CA2559699A1 - Pharmaceutical combinations containing benzoxazine for treating respiratory diseases - Google Patents

Pharmaceutical combinations containing benzoxazine for treating respiratory diseases Download PDF

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CA2559699A1
CA2559699A1 CA002559699A CA2559699A CA2559699A1 CA 2559699 A1 CA2559699 A1 CA 2559699A1 CA 002559699 A CA002559699 A CA 002559699A CA 2559699 A CA2559699 A CA 2559699A CA 2559699 A1 CA2559699 A1 CA 2559699A1
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amino
quinazoline
phenyl
methoxy
chloro
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CA2559699C (en
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Thierry Bouyssou
Ingo Konetzki
Sabine Pestel
Andreas Schnapp
Christoph Hoenke
Philipp Lustenberger
Klaus Rudolf
Michael P. Pieper
Michel Pairet
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Boehringer Ingelheim International GmbH
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Priority claimed from DE102004019540A external-priority patent/DE102004019540A1/en
Priority claimed from DE102004052987A external-priority patent/DE102004052987A1/en
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    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
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    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • 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

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
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  • Pregnancy & Childbirth (AREA)
  • Virology (AREA)
  • Reproductive Health (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)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

The invention relates to novel pharmaceutical combinations containing at least one active ingredient (2) in addition to at least one, preferably one, compound of general formula (1) wherein the radicals R1, R2 and R3 have the designations cited in the patent claims and in the description. The invention also relates to a method for producing said combinations and to the use thereof as medicaments.

Claims (53)

