EP1483231A1 - Nouveaux sels d'acide cinnamique, procedes de production et d'utilisation comme medicaments - Google Patents

Nouveaux sels d'acide cinnamique, procedes de production et d'utilisation comme medicaments

Info

Publication number
EP1483231A1
EP1483231A1 EP03717188A EP03717188A EP1483231A1 EP 1483231 A1 EP1483231 A1 EP 1483231A1 EP 03717188 A EP03717188 A EP 03717188A EP 03717188 A EP03717188 A EP 03717188A EP 1483231 A1 EP1483231 A1 EP 1483231A1
Authority
EP
European Patent Office
Prior art keywords
acid
enantiomers
hydrogen
salts
formula
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.)
Withdrawn
Application number
EP03717188A
Other languages
German (de)
English (en)
Inventor
Rainer Soyka
Günter Linz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from DE2002109243 external-priority patent/DE10209243A1/de
Priority claimed from DE2002116124 external-priority patent/DE10216124A1/de
Application filed by Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Publication of EP1483231A1 publication Critical patent/EP1483231A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/06—Antiabortive agents; Labour repressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to novel cinnamic salts of salmeterol, processes for their preparation and their use as medicaments.
  • R 3 is hydrogen, C-
  • R 1 and R 2 are identical or different, hydrogen, methyl, ethyl, propyl, butyl,
  • R 3 is hydrogen, methyl, ethyl, methoxy, fluorine, chlorine, bromine or -CF 3, preferably hydrogen or fluorine, optionally in the form of their enantiomers, mixtures of the enantiomers or racemates.
  • R 1 and R 2 are identical or different, hydrogen, fluorine, chlorine, -CF 3 or phenyl
  • R 3 is hydrogen or fluorine, preferably hydrogen, optionally in the form of their enantiomers, mixtures of the enantiomers or racemates.
  • R1 is hydrogen;
  • R 2 is -CF 3 or phenyl;
  • R 3 is hydrogen, optionally in the form of their enantiomers, mixtures of the enantiomers or racemates.
  • R 1 and R 2 are chlorine
  • R 3 is hydrogen, optionally in the form of their enantiomers, mixtures of the enantiomers or racemates.
  • alkyl groups are branched and unbranched alkyl groups having 1 to 4 carbon atoms. Examples include: methyl, ethyl, propyl or butyl. If appropriate, the abbreviations Me, Et, Prop or Bu are also used to designate the groups methyl, ethyl, propyl or butyl. Unless otherwise stated, the definitions of propyl and butyl include all conceivable isomeric forms of the respective radicals. For example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl, etc.
  • alkyloxy groups unless otherwise stated, branched and unbranched alkyl groups having 1 to 4 carbon atoms which are linked via an oxygen atom.
  • methylox, ethyloxy, propyloxy or butyloxy are mentioned.
  • methyloxy, ethyloxy, Propyloxy or butyloxy are optionally also the abbreviations MeO, EtO, PropO or BuO- used.
  • the definitions propoxy and butoxy include all conceivable isomeric forms of the respective radicals.
  • propyloxy includes n-propyloxy and iso-propyloxy
  • butyloxy includes iso-butyloxy, sec-butyloxy and tert-butyloxy, etc.
  • alkyloxy instead of the term alkyloxy, the term alkoxy is also used.
  • methoxy, ethoxy, propoxy or butoxy are also used to designate the groups methyloxy, ethyloxy, propyloxy or butyloxy.
  • Halogen is in the context of the present invention for fluorine, chlorine, bromine or iodine. Unless otherwise indicated, fluorine and bromine are preferred halogens.
  • the group CO denotes a carbonyl group.
  • the salts of formula 1 represent novel acid addition salts of the salmeterol known in the art.
  • Salmeterol has a center of chirality.
  • the present invention relates to the salts of formula - in racemic or enantiomerically pure form. Here, both the (R) - and the (S) - enantiomer is of particular importance. Furthermore, the present invention relates to the salts of the formula I in the form of non-racemic mixtures of the two enantiomers.
  • the radicals R 1, R 2 and R 3 may, if they are not hydrogen, ortho, of the link to be arranged ethylene bridge each meta or para position relative to. If none of the radicals R 1 , R 2 and R 3 is hydrogen, the radical R 3 is preferably in the para position and the radicals R 1 and R 2 are linked in the ortho and / or meta position. If one of the radicals R 1 , R 2 and R 3 is hydrogen, preferably at least one of the other radicals is linked in the meta or para position, particularly preferably in the para position. If none of the radicals R " 1, R 2 and R 3 is hydrogen, the compounds of the general formula 1 are particularly preferred according to the invention, in which the radicals R 1 , R 2 and R 3 have the same meaning.
  • the preparation of the salts 1 according to the invention from the free base of salmeterol can be carried out analogously to processes known in the prior art for the formation of acid addition salts starting from secondary amines. It involves the reaction of the free base salmeterol with carboxylic acids of the formula 2 wherein the radicals R, R 2 and R 3 - d H ee vorstrehend g 0 e " called meanings may have, in suitable solvents, preferably organic solvents.
  • the acid 2 is taken up in a suitable solvent, preferably an organic solvent, more preferably a solvent selected from the group consisting of ethyl acetate, methanol, ethanol, isopropanol and diethyl ether or mixtures thereof.
