP0000479B1 (en
Inventor
Karl-Heinz Dr. Weber
Adolf Dr. Langbein
Claus Dr. Schneider
Erich Dr. Lehr
Karin Dr. Böke
Franz Josef Dr. Kuhn
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CH Boehringer Sohn AG and Co KG
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CH Boehringer Sohn AG and Co KG
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Priority claimed from DE19772732921 external-priority patent/DE2732921A1/en
Priority claimed from DE19772732943 external-priority patent/DE2732943A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine

Definitions

  • alkyl in the general formula I also means the terms "hydroxyalkyl” and "haloalkyl” for a straight-chain or branched alkyl radical having 1 to 3 carbon atoms. In the case of the straight-chain or branched alkyl radical having 1-17 carbon atoms (R 4 ), radicals having 1-6 carbon atoms are preferred.
  • Halogen means the halogen atoms fluorine, chlorine, bromine and iodine.
  • a dialkylaminoalkyl radical should be understood to mean the dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl radical.
  • the substituent on the phenyl ring can be in the o-, m- or p-position.
  • the pyridyl radical can be connected to the piperazine nitrogen in the 2-, 3- or 4-position.
  • alkyl DT-OS 24 05 682
  • DBP 24 35 041 cycloalkyl
  • DT-OS 24 60 776 a nitrogen or sulfur containing 5- or 6-membered ring
  • the compounds which are also water-soluble in salt form, with hydroxyalkyl have a favorable influence on the sleep-wake behavior in the cat, whereby the SWS (slow wave sleep, deep sleep) extends, active and relaxed wakefulness shortens and the REM phases (rapid eye movement) little increased or unchanged.
  • Biochemical methods also provide information on the neuroleptic properties of the acylpiperazinyl compounds.
  • R 1 is hydrogen, alkyl, hydroxyalkyl, haloalkyl or dialkylaminoalkyl
  • R 1 is hydrogen, alkyl, hydroxyalkyl, haloalkyl or dialkylaminoalkyl
  • reaction of compounds of general formula II with a piperazine of formula III is carried out either without a solvent or in higher-boiling solvents such as benzene, toluene, dioxane, tetrahydrofuran, chlorinated hydrocarbons such as carbon tetrachloride or methylene chloride, preferably at the boiling point of the solvent used.
  • the reaction time depends on the starting material used and can range from a few minutes to several hours.
  • dehydrogenation of compounds of the general formula IV is carried out using suitable dehydrating agents such as, for example, halogens or also compounds of the higher oxidation states of chromium or manganese, for example a chromate, a bichromate or a permanganate.
  • suitable dehydrating agents such as, for example, halogens or also compounds of the higher oxidation states of chromium or manganese, for example a chromate, a bichromate or a permanganate.
  • Chlorinated hydrocarbons such as chloroform or methylene chloride may be mentioned as suitable solvents for the reaction with a halogen.
  • the oxidation with the mentioned chromium or manganese compounds takes place in solvents such as acetone, tetrahydrofuran or dioxane.
  • the reaction temperature is generally between 0 ° C and the boiling point of the solvent used.
  • R 1 is an alkyl radical
  • a compound of the general formula I in which R 1 is a hydrogen atom can be alkylated in a conventional manner.
  • Alkyl halides, dialkyl sulfates or esters of toluenesulfonic acid are preferably used as the alkylating agent; solvents such as tetrahydrofuran, dimethylformamide or lower alcohols are used, but the alkylation can also be carried out without the addition of a solvent.
  • the acylation of compounds of the formula I in which R 1 is hydrogen with a carboxylic acid halide or anhydride can be carried out using an excess of acylating agent or in a suitable inert solvent such as dioxane, tetrahydrofuran, benzene, toluene or xylene.
  • a suitable inert solvent such as dioxane, tetrahydrofuran, benzene, toluene or xylene.
  • an inorganic or organic base for example pyridine, triethylamine, potash or potassium bicarbonate, has proven useful to scavenge the acid.
  • the reaction temperature and reaction time can vary within wide limits, depending on the starting material used. For example, the reaction temperature can be between room temperature and the boiling point of the solvent or acylating agent used; the response time can range from a few minutes to several hours.
  • Such end products of the general formula I, in which R 1 is hydrogen, alkyl, hydroxyalkyl, haloalkyl or dialkylaminoalkyl form stable water-soluble salts.
  • Suitable for salt formation are all acids which form physiologically acceptable acid addition salts such as hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid, cyclohexylsulfamic acid, citric acid, tartaric acid, ascorbic acid, maleic acid, formic acid, salicylic acid, methane or toluenesulfonic acid.
  • the starting compounds of general formula V can e.g. are obtained by reacting appropriately substituted 1-halo-4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepines with a piperazine or by dehydrogenating a 1-piperazinyl-4H-s-triazolo [3, 4c] thieno [2,3e] 5,6-dihydro-; 1,4-diazepines as described above.
  • the end products of the general formula I have valuable therapeutic properties and can be used as anxiolytics, tranquilizers, sedatives and neuroleptics.
  • the main effect can be different for the individual compounds, so that the focus is on the neuroleptic area, on other compounds on the sleep-promoting area, etc.
  • the new compounds are therefore particularly suitable for eliminating psychomotor excitement and anxiety, such as they occur, for example, in schizophrenia, and also for the treatment of convulsions and sleep disorders of various origins.
  • the single dose of the substances according to the invention is 0.05 to 50, preferably 0.1 to 25 mg (oral) and 5 to 150 mg as a daily dose.
  • the compounds 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 other pharmacologically active substances such as spasmolytics or ⁇ -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, carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • 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, carboxymethyl cellulose, cellulose acetate phthalate
  • coated tablets can be produced by coating cores produced analogously to the tablets with agents usually used in coated tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the core can also be used to achieve a deposit effect or to avoid incompatibilities consist of several layers.
  • 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 aids or thickeners, such as sodium carboxymethyl cellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.
  • a sweetener such as saccharin, cyclamate, glycerol or sugar
  • a taste-improving agent e.g.
  • Flavorings such as vanillin or orange extract
  • suspending aids or thickeners 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.
  • 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.
  • inert carriers such as milk sugar or sorbitol
  • Suitable suppositories can be produced, for example, by mixing them with carrier agents such as neutral fats or polyethylene glycol or its derivatives.
  • the corresponding salts are obtained in quantitative yield from the base dissolved in hot alcohol by adding 1 mol of maleic acid, tartaric acid or methanesulfonic acid.
  • the hydrochloride available with alcoholic hydrochloric acid has an mp of 210 ° C (dec.).
  • 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
  • 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.
  • the finely powdered substance is stirred into the molten suppository mass, which has been cooled to 40 ° C., using an immersion homogenizer.
  • the mass is poured into slightly pre-cooled molds at 35 ° C.
  • the active ingredient and excipients are dissolved in a sufficient amount of water and brought to the desired concentration with the necessary amount of water.
  • the solution is filtered and filled into 1 ml ampoules under aseptic conditions. Finally, the ampoules are sterilized and sealed. Each ampoule contains 0.5 mg of active ingredient.

Abstract

Die Erfindung umfaßt neue substituierte 1 Piperazinyl-4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine der Formel <IMAGE> in der R¹ Wasserstoff, einen geradkettigen oder verzweigten Alkyl-, Halogenalkyl-, Hydroxyalkyl- oder Dialkylaminoalkylrest, einen gegebenenfalls durch Methyl, Methoxy, Nitro oder Halogen substituierten Phenylrest oder einen Pyridyloder Pyrimidinlyrest oder den Rest R<4>-CO-, R² Wasserstoff, Fluor, Chlor, oder Brom, R³ Chlor oder Brom oder einen Alkylrest und R<4> Wasserstoff Alkyl mit 1 - 17 Kohlenstoffatomen, Alkoxy mit 1 - 2 Kohlenstoffatomen, Phenyl, Tolyl, Methoxyphenyl, Halogenphenyl, Nitrophenyl oder Pyridyl bedeuten, Verfahren zu ihrer Herstellung und ihre Verwendung in Arzneimitteln. Beansprucht werden auch die wasserlöslichen Säureadditionssalze der Verbindungen der Formel I, in denen R¹ Wasserstoff, Alkyl, Hydroxyalkyl, Halogenalkyl oder Dialkylaminoalkyl bedeutet. Die Verbindungen besitzen anxiolytische, sedierende, tranquilisierende und neuroleptische Eigenschaften.The invention encompasses new substituted 1 piperazinyl-4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepines of the formula <IMAGE> in which R¹ is hydrogen, a straight-chain or branched alkyl, haloalkyl, hydroxyalkyl - Or dialkylaminoalkyl radical, a phenyl radical optionally substituted by methyl, methoxy, nitro or halogen or a pyridyl or pyrimidinly radical or the radical R 4 -CO-, R 2 hydrogen, fluorine, chlorine or bromine, R 3 chlorine or bromine or an alkyl radical and R <4> Hydrogen means alkyl with 1-17 carbon atoms, alkoxy with 1-2 carbon atoms, phenyl, tolyl, methoxyphenyl, halophenyl, nitrophenyl or pyridyl, processes for their preparation and their use in medicaments. The water-soluble acid addition salts of the compounds of the formula I in which R 1 is hydrogen, alkyl, hydroxyalkyl, haloalkyl or dialkylaminoalkyl are also claimed. The compounds have anxiolytic, sedative, tranquilizing and neuroleptic properties.

