EP2247581A2 - Sel cristallin énantiomériquement pur d'un bétamimétique et son utilisation comme médicament - Google Patents

Sel cristallin énantiomériquement pur d'un bétamimétique et son utilisation comme médicament

Info

Publication number
EP2247581A2
EP2247581A2 EP09713289A EP09713289A EP2247581A2 EP 2247581 A2 EP2247581 A2 EP 2247581A2 EP 09713289 A EP09713289 A EP 09713289A EP 09713289 A EP09713289 A EP 09713289A EP 2247581 A2 EP2247581 A2 EP 2247581A2
Authority
EP
European Patent Office
Prior art keywords
amino
compound
hydrochloride salt
quinazoline
phenyl
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Withdrawn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
EP09713289A
Other languages
German (de)
English (en)
Inventor
Ulrike Werthmann
Marco Santagostino
Adil Duran
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 International GmbH
Original Assignee
Boehringer Ingelheim International GmbH
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
Application filed by Boehringer Ingelheim International GmbH filed Critical Boehringer Ingelheim International GmbH
Priority to EP09713289A priority Critical patent/EP2247581A2/fr
Publication of EP2247581A2 publication Critical patent/EP2247581A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/18—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 2
    • 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

Definitions

  • the present invention relates to a crystalline, enantiomerically pure hydrochloride salt of N- (5 - ⁇ (R) -2- [3- (4,4-diethyl-2-oxo-1H-benzo [d] [1,3] oxazine -1-yl) -1, 1-dimethyl-propylamino] -1-hydroxy-ethyl ⁇ -2-hydroxyphenyl) -methanesulfonamide having a melting point of 215 ° C and the structure
  • Betamimetics ( ⁇ -adrenergic agents) are known in the art. For example, reference may be made in this regard to the disclosure of US 4,460,581, which suggests betamimetics for the treatment of a wide variety of diseases.
  • Particularly desirable is the provision of a drug which can be therapeutically useful by a single application per day (single dose) can be used.
  • An application once a day has the advantage that the patient can get used to the regular intake of the drug at certain times of day relatively quickly.
  • the enantiomerically pure compound according to formula 1 represents a long-acting betamimetic.
  • inhalation application when used as a medicament for the treatment of respiratory diseases preferably takes place by inhalation.
  • suitable inhalable powders which are filled into suitable capsules (inhalettes) by means of appropriate powder inhalers may be used.
  • inhalation application can also be carried out by application of suitable inhalation aerosols.
  • suitable inhalation aerosols include powdered inhalation aerosols containing, for example, HFA134a, HFA227 or their mixture as a propellant gas.
  • Proper preparation of the aforementioned compositions useful for the inhalative administration of a drug relies on various parameters associated with the nature of the drug itself. Without limitation, examples of these parameters are the effective stability of the starting material under various environmental conditions, stability in the course of preparation of the pharmaceutical formulation, and stability in the final compositions of the drug.
  • the drug used to make the above drug compositions should be as pure as possible and its long-term storage stability must be ensured under various environmental conditions. This is absolutely necessary in order to prevent the use of pharmaceutical compositions in which, in addition to the actual active substance, for example, degradation products thereof are contained. In such a case, an active ingredient content found in capsules could be lower than specified.
  • the ingestion of moisture may reduce the level of drug during manufacture if the drug is exposed to the environment without any protection from moisture.
  • a uniform distribution of the drug in the formulation is also a critical factor, especially if a low dosage of the drug is required.
  • Another aspect that is significant in the case of inhalants, which are to be applied by means of a powder, is the fact that only particles of a certain particle size reach the lungs during inhalation.
  • the particle size of these respirable particles (inhalable fraction) is in the range between 2 and 5 microns.
  • a grinding process is also required.
  • a specific problem that may arise in the milling process for producing the desired drug formulation is the energy input and stress on the surface of the crystals resulting from this process. Under certain circumstances this can lead to polymorphic changes, to a transformation to the amorphous shape or to a change of the crystal lattice. Since the same crystalline morphology of the active substance must always be ensured for the pharmaceutical grade of a pharmaceutical formulation, increased demands must be placed on the stability and properties of the crystalline active substance against this background as well.