  • a suitable solvent preferably an organic solvent, more preferably a solvent selected from the group consisting of ethyl acetate, methanol, ethanol, isopropanol and diethyl ether or mixtures thereof.
  • the abovementioned solvents can also be used in mixtures with tert-butyl methyl ether or cyclohexane.
  • the acids 2 taken up in one of the abovementioned solvents are dissolved by heating, preferably with heating to the boiling point of the solvent. Salmeterol, optionally dissolved in one of the abovementioned solvents, is added to this solution. From the resulting solution, the salts 1 are optionally crystallized with cooling and isolated.
  • the compounds of formula 1_ are characterized by a variety of possible applications in the therapeutic field. Worthy of mention are those applications for which the salts of the formula 1 according to the invention can be used as betamimetics due to their pharmaceutical activity.
  • bronchial asthma usually irritation-induced, paroxysmal bronchospasm with mucosal swelling and increased mucus production
  • COPD chronic obstructive bronchitis
  • the inhibition of early onset labor and imminent abortion in obstetrics tocolytic
  • the therapy of circulatory shock vadilation and increase in cardiac output
  • itching and inflammation of the skin The salts of the formula are preferably used in the treatment of asthma or COPD.
  • the salts of formula 1 can be used alone or in combination with other active ingredients. These are, in particular, anticholinergics, antiallergics, leukotriene antagonists, dopamine agonists, PDEIV inhibitors and corticosteroids, and combinations of active substances thereof.
  • anticholinergics include ipratropium bromide, oxitropium bromide and, in particular, tiotropium bromide.
  • Medicament combinations which, in addition to the compound of the formula 1 according to the invention, contain the tiotropium bromide as further active ingredient are particularly preferred according to the invention. Of particular importance are those drug combinations which, in addition to the compound of formula ⁇ _, contain crystalline tiotropium bromide monohydrate which can be obtained by the experimental procedure given in the experimental section.
  • This combination is of particular importance in the treatment of asthma or COPD, especially COPD.
  • corticosteroids which may optionally be used in combination with the compound of the formula 1 are compounds which are selected from the group consisting of flunisolides, beclomethasones, triamcinolones, budesonide, fluticasones, mometasones, ciclesonides, rofleponides and Dexametasone.
  • the corticosteroids selected from the group consisting of flunisolides, beclomethasones, triamcinolones, budesonide, fluticasones, mometasones, ciclesonides and dexametasone are preferred, in which case the budesonide, fluticasone, mometasone and ciclesonide, in particular budesonide and fluticasone, have a special effect Meaning.
  • corticosteroids instead of the term corticosteroids only the term steroids is used.
  • Reference to steroids in the context of the present invention includes reference to salts or derivatives that may be formed by the steroids.
  • Examples of possible salts or derivatives are: sodium salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
  • the corticosteroids may also be in the form of their hydrates.
  • dopamine agonists which may optionally be used in combination with the compound of formula 1, are compounds which are selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole , Roxindol, Ropinirole, Talipexole, Terguride and Viozan.
  • dopamine agonists are preferably used as combination partners with the compound of the formula 1, which are selected from the group consisting of pramipexole, talipexole and viozan, with pramipexole being of particular importance.
  • a reference to the aforementioned dopamine agonists in the context of the present invention includes a reference to their optionally existing pharmacologically acceptable acid addition salts and optionally their hydrates.
  • physiologically acceptable acid addition salts which can be formed from the aforementioned dopamine agonists are, for example, pharmaceutically acceptable salts selected from the salts of hydrochloric acid, bromine hydrogen, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid , Tartaric acid and maleic acid are.
  • antiallergics which can be used according to the invention with the compound of formula ⁇ as a combination, may be mentioned epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetinden, clemastine, bamipine, cexchlorpheniramine, pheniramine, Doxylamine, chlorphenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclozin.
  • Preferred antiallergic agents which can be used in combination with the compound of the formula 1 in the context of the present invention are selected from the group consisting of epinastin,
  • Reference to the aforementioned antiallergic agents in the context of the present invention includes a reference to their optionally existing pharmacologically acceptable acid addition salts.