Description

Die Erfindung betrifft neue substituierte 1-Piperazinyl-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepine der allgemeinen Formel

Figure imgb0001
in der

  • R1 Wasserstoff, einen geradkettigen oder verzweigten Alkyl-, Halogenalkyl-, Hydroxyalkyl- oder Dialkylaminoalkylrest, einen gegebenenfalls durch Methyl, Methoxy, Nitro oder Halogen substituierten Phenylrest oder einen Pyridyl- oder Pyrimidinylrest oder den Rest R4 - CO -,
  • R2 Wasserstoff, Fluor, Chlor oder Brom,
  • R3 Chlor oder Brom oder einen Alkylrest und
  • R Wasserstoff, Alkyl mit 1 - 17 Kohlenstoffatomen, Alkoxy mit l - 2 Kohlenstoffatomen, Phenyl, Tolyl, Methoxyphenyl, Halogenphenyl, Nitrophenyl oder Pyridyl bedeuten, Verfahren zu ihrer Herstellung und ihre Verwendung als Wirkstoffe in Arzneimitteln.
The invention relates to new substituted 1-piperazinyl-4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepines of the general formula
Figure imgb0001
 in the
  • R 1 is hydrogen, a straight-chain or branched alkyl, haloalkyl, hydroxyalkyl or dialkylaminoalkyl radical, a phenyl radical which is optionally substituted by methyl, methoxy, nitro or halogen or a pyridyl or pyrimidinyl radical or the radical R 4 - CO -,
  • R 2 is hydrogen, fluorine, chlorine or bromine,
  • R 3 is chlorine or bromine or an alkyl radical and
  • R is hydrogen, alkyl of 1-17 carbon atoms, alkoxy of 1-2 carbon atoms, phenyl, tolyl, methoxyphenyl, halophenyl, nitrophenyl or pyridyl, processes for their preparation and their use as active ingredients in medicinal products.

In der allgemeinen Formel I steht die Bezeichnung "Alkyl", soweit nicht anders vermerkt, auch in den AusdrUcken "Hydroxyalkyl" und "Halogenalkyl" für einen geradkettigen oder verzweigten Alkylrest mit 1 - 3 Kohlenstoffatomen. Bei dem geradkettigen oder verzweigten Alkylrest mit 1 - 17 Kohlenstoffatomen (R4) sind'Reste mit 1 - 6 Kohlenstoffatomen bevorzugt.Unless otherwise stated, the term "alkyl" in the general formula I also means the terms "hydroxyalkyl" and "haloalkyl" for a straight-chain or branched alkyl radical having 1 to 3 carbon atoms. In the case of the straight-chain or branched alkyl radical having 1-17 carbon atoms (R 4 ), radicals having 1-6 carbon atoms are preferred.

"Halogen" bezeichnet die Halogenatome Fluor, Chlor, Brom und Jod."Halogen" means the halogen atoms fluorine, chlorine, bromine and iodine.

Unter einem Dialkylaminoalkylrest soll der Dimethylaminomethyl-, Dimethylaminoäthyl-., Diäthylaminomethyl- oder Diäthylaminoäthylrest verstanden werden.A dialkylaminoalkyl radical should be understood to mean the dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl radical.

Der Substituent am Phenylring kann in o-, m- oder p-Stellung stehen.The substituent on the phenyl ring can be in the o-, m- or p-position.

Der Pyridylrest kann in 2-, 3- oder 4-Stellung mit dem Piperazin-Stickstoff verbunden sein.The pyridyl radical can be connected to the piperazine nitrogen in the 2-, 3- or 4-position.

Thieno-triazolo-diazepine sind als anxiolytisch, muskelrelaxierend und antikonvulsiv wirkend bekannt. Es handelt sich hierbei um solche Verbindungen, die am Triazoloring beispielsweise durch Alkyl (DT-OS 24 05 682), Cycloalkyl (DBP 24 35 041), einen Sauerstoff enthaltenden 5= oder 6-gliedrigen Ring (DT-AS 24 45 430) oder einen Stickstoff oder Schwefel enthaltenden 5- oder 6-gliedrigen Ring (DT-OS 24 60 776) substituiert sind.Thieno-triazolo-diazepines are known to be anxiolytic, muscle relaxant and anticonvulsant. These are compounds which are attached to the triazole ring, for example by alkyl (DT-OS 24 05 682), cycloalkyl (DBP 24 35 041), an oxygen-containing 5 = or 6-membered ring (DT-AS 24 45 430) or a nitrogen or sulfur containing 5- or 6-membered ring (DT-OS 24 60 776) are substituted.

Die neuen Verbindungen weisen gegenüber den bekannten Stoffen verschiedene Vorteile auf:

  • So zeigen beispielsweise Verbindungen, bei denen Rl für einen niederen Alkylrest steht, insbesondere anxiolytische Eigenschaften. Sie können Salze bilden und sind als solche wasserlöslich.
The new compounds have various advantages over the known substances:
  • For example, compounds in which R 1 represents a lower alkyl radical have, in particular, anxiolytic properties. They can form salts and as such are water soluble.

Die ebenfalls in Salzform wasserlöslichen Verbindungen mit Hydroxyalkyl haben einen günstigen Einfluß auf das Schlaf-Wach-Verhalten an der Katze, wobei der SWS (slow wave sleep, Tiefschlaf) verlängert, aktiver und relaxierter Wachzustand verkürzt und die REM-Phasen (rapid eye movement) wenig vermehrt oder unverändert bleiben.The compounds, which are also water-soluble in salt form, with hydroxyalkyl have a favorable influence on the sleep-wake behavior in the cat, whereby the SWS (slow wave sleep, deep sleep) extends, active and relaxed wakefulness shortens and the REM phases (rapid eye movement) little increased or unchanged.

Derivate mit R1 = Acyl und Heteroaryl zeigen neben der ausgeprägten tranquilisierenden und anxiolytischen Komponente auch gute Wirkung auf die Strafvermeidereaktion (active avoidance) bei Ratten, und zwar zeigen hier beide Wirkungsqualitäten zeitlich verschobene Maxima. Hierbei tritt zunächst die neuroleptische Eigenschaft und später erst die anxiolytische Eigenschaft in den Vordergrund.Derivatives with R 1 = acyl and heteroaryl, in addition to the pronounced tranquilizing and anxiolytic component, also have a good effect on the punitive avoidance response (active avoidance) in rats, namely that both effects show delayed maxima. Here the neuroleptic property comes first and only later the anxiolytic property.

Auch mit biochemischen Methoden erhält man Hinweise auf neuroleptische Eigenschaften der Acyl-piperazinyl-Verbindungen.Biochemical methods also provide information on the neuroleptic properties of the acylpiperazinyl compounds.

Verbindungen, in denen R1 Wasserstoff, Alkyl, Hydroxyalkyl, Halogenalkyl oder Dialkylaminoalkyl bedeutet, können zudem in stabile wasserlösliche Säureadditionssalze überführt werden, wodurch eine parenterale Verabreichung und dadurch eine Verwendung dieser Verbindungen als Kuzr- beziehungsweise Ultrakurznarkotica möglich wird.Compounds in which R 1 is hydrogen, alkyl, hydroxyalkyl, haloalkyl or dialkylaminoalkyl can also be converted into stable water-soluble acid addition salts, which enables parenteral administration and thereby the use of these compounds as Kuzr or ultrashort anesthetics.

Man kann die neuen Verbindungen erhalten

  • a) durch Umsetzung von Triazolo-thieno-diazepinen der allgemeinen Formel
    Figure imgb0002
    in der R2 und R3 die oben angegebene Bedeutung haben und Hal ein Halogenatom bedeutet, mit Piperazinen der allgemeinen Formel
    Figure imgb0003
    in der R1 die oben angegebene Bedeutung hat, oder
  • b) durch Dehydrierung von Verbindungen der allgemeinen Formel
    Figure imgb0004
    in der R1, R2 und R3 die oben angegebene Bedeutung haben.
You can get the new connections
  • a) by reacting triazolo-thienodiazepines of the general formula
    Figure imgb0002
     in which R 2 and R 3 have the meaning given above and Hal represents a halogen atom, with piperazines of the general formula
    Figure imgb0003
     in which R 1 has the meaning given above, or
  • b) by dehydrogenation of compounds of the general formula
    Figure imgb0004
     in which R 1 , R 2 and R 3 have the meaning given above.

Solche Verbindungen, in denen R1 den Rest R4 - CO - bedeutet, können ferner erhalten werden durch

  • c) Acylierung einer Verbindung der allgemeinen Formel
    Figure imgb0005
    in der die Reste R und R3 die oben angegebene Bedeutung haben.
Compounds in which R 1 is R 4 - CO - can also be obtained by
  • c) acylation of a compound of the general formula
    Figure imgb0005
     in which the radicals R and R 3 have the meaning given above.

Die Umsetzung von Verbindungen der allgemeinen Formel II mit einem Piperazin der Formel III erfolgt entweder ohne Lösungsmittel oder in höher siedenden Lösungsmitteln wie Benzol, Toluol, Dioxan, Tetrahydrofuran, Chlorkohlenwasserstoffen wie Tetrachlorkohlenstoff oder Methylenchlorid, vorzugsweise bei der Siedetemperatur des jeweils verwendeten Lösungsmittels. Die Reaktionsdauer ist abhängig vom eingesetzten Ausgangsmaterial und kann wenige Minuten bis mehrere Stunden betragen.The reaction of compounds of general formula II with a piperazine of formula III is carried out either without a solvent or in higher-boiling solvents such as benzene, toluene, dioxane, tetrahydrofuran, chlorinated hydrocarbons such as carbon tetrachloride or methylene chloride, preferably at the boiling point of the solvent used. The reaction time depends on the starting material used and can range from a few minutes to several hours.