  • Micronization occurs, as well as the surface energy of a particulate system increases. Since every system strives to achieve an energy minimum from a thermodynamic point of view, for particulate systems which have an inhalable particle size and thus a specific surface area of typically between 1m 2 / g and 10m 2 / g, high demands are placed on the crystallinity of the micronized drug substance become. It should be noted that the crystalline order is thermodynamically favored over disordered systems and thus crystalline particulate systems are more physically stable from a thermodynamic point of view, especially if the specific crystal structure is particularly stable from a thermodynamic point of view compared to other crystal structures.
  • An object to be solved according to the invention is therefore, in particular, the provision of a thermodynamically particularly stable form of the compound of the formula 1.
  • the present invention accordingly provides the crystalline, enantiomerically pure compound N- (5- ⁇ (R) -2- [3- (4,4-diethyl-2-oxo-4H-benzo [d] [1,3] oxazine) 1 -yl) -1, 1-dimethyl-propylamino] -1-hydroxyethyl ⁇ -2-hydroxy-phenyl) -methanesulfonamide having the structure:
  • the term enantiomerically pure describes compounds of the formula I which are present in an enantiomeric purity of at least 85% ee, preferably of at least 90% ee, particularly preferably of> 95% ee.
  • ee enantiomeric excess
  • the crystalline, enantiomerically pure compound 1 can be characterized by a melting point of 215 ⁇ 3 ° C. This characterization preferably takes place by means of thermal analysis (DSC / TG). This new form is further characterized by an X-ray powder diagram (see Figure 1) with characteristic X-ray reflections according to Table 1.
  • the crystalline, enantiomerically pure compound 1 is characterized in that it is thermally stable under thermal stress up to 210 0 C (see Figure 2).
  • the crystalline, enantiomerically pure compound 1 is distinguished by the following water sorption behavior: in the air humidity range between 10 and 90% n.F. 1 absorbs less than 0.5% by weight of water.
  • compositions characterized in that they contain the inventive crystalline, enantiomerically pure compound 1.
  • these compositions are used for the treatment of respiratory diseases.
  • the present invention further relates to the use of the crystalline, enantiomerically pure compound 1 for the manufacture of a medicament for the treatment of respiratory diseases.
  • the present invention preferably relates to the use of the above-mentioned crystalline and enantiomerically pure compounds of the formula 1 for the manufacture of a medicament for the treatment of respiratory diseases selected from the group consisting of obstructive pulmonary diseases of different origin, pulmonary emphysema of different origin, restrictive lung diseases, interstitial lung diseases, cystic Fibrosis, bronchitis different
  • Preferred is the use of the crystalline and enantiomerically pure compound of formula 1 for the manufacture of a medicament for the treatment of obstructive lung diseases selected from the group consisting of COPD (chronic obstructive pulmonary disease), bronchial asthma, pediatric asthma, severe asthma, acute asthma. Seizure and chronic bronchitis, wherein the use for the preparation of a medicament for the treatment of asthma bronchial is particularly preferred according to the invention.
  • COPD chronic obstructive pulmonary disease
  • bronchial asthma pediatric asthma
  • severe asthma acute asthma
  • Seizure and chronic bronchitis wherein the use for the preparation of a medicament for the treatment of asthma bronchial is particularly preferred according to the invention.
  • the crystalline and enantiomerically pure compound of the formula 1 for the manufacture of a medicament for the treatment of pulmonary emphysema, which has its origin in COPD (chronic obstructive pulmonary disease) or ⁇ 1-proteinase inhibitor deficiency.
  • crystalline and enantiomerically pure compound of formula 1 for the preparation of a medicament for the treatment of restrictive lung diseases selected from the group consisting of allergic alveolitis, occupational noxious-induced restrictive lung diseases such as asbestosis or silicosis and restriction due to lung tumors, such as lymphangiosis carcinomatosa, bronchoalveolar carcinoma and lymphomas.
  • restrictive lung diseases selected from the group consisting of allergic alveolitis, occupational noxious-induced restrictive lung diseases such as asbestosis or silicosis and restriction due to lung tumors, such as lymphangiosis carcinomatosa, bronchoalveolar carcinoma and lymphomas.
  • interstitial lung diseases selected from the group consisting of infectious pneumonia, such as due to infection with viruses, bacteria, fungi, protozoa, helminths or other agents, pneumonitis due to differential causes such as aspiration and left ventricular failure, radiation-induced pneumonitis or fibrosis, collagenosis such as lupus erythematosus, systemic scleroderma or sarcoidosis, granulomatosis such as Boeck's disease, idiopathic interstitial pneumonia or idiopathic pulmonary fibrosis (IPF ).
  • infectious pneumonia such as due to infection with viruses, bacteria, fungi, protozoa, helminths or other agents
  • pneumonitis due to differential causes such as aspiration and left ventricular failure
  • radiation-induced pneumonitis or fibrosis collagenosis such as lupus erythematosus, systemic scleroderma or sarcoidosis
  • crystalline and enantiomerically pure compound of formula 1 for the manufacture of a medicament for the treatment of cystic fibrosis or cystic fibrosis.