  • PDE-IV inhibitors which can be used in combination with the compound of the formula 1 according to the invention are compounds which are selected from the group consisting of enprofylline, roflumilast, Ariflo, Bay-198004, CP-325,366, BY343, D-4396 (Sch-351591), V-11294A and AWD-12-281.
  • Preferred PDE IV inhibitors are selected from the group consisting of Enprofylline, Roflumilast, Ariflo and AWD-12-281.
  • Reference to the aforementioned PDE-IV inhibitors in the context of the present invention includes reference to their optionally existing pharmacologically acceptable acid addition salts.
  • physiologically acceptable acid addition salts which can be formed by the abovementioned PDE-IV inhibitors
  • pharmaceutically acceptable salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, Acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
  • the salts selected from the group consisting of acetate, hydrochloride, hydrobromide, sulfate, phosphate and methanesulfonate are preferred in this context.
  • Suitable application forms for the application of the salts of the formula 1 are, for example, tablets, capsules, suppositories and powders etc.
  • the proportion of the pharmaceutically active compound (s) should in each case be in the range from 0.05 to 90% by weight, preferably from 0.1 to 50 Wt .-% of the total composition.
  • Corresponding tablets can be prepared, for example, by mixing the active substance (s) with known excipients, 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 obtain the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • excipients 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 obtain the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • excipients for example iner
  • Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the core can also consist of several layers.
  • the dragee wrapper to achieve a depot effect of several layers, wherein the above mentioned in the tablets excipients can be used.
  • Juices of the active compounds or active compound combinations according to the invention may 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. They may also contain suspending aids or thickening agents, such as sodium carboxymethylcellulose, 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 thickening agents such as sodium carboxymethylcellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.
  • the capsules containing one or more active ingredients or combinations of active substances can be prepared, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatine capsules.
  • suitable suppositories can be prepared, for example, by mixing with suitable carriers, such as neutral fats or polyethylene glycol or its derivatives.
  • auxiliaries for example, water, pharmaceutically acceptable organic solvents, such as paraffins (for example, petroleum fractions), oils vegetable
  • Origin e.g., peanut or sesame oil
  • mono or polyfunctional alcohols e.g., mono or polyfunctional alcohols
  • Ethanol or glycerol carriers such as e.g. ground natural minerals (e.g., kaolin,
  • Clays, talc, chalk synthetic minerals (e.g.
  • Silicates and silicates examples include sugars (e.g., cane, milk and dextrose), emulsifying agents (e.g., lignin, liquor liquors, methylcellulose, starch and
  • Polyvinylpyrrolidone and lubricants (e.g., magnesium stearate, talc, stearic acid, and sodium lauryl sulfate).
  • lubricants e.g., magnesium stearate, talc, stearic acid, and sodium lauryl sulfate.
  • the application is carried out in the usual way, in the treatment of asthma or COPD, preferably by inhalation.
  • the compounds may be used in the form of inhalable powders, propellant-containing inhalable solutions or suspensions or propellant-free inhalable solutions or suspensions.
  • the usable during the use of the invention, preferably used for reaching inhalation powder can contain the salts 1 , either alone or in admixture with suitable physiologically acceptable excipients.
  • suitable physiologically acceptable excipients eg glucose or arabinose
  • disaccharides eg lactose, sucrose, maltose
  • oligosaccharides and polysaccharides eg dextranes
  • polyalcohols eg sorbitol, mannitol, xylitol
  • salts eg sodium chloride, calcium carbonate
  • lactose Preferably, mono- or disaccharides are used, wherein the use of lactose or glucose, in particular, but not exclusively in the form of their hydrates, is preferred. Lactose, most preferably lactose monohydrate, is used as adjuvant for the purposes of the invention.
  • the propellant-containing inhalable inhalation aerosols which can be used in the context of the use according to the invention can dissolve the salts 1 in propellant gas or contain them in dispersed form.
  • the propellant gases which can be used for the preparation of the inhalation aerosols are known from the prior art. Suitable propellant gases are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as preferably fluorinated derivatives of methane, Ethane, propane, butane, cyclopropane or cyclobutane.
  • the abovementioned propellant gases can be used alone or in mixtures thereof.
  • Particularly preferred propellant gases are fluorinated alkane derivatives selected from TG 134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,1,3,3,3,3-heptafluoropropane) and mixtures thereof.