Die Dehydrierung von Verbindungen der allgemeinen Formel IV . erfolgt unter Verwendung geeigneter Dehydrierungsmittel wie z.B.'von Halogenen oder auch von Verbindungen der höheren Oxydationsstufen des Chroms oder Mangans, beispielsweise eines Chromats, eines Bichromats oder eines Permanganats.The dehydrogenation of compounds of the general formula IV. is carried out using suitable dehydrating agents such as, for example, halogens or also compounds of the higher oxidation states of chromium or manganese, for example a chromate, a bichromate or a permanganate.

Als geeignete Lösungsmittel für die.Umsetzung mit einem Halogen seien Chlorkohlenwasserstoffe wie Chloroform oder Methylenchlorid genannt. Die Oxydation mit den erwähnten Verbindungen des Chroms oder Mangans erfolgt in Lösungsmitteln wie Aceton, Tetrahydrofuran oder Dioxan. Je nach Art des Oxydationsmittels liegt die Reaktionstemperatur im allgemeinen zwischen 0°C und der Siedetemperatur des verwendeten Lösungsmittels.Chlorinated hydrocarbons such as chloroform or methylene chloride may be mentioned as suitable solvents for the reaction with a halogen. The oxidation with the mentioned chromium or manganese compounds takes place 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.

Bedeutet R1 einen Alkylrest, so kann eine Verbindung der allgemeinen Formel I, in der R1 ein Wasserstoffatom bedeutet, in üblicher Weise alkyliert werden. Als Alkylierungsmittel dienen vorzugsweise Alkylhalogenide, Dialkylsulfate oder Ester der Toluolsulfonsäure; man verwendet hierbei Lösungsmittel wie Tetrahydrofuran, Dimethylformamid oder niedere Alkohole, man kann die Alkylierung jedoch auch ohne Zusatz eines Lösungsmittels durchführen.If R 1 is an alkyl radical, a compound of the general formula I in which R 1 is a hydrogen atom can be alkylated in a conventional manner. Alkyl halides, dialkyl sulfates or esters of toluenesulfonic acid are preferably used as the alkylating agent; solvents such as tetrahydrofuran, dimethylformamide or lower alcohols are used, but the alkylation can also be carried out without the addition of a solvent.

Im Falle der Einführung eines Hydroxyalkylrestes empfiehlt sich die Umsetzung mit einem Alkylenoxyd.If a hydroxyalkyl radical is introduced, reaction with an alkylene oxide is recommended.

Die Acylierung von Verbindungen der Formel I, in denen R1 Wasserstoff bedeutet, mit einem Carbonsäurehalogenid beziehungsweise -anhydrid kann unter Verwendung eines Überschusses an Acylierungsmittel oder aber in einem geeigneten inerten Lösungsmittel wie Dioxän, Tetrahydrofuran, Benzol, Toluol oder Xylol erfolgen. In manchen Fällen hat sich der Zusatz einer anorganischen oder organischen Base, beispielsweise von Pyridin, Triäthylamin, Pottasche oder Kaliumbicarbonat zum Abfangen der Säure als nützlich erwiesen. Reaktionstemperatur und Reaktionszeit können, je nach dem eingesetzten Ausgangsmaterial, in weiten Grenzen-variieren. So kann die Reaktionstemperatur zwischen Raumtemperatur und dem Siedepunkt des verwendeten Lösungsmittels beziehungsweise des Acylierungsmittels liegen; die Reaktionszeit kann wenige Minuten bis mehrere Stunden betragen.The acylation of compounds of the formula I in which R 1 is hydrogen with a carboxylic acid halide or anhydride can be carried out using an excess of acylating agent or in a suitable inert solvent such as dioxane, tetrahydrofuran, benzene, toluene or xylene. In some cases, the addition of an inorganic or organic base, for example pyridine, triethylamine, potash or potassium bicarbonate, has proven useful to scavenge the acid. The reaction temperature and reaction time can vary within wide limits, depending on the starting material used. For example, the reaction temperature can be between room temperature and the boiling point of the solvent or acylating agent used; the response time can range from a few minutes to several hours.

Solche Endprodukte der allgemeinen Formel I, in denen R1 Wasserstoff, Alkyl, Hydroxyalkyl, Halogenalkyl oder Dialkylaminoalkyl bedeutet, bilden stabile wasserlösliche Salze. Zur Salzbildung geeignet sind alle Säuren, die physiologisch verträgliche Säureadditionssalze bilden wie Halogenwasserstoffsäuren, Schwefelsäure, Phosphorsäure, Salpetersäure, Cyclohexylsulfaminsäure, Zitronensäure, Weinsäure, Ascorbinsäure, Maleinsäure, Ameisensäure, Salicylsäure, Methan- oder Toluolsulfonsäure.Such end products of the general formula I, in which R 1 is hydrogen, alkyl, hydroxyalkyl, haloalkyl or dialkylaminoalkyl, form stable water-soluble salts. Suitable for salt formation are all acids which form physiologically acceptable acid addition salts such as hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid, cyclohexylsulfamic acid, citric acid, tartaric acid, ascorbic acid, maleic acid, formic acid, salicylic acid, methane or toluenesulfonic acid.

Nach den vorstehenden Verfahren können beispielsweise die folgenden Endprodukte, gegebenenfalls in Form eines physiologisch verträglichen Säureadditionssalzes, erhalten werden:

