EP0000479B1 - 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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Publication number
EP0000479B1
EP0000479B1 EP78100263A EP78100263A EP0000479B1 EP 0000479 B1 EP0000479 B1 EP 0000479B1 EP 78100263 A EP78100263 A EP 78100263A EP 78100263 A EP78100263 A EP 78100263A EP 0000479 B1 EP0000479 B1 EP 0000479B1
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Prior art keywords
thieno
triazolo
formula
piperazinyl
hydroxy
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German (de)
French (fr)
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EP0000479A1 (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 DE19772732943 external-priority patent/DE2732943A1/en
Priority claimed from DE19772732921 external-priority patent/DE2732921A1/en
Application filed by CH Boehringer Sohn AG and Co KG filed Critical CH Boehringer Sohn AG and Co KG
Publication of EP0000479A1 publication Critical patent/EP0000479A1/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

  • 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 2405682), cycloalkyl (DBP 2435041), an oxygen-containing 5- or 6-membered ring (DT-AS 2445430) or a nitrogen or sulfur-containing 5- or 6-membered ring (DT-OS 2460776) are substituted.
  • 8-bromo-6- (o-chlorophenyl) -1- [N- (2-hydroxyethyl) piperazinyl] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine Salts form and, in this form, have a water solubility of 0.5% which is important for the diazepine substance class. This allows parenteral use of the compound, e.g. in the anesthetic preparation.
  • 8-bromo-6- (o-chlorophenyl) -1-methyl-4H-s-triazalo [3,4c] thieno [2,3e] 1,4-diazepine extends deep and REM sleep and impresses to a much greater extent the engine coordination.
  • reaction of compounds of general formula II with a piperazine of formula 111 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 dehydrogenation agents such as, for example, halogens or else compounds of the higher oxidation states of chromium or manganese, for example a chromate, a bichromate or a permanganate.
  • suitable dehydrogenation agents such as, for example, halogens or else 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.
  • the 8-bromo-6- (o-chlorophenyl) -1- [N- (2-hydroxyethyl) piperazinyl] -4H-s-triazolo [3,4c] thieno no [2,3e] forms 1,4-diazepine 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 the general formula II are known from the literature.
  • Starting compounds of the general formula IV are obtained by reacting a compound of the formula in the Hal means a halogen atom, with a piperazine derivative of the formula 111 under the conditions given under a) and then replacing the ring oxygen atom with a nitrogen atom, as described, for example, in German application P 2531678.
  • 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 pharmcologically 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 conventionally used in coated tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the core can also consist of several layers to achieve a deposit effect or to avoid incompatibilities.
  • 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. You can also use suspension aids. or thickeners, such as sodium carboxymethyl cellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective substances, 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
  • You can also use suspension aids. or thickeners, such as sodium carboxymethyl cellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective substances, 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 carriers, such as neutral fats or polyethylene glycol or its derivatives.
  • 1 coated tablet contains:
  • 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.
  • 1 suppository contains:
  • 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 the 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.

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  • Organic Chemistry (AREA)
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  • Neurosurgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biomedical Technology (AREA)
  • Public Health (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Anesthesiology (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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 die 2-Hydroxyäthylgruppe oder den 2-Pyridylrest bedeutet, 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 represents the 2-hydroxyethyl group or the 2-pyridyl radical, process for their preparation and their use as active ingredients in medicinal products.

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 2405682), Cycloalkyl (DBP 2435041), einen Sauerstoff enthaltenden 5- oder 6gliedrigen Ring (DT-AS 2445430) oder einen Stickstoff oder Schwefel enthaltenden 5- oder 6gliedrigen Ring (DT-OS 2460776) 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 2405682), cycloalkyl (DBP 2435041), an oxygen-containing 5- or 6-membered ring (DT-AS 2445430) or a nitrogen or sulfur-containing 5- or 6-membered ring (DT-OS 2460776) are substituted.

