EP0386145A1 - Thienotricyclene - Google Patents
ThienotricycleneInfo
- Publication number
- EP0386145A1 EP0386145A1 EP89900602A EP89900602A EP0386145A1 EP 0386145 A1 EP0386145 A1 EP 0386145A1 EP 89900602 A EP89900602 A EP 89900602A EP 89900602 A EP89900602 A EP 89900602A EP 0386145 A1 EP0386145 A1 EP 0386145A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- methyl
- acetyl
- piperazinyl
- thieno
- dihydro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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
- C07D495/02—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 two hetero rings
- C07D495/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
Definitions
- the invention relates to the new use of a dihydrothienobenzodiazepinone for the production of medicaments for the treatment of bronchial diseases, the enantiomerically pure forms of this dihydrothienobenzodiazepinone, processes for their preparation and their use.
- European patent 0039519 discloses dihydrothienobenzodiazepinones and their use in the treatment of diseases of the stomach or intestine. Furthermore, it is known that dibenzodiazepinones or pyrido-benzodiazepinones can exist in two chiral conformations which are mirror images of one another, where in certain cases the conformer mixtures can be split into the optical antipodes depending on the substitution (DE-OS 35 31 682).
- the invention therefore relates to the use of 4,9-dihydro-3-methyl-4 - [(4-methyl-1-piperazinyl) acetyl] -10H-thieno [3,4-b] [1,5] benzodiazepine -10-ons and its pharmacologically acceptable salts for the manufacture of medicaments for the treatment and prophylaxis of diseases of the bronchi.
- Another object of the invention is the use of the (+) - enantiomer of Telenzepin, ie the (+) - 4,9-dihydro-3-methyl-4 - [(4-methyl-1-piperazinyl) ace tyl] -10H-thieno [3,4-b] [1,5] benzodiazepin-10-one and its pharmacologically acceptable salts for the manufacture of medicaments for the treatment and prophylaxis of diseases of the bronchi.
- the invention further relates to medicaments which contain the compound (+) - 4,9-dihydro-3-methyl-4 - [(4-methyl-1-piperazinyl) acetyl] -10H-thieno- [3,4-b ] - [1,5] benzodiazepin-10-one and / or their pharmacologically acceptable salts.
- Suitable salts in this connection are preferably pharmacologically acceptable salts with inorganic and organic acids commonly used in galenics. Examples include the salts with fumaric acid (fumarate), tartaric acid (tartrate) or maleic acid (maleates). Dihydrochloride may be mentioned as the preferred acid addition salt.
- the pharmaceuticals are prepared by processes known per se, the compounds as such or, if appropriate, in combination with suitable pharmaceutical auxiliaries or carriers in the form of tablets, dragées, capsules, suppositories, plasters (for example as TTS), emulsions, suspensions, Aerosols or solutions are used. If the new pharmaceutical preparations contain pharmaceutical carriers in addition to the active ingredient, the active ingredient content of these mixtures is 0.5 to 95, preferably 15 to 75 percent by weight. the total mix.
- auxiliaries and excipients suitable for the desired pharmaceutical formulations based on his specialist knowledge.
- active ingredient carriers for example antioxidants, dispersants, solubilizers, dyes or, in particular, permeation promoters and complexing agents (e.g. cyclodextrins) can be used.
- the medicinal products are used in any suitable formulation, provided that the formation or maintenance of sufficient active substance levels is ensured. This can be achieved, for example, by oral or parenteral administration in suitable doses.
- the pharmaceutical preparation of the active ingredient is usually in the form of unit doses which are tailored to the desired administration.
- a unit dose may be a tablet, a coated tablet, a capsule, a suppository or one measured volume of a powder, granules, solution, emulsion or suspension.
- unit dose is understood to mean a physically determined unit which contains an individual amount of the active ingredient in combination with a pharmaceutical carrier, the active ingredient content of which corresponds to a fraction or multiples of a single therapeutic dose.
- a single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half, a third or a quarter of a daily dose. If only a fraction, such as half or a quarter, of the unit dose is required for a single therapeutic administration, the unit dose is advantageously divisible, e.g. in the form of a tablet with a score line.
- the pharmaceutical preparations according to the invention when they are in unit doses and for application e.g. are intended for humans, contain about 0.1 to 10 mg, advantageously 0.5 to 5 mg and in particular 1 to 4 mg of active ingredient.