1) Medicament combinations which contain in addition to one or more compounds of general formula 1 wherein n denotes 1 or 2;
R1 denotes hydrogen, halogen, C1-C4-alkyl or -O-C1-C4-alkyl;
R2 denotes hydrogen, halogen, C1-C4-alkyl or -O-C1-C4-alkyl;
R3 denotes C1-C4-alkyl, OH, halogen, -O-C1-C4-alkyl, -O-C1-C4-alkylene-COOH, -O-C1-C4-alkylene-CO-O-C1-C4-alkyl, at least one other active substance 2.
2) Medicament combinations according to claim 1, which contain in addition to one or more compounds of formula 1 as an additional active substance 2 one or more compounds which are selected from the categories of the anticholinergics 2a , PDE IV
inhibitors 2b , steroids 2c , LTD4-antagonists 2d and EGFR-inhibitors 2e).
3) Medicament combinations according to claim 1 or 2, which contain one or more compounds of general formula 1, wherein n denotes 1 or 2;
R1 denotes hydrogen, fluorine, chlorine, methyl or methoxy;
R2 denotes hydrogen, fluorine, chlorine, methyl or methoxy;
R3 denotes C1-C4-alkyl, OH, fluorine, chlorine, bromine, -O-C1-C4-alkyl, -O-C1-C4-alkylene-COOH, -O-C1-C4-alkylene-CO-O-C1-C4-alkyl.
4) Medicament combinations according to claim 1, 2 or 3, which contain one or more compounds of general formula 1, wherein n denotes 1;
R1 denotes hydrogen or C1-C4-alkyl;
R2 denotes hydrogen or C1-C4-alkyl;
R3 denotes C1-C4-alkyl, OH, -O-C1-C4-alkyl, -O-C1-C4-alkylene-COOH or -O-C1-C4- alkylene-CO-O-C1-C4-alkyl.
5) Medicament combinations according to one of claims 1 to 4, which contain one or more compounds of general formula 1 in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates.
6) Medicament combinations according to one of claims 1 to 5, which contain one or more compounds of general formula 1 in the form of the acid addition salts with pharmacologically acceptable acids as well as optionally in the form of the solvates and/or hydrates.
7) Medicament combinations according to one of claims 1 to 6, which contain, in addition to one or more compounds of general formula 1 an anticholinergic (2a) as an additional active substance 2.
8) Medicament combinations according to claim 7, which contain in addition to one or more compounds of general formula 1 an anticholinergic (2a) selected from the group comprising tiotropium salts (2a.1), oxitropium salts (2a.2), flutropium salts (2a.3), ipratropium salts (2a.4), glycopyrronium salts (2a.5), trospium salts (2a.6).
9) Medicament combinations according to claim 7, which contain in addition to one or more compounds of general formula 1 an anticholinergic of formula 2a.7 wherein X- denotes an anion with a single negative charge, preferably an anion selected from among the fluoride, chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetat, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate, optionally in the form of the racemates, enantiomers or hydrates thereof.
10) Medicament combinations according to claim 7, which contain in addition to one or more compounds of general formula 1 an anticholinergic of formula 2a.8 wherein R denotes either methyl (2a.8.1) or ethyl (2a.8.2) and wherein X- may have the meanings given in claim 9.
11) Medicament combinations according to claim 7, which contain in addition to one or more compounds of general formula 1 an anticholinergic of formula 2a.9 wherein A denotes a double-bonded group selected from the groups X- denotes one of the anions with a single negative charge specified in claim 9;
R1 and R2 which may be identical or different denote a group selected from methyl, ethyl, n-propyl and iso-propyl, which may optionally be substituted by hydroxy or fluorine, preferably unsubstituted methyl;
R3, R4, R5 and R6, which may be identical or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF3 or NO2;
R7 denotes hydrogen, methyl, ethyl, methyloxy, ethyloxy, -CH2-F, -CH2-CH2-F, -O-CH2-F, -O-CH2-CH2-F, -CH2-OH, -CH2-CH2-OH, CF3, -CH2-OMe, -CH2-CH2-OMe, -CH2-OEt, -CH2-CH2-OEt, -O-COMe, -O-COEt, -O-COCF3, -O-COCF3, fluorine, chlorine or bromine, optionally in the form of the racemates, enantiomers or hydrates thereof.
12) Medicament combinations according to claim 7, which contain in addition to one or more compounds of general formula 1 an anticholinergic of formula 2a.10 wherein A, X-, R1 and R2 may have the meanings given in claim 11 and wherein R7, R8, R9, R10, R11 and R12, which may be identical or different, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CN, CF3 or NO2, while at least one of the groups R7, R8, R9, R10, R11 and R12 may not be hydrogen, optionally in the form of the racemates, enantiomers or hydrates thereof.
13) Medicament combinations according to claim 7, which contain in addition to one or more compounds of general formula 1 an anticholinergic of formula 2a.11 wherein A and X- may have the meanings given in claim 11 and wherein R15 denotes hydrogen, hydroxy, methyl, ethyl, -CF3, CHF2 or fluorine;
R1' and R2' which may be identical or different, denote C1-C5-alkyl, which may optionally be substituted by C3-C6-cycloalkyl, hydroxy or halogen, or R1' and R2' together denote a -C3-C5-alkylene bridge ;