  • bronchitis due to bacterial or viral infection, allergic bronchitis and toxic bronchitis.
  • ARDS adult respiratory distress syndrome
  • crystalline and enantiomerically pure compound of formula 1 for the manufacture of a medicament for the treatment of pulmonary edema, for example toxic pulmonary edema after aspiration or inhalation of toxic substances and foreign substances.
  • the present invention relates to the use of the crystalline and enantiomerically pure compound of formula 1 for the manufacture of a medicament for the treatment of asthma or COPD.
  • the present invention relates to the use of the crystalline and enantiomerically pure compound of formula 1 for the manufacture of a medicament for the treatment of asthma or COPD.
  • the crystalline and enantiomerically pure compound of formula 1 for the manufacture of a medicament for the once-daily treatment of inflammatory and obstructive airway diseases, particularly preferably once-daily treatment of asthma or COPD.
  • the present invention relates to a method for the treatment of the aforementioned diseases, characterized in that one or more of the above-mentioned crystalline and enantiomerically pure compound of formula 1 are administered in therapeutically effective amounts.
  • the present invention preferably relates to methods for the treatment of asthma or COPD, characterized in that the above-mentioned crystalline and enantiomerically pure compound of formula 1 are administered in therapeutically effective amounts once a day.
  • compositions which contain the crystalline, enantiomerically pure compound 1 in an inhalation solution or an inhalable powder formulation.
  • pharmaceutical compositions containing the inventive crystalline, enantiomerically pure compound 1 and further active ingredient, one or more compounds selected from the classes of the anticholinergics, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, dopamine agonists, H 1 antihistamines and PI3 kinase inhibitors or two or three combinations thereof.
  • the present invention relates to a method for the treatment of the aforementioned diseases, characterized in that the above-mentioned crystalline, enantiomerically pure compound of the formula 1 are administered in therapeutically effective amounts.
  • the present invention preferably relates to methods for the treatment of asthma or COPD, characterized in that the above-mentioned crystalline, enantiomerically pure compound of the formula 1 are administered in therapeutically effective amounts once a day.
  • Suitable application forms for the application of the crystalline, enantiomerically pure compound of the formula 1 are, for example, tablets, capsules, suppositories, powders, etc.
  • the proportion of the pharmaceutically active compound 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.
  • 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, and a taste-improving agent, for example 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. P01-2351
  • inhalable dosage forms are inhalable powders and propellant-containing metered dose inhalers.
  • the compound of the formula 1 which is particularly preferably used in crystalline, enantiomerically pure form according to the invention is preferably used for the preparation of inhalable powders.
  • Inhalable powders which can be used according to the invention can contain the crystalline, enantiomerically pure compound of the formula 1, either alone or in admixture with suitable physiologically acceptable auxiliaries.
  • physiologically acceptable excipients can be used to prepare these inhalable powders according to the invention: monosaccharides (eg glucose or arabinose), disaccharides (eg lactose, sucrose, maltose), oligo- and polysaccharides (eg Dextran), polyalcohols (eg sorbitol, mannitol, xylitol), salts (eg sodium chloride, calcium carbonate) or mixtures of these excipients with each other.
  • monosaccharides eg glucose or arabinose
  • disaccharides eg lactose, sucrose, maltose
  • oligo- and polysaccharides eg Dextran
  • polyalcohols eg sorbitol, mannitol, xylitol
  • salts eg sodium chloride, calcium carbonate
  • Lactose most preferably lactose monohydrate, is used as adjuvant for the purposes of the invention.
  • the auxiliaries have a maximum mean particle size of up to 250 ⁇ m, preferably between 10 and 150 ⁇ m, particularly preferably between 15 and 80 ⁇ m. If appropriate, it may seem appropriate to add finer excipient fractions having a mean particle size of 1 to 9 .mu.m to the abovementioned excipients. The latter finer excipients are also selected from the aforementioned group of usable excipients.
  • micronized active ingredient preferably having an average particle size of 0.5 to 10 .mu.m, more preferably from 1 to 5 .mu.m, the excipient or the excipient mixture admixed.
  • Methods for producing the inhalable powders according to the invention by grinding and micronizing as well as by final mixing of the constituents are known from the prior art.
  • inhalable powders according to the invention can be applied by means of inhalers known from the prior art.
  • Propellant gas-containing inhalation aerosols may contain in the propellant the crystalline, enantiomerically pure compounds 1 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 fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
  • the abovementioned propellant gases can be used alone or in mixtures thereof.