- the therapeutic administration of the pharmaceutical preparation can take place 1 to 4 times a day at fixed or varying times, e.g. before meals and / or in the evening. However, it may be necessary to deviate from the doses mentioned, depending on the type, body weight and age of the individual to be treated, the type and severity of the disease, the type of preparation and administration of the medicinal product and the period or Interval within which the administration takes place. In some cases it may be sufficient to make do with less than the above-mentioned amount of active ingredient, while in other cases the above-mentioned amount of active ingredient has to be exceeded. In acute cases, a higher dose is given at the start of treatment. After the desired effect has been reached, the dose is reduced.
- Any specialist on the basis of his specialist knowledge, can determine the optimum dosage and type of application of the active ingredients required in each case.
- the pharmaceutical preparations usually consist of the active ingredient and inert, non-toxic, pharmaceutically acceptable medicinal Schung or diluent in solid, semi-solid or liquid form or as a coating agent, for example in the form of a capsule, a tablet cover, a bag or another container, for the therapeutically active ingredient.
- a carrier can serve, for example, as a mediator for the absorption of medicinal products by the body, as a formulation aid, as a sweetener, as a taste corrector, as a colorant or as a preservative.
- Tablets, dragees, hard and soft capsules e.g. come from gelatin, dispersible powders, granules, aqueous and oily suspensions, emulsions, solutions or syrups.
- Tablets can contain inert diluents, e.g. Calcium carbonate, calcium phosphate, sodium phosphate or lactose; Granulating and distributing agents, e.g. Corn starch or alginates; Binders, e.g. Starch, gelatin or akazi engummi; and lubricants, e.g. Aluminum or magnesium stearate, talc or silicone oil. They can also be given a coating which can also be such that it causes a delayed dissolution and absorption of the drug in the gastrointestinal tract, so that e.g. better tolerance, protracting or retardation is achieved.
- Gelatin capsules can mix the drug with a solid, e.g. Calcium carbonate or kaolin, or an oily, e.g. Olive, peanut or paraffin oil, diluents included.
- Aqueous suspensions may include suspending agents, e.g. Sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth or acacia; Dispersing and wetting agents, e.g. Polyoxyethylene stearate, hepta-decaethyl enoxycetanol, polyoxyethylene sorbitol monooleate, polyoxyethylene sorbitan monooleate or lecithin; Preservatives, e.g. Methyl or propyl hydroxy benzoates; Flavoring agents; Sweeteners, e.g. Sucrose, lactose, sodium cyclamate, dextrose, invert sugar syrup.
- suspending agents e.g. Sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth or a
- Oily suspensions can e.g. Peanut, olive, sesame, coconut or paraffin oil and thickening agents such as e.g. Beeswax, hard paraffin or cetyl alcohol; also sweeteners, flavoring agents and antioxidants.
- Peanut olive, sesame, coconut or paraffin oil and thickening agents such as e.g. Beeswax, hard paraffin or cetyl alcohol; also sweeteners, flavoring agents and antioxidants.
- the drugs can be dispersed in water in powder and granules. contain with dispersing, wetting and suspending agents, for example those mentioned above, and with sweeteners, flavoring agents and colorants.
- Emulsions can e.g. Olive, peanut or paraffin oil in addition to emulsifiers, e.g. Acacia, tragacanth, phosphatides, sorbitan monooleate, polyoxyethylene sorbitan monooleate, and sweetening and flavoring agents.
- emulsifiers e.g. Acacia, tragacanth, phosphatides, sorbitan monooleate, polyoxyethylene sorbitan monooleate, and sweetening and flavoring agents.
- Suppositories are used for the rectal application of the medicinal products, which are produced with the help of binders melting at rectal temperature, for example cocoa butter or polyethylene glycol.
- sterile injectable if necessary short-term, aqueous suspensions, isotonic salt solutions or other solutions, the dispersing or wetting agents and / or pharmacologically acceptable diluents, e.g. Propylene or butylene glycol.
- Inhaled application of the active ingredients is also preferred for use as a bronchospasmolytic.
- These are administered either directly as a powder or by atomizing solutions or suspensions that contain the active ingredients.
- the atomization can be carried out in a conventional manner, for example by compressed air nebulizers or ultrasound nebulizers.