  • 8-Brom-6-(o-chlorphenyl)-1-(N-(p-chlorphenyl)-piperazixyl]-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin,
  • 8-Brom-6-(o-chlorphenyl)-1-(N-phenyl-piperazinyl)-4H-s-triazolo(3,4c]thieno(2,3e]1,4-diazepin,
  • 8-Brom-6-(o-chlorphenyl)-1-[N-(o-tolyl)-piperazinyl]-4H-s-triazolo[3,4c]thieno[2,3e]l,4-diazepin,
  • 8-Brom-6-(o-chlorphenyl)-1-[N-(o-chlorphenyl)-piperazinyl]-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin,
  • 8-Brom-6-(o-chlorphenyl)-1-[N-(2-methoxyphenyl)-piperazinyl]-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin,
  • 8-Brom-6-(o-chlorphenyl)-1-[N-(p-fluorphenyl)-piperazinyl]-4H-s-triazolo[3,4.c]thieno[2,3e]1,4-diazepin,
  • 8-Brom-6-(o-chlorphenyl)-1-(N-(2-hydroxyäthyl)-piperazinyl]-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin,
  • 8-Brom-6-(o-chlorphenyl)-1-(N-(o-nitrophenyl)-piperazinyl]-4H-s-triazolo(3,4c]thieno(2,3e]1,4-diazepin,
  • 8-Brom-6-(o-bromphenyl)-1-(N-phenyl-piperazinyl]-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin,
  • 8-Brom-6-(o-bromphenyl)-1-[N-(2-pyridyl)-piperazinyl]-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin,
  • 8-Chlor-6-(o-chlorphenyl)-1-[N-(3-pyridyl)-piperazinyl]-4H-s-triazolo(3,4c]thieno[2,3e]1,4-diazepin,
  • 8-Brom-6-(o-chlorphenyl)-1-[N-(4-pyridyl)-piperazinyl]-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin,
  • 8-Brom-6-(o-fluorphenyl)-piperazinyl-4H-s-triazolo[3,4c] thieno[2,3e]1,4-diazepin,
  • 8-Methyl-6-(o-chlorphenyl)-1-(N-methyl-piperazinyl)-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin,
  • 8-Brom-6-(o-chlorphenyl)-1-(N-äthyl-piperazinyl)-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin,
  • 8-Brom-5-(o-chlorphenyl)-1-(N-isopropyl-piperazinyl)-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin,
  • 8-Brom-6-(o-bromphenyl)-1-piperazinyl-4H-s-triazolo[3,4c] thieno[2,3e]1,4-diazepin,
  • 8-Brom-6-(o-chlorphenyl)-1-[N-(B-hydroxyisopropyl)-piperazinyl]-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin,
  • 8-Brom-6-(o-chlorphenyl)-1-[N-(B-chloräthyl)-piperazinyl]-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin,
  • 8-Chlor-6-(o-chlorphenyl)-1-piperazinyl-4H-s-triazolo[3,4c] thieno[2,3e]1,4-diazepin,
  • 8-Brom-6-(o-chlorphenyl)-1-[N-(B-dimethylaminoäthyl)-piperazinyl]-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin,
  • 8-Brom-6-(o-chlorphenyl)-1-[N-(dimethylaminomethyl)-piperazinyl]-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin,
  • 8-Brom-6-(o-chlorphenyl)-1-N-formylpiperazino-4H-s-triazolo [3,4c]thieno[2,3e]1,4-diazepin,
  • 1-(N-Acetylpiperazino)-8-brom-6-(o-chlorphenyl)-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin,
  • 1-(N-Acetylpiperazino)-8-äthyl-6-(o-chlorphenyl)-4H-s-triazalo[3,4c]thieno[2,3e]1,4-diazepin,
  • 1-(N-Acetylpiperazino)-8-chlor-6-(o-chlorphenyl)-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin,
  • 1-(N-Acetylpiperazino)-8-brom-6-(o-fluorphenyl)-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin,
  • 1-(N-Acetylpiperazino)-8-brom-6-(o-bromphenyl)-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin,
  • 8-Brom-6-(o-chlorphenyl)-1-[N-(γ-hydroxypropyl)-piperazinyl]-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin,
  • 8-Brom-5-(o-chlorphenyl)-1-(N-stearylpiperazino)-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin,
  • 8-Brom-1-(N-caproylpiperazino)-6-(o-chlorphenyl)-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin,
  • 8-Brom-6-(o-chlorphenyl)-1-(N-benzoylpiperazino)-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin,
  • 8-Brom-6-(o-chlorphenyl)-1-[N-(p-fluorbenzoyl)-piperazino]-4H-s-triazolo[3,4c]-thieno[2,3e]1,4-diazepin,
  • 8-Brom-6-(o-chlorphenyl)-1-[N-(o-methylbenzoyl)-piperazino]-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin,
  • 8-Brom-6-(o-chlorphenyl)-1-[N-(o-chlorbenzoyl)-piperazino]-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin,
  • 8-Brom-6-(o-chlorphenyl)-1-[N-(p-nitrobenzoyl)-piperazino]-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin,
  • 8-Brom-6-(o-chlorphenyl)-1-(N-nicotinoyl-piperazino)-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin,
  • 8-Brom-6-(o-chlorphenyl)-1-(N-picolinoyl-piperazino)-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin,
  • 1-(N-Äthoxycarbonyl-piperazino)-8-brom-6-(o-chlorphenyl)-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin.
For example, the following end products, optionally in the form of a physiologically acceptable acid addition salt, can be obtained by the above processes:
  • 8-bromo-6- (o-chlorophenyl) -1- (N- (p-chlorophenyl) piperazixyl] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 8-bromo-6- (o-chlorophenyl) -1- (N-phenyl-piperazinyl) -4H-s-triazolo (3,4c] thieno (2,3e] 1,4-diazepine,
  • 8-bromo-6- (o-chlorophenyl) -1- [N- (o-tolyl) piperazinyl] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 8-bromo-6- (o-chlorophenyl) -1- [N- (o-chlorophenyl) piperazinyl] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 8-bromo-6- (o-chlorophenyl) -1- [N- (2-methoxyphenyl) piperazinyl] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 8-bromo-6- (o-chlorophenyl) -1- [N- (p-fluorophenyl) piperazinyl] -4H-s-triazolo [3,4.c] thieno [2,3e] 1,4-diazepine,
  • 8-bromo-6- (o-chlorophenyl) -1- (N- (2-hydroxyethyl) piperazinyl] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 8-bromo-6- (o-chlorophenyl) -1- (N- (o-nitrophenyl) piperazinyl] -4H-s-triazolo (3,4c] thieno (2,3e] 1,4-diazepine,
  • 8-bromo-6- (o-bromophenyl) -1- (N-phenyl-piperazinyl] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 8-bromo-6- (o-bromophenyl) -1- [N- (2-pyridyl) piperazinyl] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 8-chloro-6- (o-chlorophenyl) -1- [N- (3-pyridyl) piperazinyl] -4H-s-triazolo (3,4c] thieno [2,3e] 1,4-diazepine,
  • 8-bromo-6- (o-chlorophenyl) -1- [N- (4-pyridyl) piperazinyl] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 8-bromo-6- (o-fluorophenyl) piperazinyl-4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 8-methyl-6- (o-chlorophenyl) -1- (N-methyl-piperazinyl) -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 8-bromo-6- (o-chlorophenyl) -1- (N-ethyl-piperazinyl) -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 8-bromo-5- (o-chlorophenyl) -1- (N-isopropyl-piperazinyl) -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 8-bromo-6- (o-bromophenyl) -1-piperazinyl-4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 8-bromo-6- (o-chlorophenyl) -1- [N- (B-hydroxyisopropyl) piperazinyl] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 8-bromo-6- (o-chlorophenyl) -1- [N- (B-chloroethyl) piperazinyl] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 8-chloro-6- (o-chlorophenyl) -1-piperazinyl-4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 8-bromo-6- (o-chlorophenyl) -1- [N- (B-dimethylaminoethyl) piperazinyl] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 8-bromo-6- (o-chlorophenyl) -1- [N- (dimethylaminomethyl) piperazinyl] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 8-bromo-6- (o-chlorophenyl) -1-N-formylpiperazino-4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 1- (N-acetylpiperazino) -8-bromo-6- (o-chlorophenyl) -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 1- (N-acetylpiperazino) -8-ethyl-6- (o-chlorophenyl) -4H-s-triazalo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 1- (N-acetylpiperazino) -8-chloro-6- (o-chlorophenyl) -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 1- (N-acetylpiperazino) -8-bromo-6- (o-fluorophenyl) -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 1- (N-acetylpiperazino) -8-bromo-6- (o-bromophenyl) -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 8-bromo-6- (o-chlorophenyl) -1- [N- (γ-hydroxypropyl) piperazinyl] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 8-bromo-5- (o-chlorophenyl) -1- (N-stearylpiperazino) -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 8-bromo-1- (N-caproylpiperazino) -6- (o-chlorophenyl) -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 8-bromo-6- (o-chlorophenyl) -1- (N-benzoylpiperazino) -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 8-bromo-6- (o-chlorophenyl) -1- [N- (p-fluorobenzoyl) piperazino] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 8-bromo-6- (o-chlorophenyl) -1- [N- (o-methylbenzoyl) piperazino] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 8-bromo-6- (o-chlorophenyl) -1- [N- (o-chlorobenzoyl) piperazino] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 8-bromo-6- (o-chlorophenyl) -1- [N- (p-nitrobenzoyl) piperazino] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 8-bromo-6- (o-chlorophenyl) -1- (N-nicotinoyl-piperazino) -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 8-bromo-6- (o-chlorophenyl) -1- (N-picolinoyl-piperazino) -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine,
  • 1- (N-ethoxycarbonyl-piperazino) -8-bromo-6- (o-chlorophenyl) -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine.

Die Ausgangsverbindungen der allgemeinen Formel II sind literaturbekannt. Ausgangsverbindungen der allgemeinen Formel IV erhält man durch Umsetzung von.Verbindungen der Formel

Figure imgb0006
in der

  • R 2 und R3 die oben genannte Bedeutung haben und Hal ein Halogenatom bedeutet, mit einem Piperazinderivat der allgemeinen Formel III-unter den bei a) angegebenen Bedingungen und anschließendem Austausch des Ring-Sauerstoff-Atoms durch ein Stickstoffatom, wie er z.B. in der deutschen Anmeldung P 25 31 678 beschrieben worden ist.
The starting compounds of the general formula II are known from the literature. Starting compounds of the general formula IV are obtained by reacting compounds of the formula
Figure imgb0006
 in the
  • R 2 and R 3 have the meaning given above and Hal represents a halogen atom, with a piperazine derivative of the general formula III-under the conditions specified in a) and subsequent replacement of the ring oxygen atom by a nitrogen atom, as described, for example, in German Application P 25 31 678 has been described.

Die Ausgangsverbindungen der allgemeinen Formel V können z.B. erhalten werden durch Umsetzung entsprechend substituierter 1-Halogen-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepine mit einem Piperazin oder durch Dehydrierung eines 1-Piperazinyl-4H-s-triazolo[3,4c]thieno[2,3e]5,6-dihydro- ; 1,4-diazepins, wie vorstehend beschrieben.The starting compounds of general formula V can e.g. are obtained by reacting appropriately substituted 1-halo-4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepines with a piperazine or by dehydrogenating a 1-piperazinyl-4H-s-triazolo [3, 4c] thieno [2,3e] 5,6-dihydro-; 1,4-diazepines as described above.

Die Endprodukte der allgemeinen Formel I weisen wertvolle therapeutische Eigenschaften auf und können als Anxiolytikca, Tranquilizer, Sedativa und Neuroleptica eingesetzt werden. Die Hauptwirkung kann bei den einzelnen Verbindungen verschieden sein, so daß der Schwerpunkt einmal auf neuroleptischem, bei anderen Verbindungen auf schlafförderndem Gebiet usw. liegt.The end products of the general formula I have valuable therapeutic properties and can be used as anxiolytics, tranquilizers, sedatives and neuroleptics. The main effect can be different for the individual compounds, so that the focus is on the neuroleptic area, on other compounds on the sleep-promoting area, etc.

Die neuen Verbindungen sind daher besonders geeignet zur Behebung psychomotorischer Erregungs- und Angstzustände, wie sie beispielsweise bei Schizophrenie auftreten, ferner zur Behandlung von Krampfzuständen und Schlafstörungen verschiedener Genese.The new compounds are therefore particularly suitable for eliminating psychomotor excitement and anxiety, such as they occur, for example, in schizophrenia, and also for the treatment of convulsions and sleep disorders of various origins.

Als besonders wirksam haben sich solche Endprodukte der allgemeinen Formel I erwiesen, in denen R1 Wasserstoff, eine Alkyl- oder Hydroxyalkylgruppe, einen Phenyl- oder einen Pyridylrest oder den Rest R - CO - , R Chlor, R3 Brom und R4 Wasserstoff oder Methyl bedeutet.End products of the general formula I in which R 1 is hydrogen, an alkyl or hydroxyalkyl group, a phenyl or a pyridyl radical or the radical R - CO -, R chlorine, R 3 bromine and R 4 hydrogen or have proven to be particularly effective Methyl means.