  • the propellant-containing inhalation aerosols which can be used in the context of the use according to the invention can also contain further constituents, such as co-solvents, stabilizers, surfactants, antioxidants, lubricants and pH-adjusting agents. All of these ingredients are known in the art.
  • suitable solvents are aqueous or alcoholic, preferably ethanolic, solutions.
  • the solvent may be water only or it may be a mixture of water and ethanol.
  • the relative proportion of ethanol to water is not limited, but the maximum limit is preferably up to 70% by volume, in particular up to 60% by volume and more preferably up to 30% by volume.
  • the remaining volume percentages are filled up with water.
  • the solutions or suspensions containing 1 are optionally adjusted with suitable acids to a pH of from 2 to 7, preferably from 2 to 5. To adjust this pH, acids selected from inorganic or organic acids can be used.
  • Examples of particularly suitable inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid.
  • Examples of particularly suitable organic acids are: ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid and others.
  • Preferred inorganic acids are hydrochloric acid, sulfuric acid.
  • ascorbic acid, fumaric acid and citric acid are preferable.
  • mixtures of said acids may also be employed, particularly in the case of acids which, in addition to their acidification properties, also possess other properties, e.g. as flavorants, antioxidants or complexing agents, such as citric acid or ascorbic acid.
  • Hydrochloric acid is particularly preferably used according to the invention for adjusting the pH.
  • the tablets in addition to the specified carriers and additives, such as sodium citrate, calcium carbonate and Dicalcium phosphate together with various additives, such as starch, preferably potato starch, gelatin and the like. Further, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc may be used for tableting. In the case of aqueous suspensions, the active ingredients may be added to the abovementioned excipients with various flavor enhancers or dyes.
  • additives such as sodium citrate, calcium carbonate and Dicalcium phosphate together with various additives, such as starch, preferably potato starch, gelatin and the like.
  • lubricants such as magnesium stearate, sodium lauryl sulfate, and talc may be used for tableting.
  • the active ingredients may be added to the abovementioned excipients with various flavor enhancers or dyes.
  • the dosage of the compounds according to the invention is naturally highly dependent on the mode of administration and the disease to be treated.
  • the salts of the formula 1 are already characterized by high efficacy at doses in the range of .mu.g / g. Even above the ⁇ g range, the compounds of formula 1 can be usefully used.
  • the dosage can then also be in the gram range, for example.
  • the salts of the formula 1 according to the invention can be used in combination with, for example, crystalline tiotropium bromide monohydrate. Insofar as the latter is not yet known in the prior art, its representation is described below.
  • Tiotropium bromide can be obtained as described in European patent application EP 418 716 A1. From this, crystalline tiotropium bromide monohydrate is obtainable according to the procedure described below. 15.0 kg of tiotropium bromide are introduced into 25.7 kg of water in a suitable reaction vessel. The mixture is heated to 80-90 ° C and stirred at a constant temperature until a clear solution is formed. Activated carbon (0.8 kg), moist with water, is slurried in 4.4 kg of water, this mixture is added to the tiotropium bromide-containing solution and rinsed with 4.3 kg of water.
  • the resulting mixture is stirred for at least 15 minutes at 80-90 ° C and then filtered through a heated filter in a pre-heated to 70 ° C jacket temperature apparatus.
  • the filter is rinsed with 8.6 kg of water.
  • the contents of the apparatus are cooled at 3-5 ° C per 20 minutes to a temperature of 20-25 ° C. With cold water cooling, the apparatus is further cooled to 10-15 ° C and the crystallization is completed by at least one hour stirring.
  • the Crystallisate is isolated on a Nutschentrockner, washed the isolated crystal slurry with 9 L of cold water (10-15 ° C) and cold acetone (10-15 ° C). The resulting crystals are dried at 25 ° C for 2 hours in a stream of nitrogen. Yield: 13.4 kg of crystalline tiotropium bromide monohydrate (86% of theory)
  • the finely ground active substance, lactose and part of the corn starch are mixed together.
  • the mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet granulated and dried.
  • the granules, the remainder of the corn starch and the magnesium stearate are sieved and mixed together.
  • the mixture is compressed into tablets of suitable shape and size.
  • Sorbitan trioleate 0.1 monofluorotrichloromethane
  • the above-mentioned numerical values are given in% by weight.
  • the suspension is filled in a conventional aerosol container with metering valve. Per actuation preferably 5O vl suspension are delivered. If desired, the active ingredient can also be metered in higher (for example 0.02% by weight).
  • the preparation of the inhalation powder is carried out in the usual manner by mixing the individual components.
  • the preparation of the inhalation powder is carried out in the usual manner by mixing the individual components.