  • Particularly preferred propellants are halogenated alkane derivatives selected from TG134a and TG227 and mixtures thereof.
  • the propellant-containing inhalation aerosols may also contain other ingredients such as co-solvents, stabilizers, surfactants, antioxidants, lubricants, and pH adjusters. All of these ingredients are known in the art.
  • 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 compounds of the formula When administered by inhalation, the compounds of the formula are already characterized by a high efficacy at doses in the ⁇ g range. Even above the ⁇ g range, the compounds of the formula can be used meaningfully.
  • the dosage can then also be in the milligram range, for example.
  • a further aspect of the present invention relates to the abovementioned pharmaceutical formulations, characterized by a content of the compound of the formula 1 as such, particularly preferably the above-mentioned inhalable pharmaceutical formulations.
  • 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.
  • the finely ground active ingredient, a portion of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved and processed with the remainder of the corn starch and water to a granulate which is dried and sieved. To this is added the sodium carboxymethyl starch and the magnesium stearate, mixed and pressed the mixture into tablets of suitable size.
  • the suspension is filled in a conventional aerosol container with metering valve. Per actuation preferably 50 ul suspension are delivered. If desired, the active ingredient can also be metered in higher (for example 0.02% by weight).
  • the preparation of the inhalable powder is carried out in the usual manner by mixing the individual components.
  • This solution can be prepared in the usual way.
  • the active ingredient is dissolved at its own pH or optionally at pH 5.5 to 6.5 in water and treated with sodium chloride as isotonic.
  • the resulting solution is filtered pyrogen-free and the filtrate filled under aseptic conditions in ampoules, which are then sterilized and sealed.
  • the vials contain 5 mg, 25 mg and 50 mg active ingredient.
  • Example 1d of WO-A-2007/054484 for the synthesis of 2, reference is made to Example 1d of WO-A-2007/054484 in connection with the synthesis described in WO-A-2007/054484 for the preparation of the optically pure R-enantiomer N- (5 - ⁇ (R) -2- [3- (4,4-diethyl-2-oxo-4H-benzo [d] [1,3] oxazin-1-yl) -1, 1-dimethyl-propylamino] -1-hydroxy-ethyl ⁇ 2-hydroxy-phenyl) -methanesulfonamide according to the formula 2.
  • the software TREOR (part of the STOE Stadi P software package) was used to index the peaks of the X-ray powder diagram.
  • DSC 822 from Mettler Toldeo; Heating rate: 10 K / min; Crucible type: perforated aluminum crucible; Atmosphere: N 2 , 80 ml / min flow rate; Weighing: 3-10 mg.
  • TGA / SDTA 851 from the company Mettler Toledo with IR coupling (Nicolet FT-IR 4700) for the analysis of the heated volatiles; Heating rate: 10 K / min; Crucible type: open alumina crucible; Atmosphere: N 2 , 20 ml / min flow rate; Weighing: 15-25 mg.
  • SORPTION PROFILE (DSV DIAGRAM, KINETIC & ISOTH ERM-PLOT, FIGURE 3)
  • the crystalline and enantiomerically pure compound of formula 1 may be alone or in
  • the crystalline and enantiomerically pure compound of formula 1 may also be used in combination with W, wherein W represents a pharmacologically active agent and is (for example) selected from the group consisting of anticholinergics, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, dopamine agonists, H 1 antihistamines and PI3 kinase inhibitors.
  • W represents a pharmacologically active agent and is (for example) selected from the group consisting of anticholinergics, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, dopamine agonists, H 1 antihistamines and PI3 kinase inhibitors.
  • W represents a pharmacologically active agent and is (for example) selected from the group consisting of anticholinergics, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, dopamine agonists, H 1 antihistamine
  • W represents an anticholinergic agent combined with a betamimetic, corticosteroid, PDE4 inhibitor, EGFR inhibitor or LTD4 antagonist,
  • W represents a corticosteroid combined with a PDE4 inhibitor, EGFR inhibitor or LTD4 antagonist
  • W represents a PDE4 inhibitor combined with an EGFR inhibitor or LTD4 antagonist - W represents an EGFR inhibitor combined with a LTD4 antagonist.
  • Preferred anticholinergic compounds are compounds which are selected from the group consisting of tiotropium salts, preferably the bromide salt, oxitropium salts, preferably the bromide salt, flutropium salts, preferably the bromide salt, ipratropium salts, preferably the bromide salt, glycopyrronium salts, preferably the bromide salt, aclidinium salts the bromide salt, trospium salts, preferably the chloride salt, tolterodine.
  • the cations are the pharmacologically active ingredients.
  • the aforementioned salts may preferably contain chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate , Benzoate or p-toluenesulfonate, with chloride, bromide, iodide, sulfate, methanesulfonate or p-toluenesulfonate being preferred as counterions.
  • the chlorides, bromides, iodide and methanesulfonate are particularly preferred. Further named compounds are 2,2-diphenylpropionic acid tropol ester methobromide; 2,2-diphenylpropionic acid copoprene methobromide; 2-fluoro-2,2- P01-2351