- Administration from spray cans, in particular those with a conventional metering valve (metering aerosols) is particularly advantageous.
- Dosing aerosols make it possible to provide a defined amount of active ingredient per spray.
- So-called synchronous inhalers are particularly advantageous here, allowing the active ingredient to be administered synchronously with inhalation. Suitable synchronous inhalation devices are e.g. in DE-PS 1945257, DE-PS 1917911 and DE-OS 2055734.
- the active ingredients are preferably used in micronized form, particle sizes of less than 10 ⁇ m being advantageous.
- the active compounds are dispersed in customary blowing agents, preferably with the aid of a dispersant.
- Mixtures of trichlorofluoromethane (Frigen ® 11) are particularly suitable as blowing agents. and dichlorodifluoromethane (Frigen ® 12), where trichlorofluoromethane can be replaced in whole or in part by 1,1,2-trichlorotrifluoroethane (Frigen ® 113).
- Particularly suitable dispersants are the sorbitan esters (Spane ® from Atlas GmbH) and lecithin which are customary for this purpose.
- the dispersant is dissolved in the less volatile propellant component, which is refrigerated.
- the micronized active ingredient or the micronized active ingredients are stirred into the solution.
- the dispersion is filled into spray cans. After crimping, the more volatile blowing agent component is pressed on.
- the active ingredient (s) can, if appropriate, also be formulated in microencapsulated form with one or more of the stated excipients or additives.
- Bronchial diseases such as chronic abstructive respiratory diseases of various origins (e.g. bronchitis, bronchial asthma) in humans or animals may be mentioned, which can be treated with telenzepin or (+) -telenzepin due to the excellent bronchospasmolytic properties.
- the invention thus also relates to a method for the treatment of mammals, in particular humans, who are suffering from the bronchi.
- the method is characterized in that a therapeutically effective and pharmacologically acceptable amount of telenzepine or (+) -telenzepin is administered to the individual suffering from the bronchi.
- Telenzepin is known from European patent 0039519.
- the (+) - enantiomer of telenzepine is produced by a new process which is also the subject of the invention.
- Suitable compounds of the formula II are in principle all chiral, configuratively uniform compounds which are able to react with the compound I or its anion with elimination of the leaving group X and whose rest R can be split off again smoothly and without undesired side reactions after the diastereomer separation .
- the leaving groups X include in particular all nucleophilically detachable atoms or groups, such as halogen atoms (J, Br or in particular Cl) or hydroxyl groups activated by esterification (for example with sulfonic acids)
- Suitable residues R are all configuratively uniform residues which can be derived from naturally occurring or synthetically accessible chiral compounds and which can be cleaved solvolytically from the compounds III under mild, preferably slightly acidic conditions. R may be mentioned in particular
- glycosyl residues which are derived from glycopyranoses, glycofuranoses or oligosaccharides and which, if desired, are partially or fully protected with protective groups customary in carbohydrate chemistry, or
- radicals R are radicals of the formula IV
- R1 together with the oxygen atom to which it is attached represents a glycosyl residue, a chiral terpene alcohol residue, or another chiral alcohol residue
- glycosyl residues R1-O- are the residues which are derived from naturally occurring mono- or disaccharides, such as arabinose, fructose, galactose, glucose, lactose, mannose, ribose, xylose, maltose, sorbose or N-acetyl-D-glucosamine derive.
- terpene alcohol residues R1-O- those residues may be mentioned which are derived from a naturally occurring or synthetically easily accessible terpene alcohol.
- terpene alcohols are: isopulegol, neomenthol, isomenthol, menthol, carveol, dihydrocarveol, terpinen-4-ol, mirtenol, citronellol, isobomeol, borneol, fenchol and in particular isopinocampheol.
- chiral alcohol residues R1-0- may be mentioned, for example, the residues derived from the following alcohols: almond acid esters, cinchonidine, cin chonin, ephedrine, serine methyl ester, sitosterol, 3-hydroxy-2-methyl-propionic acid methyl ester and lactic acid ethyl ester.
- a particularly preferred radical R is the isopinocampheyloxymethyl radical.
- Deprotonating agents which can be used are the bases usually used for analogous reactions in organic chemistry, for example hydroxides, such as sodium hydroxide or potassium hydroxide, or carbonates, such as potassium carbonate, or alcoholates, such as sodium methylate or sodium ethylate, or amines, such as pyridine, triethylamine or ethyldiisopropylamine , or metal organic compounds, such as tert-butyllithium, or preferably hydrides, such as sodium hydride.