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pulmonology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Dermatology (AREA)
  • Vascular Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Urology & Nephrology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Pregnancy & Childbirth (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Otolaryngology (AREA)
  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux sels d'acide cinnamique de salmétérol ainsi que des procédés de production et d'utilisation de ces sels comme médicaments.
EP03717188A 2002-03-04 2003-02-19 Nouveaux sels d'acide cinnamique, procedes de production et d'utilisation comme medicaments Withdrawn EP1483231A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE2002109243 DE10209243A1 (de) 2002-03-04 2002-03-04 Neue Arzneimittelkombination zur Inhalation
DE10209243 2002-03-04
DE2002116124 DE10216124A1 (de) 2002-04-12 2002-04-12 Neue Zimtsäuresalze, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel
DE10216124 2002-04-12
PCT/EP2003/001644 WO2003074469A1 (fr) 2002-03-04 2003-02-19 Nouveaux sels d'acide cinnamique, procedes de production et d'utilisation comme medicaments

Publications (1)

Publication Number Publication Date
EP1483231A1 true EP1483231A1 (fr) 2004-12-08

Family

ID=27789722

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03717188A Withdrawn EP1483231A1 (fr) 2002-03-04 2003-02-19 Nouveaux sels d'acide cinnamique, procedes de production et d'utilisation comme medicaments

Country Status (9)

Country Link
EP (1) EP1483231A1 (fr)
JP (1) JP2005519110A (fr)
AR (1) AR038622A1 (fr)
AU (1) AU2003221482A1 (fr)
CA (1) CA2477714C (fr)
PE (1) PE20030933A1 (fr)
TW (1) TW200404759A (fr)
UY (1) UY27686A1 (fr)
WO (1) WO2003074469A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2265276B1 (es) * 2005-05-20 2008-02-01 Laboratorios Almirall S.A. Derivados de 4-(2-amino-1-hidroxietil)fenol como agonistas del receptor beta2 adrenergico.