Die Einzeldosis der erfindungsgemäßen Substanzen liegt bei 0,05 bis 50, vorzugsweise 0,1 bis 25 mg (oral) und 5 bis 150 mg als Tagesdosis.The single dose of the substances according to the invention is 0.05 to 50, preferably 0.1 to 25 mg (oral) and 5 to 150 mg as a daily dose.

Die erfindungsgemäß erhältlichen Verbindungen können allein oder in Kombination mit anderen erfindungsgemäßen Wirkstoffen, gegebenenfalls auch in Kombination mit weiteren pharmakologisch aktiven Wirkstoffen wie Spasmolytica oder ß-Rezeptorenblocker zur Anwendung gelangen. Geeignete Anwendungsformen sind beispielsweise Tabletten, Kapseln, Zäpfchen, Lösungen, Säfte, Emulsionen oder dispersible Pulver. Entsprechende Tabletten können beispielsweise durch Mischen des oder der Wirkstoffe mit bekannten Hilfsstoffen, beispielsweise inerten Verdünnungsmitteln, wie Calciumcarbonat, Calciumphosphat oder Milchzucker, Sprengmitteln, wie Maisstärke oder Alginsäure, Bindemitteln, wie Stärke oder Gelatine, Schmiermitteln, wie Magnesiumstearat oder Talk, und/oder Mitteln zur Erzielung des Depoteffektes, wie Carboxypolymethylen, Carboxymethylcellulose, Celluloseacetatphthalat, oder Polyvinylacetat erhalten werden. Die Tabletten können auch aus mehreren Schichten bestehen.The compounds 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 other pharmacologically active substances such as spasmolytics 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, carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets can also consist of several layers.

Entsprechend können Dragees durch Überziehen von analog den Tabletten hergestellten Kernen mit üblicherweise in Dragee- überzügen verwendeten Mitteln, beispielsweise Kollidon oder Schellack, Gummi arabicum, Talk, Titandioxid oder Zucker, hergestellt werden. Zur Erzielung eines Depoteffektes oder zur Vermeidung von Inkompatibilitäten kann der Kern'auch aus mehreren Schichten bestehen. Desgleichen kann auch die Drageehülle zur Erzielung eines Depoteffektes aus mehreren Schichten bestehen, wobei die oben bei den Tabletten erwähnten Hilfsstoffe verwendet werden können.Correspondingly, coated tablets can be produced by coating cores produced analogously to the tablets with agents usually used in coated tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. The core can also be used to achieve a deposit effect or to avoid incompatibilities consist of several layers. 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.

Säfte der erfindungsgemäßen Wirkstoffe beziehungsweise Wirkstoffkombinationen können zusätzlich noch ein Süßungsmittel, wie Saccharin, Cyclamat, Glycerin oder Zucker sowie ein geschmacksverbesserndes Mittel, z.B. Aromastoffe, wie Vanillin oder Orangenextrakt, enthalten. Sie können außerdem Suspendierhilfsstoffe oder Dickungsmittel, wie Natriumcarboxymethylcellulose, Netzmittel, beispielsweise Kondensationsprodukte von Fettalkoholen mit Äthylenoxid, oder Schutzstoffe, wie p-Hydroxybenzoate, enthalten.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 aids or thickeners, such as sodium carboxymethyl cellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.

Injektionslösungen werden in üblicher Weise, z.B. unter Zusatz von Konservierungsmitteln, wie p-Hydroxybenzoaten, oder Stabilisatoren, wie Alkalisalzen der Äthylendiamintetraessigsäure hergestellt und in Injektionsflaschen oder Ampullen abgefüllt.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.

Die eine oder mehrere Wirkstoffe beziehungsweise Wirkstoffkombinationen enthaltenden Kapseln können beispielsweise hergestellt werden, indem.man die Wirkstoffe mit inerten Trägern, wie Milchzucker oder Sorbit, mischt und in Gelatinekapseln einkapselt.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.

Geeignete Zäpfchen lassen sich beispielsweise durch Vermischen mit dafür vorgesehenen Trägermitteln, wie Neutralfetten oder Polyäthylenglykol beziehungsweise dessen Derivaten, herstellen.Suitable suppositories can be produced, for example, by mixing them with carrier agents such as neutral fats or polyethylene glycol or its derivatives.

Beispiel 1example 1 8-Hrom-6-(o-chlorphenyl)-1-[N-(2-hydroxyäthyl)-piperazinyl]-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin8-Hrom-6- (o-chlorophenyl) -1- [N- (2-hydroxyethyl) piperazinyl] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine

0,07 Mol = 31 g 1,8-Dibrom-6-(o-chlorphenyl)-4H-s-triazolo [3,4c]thieno[2,3e]1,4-diazepin, 17 g (0,14 Mol) N-(2-Hydroxyäthyl)-piperazin und 800 ml Xylol werden 24 Stunden unter Rückfluß gekocht. Man saugt das Reaktionsgemisch noch warm über Kieselgur-Kohle ab und dampft das Filtrat im Vakuum ein. Der Rückstand wird in Methylenchlorid aufgenommen und die Lösung mit Wasser gewaschen. Nach dem Trocknen und Eindampfen erhält man 28,5 g = 81 % d.Th. der Titelverbindung vom Fp. 125 - 126°C (aus Essigester).0.07 mol = 31 g 1,8-dibromo-6- (o-chlorophenyl) -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine, 17 g (0.14 mol ) N- (2-Hydroxyethyl) piperazine and 800 ml of xylene are under for 24 hours Reflux cooked. The reaction mixture is suctioned off while warm over kieselguhr charcoal and the filtrate is evaporated in vacuo. The residue is taken up in methylene chloride and the solution washed with water. After drying and evaporation, 28.5 g = 81% of theory the title compound of mp 125-126 ° C (from ethyl acetate).

Die Base wird mit wenig Alkohol suspendiert und mit einem kleinen Überschuß alkoholischer Salzsäure versetzt. Nach Zugabe von Äther kristallisiert das gut wasserlösliche Hydrochlorid der Titelverbindung, Fp. 211 - 220°C (Zers.).The base is suspended with a little alcohol and a small excess of alcoholic hydrochloric acid is added. After adding ether, the readily water-soluble hydrochloride of the title compound, mp. 211-220 ° C. (dec.) Crystallizes.

In analoger Weise erhält man aus der in heißem Alkohol gelösten Base durch Zusatz von 1 Mol Maleinsäure, Weinsäure beziehungsweise Methansulfonsäure die entsprechenden Salze in quantitativer Ausbeute.In an analogous manner, the corresponding salts are obtained in quantitative yield from the base dissolved in hot alcohol by adding 1 mol of maleic acid, tartaric acid or methanesulfonic acid.

Maleat: Fp. 201 - 202°C ;Tartrat: Fp. 228.- 229°CMaleate: mp. 201-202 ° C; tartrate: mp. 228-229 ° C

Methansulfonat: Fp. 241 - 242°CMethanesulfonate: mp 241-242 ° C

Beispiel 2 Example 2 8-Brom-6-(o-chlorphenyl)-1-piperazinyl-4H-s-triazolo[3,4c] thieno[2,3e]1,4-diazepin8-bromo-6- (o-chlorophenyl) -1-piperazinyl-4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine

0,01 Mol = 4,5 g 1,8-Dibrom-6-(o-chlorphenyl)-4H-s-triazolo [3,4c]thieno[2,3e]1,4-diazepin werden mit 0,02 Mol = 1,8 g Piperazin verrieben und 15 Minuten auf 160°C erhitzt. Die erkaltete Schmelze wird zwischen Methylenchlorid und Wasser verteilt. Nach Abtrennen der wässrigen Phase wird die Methylenchloridschicht mit 100 ml 2 n Salzsäure extrahiert. Die Auszüge werden mit Ammoniak alkalisch gestellt und das Reaktionsprodukt erneut in Methylenchlorid aufgenommen. Nach dem Trocknen und Eindampfen erhält man aus Essigester 3,8 g = 82 % d. Th. der gewünschten Verbindung vom Fp. 246 - 248°C. Mit alkoholischer Salzsäure erhält man das Hydrochlorid vom Fp. 240°C (Zers.).0.01 mol = 4.5 g of 1,8-dibromo-6- (o-chlorophenyl) -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine are mixed with 0.02 mol = 1, 8 g of piperazine triturated and heated for 15 minutes 160 ° C. The cooled melt is distributed between methylene chloride and water. After the aqueous phase has been separated off, the methylene chloride layer is extracted with 100 ml of 2N hydrochloric acid. The extracts are made alkaline with ammonia and the reaction product is taken up again in methylene chloride. After drying and evaporation, 3.8 g = 82% of theory are obtained from ethyl acetate. Th. Of the desired compound of mp. 246 - 248 ° C. With alcoholic hydrochloric acid to obtain the hydrochloride of mp. 2 4 0 ° C (Z repl.).