Die neuen Verbindungen weisen gegenüber den bekannten Stoffen verschiedene Vorteile auf:The new compounds have various advantages over the known substances:

So kann das 8-Brom-6-(o-chlorphenyl)-1-[N-(2-hydroxyäthyl)-piperazinyl]-4H-s-triazolo [3,4c]thieno[2,3e]1,4-diazepin Salze bilden und besitzt in dieser Form eine für die Substanzklasse der Diazepine bedeutende Wasserlöslichkeit von 0,5%. Diese gestattet die parenterale Anwendung der Verbindung, z.B. in der Narkosevorbereitung. 8-Brom-6-(o-chlorphenyl)-1-[N-(2-pyridyl)-piperazinyl]-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin bildet keine Salze; im Gegensatz zu den bekannten Benzodiazepinen wird das Schlaf-Wach-Verhalten der Katze global wenig beeinflusst; Tief- und REMschlaflatenz werden nicht verändert. Eine ausgeprägte Schlafinduktion ist nicht gegeben, der REMschlafanteil wird nicht vermindert. Im Gegensatz zu 8-Brom-6-(o-chlorphenyl)-1-[N-(2-pyridyl)-piperazinyl]-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin verlängert 8-Brom-6-(o-chlorphenyl)-1-methyl-4H-s-triazalo[3,4c]thieno[2,3e]1,4-diazepin den Tief-und den REMschlaf und beeindruckt in wesentlich stärkerem Mass die Motorkoordination.For example, 8-bromo-6- (o-chlorophenyl) -1- [N- (2-hydroxyethyl) piperazinyl] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine Salts form and, in this form, have a water solubility of 0.5% which is important for the diazepine substance class. This allows parenteral use of the compound, e.g. in the anesthetic preparation. 8-bromo-6- (o-chlorophenyl) -1- [N- (2-pyridyl) piperazinyl] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine does not form salts ; In contrast to the known benzodiazepines, the cat's sleep-wake behavior is not influenced globally; Deep and REM sleep latency are not changed. There is no pronounced sleep induction, the REM sleep percentage is not reduced. In contrast to 8-bromo-6- (o-chlorophenyl) -1- [N- (2-pyridyl) piperazinyl] -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine 8-bromo-6- (o-chlorophenyl) -1-methyl-4H-s-triazalo [3,4c] thieno [2,3e] 1,4-diazepine extends deep and REM sleep and impresses to a much greater extent the engine coordination.

Man kann die beiden Verbindungen erhalten

  • a) durch Umsetzung eines Triazolo-thieno-diazepins der allgemeinen Formel
    Figure imgb0002
    in der
    Hal ein Halogenatom bedeutet, mit einem Piperazin der Formel
    Figure imgb0003
    in der
    R1 die oben angegebene Bedeutung hat, oder
  • b) durch Dehydrierung einer Verbindung der allgemeinen Formel
    Figure imgb0004
    in der
    R1 die oben angegebene Bedeutung hat.
  • c) Die 2-Hydroxyäthylpiperazinylverbindung ist ausserdem herstellbar durch Umsetzung des 8-Brom-6-(o-chlorphenyl)-1 -piperazinyl-4H-s-triazolo[3,4c]thieno[2,3e]-1,4-diazepins mit Äthylenoxyd.
You can get the two connections
  • a) by reacting a triazolo-thienodiazepine of the general formula
    Figure imgb0002
     in the
    Hal represents a halogen atom, with a piperazine of the formula
    Figure imgb0003
     in the
    R 1 has the meaning given above, or
  • b) by dehydrogenation of a compound of the general formula
    Figure imgb0004
     in the
    R 1 has the meaning given above.
  • c) The 2-hydroxyethylpiperazinyl compound can also be prepared by reacting the 8-bromo-6- (o-chlorophenyl) -1-piperazinyl-4H-s-triazolo [3,4c] thieno [2,3e] -1,4-diazepine with ethylene oxide.

Die Umsetzung von Verbindungen der allgemeinen Formel II mit einem Piperazin der Formel 111 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 111 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 dehydrogenation agents such as, for example, halogens or else 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.
Das 8-Brom-6-(o-chlorphenyl)-1-[N-(2-hydroxyäthyl)-piperazinyl]-4H-s-triazolo[3,4c]thieno no[2,3e]1,4-diazepin bildet 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.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.
The 8-bromo-6- (o-chlorophenyl) -1- [N- (2-hydroxyethyl) piperazinyl] -4H-s-triazolo [3,4c] thieno no [2,3e] forms 1,4-diazepine 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.