  • Difluorbenzil Difluorbenzilkladishercyclopropyltropinester methobromide; 9-hydroxy-xanthene-9-carboxylic acid tropol ester methobromide; ⁇ -hydroxy-xanthene---carboxylic acid copoprene methobromide; 9-methyl-xanthene-9-carboxylic acid tropol ester -methobromide; 9-methyl-xanthene---carboxylic acid copinester methobromide; 9-ethyl-xanthene-9-carboxylic acid tropol ester methobromide; 9-Difluoromethyl-xanthene-9-carboxylic acid tropol ester methobromide; 9-hydroxymethyl-xanthene-9-carboxylic acid copinester methobromide.
  • Preferred corticosteroids are compounds selected from the group consisting of prednisolone, prednisone, butixocortepionate, flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, dexamethasone, betamethasone, deflazacort, RPR-106541, NS -126, ST-26 and 6,9-difluoro-17 - [(2-furanylcarbonyl) oxy] -11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionic acid (S) -fluoromethylester; 6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothioic acid (S) - (2-oxo-tetrahydrofuran-3S-yl)
  • salts and derivatives of the steroids may be: alkali metal salts, for example sodium or potassium salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or even furoates.
  • Preferred PDE4 inhibitors are compounds selected from the group consisting of enprofylline, theophylline, roflumilast, ariflo (cilomilast), tofimilast, pumafentrin, lirimilast, arofylline, atizoram, D-4418, bay 198004, BY343, CP-325,366, D-4396 (Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585, V- 11294A, CI-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370 and N- (3,5-dichloro-1-oxo-pyridin-4-yl) -4-difluoromethoxy 3-cyclopropylmethoxybenzamid; (-) p - [(4aR *, 10bS *) - 9
  • the acid addition salts of the betamimetics are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate ,
  • Preferred LTD4 antagonists here are compounds selected from the group consisting of montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078 , VUF-K-8707, L-733321 and 1 - (((R) - (3- (2- (6,7-Difluoro-2-quinolinyl) ethenyl) phenyl) -3- (2- (2-hydroxy -2- P01-2351
  • the acid addition salts of the betamimetics are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
  • salts or derivatives which the LTD4-antagonists are capable of forming include: alkali metal salts, such as, for example, sodium or potassium salts, alkaline earth salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogenphosphates, palmitates, pivalates or furoates.
  • alkali metal salts such as, for example, sodium or potassium salts, alkaline earth salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogenphosphates, palmitates, pivalates or furoates.
  • the EGFR inhibitors used are preferably compounds selected from the group consisting of cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and 4 - [(3-chloro-4-fluorophenyl) amino] -6- ⁇ [4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] amino ⁇ -7-cyclopropylmethoxyquinazoline; 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ⁇ [4- (N, N-diethylamino) -1-oxo-2-buten-1-ylamino] -cyclopropylmethoxyquinazoline; 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ⁇ [4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl] amino ⁇ -7-cycloprop
  • the acid addition salts of the betamimetics are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
  • Preferred dopamine agonists are compounds selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexole, terguride and viozane, optionally in the form of their racemates, enantiomers , Diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates.
  • the acid addition salts of the betamimetics are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
  • H 1 -Antihistaminika here are preferably compounds used, which are selected from the group consisting of epinastine, cetirizine, azelastine,
  • Fexofenadine levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetinden, clemastine, bamipine, cexchlorpheniramine, pheniramine, doxylamine, chlorphenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclocine, optionally in the form of their racemates, enantiomers, diastereomers and optionally in Form of their pharmacologically acceptable acid addition salts, solvates or hydrates.
  • the acid addition salts of the betamimetics are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pulmonology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne un sel cristallin énantiomériquement pur d'hydrochlorure de N-(5-{2-[3-(4,4-diéthyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-diméthyl-propylamino]-1-hydroxy-éthyl}-2-hydroxy-phényl)-méthanesulfonamide, de préférence de N-(5-{(R)-2-[3-(4,4-diéthyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-diméthyl-propylamino]-1-hydroxy- éthyl}-2-hydroxy-phényl)-méthanesulfonamide et son effet en tant que bétamimétique, seul ou en association avec un ou plusieurs autres principes actifs pour le traitement des affections des voies respiratoires.
EP09713289A 2008-02-22 2009-02-17 Sel cristallin énantiomériquement pur d'un bétamimétique et son utilisation comme médicament Withdrawn EP2247581A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP09713289A EP2247581A2 (fr) 2008-02-22 2009-02-17 Sel cristallin énantiomériquement pur d'un bétamimétique et son utilisation comme médicament