R13, R14, R13' and R14' which may be identical or different, denote hydrogen, -C1-C4-alkyl, -C1-C4-alkyloxy, hydroxy, -CF3, -CHF2, CN, NO2 or halogen, optionally in the form of the racemates, enantiomers or hydrates thereof.
14) Medicament combinations according to claim 7, which contain in addition to one or more compounds of general formula 1 an anticholinergic of formula 2a.12 wherein X- may have the meanings given in claim 11 and wherein D and B which may be identical or different, preferably identical, denote O, S, NH, CH2, CH=CH or N(C1-C4-alkyl);
R16 denotes hydrogen, hydroxy, -C1-C4-alkyl, -C1-C4-alkyloxy, -C1-C4-alkylene-halogen, -O-C1-C4-alkylene-halogen, -C1-C4-alkylene-OH, -CF3, CHF2, -C1-C4-alkylene-C1-C4-alkyloxy, -O-COC1-C4-alkyl, -O-COC1-C4-alkylene-halogen, -C1-C4-alkylene-C3-C6-cycloalkyl, -O-COCF3 or halogen;
R1'' and R2'' which may be identical or different, denote -C1-C5-alkyl, which may optionally be substituted by -C3-C6-cycloalkyl, hydroxy or halogen, or R1'' and R2'' together denote a -C3-C5-alkylene bridge ;
R17, R18, R17' and R18', which may be identical or different, denote hydrogen, -C1-C4-alkyl, -C1-C4-alkyloxy, hydroxy, -CF3, -CHF2, CN, NO2 or halogen;
R x and R x' which may be identical or different, denote hydrogen, -C1-C4-alkyl, -C1-C4-alkyloxy, hydroxy, -CF3, -CHF2, CN, NO2 or halogen, or R x and R x' together denote a single bond or one of the double-bonded groups O, S, NH, CH2, CH2-CH2, N(C1-C4-alkyl), CH(C1-C4-alkyl) and -C(C1-C4-alkyl)2, optionally in the form of the racemates, enantiomers or hydrates thereof.
15) Medicament combinations according to claim 7, which contain in addition to one or more compounds of general formula 1 an anticholinergic of formula 2a.13 wherein X- may have the meanings given in claim 11 and wherein A' denotes a double-bonded group selected from R19 denotes hydroxy, methyl, hydroxymethyl, ethyl, -CF3, CHF2 or fluorine;
R1''' and R2''' which may be identical or different, denote C1-C5-alkyl, which may optionally be substituted by C3-C6-cycloalkyl, hydroxy or halogen, or R1''' and R2''' together denote a -C3-C5-alkylene bridge ;
R20, R21, R20' and R21' which may be identical or different, denote hydrogen, -C1-C4-alkyl, -C1-C4-alkyloxy, hydroxy, -CF3, -CHF2, CN, NO2 or halogen, optionally in the form of the racemates, enantiomers or hydrates thereof.
16) Medicament combinations according to one of claims 1 to 6, which contain in addition to one or more compounds of general formula 1 as an additional active substance 2 a PDE IV-inhibitor (2b).
17) Medicament combinations according to claim 16, wherein the PDE IV-inhibitor 2b is selected from the group comprising enprofyllin, theophyllin, roflumilast, ariflo (cilomilast), CP-325.366, BY343, D-4396 (Sch-351591), AWD-12-281 (GW-842470), N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide, NCS-613, pumafentine, (-)p-[(4.alpha.R*,10bS*)-9-ethoxy-1,2,3,4,4a.10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide, (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone, 3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N'-[N-2-cyano-S-methyl-isothioureido]benzyl)-2-pyrrolidone, cis[4-cyano-4-(3-cyclopentyloxy-methoxyphenyl)cyclohexane-1-carboxylic acid], 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one, cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol], (R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate, (S)-(-)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate, CDP840, Bay-198004, D-4418, PD-168787, T-440, T-2585, arofyllin, atizoram, V-11294A, Cl-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370, 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H pyrazolo[3,4-c]-1,2,4-triazolo[4.3-a]pyridine and 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine, optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof.
18) Medicament combinations according to one of claims 1 to 6, which contain in addition to one or more compounds of general formula 1 a steroid 2c as an additional active substance 2.
19) Medicament combinations according to claim 18, wherein the steroid 2c is selected from the group comprising prednisolone (2c.1), prednisone (2c.2), butixocortpropionate (2c.3), RPR-106541 (2c.4), flunisolide (2c.5), beclomethasone (2c.6), triamcinolone (2c.7), budesonide (2c.8), fluticasone (2c.9), mometasone (2c.10), ciclesonide (2c.11), rofleponide (2c.12), ST-126 (2c.13), dexamethasone (2c.14), (S)-fluoromethyl 6.alpha.,9.alpha.-difluoro-17.alpha.-[(2-furanylcarbonyl)oxy]-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothionate (2c.15), (S)-(2-oxo-tetrahydro-furan-3S-yl) 6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.alpha.-propionyloxy-androsta-1,4-diene-17.beta.-carbothionate (2c.16) and etiprednol-dichloroacetate (2c.17), optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the salts and derivatives thereof, the solvates and/or hydrates thereof.
