Classifications

• • 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.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Medicinal Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Veterinary Medicine (AREA)
• General Chemical & Material Sciences (AREA)
• Public Health (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (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)

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• 1978
  • 1978-06-26 FI FI782025A patent/FI63033C/fi not_active IP Right Cessation
  • 1978-06-28 EP EP78100263A patent/EP0000479B1/fr not_active Expired
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  • 1978-07-19 LU LU80002A patent/LU80002A1/de unknown
  • 1978-07-19 SU SU782638749A patent/SU725564A3/ru active
  • 1978-07-19 IT IT50381/78A patent/IT1107490B/it active
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  • 1978-07-21 FR FR7821744A patent/FR2398070A1/fr active Granted
  • 1978-08-24 ES ES472812A patent/ES472812A1/es not_active Expired
• 1979
  • 1979-04-04 SU SU792746903A patent/SU793402A3/ru active

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