Beispiel 3Example 3 8-Brom-6-(o-chlorphenyl)-1-(N-methylpiperazinyl)-4H-s-triazolor[3.4c]thienof[2.3e].4-diazeoin8-bromo-6- (o-chlorophenyl) -1- (N-methylpiperazinyl) -4H-s-triazolor [3.4c] thienof [2.3e] .4-diazeoin

4,6 g (0,01 Mol) 8-Brom-6-(o-chlorphenyl)-1-piperazinyl-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin werden in 200 ml Tetrahydrofuran mit 1,2 ml (0,02 Mol) Methyljodid 3 Stunden bei 40 - 50°C gerührt. Die Titelverbindung läßt sich säulenchromatographisch abtrennen.4.6 g (0.01 mol) of 8-bromo-6- (o-chlorophenyl) -1-piperazinyl-4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine are dissolved in 200 ml of tetrahydrofuran with 1.2 ml (0.02 mol) of methyl iodide for 3 hours at 40-50 ° C. The title compound can be separated off by column chromatography.

Die Ausbeute beträgt 3 g = 63 % d.Th., Fp. 206 - 208°C. Das mit alkoholischer Salzsäure erhältliche Hydrochlorid hat einen Fp. von 210°C (Zers.).The yield is 3 g = 63% of theory, mp. 206-208 ° C. The hydrochloride available with alcoholic hydrochloric acid has an mp of 210 ° C (dec.).

Beispiel 4Example 4 8-Brom-6-(o-chlorphenyl)-1-N-(2-pyridyl)-piperazinyl]-4H-s-triazQlo[3,4c]thieno[2,3e]1,4-diazepin8-bromo-6- (o-chlorophenyl) -1-N- (2-pyridyl) piperazinyl] -4H-s-triazQlo [3,4c] thieno [2,3e] 1,4-diazepine

0,04 Mol = 19 g 1,8-Dibrom-6-(o-chlorphenyl)-4H-s-triazolo0.04 mol = 19 g 1,8-dibromo-6- (o-chlorophenyl) -4H-s-triazolo

[3,4c]thieno[2,3e]1,4-diazepin werden mit.0,08 Mol = 13,4 g N-[Pyridyl-(2)]-piperazin und 150 ml Xylol 24 Stunden unter Rückfluß gekocht. Das ausgefallene N-[Pyridyl-(2)]-piperazin-Hydrobromid wird abgesaugt. Im Filträt befindet sich die Titelverbindung, die man nach Eindampfen und Umkristallisieren aus Äthanol isoliert und reinigt.[3,4c] thieno [2,3e] 1,4-diazepine are refluxed with 0.08 mol = 13.4 g of N- [pyridyl- (2)] - piperazine and 150 ml of xylene for 24 hours. The precipitated N- [pyridyl- (2)] - piperazine hydrobromide is suctioned off. The title compound is located in the portrait, which is isolated and purified after evaporation and recrystallization from ethanol.

Ausbeute: 13,2 g = 61 % d.Th., Fp. 215 - 216°C.Yield: 13.2 g = 61% of theory, mp. 215-216 ° C.

Beispiel 5Example 5 8-Brom-6-(o-chlorphenyl)-1-(N-methylpiperazinyl)-4H-s-triazol[3.4c]thieno[2,3e]1,4-diazepin8-bromo-6- (o-chlorophenyl) -1- (N-methylpiperazinyl) -4H-s-triazole [3.4c] thieno [2,3e] 1,4-diazepine

3,5 g (0,075 Mol)1,8-Dibrom-6-(o-chlorphenyl)-4H-s-triazoio [3,4c]thieno[2,3e]4,1-oxazepin werden mit 2 ml Methylpiperazin und 100 ml Xylol 4 Stunden unter Rückfluß gekocht. Man saugt ab und dampft das Filtrat im Vakuum ein. Der Rückstand wird in Methylenchlorid aufgenommen, mit Wasser gewaschen, getrocknet, eingedampft und mit Isopropyläther zur Kristallisation gebracht. Man erhält 2,9 g = 80 % d. Th. 8-Brom-6-(o-chlorphenyl)-1-(N-methylpiperazinyl)-4H-s-triazolo[3,4c] thieno(2,3e]4,1-oxazepin vom Fp. 150 - 153°C.3.5 g (0.075 mol) of 1,8-dibromo-6- (o-chlorophenyl) -4H-s-triazoio [3,4c] thieno [2,3e] 4,1-oxazepine are mixed with 2 ml of methylpiperazine and 100 ml of xylene boiled under reflux for 4 hours. It is suctioned off and the filtrate is evaporated in vacuo. The residue is taken up in methylene chloride, washed with water, dried, evaporated and brought to crystallization using isopropyl ether. 2.9 g = 80% of theory are obtained. Th. 8-bromo-6- (o-chlorophenyl) -1- (N-methylpiperazinyl) -4H-s-triazolo [3,4c] thieno (2,3e] 4,1-oxazepine, mp 150-153 ° C.

2,4 g (0,005 Mol) des Oxazepins werden mit 2u ml konzentrierter Bromwasserstoffsäure 30 Minuten bei Raumtemperatur gerührt. Man gießt auf 200 ml Eiswasser und macht unter Eiskühlung ammoniakalisch. Anschließend wird das Produkt in ; Methylenchlorid aufgenommen, die Lösung getrocknet und auf 30 ml eingedampft. Hierzu gibt man 2,5 ml Thionylchlorid und rührt 2 Stunden bei Raumtemperatur. Dann wird das Reaktionsgemisch zur Trockne verdampft und der Rückstand mit 30 ml Methanol versetzt, das vorher mit Ammoniak gasättigt wurde. Man erhitzt 15 Minuten im Autoklaven auf 60°C, dampft das Methanol ab, nimmt in Methylenchlorid auf und wäscht die Salze mit Wasser aus. Aus der Methylenchloridphase erhält man die Dihydroverbindung, die ohne Reinigung mit 100 ml Aceton und 1 g pulverisiertem Kaliumpermanganat 4 Stunden bei Raumtemperatur gerührt wird. Man saugt den Braunstein ab und erhält schließlich aus dem Filtrat 1,2 g = 50 % d. Th. der Titelverbindung vom Fp. 206 - 208°C.2.4 g (0.005 mol) of the oxazepine are stirred with 2 u ml of concentrated hydrobromic acid at room temperature for 30 minutes. Pour onto 200 ml of ice water and make ammoniacal with ice cooling. Then the product is in; Methylene chloride added, the solution dried and evaporated to 30 ml. 2.5 ml of thionyl chloride are added and the mixture is stirred at room temperature for 2 hours. Then the reaction mixture is evaporated to dryness and the residue is mixed with 30 ml of methanol, which was previously saturated with ammonia. The mixture is heated in an autoclave at 60 ° C. for 15 minutes, the methanol is evaporated off, taken up in methylene chloride and the salts are washed out with water. The dihydro compound is obtained from the methylene chloride phase and is stirred for 4 hours at room temperature without purification with 100 ml of acetone and 1 g of powdered potassium permanganate. The manganese dioxide is suctioned off and 1.2 g = 50% of theory is finally obtained from the filtrate. Th. Of the title compound of mp 206 - 208 ° C.

Beispiel 6Example 6 1-(N-Acetylpiperazino)-8-brom-5-(o-chlorphenyl)-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin1- (N-Acetylpiperazino) -8-bromo-5- (o-chlorophenyl) -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine

4,6 g .(0,01 Mol) 8-Brom-6-(o-chlorphenyl)-1-piperazino-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin werden in 100 ml Essigsäureanhydrid 20 Minuten gerührt. Man gießt das Reaktionsgemisch auf Eis und macht mit Ammoniak alkalisch. Die Acetylverbindung wird in Methylenchlorid aufgenommen, die Methylenchloridphase getrocknet und der Rückstand durch Ätherzugabe zur Kristallisation gebracht. Ausbeute: 3,8 g = 76 % d.Th. vom Fp. 247 - 249°C.4.6 g. (0.01 mol) of 8-bromo-6- (o-chlorophenyl) -1-piperazino-4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine are described in 100 ml of acetic anhydride stirred for 20 minutes. The reaction mixture is poured onto ice and made alkaline with ammonia. The acetyl compound is taken up in methylene chloride, the methylene chloride phase is dried and the residue is crystallized by adding ether. Yield: 3.8 g = 76% of theory mp 247-249 ° C.

Beisbiel 7Example 7 8-Brom-6-(o-chlornhenyl)-1-(N-äthoxycarbonylpiperaains)-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin8-bromo-6- (o-chloronhenyl) -1- (N-ethoxycarbonylpiperaain) -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine

4,6 g (0,01 Mol) 8-Brom-6-(o-chlorphenyl)-1-piperazino-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin werden in 100 ml Tetrahydrofuran mit 2 ml Chlorameisensäureäthylester 30 Minuten bei Raumtemperatur gerührt. Man dampft ein, gießt Wasser und Methylenchlorid hinzu, macht mit Ammoniak alkalisch und chromatographiert den Rückstand aus der getrockneten Methylenchloridphase.4.6 g (0.01 mol) of 8-bromo-6- (o-chlorophenyl) -1-piperazino-4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine are dissolved in 100 ml of tetrahydrofuran with 2 ml of ethyl chloroformate for 30 minutes stirred at room temperature. It is evaporated, water and methylene chloride are added, the mixture is made alkaline with ammonia and the residue is chromatographed from the dried methylene chloride phase.

Ausbeute: 4,8 g = 91 % d.Th., Fp. 216 - 218°C.Yield: 4.8 g = 91% of theory, mp. 216-218 ° C.