- hydroxides such as sodium hydroxide or potassium hydroxide
- carbonates such as potassium carbonate
- alcoholates such as sodium methylate or sodium ethylate
- amines such as pyridine, triethylamine or ethyldiisopropylamine
- metal organic compounds such as tert-butyllithium, or preferably hydrides, such as sodium hydride.
- the deprotonation of compound I and subsequent reaction with compound II is carried out in inert - depending on the deprotonating agent - protic or aprotic solvents.
- inert - depending on the deprotonating agent - protic or aprotic solvents.
- methanol, isopropanol, dimethyl sulfoxide, acetone, acetonitrile, dioxane and preferably dimethylformamide are suitable.
- the deprotonation of compound I is - depending on the reactivity of the deprotonating agent - preferably at temperatures between -30 ° C and
- the diastereomer mixture obtained after the reaction of I with II is separated in a manner known per se, for example by chromatography on suitable columns or preferably by fractional crystallization. If the separation is to be carried out by crystallization, it is expedient to convert the resulting distereomers into suitable, easily crystallizing salts. Oxalate, tosilate, fumarate and in particular maleate are suitable as such.
- the release of the compounds III from their salts after diastereo Mer separation is carried out with the help of suitable, not too strong bases.
- suitable, not too strong bases for example, hydrogen carbonates such as sodium hydrogen carbonate are suitable for this.
- the conformatively uniform compounds I are released from the optically pure diastereomers by solvolysis under gentle, slightly acidic conditions.
- An example of a suitable reagent for solvolysis has been anhydrous formic acid with an addition of hydrogen chloride.
- the compounds of the formula II are known or can be obtained in an analogous manner from known compounds in a manner familiar to those skilled in the art.
- the compounds II in which R has the meaning of the formula IV and X represents a chlorine atom can be obtained by chloromethylation of corresponding alcohols [e.g. in analogy to R.C. Ronald et al., J. Org. Chem. 45 (1980) 2224].
- Another object of the invention is therefore the (+) - 4,9-dihydro-3-methyl-4- [(4-methyl-1-piperazinyl) acetyl] -10H-thieno [3,4-b] [1 , 5] benzodi azepin-10-one and its salts.
- Suitable salts in this connection are preferably pharmacologically acceptable salts with inorganic and organic acids commonly used in galenics.
- Dihydrochloride may be mentioned as the preferred acid addition salt.
- the excellent bronchial therapeutic properties of the two compounds are particularly expressed in a unique bronchospasmolytic activity.
- This bronchospasmolytic activity can be observed even with the administration of very low doses.
- Particularly surprising in this context is the high specificity, which according to IV. -Injection of continuous onset and not excessive effect, and above all the very long-lasting bronchospasmolytic effect, which makes the substances appear to be outstandingly suitable for the therapy of asthmatic diseases, due to the unexpected and outstandingly long duration of action, the substances in particular for therapy nocturnal asthma attacks.
- stomach and intestinal protection means the prevention and treatment of gastrointestinal diseases, in particular gastrointestinal inflammatory diseases and lesions (such as, for example, ulcer ventriculi, duodenal ulcer, gastritis, hyperacid or drug-induced irritable stomach), which are caused, for example, by microorganisms, bacterial toxins , Drugs (e.g. certain anti-inflammatory drugs and anti-rheumatic drugs), chemicals (e.g. ethanol), stomach acid or stressful situations can be caused.
- gastrointestinal inflammatory diseases and lesions such as, for example, ulcer ventriculi, duodenal ulcer, gastritis, hyperacid or drug-induced irritable stomach
- Drugs e.g. certain anti-inflammatory drugs and anti-rheumatic drugs
- chemicals e.g. ethanol
- the (+) conformer and its pharmacologically tolerated salts are also outstandingly suitable for use in human and veterinary medicine for the treatment and / or prophylaxis of diseases of the stomach and intestines and those diseases which are based on excessive gastric acid secretion .
- Another object of the invention is therefore the compound (+) - 4,9-dihydro-3-methyl-4 - [(4-methyl-1-piperazinyl) acetyl] -10H-thieno [3,4-b] [ 1,5] benzodiazepin-10-one for use in the treatment and / or prophylaxis of diseases of the stomach and intestines and those diseases which are based on excessive gastric acid secretion.