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZW6584A1 (en) * 1983-04-18 1985-04-17 Glaxo Group Ltd Phenethanolamine derivatives
GB8310477D0 (en) * 1983-04-18 1983-05-25 Glaxo Group Ltd Chemical compounds
US4791108A (en) * 1987-04-13 1988-12-13 Syntex (U.S.A.) Inc. Sulfonyl-decahydro-8H-isoquino[2,1-G][1,6]-naphthyridines and related compounds useful as α2 -blockers
IL95590A (en) * 1989-09-08 1996-06-18 Glaxo Group Ltd Medicinal preparations containing Salmetrol and Pluticasone Propionate
RU2081108C1 (ru) * 1991-10-16 1997-06-10 Циба-Гейги АГ Аддитивные соли кислот с основанием и фармацевтическая композиция, обладающая противоопухолевой активностью

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO03074469A1 *

Also Published As

Publication number Publication date
WO2003074469A1 (fr) 2003-09-12
AR038622A1 (es) 2005-01-19
TW200404759A (en) 2004-04-01
CA2477714C (fr) 2011-01-25
CA2477714A1 (fr) 2003-09-12
PE20030933A1 (es) 2003-12-15
JP2005519110A (ja) 2005-06-30
UY27686A1 (es) 2003-10-31
AU2003221482A1 (en) 2003-09-16

Similar Documents

Publication Publication Date Title
EP1562892A1 (fr) Nouveaux derives de dihydroxymethylphenyle, procedes pour leur preparation, et utilisation desdits derives comme medicament
EP1562603B1 (fr) Nouveaux medicaments destines au traitement de la bronchopneumopathie chronique obstructive
EP1551792A1 (fr) Nouveaux betamimetiques a duree d'action prolongee, procedes de production et d'utilisation comme medicaments
EP1472250B1 (fr) Substances anticholinergiques, procédé de préparation associé et utilisation comme médicament
EP1472251B1 (fr) Nouveaux esters d'acide carboxylique de fluorene, procede permettant de les produire et leur utilisation comme medicaments
EP1328524B1 (fr) Nouveaux anticholinergiques, leurs procedes de production et leur utilisation en tant que medicaments
EP1472249B1 (fr) Esters d'acide xanthenecarboxylique de tropenol et de scopine servant d'antagonistes m3, procedes pour les produire et leur utilisation en tant que medicaments
WO2002032899A1 (fr) Agents anticholinergiques pouvant etre employes en tant que medicaments, et procedes de fabrication
EP1720546A1 (fr) Nouveaux beta-2-agonistes a action longue duree et leur utilisation comme medicaments
WO2005111002A2 (fr) Derives de cycloalkyle substitues, leur procede de production et leur utilisation comme medicaments
WO2005066140A1 (fr) Derives 3-hydroxymethyl-4-hydroxyphenyle pour le traitement de maladies des voies respiratoires
US6680345B2 (en) Salicylic acid salts of salmeterol
DE10258695A1 (de) Neuer, langwirksamer Beta-agonist, Verfahren zu dessen Herstellung und dessen Verwendung als Arzneimittel
US6756508B2 (en) Cinnamic acid salts, processes for their preparation, and their use as medicaments
EP1497288B1 (fr) Nouveaux esters d'heterocycles d'azote substitues par un hydroxy utilises comme antagonistes du recepteur m3 muscarinique, leur procede de production et leur utilisation comme medicaments
EP1483231A1 (fr) Nouveaux sels d'acide cinnamique, procedes de production et d'utilisation comme medicaments
EP1429751A1 (fr) Sels d'acide salicylique, procedes de production et d'utilisation desdits sels en tant que medicaments
DE10216124A1 (de) Neue Zimtsäuresalze, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel
DE10216125A1 (de) Salicylsäuresalze, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel
EP1487831B1 (fr) Esters de tropenol d'acide difurylglycolique utilises comme anticholinergiques

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20041004

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT SE SI SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO

17Q First examination report despatched

Effective date: 20090106

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 9/00 20060101AFI20120531BHEP

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20121103