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP08151842A EP2093219A1 (fr) 2008-02-22 2008-02-22 Forme de sel à énantiomère pur et cristalline d'un bêtamimétique et son utilisation comme médicament
PCT/EP2009/001082 WO2009103479A2 (fr) 2008-02-22 2009-02-17 Sel cristallin énantiomériquement pur d'un bétamimétique et son utilisation comme médicament
EP09713289A EP2247581A2 (fr) 2008-02-22 2009-02-17 Sel cristallin énantiomériquement pur d'un bétamimétique et son utilisation comme médicament

Publications (1)

Publication Number Publication Date
EP2247581A2 true EP2247581A2 (fr) 2010-11-10

Family

ID=39627761

Family Applications (2)

Application Number Title Priority Date Filing Date
EP08151842A Withdrawn EP2093219A1 (fr) 2008-02-22 2008-02-22 Forme de sel à énantiomère pur et cristalline d'un bêtamimétique et son utilisation comme médicament
EP09713289A Withdrawn EP2247581A2 (fr) 2008-02-22 2009-02-17 Sel cristallin énantiomériquement pur d'un bétamimétique et son utilisation comme médicament

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP08151842A Withdrawn EP2093219A1 (fr) 2008-02-22 2008-02-22 Forme de sel à énantiomère pur et cristalline d'un bêtamimétique et son utilisation comme médicament

Country Status (9)