- the invention also includes the use of the compound (+) - 4,9-dihydro-3-methyl-4 - [(4-methyl-1-piperazinyl) -acetyl] -10H-thieno [3,4-b] [1 , 5] benzodiazepin10-one for the manufacture of medicaments which are used for the treatment and / or prophylaxis of diseases of the stomach and intestines and of diseases which are based on excessive gastric acid secretion.
- the pharmaceutical preparations can also contain one or more pharmacologically active constituents of other groups of medicaments, such as antacids , for example aluminum hydroxide, magnesium aluminate; other drugs which inhibit acid secretion, such as, for example, H 2 blockers (for example cimetidine, ranitidine); Tranquilizers, such as benzodiazepines, for example diazepam; Antispasmodics such as Bietamiverin, Camylofin; Anticholinergics such as oxyphencyclimine, phencarbamide;
- the compound (+) - 4,9-Dihydro3-methyl-4 - [(4-methyl-1-piperazinyl) acetyl] -10H-thieno [3,4-b] [1,5] benzodiazepin-10-one can in addition, to prevent gastrointestinal diseases in combination with active ingredients such as anti-inflammatory drugs or anti-rheumatic drugs, to antagonize their ulcerogenic potency and thus reduce side effects.
- Telenzepin The outstanding effect of Telenzepin can be demonstrated on the model of acetylcholine-induced bronchospasm on anesthetized, spontaneously breathing guinea pigs (IV injection and IT instillation) and on awake guinea pigs (po application): Influence of i .v. -administered telenzepin on acetylcholine-induced bronchospasm in anesthetized, spontaneously breathing guinea pigs.
- Guinea pig
- Pneumotachogram Maximum flow velocities of the breathing air during the
- Detection of the effect of Telenzepin on the measurement parameters (mean and standard error of the mean, n 10) and calculation of the bronchospasmolytic activity as a percentage inhibition of the acetylcholine-related decreases of Vmax e and TV using time-response curves.
- ( ⁇ ) -Telenzepin and (+) -Telenzepin inhibit the acetylcholine-related bronchospasm in a very low dose range of 0.03 - 1 ⁇ mol / kg i.v. the effect sets in remarkably slowly despite IV administration and reaches a plateau-like maximum between 30 and 10 min, which persists over the observation period of 1 h.
- the effectiveness of (-) -Telenzepin begins much later between 0.1 and 1 ⁇ mol / kg IV. and reaches between 10 and 30 ⁇ mol / kg IV a maximum.
- the course of time effects is comparable to that of the other two forms of Telenzepin.
- Tables 1 and 2 describe the effectiveness of Telenzepin using dose-response curves of the average activity over the entire observation period of 0 - 60 min or at the time 60 min pa.
- the ED 50 values derived therefrom are shown in Tables 3 and 4.
- Guinea pig
- Pirbright White Interfauna (Tuttlingen), 290-350 g, male.
- telencepin it, dissolved in 0.1 ml / kg 0.9% NaCl + 0.1% Tween 80, acetylcholine as a spasmogen by inhalation using ultrasonic nebulization a 0.18% Ach / 0.9% NaCl solution.
- Test procedure -10 min control spasm, 0 min substance administration, +5 and +30 min test spasms. Evaluation:
- ( ⁇ ) -Telenzepin inhibits the acetylcholine-induced decrease in conductance and compliance depending on time and dose in the wide but extraordinarily low dose range of 0.001 - 1 ⁇ mol / kg i.t .; the effectiveness is
- Table 5 describes the effectiveness of ( ⁇ ) -telenzepin 5 and 30 min pa using dose-response curves.
- the ED 50 values derived therefrom are summarized in Table 6.
- Bronchospasmolytic efficacy of ( ⁇ ) -Telenzepin 5 and 30 min pa, expressed as a percentage increase in conductance and compliance in the acetylcholine-induced test spasm compared to the control ⁇ SEM, N 10).
- Guinea pig
- Pirbright White Interfauna (Tuttlingen), 250-450 g, male, 10 animals per dose and experiment.
- Thoracographic measurement of respiratory activity measurement of the latency from the start of acetylchol in nebulization to the beginning of the asthma attack; Determination of the number of animals in which the latency period of the test seizure in relation to the control seizure is at least tripled 30 min pa; from this estimate of the approx. ED 50 .