Beispiel 8Example 8 1-(N-Formylpiperazino)-8-brom-6-(o-chlorphenyl)-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin1- (N-Formylpiperazino) -8-bromo-6- (o-chlorophenyl) -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine

4,6 g (0,01 Mol) 8-Brom-6-(o-chlorphenyl)-1-piperazino-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin werden in 100 ml Ameisensäure 3 Stunden unter Rückfluß gekocht. Man gießt auf Eis, macht mit 2 n Natronlauge alkalisch, nimmt die Formylverbindung in Methylenchlorid auf und arbeitet wie unter Beispiel 6 auf.4.6 g (0.01 mol) of 8-bromo-6- (o-chlorophenyl) -1-piperazino-4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine are dissolved in 100 ml of formic acid boiled under reflux for 3 hours. The mixture is poured onto ice, made alkaline with 2N sodium hydroxide solution, the formyl compound is taken up in methylene chloride and the procedure is as in Example 6.

Ausbeute: 3,9 g =80 % d.Th., Fp. 205 - 215°C.Yield: 3.9 g = 80% of theory, mp. 205-215 ° C.

Nach den vorstehend beschriebenen Methoden werden folgende Verbinduhgen der allgemeinen Formel I erhalten:

Figure imgb0007
Figure imgb0008
 The following compounds of the general formula I are obtained by the methods described above:
Figure imgb0007
Figure imgb0008

FormulierungsbeispieleFormulation examples

Figure imgb0009
Figure imgb0009

Herstellung:Manufacturing:

Die Mischung der Wirksubstanz mit Milchzucker und Maisstärke wird mit einer 10%igen wässrigen Gelatinelösung durch ein Sieb mit 1 mm Maschenweite granuliert, bei 40°C getrocknet und nochmals durch ein Sieb getrieben. Das so erhaltene Granulat wird mit Magnesiumstearat gemischt und verpreßt. Die so erhaltenen Kerne werden in üblicher Weise mit einer Hülle überzogen, die mit Hilfe einer wässrigen Suspension von Zucker, Titandioxyd, Talkum und Gummi arabicum aufgebracht wird. Die fertigen Dragees werden mit Bienenwachs poliert. Dragee-Endgewicht: 100 mg

Figure imgb0010
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
Figure imgb0010

Herstellung:Manufacturing:

Wirkstoff und Magnesiumstearat werden mit einer wässrigen Lösung der löslichen Stärke granuliert, das Granulat getrocknet und innig mit Milchzucker und Maisstärke vermischt. Das Gemisch wird sodann zu Tabletten von 100 mg Gewichtverpreßt, die je 0,5 mg Wirkstoff enthalten.

Figure imgb0011
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.
Figure imgb0011

Herstellung:Manufacturing:

Die feingepulverte Substanz wird mit Hilfe eines Eintauch-Homogenisators in die geschmolzene und auf 40°C abgekühlte Zäpfchenmasse eingerührt. Die Masse wird bei 35°C in leicht vorgekühlte Formen gegossen.

Figure imgb0012
The finely powdered substance is stirred into the molten suppository mass, which has been cooled to 40 ° C., using an immersion homogenizer. The mass is poured into slightly pre-cooled molds at 35 ° C.
Figure imgb0012

Herstellung:Manufacturing:

Der Wirkstoff und die Hilfsstoffe werden in einer ausreichenden Menge Wasser gelöst und mit der notwendigen Menge Wasser auf die gewünschte Konzentration gebracht. Die Lösung wird filtriert und unter aseptischen Bedingungen in 1 ml Ampullen abgefüllt. Zuletzt werden die Ampullen sterilisiert und verschlossen. Jede Ampulle enthält 0,5 mg Wirkstoff.The active ingredient and excipients are dissolved in a sufficient amount of water and brought to the desired concentration with the necessary amount of water. The solution is filtered and filled into 1 ml ampoules under aseptic conditions. Finally, the ampoules are sterilized and sealed. Each ampoule contains 0.5 mg of active ingredient.

Claims (10)

1. Neue substituierte 1-Piperazinyl-4H-s-triazolo[3,4c]thieno [2,3e]1,4-diazepine der allgemeinen Formel
Figure imgb0013
in der R1 Wasserstoff, einen geradkettigen oder verzweigten Alkyl-, Halogenalkyl-, Hydroxyalkyl- oder Dialkylaminoalkylrest, einen gegebenenfalls durch Methyl, Methoxy, Nitro oder Halogen substituierten Phenylrest oder einen Pyridyl- oder Pyrimidinylrest oder den Rest R4 - CO - , R2 Wasserstoff, Fluor, Chlor oder Brom, R3 Chlor oder Brom oder einen Alkylrest.und R4 Wasserstoff, Alkyl mit 1 - 17 Kohlenstoffatomen, Alkoxy mit 1 - 2 Kohlenstoffatomen, Phenyl, Tolyl, Methoxyphenyl, Halogenphenyl, Nitrophenyl oder Pyridyl bedeuten. 1. New substituted 1-piperazinyl-4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepines of the general formula
Figure imgb0013
 in the R 1 is hydrogen, a straight-chain or branched alkyl, haloalkyl, hydroxyalkyl or dialkylaminoalkyl radical, a phenyl radical which is optionally substituted by methyl, methoxy, nitro or halogen or a pyridyl or pyrimidinyl radical or the radical R 4 - CO -, R 2 is hydrogen, fluorine, chlorine or bromine, R 3 is chlorine or bromine or an alkyl radical. And R 4 is hydrogen, alkyl having 1 to 17 carbon atoms, alkoxy having 1 to 2 carbon atoms, phenyl, tolyl, methoxyphenyl, halophenyl, nitrophenyl or pyridyl. 2. Neue substituierte 1-Piperazinyl-4H-s-triazolo[3,4c]thieno [2,3e]1,4-diazepine der allgemeinen Formel I, in der R1 Wasserstoff oder einen Alkyl- oder Hydroxyalkylrest mit'l - 3 Kohlenstoffatomen, R2 Chlor und R3 Brom bedeutet und ihre Säureadditionssalze. 2. New substituted 1-piperazinyl-4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepines of the general formula I, in which R 1 is hydrogen or an alkyl or hydroxyalkyl radical having 1 to 3 carbon atoms, R 2 chlorine and R 3 means bromine and their acid addition salts. 3. Neue substituierte 1-Piperazinyl-4H-s-triazolo[3,4c]thieno [2,3e]1,4-diazepine der allgemeinen Formel I, in der R1 einen Phenyl- oder Pyridylrest, R2 Chlor und R3 Brom bedeutet. 3. New substituted 1-piperazinyl-4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepines of the general formula I, in which R 1 is a phenyl or pyridyl radical, R 2 chlorine and R 3 means bromine. 4. Neue substituierte 1-Piperazinyl-4H-s-triazolo[3,4c]thienc [2,3e]1,4-diazepine der allgemeinen Formel I, in der R1 den Rest R4 - CO - , R2 Chlor, R3 Brom und R4 Wasserstoff oder Methyl bedeutet. 4. New substituted 1-piperazinyl-4H-s-triazolo [3,4c] thienc [2,3e] 1,4-diazepines of the general formula I, in which R 1 the rest R 4 - CO -, R 2 chlorine, R 3 bromine and R 4 represents hydrogen or methyl. 5. 8-Brom-6-(o-chlorphenyl)-1-[N-(hydroxyäthyl)-piperazinyl]-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin und dessen physiologisch verträgliche Säureadditionssalze.5. 8-bromo-6- (o-chlorophenyl) -1- [N- (hydroxyethyl) piperazinyl] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine and its physiological compatible acid addition salts. 6. 8-Brom-6-(o-chlorphenyl)-1-[N-(-2-pyridyl)-piperazinyl]-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin.6. 8-bromo-6- (o-chlorophenyl) -1- [N - (- 2-pyridyl) piperazinyl] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine . 7. 8-Brom-6-(o-chlorphenyl)-1-(N-(2-hydroxypropyl)-piperazinyl]-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin und dessen physiologisch verträgliche Säureadditionssalze.7. 8-bromo-6- (o-chlorophenyl) -1- (N- (2-hydroxypropyl) piperazinyl] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine and its physiologically tolerated acid addition salts. 8. 8-Brom-6-(o-chlorphenyl)-1-[N-(2-hydroxyisopropyl)-piperazinyl]-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin und dessen physiologisch verträgliche Säureadditionssalze.8. 8-bromo-6- (o-chlorophenyl) -1- [N- (2-hydroxyisopropyl) piperazinyl] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine and its physiologically tolerated acid addition salts. 9. Verfahren zur Herstellung neuer substituierter 1-Piperazinyl-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepine der allgemeinen Formel
Figure imgb0014
in der R1 Wasserstoff, einen geradkettigen oder verzweigten Alkyl-, Halogenalkyl-, Hydroxyalkyl- oder Dialkylaminoalkylrest, einen gegebenenfalls durch Methyl, Methoxy, Nitro oder Halogen substituierten Phenylrest oder einen Pyridyloder Pyrimidinylrest oder den Rest R4 - CO - , R 2 Wasserstoff, Fluor, Chlor oder Brom, R 3 Chlor oder Brom oder einen Alkylrest und R4 Wasserstoff, Alkyl mit 1 - 17 Kohlenstoffatomen, Alkoxy mit 1 - 2 Kohlenstoffatomen, Phenyl, Tolyl, Methoxyphenyl, Halogenphenyl, Nitrophenyl oder Pyridyl bedeutet, dadurch gekennzeichnet, daß man a) Verbindungen der allgemeinen Formel
Figure imgb0015
 in der R2 und R3 die oben genannte Bedeutung haben und Hal ein Halogenatom bedeutet, mit Piperazinen der allgemeinen Formel
Figure imgb0016
in der R1 die oben genannte Bedeutung hat, umsetzt, oder daß man b) Verbindungen der allgemeinen Formel
Figure imgb0017
in der R1, R2 und R3 die oben genannte Bedeutung haben, in an sich bekannter Weise dehydriert, oder daß man c) Verbindungen der allgemeinen Formel
Figure imgb0018
 in der R 2 und R3 die oben angegebene Bedeutung haben, in an sich bekannter Weise acyliert und daß man, sofern R1 Wasserstoff, Alkyl, Hydroxyalkyl, Halogenalkyl oder Dialkylaminoalkyl bedeutet, die so erhaltenen Endprodukte der allgemeinen Formel I gegebenenfalls in üblicher Weise in ein physiologisch verträgliches Säureadditionssalz überführt. 9. Process for the preparation of new substituted 1-piperazinyl-4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepines of the general formula
Figure imgb0014
 in the R 1 is hydrogen, a straight-chain or branched alkyl, haloalkyl, hydroxyalkyl or dialkylaminoalkyl radical, a phenyl radical which is optionally substituted by methyl, methoxy, nitro or halogen or a pyridyl or pyrimidinyl radical or the radical R 4 - CO -, R 2 is hydrogen, fluorine, chlorine or bromine, R 3 is chlorine or bromine or an alkyl radical and R 4 is hydrogen, alkyl having 1 to 17 carbon atoms, alkoxy having 1 to 2 carbon atoms, phenyl, tolyl, methoxyphenyl, halophenyl, nitrophenyl or pyridyl, characterized in that a) Compounds of the general formula
Figure imgb0015
 in which R 2 and R 3 have the meaning given above and Hal represents a halogen atom, with piperazines of the general formula
Figure imgb0016
 in which R 1 has the meaning given above, or that b) compounds of the general formula
Figure imgb0017
 in which R 1 , R 2 and R 3 have the meaning given above, in a manner known per se, or in that c) compounds of the general formula
Figure imgb0018
 in which R 2 and R 3 have the meaning given above, acylated in a manner known per se and that, if R 1 is hydrogen, alkyl, hydroxyalkyl, haloalkyl or dialkylaminoalkyl, the end products of the general formula I thus obtained, if appropriate in the customary manner transferred a physiologically acceptable acid addition salt. 10. Pharmazeutische Präparate, enthaltend als Wirkstoff Verbindungen der allgemeinen Formel I, gegebenenfalls in Form ihrer Säureadditionssalze, in Kombination mit üblichen Hilf- und/oder Trägerstoffen.10. Pharmaceutical preparations containing as active ingredient compounds of the general formula I, optionally in the form of their acid addition salts, in combination with customary auxiliaries and / or carriers.
EP78100263A 1977-07-21 1978-06-28 Substituted 1-piperazinyl-4h-s-triazolo (3,4-c)thieno(2,3-e)1,4-diazepines, process for their preparation and medicaments containing them Expired EP0000479B1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE2732943 1977-07-21
DE19772732921 DE2732921A1 (en) 1977-07-21 1977-07-21 1-Piperazino-triazolo-thieno-diazepine derivs. - useful as anxiolytics, tranquillisers, sedatives and neuroleptics
DE2732921 1977-07-21
DE19772732943 DE2732943A1 (en) 1977-07-21 1977-07-21 1-Piperazino-triazolo-thieno-diazepine derivs. - useful as anxiolytics, tranquillisers, sedatives and neuroleptics