Die Ausgangsverbindungen der allgemeinen Formel II sind literaturbekannt. Ausgangsverbindungen der allgemeinen Formel IV erhält man durch Umsetzung einer Verbindung der Formel

Figure imgb0005
in der
Hal ein Halogenatom bedeutet, mit einem Piperazinderivat der Formel 111 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 2531678 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 a compound of the formula
Figure imgb0005
 in the
Hal means a halogen atom, with a piperazine derivative of the formula 111 under the conditions given under a) and then replacing the ring oxygen atom with a nitrogen atom, as described, for example, in German application P 2531678.

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 pharmkologisch 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 pharmcologically 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 Drageeüberzügen 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 conventionally used in coated tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. The core can also consist of several layers to achieve a deposit effect or to avoid incompatibilities. Likewise, the coated tablet shell can also consist of several layers in order to achieve a depot effect, it being possible to use the auxiliaries mentioned above for the tablets.

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. You can also use suspension aids. or thickeners, such as sodium carboxymethyl cellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective substances, 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 carriers, such as neutral fats or polyethylene glycol or its derivatives.

Beispiel 1example 1 8-Brom-6-(o-chlorphenyl)-1-[N-(2-hydroxyäthyl)-piperazinyl]-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin8-bromo-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-(0-chlorpigenyl)-4H-s-triazolo-[3,4c]thieno[2,3e]1,4-diazepin, 17g g (0,014 Mol) N-(2-Hydroxyäthyl)-piperazin und 800 ml Xylol werden 24 Stunden unter Rückfluss gekocht. Man saugt das Reaktionsgemisch noch warm über Kieselgur-Kohie ab und dampft das Filtrat im Vakum ein. Der Rückstand wird in Methylenchlorid aufgenommen und die Lösung mit Wasser gewaschern. 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 of 1,8-dibromo-6- (0-chlorpi g enyl) -4H-s-triazolo [3,4-c] thieno [2,3-e] -1,4-diazepine, 17g g (0.014 Mol) N- (2-hydroxyethyl) piperazine and 800 ml of xylene are boiled under reflux for 24 hours. The reaction mixture is sucked off while still warm over kieselguhr and the filtrate is evaporated in vacuo. The residue is taken up in methylene chloride and the solution is 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 the addition of ether, the readily water-soluble hydrochloride of the title compound, mp. 211-220 ° C (dec.).

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.

  • Maleat: Fp. 201-202°C
  • Tartrat: Fp. 228-229°C
  • Methansulfonat: Fp. 241-242°C
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.
  • Maleate: mp 201-202 ° C
  • Tartrate: mp 228-229 ° C
  • Methanesulfonate: mp 241-242 ° C

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

0,04 Mol = 19g 1,8-Dibrom-6-(o-chlorphenyl)-4H-s-triazolo[3,4c]thieno[2,3e]1,4-diazepin werden mit 0,08 Mol = 13,4 g N-[Pyridy)-(2)]-piperazin und 150 ml Xylol 24 Stunden unter Rückfluss gekocht. Das ausgefallene N-[pyridyl-(2)]-piperazin-Hydrobromid wird abgesaugt. Im Filtrat befindet sich die Titelverbindung, die man nach Eindampfen und Umkristallisieren aus Äthanol isoliert und reinigt.0.04 mol = 19 g 1,8-dibromo-6- (o-chlorophenyl) -4H-s-triazolo [3,4c] thieno [2,3e] 1,4-diazepine with 0.08 mol = 13, 4 g of N- [pyridy) - (2)] - piperazine and 150 ml of xylene were boiled under reflux for 24 hours. The precipitated N- [pyridyl- (2)] - piperazine hydrobromide is suctioned off. The filtrate contains the title compound, 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.