- the number of animals in which the latency of the acetylcholine-induced test attack was at least tripled compared to the control attack as a function of the p.o.-applied ( ⁇ ) telenzepine dose is shown as follows:
- Isometric contractions (HSE force transducers, K-30; tilt and zone, BD-9 writer) of isolated vas deferens sections of rabbits (male, white New Zealanders, 2.5-3.5 kg) were recorded in the organ bath (10 ml, 31 ° C , Fumigation with carbogen, preload of the organs 0.75 g) with electrical stimulation (HSE stimulator; hook-shaped Pt electrode 1 cm below the water surface of the bath; 30 V, 0.5 ms, 0.05 Hz).
- the nutrient solution used had the following composition (mM): NaCl 118, KCl 4.7, CaCl 2 ⁇ 2H 2 O 2.5,
- the nutrient solution contains an additional 10 M yohimbine.
- Prestressing of the organs 0.25 g) with electrical stimulation HSE stimulator; hook-shaped Pt electrode on the bottom of the bath and immersed, ring-shaped Pt electrode 1 cm below the water surface of the bath; 7 V, 3 ms, 2 Hz).
- the Tyrode nutrient solution used had the following composition (mM): NaCl 130,
- Table 7 shows the pA 2 values of the substances in which the slope of the regression line was standardized to 1.00 for theoretically competitive antagonism (Tallarida et al., 1979).
- ED50 dose (interpolated) which reduces the lesion index or the HCl secretion of the rat stomach in the treated group by 50% compared to the control group.
- the ulcer provocation is carried out on 24 hours fasting rats (female, 180-200 g, 4 animals per cage on a high grating) by pylorus ligation (under diethyl ether anesthesia) and oral application of 100 mg / lOml / kg acetylsalicylic acid.
- the substances to be tested are administered intravenously (1 ml / kg) immediately after the pylorus ligation.
- the wound is closed using Michel clips. 4 hours later, the animals were killed in ether rush by atlas dislocation and gastric resection.
- the stomach is opened along the large curvature and stretched out on a cork plate after the amount of gastric juice secreted (volume) and later its HCl content (titration with sodium hydroxide solution) is determined.
- volume the amount of gastric juice secreted
- HCl content titration with sodium hydroxide solution
- the product of severity (according to the following scale of points) and number of ulcers serves as an individual lesion index. Score scale: no ulcers 0
- the ED50 denotes the dose that reduces the mean lesion index or the HCl secretion by 50% compared to the control.
- the invention concerns the use of telenzepine and (+) -telenzepine in the treatment of bronchial diseases. So, (telenzepine, a process for producing it and intermediate products for producing it.
- the invention relates to the use of Telenzepin and (-f -) - Telenzepin in the treatment of bronchial diseases.
- the invention also relates to (+) - telenzepine, a process for its production and an intermediate product for its production.
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Steroid Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
Abstract
Utilisation de télenzépine et de (+)télenzépine pour le traitement de maladies des bronches. (+)Télenzépine, son procédé de production et produits intermédiaires pour sa production.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH4991/87 | 1987-12-22 | ||
CH499187 | 1987-12-22 | ||
CH2648/88 | 1988-07-11 | ||
CH264888 | 1988-07-11 |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0386145A1 true EP0386145A1 (fr) | 1990-09-12 |
Family
ID=25691031
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP88121220A Expired - Lifetime EP0330756B1 (fr) | 1987-12-22 | 1988-12-19 | Composés thiénotricycliques pour le traitement des maladies bronchiques |
EP89900602A Pending EP0386145A1 (fr) | 1987-12-22 | 1988-12-19 | Thienotricyclene |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP88121220A Expired - Lifetime EP0330756B1 (fr) | 1987-12-22 | 1988-12-19 | Composés thiénotricycliques pour le traitement des maladies bronchiques |