Country Link
US (1) US8394791B2 (fr)
EP (2) EP2093219A1 (fr)
JP (1) JP2011512372A (fr)
AR (1) AR070464A1 (fr)
CA (1) CA2712706A1 (fr)
PE (1) PE20091396A1 (fr)
TW (1) TW200940065A (fr)
UY (1) UY31670A1 (fr)
WO (1) WO2009103479A2 (fr)

Family Cites Families (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3026534A1 (de) 1980-07-12 1982-03-18 C.H. Boehringer Sohn, 6507 Ingelheim 3,1-benzoxazin-2-one, ihre herstellung und verwendung
US4460581A (en) 1982-10-12 1984-07-17 Boehringer Ingelheim Kg (1-Hydroxy-2-amino-alkyl)-substituted benzoxazinones and benzoxazolinones
US4570630A (en) 1983-08-03 1986-02-18 Miles Laboratories, Inc. Medicament inhalation device
AU591152B2 (en) 1985-07-30 1989-11-30 Glaxo Group Limited Devices for administering medicaments to patients
SE453566B (sv) 1986-03-07 1988-02-15 Draco Ab Anordning vid pulverinhalatorer
DE3609152A1 (de) 1986-03-19 1987-09-24 Bayer Ag Verfahren zur herstellung des (-)-antipoden des (e)-1-cyclohexyl-4,4-dimethyl- 3-hydroxy-2-(1,2,4-triazol-1-yl)-pent-1-ens
SG45171A1 (en) 1990-03-21 1998-01-16 Boehringer Ingelheim Int Atomising devices and methods
IL107120A (en) 1992-09-29 1997-09-30 Boehringer Ingelheim Int Atomising nozzle and filter and spray generating device
DE4318455A1 (de) 1993-06-03 1994-12-08 Boehringer Ingelheim Kg Kapselhalterung
US5495054A (en) 1994-05-31 1996-02-27 Sepracor, Inc. Tetrahydroindeno[1,2-D][1,3,2]oxazaboroles and their use as enantioselective catalysts
DE19536902A1 (de) 1995-10-04 1997-04-10 Boehringer Ingelheim Int Vorrichtung zur Hochdruckerzeugung in einem Fluid in Miniaturausführung
DE19536903C2 (de) 1995-10-04 1998-09-10 Boehringer Ingelheim Int Vorrichtung zum Haltern eines fluidischen Bauteils
DE19545226C1 (de) 1995-12-05 1997-06-19 Boehringer Ingelheim Int Sperrspannwerk für einen federbetätigten Abtrieb
DE19653969A1 (de) 1996-12-20 1998-06-25 Boehringer Ingelheim Kg Neue wässrige Arzneimittelzubereitung zur Erzeugung treibgasfreier Aerosole
DE19742439C1 (de) 1997-09-26 1998-10-22 Boehringer Ingelheim Int Mikrostrukturiertes Filter
WO2002030928A1 (fr) 2000-10-12 2002-04-18 Boehringer Ingelheim Pharma Gmbh & Co. Kg Monohydrate cristallin, procede permettant sa preparation et son utilisation pour la preparation d'un produit pharmaceutique
DE10050995A1 (de) 2000-10-14 2002-04-18 Boehringer Ingelheim Pharma Neue Anticholinergika, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel
ME00412B (fr) 2001-06-22 2011-10-10 Boehringer Ingelheim Pharma Substance anticholinergique cristalline, son procede de production et son utilisation pour la production d'un medicament
DE10203749A1 (de) 2002-01-31 2003-08-14 Boehringer Ingelheim Pharma Neue Anticholinergika, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel
DE10203741A1 (de) 2002-01-31 2003-08-14 Boehringer Ingelheim Pharma Neue Fluorencarbonsäureester, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel
DE10203753A1 (de) 2002-01-31 2003-08-14 Boehringer Ingelheim Pharma Neue Xanthencarbonsäureester, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel
BRPI0409198A (pt) 2003-04-04 2006-05-02 Novartis Ag derivados quinolin-2-ona para o tratamento de doenças de vias aéreas
DE102004003428A1 (de) 2004-01-23 2005-08-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue langwirksame Beta-2-Agonisten, und deren Verwendung als Arzneimittel
US7244728B2 (en) 2004-03-17 2007-07-17 Boehringer Ingelheim International Gmbh Long acting betamimetics for the treatment of respiratory diseases
DE102004024454A1 (de) 2004-05-14 2005-12-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Enantiomerenreine Betaagonisten, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel
US20050255050A1 (en) 2004-05-14 2005-11-17 Boehringer Ingelheim International Gmbh Powder formulations for inhalation, comprising enantiomerically pure beta agonists
US7220742B2 (en) 2004-05-14 2007-05-22 Boehringer Ingelheim International Gmbh Enantiomerically pure beta agonists, process for the manufacture thereof and use thereof as medicaments
DE102005008921A1 (de) 2005-02-24 2006-08-31 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Arzneimittel zur Behandlung von Atemwegserkrankungen
US7423146B2 (en) 2005-11-09 2008-09-09 Boehringer Ingelheim International Gmbh Process for the manufacturing of pharmaceutically active 3,1-benzoxazine-2-ones
PE20080425A1 (es) 2006-08-22 2008-06-16 Boehringer Ingelheim Int Formulacion aerosol para la inhalacion de beta-agonistas
UY30550A1 (es) 2006-08-22 2008-03-31 Boehringer Ingelheim Int Nuevos beta-agonistas enantioméricamente puros, procedimientos para su preparacion y su uso como medicamentos
EP2056836A1 (fr) 2006-08-22 2009-05-13 Boehringer Ingelheim International GmbH Formulations de poudre pour inhalation contenant des bêta-agonistes purs sur le plan énantiomérique
PE20081358A1 (es) 2006-08-22 2008-10-31 Boehringer Ingelheim Int Combinaciones farmacologicas para el tratamiento de enfermedades de la vias aereas