FormulierungsbeispieleFormulation examples a) Drageesa) Dragees 1 Drageekern enthält:1 coated tablet contains:

Figure imgb0006
Figure imgb0006

HerstellungManufacturing

Die Mischung der Wirksubstanz mit Milchzukker 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 mgThe mixture of the active substance with milk sugar and corn starch is granulated with a 10% aqueous gelatin solution through a sieve with a mesh size of 1 mm, dried at 40 ° C. and passed through a sieve again. The granules obtained in this way are mixed with magnesium stearate and pressed. The cores obtained in this way are coated in a conventional manner with a casing which is applied with the aid of an aqueous suspension of sugar, titanium dioxide, talc and gum arabic. The finished coated tablets are polished with beeswax. Dragee final weight: 100 mg

b) Tablettenb) tablets

Figure imgb0007
Figure imgb0007

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 Gewicht verpresst, die je 0,5 mg Wirkstoff enthalten.The active ingredient and magnesium stearate are granulated with an aqueous solution of the soluble starch, the granules are dried and mixed intimately with milk sugar and corn starch. The mixture is then compressed into tablets of 100 mg weight, each containing 0.5 mg of active ingredient.

c) Suppositorienc) suppositories 1 Zäpfchen enthält:1 suppository contains:

Figure imgb0008
Figure imgb0008

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.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.

d) Ampullen (Injektionslösungen)d) ampoules (injection solutions) Zusammensetzung:Composition:

Figure imgb0009
Figure imgb0009

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 the 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 (5)

1. New substituted 1-piperazinyl-4H-s-triazolo-[3,4c]thieno[2,3e]1,4-diazpines of general formula
Figure imgb0015
wherein
R1 is hydroxy-ethyl or 2-pyridyl and a non-toxic, pharmacologically acceptable acid addition salt of the compound first mentioned.
2. 8-Bromo-6-(o-chloro-phenyl)-1-[hydroxy-ethyl)-piperazi no]-4H-s-triazolo[3,4c)thieno [2,3e]1,4-diazepine according to claim 1 or a non-toxic, pharmacologically acceptable acid addition salt thereof.
3. 8-Bromo-6-(o-chloro-phenyl)-1-[N-(2-pyridyl)-piperazinyl]-4H-s-triazolo[3,4c]thieno[2,3e] 1,4-diazepine according to claim 1.
4. Processes for the production of new substituted 1-piperaziny)-4H-2-triazolo[3,4c]thieno [2,3e]1,4-diazepines of formula
Figure imgb0016
wherein R1 is hydroxy-ethyl or 2-pyridyl comprising
a) reacting a compound of formula
Figure imgb0017
wherein Hal is halogen, with a piperazine of the formula
Figure imgb0018
wherein R1 has the same meanings as in formula 1, or
b) de-hydrogenating a compound of general formula
Figure imgb0019
wherein R' the same meanings as in formula I, or,
c) for the preparation of the 1-(2-hydroxy-ethyl)-piperazino compound, reacting 8-bromo-6-(o-chloro-phenyl)-1-piperazino-4H-s-triazolo[3,4c]thieno-[2,3e]1,4-diazepine with ethylene- oxid and in case R1 is 2-hydroxy-ethyl, converting the end product thus obtained if desired, into a physiologically acceptable acid addition salt.
5. Pharmaceutical composition containing as active ingredient compounds of general formula I according to claim 1 if desired in form of their acid addition salts in combination with conventional excipients 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)

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DE19772732943 DE2732943A1 (en) 1977-07-21 1977-07-21 1-Piperazino-triazolo-thieno-diazepine derivs. - useful as anxiolytics, tranquillisers, sedatives and neuroleptics
DE2732921 1977-07-21
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

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DE2830782A1 (en) * 1978-07-13 1980-01-24 Boehringer Sohn Ingelheim NEW SUBSTITUTED 4H-S-TRIAZOLO ANGLE CLAMP ON 3.4C ANGLE CLAMP ON THIENO ANGLE CLAMP ON 2.3E ANGLE CLAMP ON 1,4-DIAZEPINE, PROCESS FOR THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITIONS
ES2037013T3 (en) * 1986-01-21 1993-06-16 Boehringer Ingelheim Kg PROCEDURE FOR PREPARING TIENO-1,4-DIAZEPINES.

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PH12303A (en) * 1973-02-08 1979-01-16 Hoffmann La Roche Thienotriazolodiazepine derivatives
AT338799B (en) * 1974-03-02 1977-09-12 Boehringer Sohn Ingelheim PROCESS FOR PREPARING NEW SUBSTITUTED 6-ARYL-4H-S-TRIAZOLO- (3,4C) -THIENO- (2,3E) -1,4-DIAZEPINE AND THEIR SALTS
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
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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
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
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

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