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EP0000479A1 true EP0000479A1 (en) 1979-02-07
EP0000479B1 EP0000479B1 (en) 1981-01-07

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EP (1) EP0000479B1 (en)
JP (1) JPS5422395A (en)
AT (1) AT363949B (en)
AU (1) AU515885B2 (en)
CA (1) CA1087182A (en)
CH (1) CH642374A5 (en)
CS (1) CS209897B2 (en)
DD (1) DD137934A5 (en)
DE (1) DE2860404D1 (en)
DK (1) DK150306C (en)
ES (2) ES471886A1 (en)
FI (1) FI63033C (en)
FR (1) FR2398070A1 (en)
GB (1) GB2001972B (en)
GR (1) GR65022B (en)
HU (1) HU176485B (en)
IE (1) IE47336B1 (en)
IL (1) IL55169A (en)
IT (1) IT1107490B (en)
LU (1) LU80002A1 (en)
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NO (1) NO149889C (en)
NZ (1) NZ187915A (en)
PH (1) PH14236A (en)
PL (1) PL115061B1 (en)
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2430949A1 (en) * 1978-07-13 1980-02-08 Boehringer Sohn Ingelheim NOVEL 4H-S-TRIAZOLO (3,4C) THIENO (2,3E) 1,4-DIAZEPINES, PROCESSES FOR THEIR PREPARATION AND MEDICAMENTS CONTAINING THEM
EP0230942A2 (en) * 1986-01-21 1987-08-05 Boehringer Ingelheim Kg Thieno-1,4-diazepines

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3894025A (en) * 1974-03-21 1975-07-08 Upjohn Co 1-Piperazino-6-phenyl-4H-s-triazolo{8 4,3-a{9 {8 1,4{9 -benzodiazepine compounds
FR2262525A1 (en) * 1974-03-02 1975-09-26 Boehringer Sohn Ingelheim

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PH12303A (en) * 1973-02-08 1979-01-16 Hoffmann La Roche Thienotriazolodiazepine derivatives
JPS5747916B2 (en) * 1974-05-13 1982-10-13
DE2503235A1 (en) * 1975-01-27 1976-07-29 Boehringer Sohn Ingelheim Bromo substd. thieno-triazolo-diazepines prepn. - by reacting silver or thallium salts of carboxy cpds. with bromine
DE2531678C3 (en) * 1975-07-16 1979-06-28 C.H. Boehringer Sohn, 6507 Ingelheim Thieno [2,3e] triazole [3,4c] 5,6-dihydro-1,4-diazepines and processes for their preparation
DE2533924C3 (en) * 1975-07-30 1979-05-03 C.H. Boehringer Sohn, 6507 Ingelheim Process for the preparation of 6-aryl-4H-striazolo [3,4-c] thieno [2,3-e] 1,4-diazepines

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2262525A1 (en) * 1974-03-02 1975-09-26 Boehringer Sohn Ingelheim
US3894025A (en) * 1974-03-21 1975-07-08 Upjohn Co 1-Piperazino-6-phenyl-4H-s-triazolo{8 4,3-a{9 {8 1,4{9 -benzodiazepine compounds

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2430949A1 (en) * 1978-07-13 1980-02-08 Boehringer Sohn Ingelheim NOVEL 4H-S-TRIAZOLO (3,4C) THIENO (2,3E) 1,4-DIAZEPINES, PROCESSES FOR THEIR PREPARATION AND MEDICAMENTS CONTAINING THEM
EP0230942A2 (en) * 1986-01-21 1987-08-05 Boehringer Ingelheim Kg Thieno-1,4-diazepines
EP0230942A3 (en) * 1986-01-21 1989-03-08 Boehringer Ingelheim Kg Thieno-1,4-diazepines

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EP0000479B1 (en) 1981-01-07
IT7850381A0 (en) 1978-07-19
JPS5422395A (en) 1979-02-20
IL55169A (en) 1982-04-30
SE7808019L (en) 1979-01-22
FI63033B (en) 1982-12-31
GR65022B (en) 1980-06-16
DE2860404D1 (en) 1981-02-26
FR2398070B1 (en) 1982-05-21
NO149889C (en) 1984-07-11
IE47336B1 (en) 1984-02-22
NO149889B (en) 1984-04-02
AU515885B2 (en) 1981-05-07
SU725564A1 (en) 1980-03-30
NO782499L (en) 1979-01-23
GB2001972B (en) 1982-01-06
RO75609A (en) 1981-01-30
FR2398070A1 (en) 1979-02-16
SU793402A3 (en) 1980-12-30
DD137934A5 (en) 1979-10-03
FI782025A (en) 1979-01-22
CA1087182A (en) 1980-10-07
IT1107490B (en) 1985-11-25
CH642374A5 (en) 1984-04-13
NL7807762A (en) 1979-01-23
PH14236A (en) 1981-04-09
US4180573A (en) 1979-12-25
AT363949B (en) 1981-09-10
SU725564A3 (en) 1980-03-30
NZ187915A (en) 1980-10-08
PL208542A1 (en) 1979-06-04
DK150306C (en) 1987-11-09
PL115061B1 (en) 1981-03-31
IE781456L (en) 1979-01-21
FI63033C (en) 1983-04-11
CS209897B2 (en) 1981-12-31
DK325178A (en) 1979-01-22
ES472812A1 (en) 1979-02-16
DK150306B (en) 1987-02-02
JPS6254114B2 (en) 1987-11-13
IL55169A0 (en) 1978-09-29
GB2001972A (en) 1979-02-14
ES471886A1 (en) 1979-02-01
SE439920B (en) 1985-07-08
AU3820978A (en) 1980-01-24
PT68330A (en) 1978-08-01
ATA498978A (en) 1981-02-15
LU80002A1 (en) 1979-09-06
HU176485B (en) 1981-03-28

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