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2009103479A2 *

Also Published As

Publication number Publication date
US20110262369A1 (en) 2011-10-27
CA2712706A1 (fr) 2009-08-27
AR070464A1 (es) 2010-04-07
EP2093219A1 (fr) 2009-08-26
WO2009103479A3 (fr) 2009-12-10
WO2009103479A2 (fr) 2009-08-27
JP2011512372A (ja) 2011-04-21
TW200940065A (en) 2009-10-01
PE20091396A1 (es) 2009-09-24
UY31670A1 (es) 2009-09-30
US8394791B2 (en) 2013-03-12

Similar Documents

Publication Publication Date Title
EP1789405B1 (fr) Nouveaux beta-agonistes enantiomeriquement purs, leur procede de production et leur utilisation comme medicament
EP1730126B1 (fr) Nouveaux derives de benzoxazinone comme beta-mimetiques de longue duree et leur utilisation pour le traitement des maladies des voies respiratoires
US8034809B2 (en) Enantiomerically pure beta agonists, process for the manufacture thereof and use thereof as medicaments
EP1472251B1 (fr) Nouveaux esters d'acide carboxylique de fluorene, procede permettant de les produire et leur utilisation comme medicaments
WO2008023004A1 (fr) Agonistes bêta à énantiomère unique, leur procédé de production et leur utilisation en tant que médicaments
AU2006259202B2 (en) Process for preparing tiotropium salts, tiotropium salts as such and pharmaceutical compositions thereof
KR20100088148A (ko) 베타미메티카의 결정성 수화물 및 이의 약제로서의 용도
WO2007104772A1 (fr) Nouveaux agonistes beta enantiomeriquement purs, son procede de fabrication et son utilisation en tant que medicament
WO2008017638A1 (fr) Nouveaux agonistes beta énantiomériquement purs, procédés pour leur préparation et leur utilisation comme médicament
EP1901776B1 (fr) Nouvelles combinaisons de medicaments permettant de traiter des maladies des voies respiratoires et contenant des agonistes beta-2 a action prolongee et au moins une autre substance active
EP2247581A2 (fr) Sel cristallin énantiomériquement pur d'un bétamimétique et son utilisation comme médicament
EP2298415A1 (fr) Procédé de micronisation
CA2642239A1 (fr) Combinaisons medicamenteuses pour le traitement de pathologies des voies respiratoires
HK1134079A (en) Single enantiomer beta agonists method for production and use thereof as a medicament

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: 20100922

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA RS

DAX Request for extension of the european patent (deleted)
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: 20140902