Country Status (10)
Country | Link |
---|---|
US (1) | US5140025A (fr) |
EP (2) | EP0330756B1 (fr) |
AT (1) | ATE135912T1 (fr) |
AU (1) | AU2824289A (fr) |
CA (1) | CA1325804C (fr) |
DE (1) | DE3855159D1 (fr) |
IL (1) | IL88726A (fr) |
NZ (1) | NZ227415A (fr) |
PT (1) | PT89303B (fr) |
WO (1) | WO1989005644A2 (fr) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
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DE4003322C1 (fr) * | 1990-02-05 | 1991-06-20 | Byk Gulden Lomberg Chemische Fabrik Gmbh, 7750 Konstanz, De | |
US20040152720A1 (en) * | 2002-12-20 | 2004-08-05 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Powdered medicaments containing a tiotropium salt and salmeterol xinafoate |
EP1768674A1 (fr) * | 2004-07-16 | 2007-04-04 | ProteoSys AG | Antagonistes muscariniques avec activite modulatrice parp et sir en tant qu'agents cytoprotecteurs |
US7893053B2 (en) | 2006-06-16 | 2011-02-22 | Theracos, Inc. | Treating psychological conditions using muscarinic receptor M1 antagonists |
US8748419B2 (en) | 2006-06-16 | 2014-06-10 | Theracos, Inc. | Treating obesity with muscarinic receptor M1 antagonists |
WO2011163231A2 (fr) | 2010-06-21 | 2011-12-29 | Theracos, Inc. | Thérapie combinée pour le traitement du diabète |
CN103044419A (zh) * | 2012-09-04 | 2013-04-17 | 苏州弘森药业有限公司 | 一种合成盐酸哌仑西平的方法 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
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IL62792A (en) * | 1980-05-07 | 1985-02-28 | Byk Gulden Lomberg Chem Fab | Acylated dihydrothienodiazepinone compounds,process for their preparation,and medicaments containing them |
US4381301A (en) * | 1980-05-07 | 1983-04-26 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Substituted tricyclic thieno compounds, their synthesis, their use, their compositions and their medicaments |
WO1986006278A1 (fr) * | 1985-04-19 | 1986-11-06 | University Patents, Inc. | Methode de traitement des maladies relatives a l'obstruction des voies respiratoires |
DE3531682A1 (de) * | 1985-09-05 | 1987-03-12 | Thomae Gmbh Dr K | (+)-6-chlor-5,10-dihydro-5-((1-methyl-4- piperidinyl)acetyl)-11h-dibenzo(b,e)(1,4) diazepin-11-on, seine isolierung und verwendung als arzneimittel |
-
1988
- 1988-12-19 US US07/499,403 patent/US5140025A/en not_active Expired - Fee Related
- 1988-12-19 DE DE3855159T patent/DE3855159D1/de not_active Expired - Fee Related
- 1988-12-19 AT AT88121220T patent/ATE135912T1/de not_active IP Right Cessation
- 1988-12-19 EP EP88121220A patent/EP0330756B1/fr not_active Expired - Lifetime
- 1988-12-19 IL IL8872688A patent/IL88726A/en not_active IP Right Cessation
- 1988-12-19 EP EP89900602A patent/EP0386145A1/fr active Pending
- 1988-12-19 WO PCT/EP1988/001173 patent/WO1989005644A2/fr not_active Application Discontinuation
- 1988-12-19 AU AU28242/89A patent/AU2824289A/en not_active Abandoned
- 1988-12-20 NZ NZ227415A patent/NZ227415A/en unknown
- 1988-12-21 CA CA000586542A patent/CA1325804C/fr not_active Expired - Fee Related
- 1988-12-21 PT PT89303A patent/PT89303B/pt not_active IP Right Cessation
Non-Patent Citations (1)
Title |
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See references of WO8905644A2 * |
Also Published As
Publication number | Publication date |
---|---|
EP0330756A3 (en) | 1989-11-29 |
IL88726A0 (en) | 1989-07-31 |
US5140025A (en) | 1992-08-18 |
WO1989005644A2 (fr) | 1989-06-29 |
CA1325804C (fr) | 1994-01-04 |
AU2824289A (en) | 1989-07-19 |
ATE135912T1 (de) | 1996-04-15 |
NZ227415A (en) | 1991-12-23 |
IL88726A (en) | 1994-11-11 |
EP0330756B1 (fr) | 1996-03-27 |
DE3855159D1 (de) | 1996-05-02 |
PT89303A (pt) | 1989-12-29 |
EP0330756A2 (fr) | 1989-09-06 |
PT89303B (pt) | 1995-01-31 |
WO1989005644A3 (fr) | 1989-11-16 |
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