20) Medicament combinations according to one of claims 1 to 6, which contain in addition to one or more compounds of general formula 1 an LTD4-antagonist 2d as an additional active substance 2.
21 ) Medicament combinations according to claim 20, wherein the LTD4 antagonist 2d is selected from the group comprising montelukast (2d.1), 1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2- hydroxy-2-propyl)phenyl)thio)-methylcyclopropane-acetic acid (2d.2), 1-(((1(R)-3(3-(2-(2.3-dichlorothieno[3,2-b]pyridin-5-yI)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)-cyclopropaneacetic acid (2d.3), pranlukast (2d.4), zafirlukast (2d.5), [2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic acid (2d.6), MCC-847 (ZD-3523) (2d.7), MN-001 (2d.8) , MEN-91507 (LM-1507) (2d.9), VUF-5078 (2d.10), VUF-K-(2d.11) and L-733321 (2d.12), optionally in the form of the racemates, enantiomers or diastereomers thereof, optionally in the form of the pharmacologically acceptable acid addition salts thereof as well as optionally in the form of the salts and derivatives thereof, the solvates and/or hydrates thereof.
22) Medicament combinations according to one of claims 1 to 6, which contain in addition to one or more compounds of general formula 1 an EGFR-inhibitor 2e as an additional active substance 2.
23) Medicament combinations according to claim 22, wherein EGFR inhibitors 2e are selected from the group comprising 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]
amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2.3-d]pyrimidine, 3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline, 4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]
amino}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-{[4-(5.5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy} -7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6- {trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-( 1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-((3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-((3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-((3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline, Cetuximab, Trastuzumab, ABX-EGF and Mab ICR-62, optionally in the form of the racemates, enantiomers or diastereomers thereof, optionally in the form of the pharmacologically acceptable acid addition salts thereof, the solvates and/or hydrates thereof.
24) Medicament combinations according to one of claims 1 to 6, characterised in that they also contain, in addition to therapeutically effective amounts of 1, therapeutically effective amounts of an anticholinergic (2a) according to one of claims 7 - 15 as well as therapeutic amounts of a PDEIV- inhibitor (2b) according to one of claims 16 and 17, as well as optionally a pharmaceutically acceptable carrier.
25) Medicament combinations according to one of claims 1 to 6, characterised in that they also contain, in addition to therapeutically effective amounts of 1, therapeutically effective amounts of an anticholinergic (2a) according to one of claims 7 -15, as well as therapeutic amounts of a steroid (2c) according to one of claims 18 and 19, as well as optionally a pharmaceutically acceptable carrier.
26) Medicament combinations according to one of claims 1 to 6, characterised in that they also contain, in addition to therapeutically effective amounts of 1, therapeutically effective amounts of an anticholinergic (2a) according to one of claims 7 -15, as well as therapeutic amounts of an LTD4-antagonist (2d) according to one of claims 20 and 21, as well as optionally a pharmaceutically acceptable carrier.
27) Medicament combinations according to one of claims 1 to 6, characterised in that they also contain, in addition to therapeutically effective amounts of 1, therapeutically effective amounts of an anticholinergic (2a) according to one of claims 7 -15, as well as therapeutic amounts of an EGFR-inhibitor (2e) according to one of claims 22 and 23, as well as optionally a pharmaceutically acceptable carrier.
28) Medicament combinations according to one of claims 1 to 6, characterised in that they also contain, in addition to therapeutically effective amounts of 1, therapeutically effective amounts of a PDEIV- inhibitor (2b) according to one of claims 16 and 17, as well as therapeutic amounts of a steroid (2c) according to one of claims 18 and 19, as well as optionally a pharmaceutically acceptable carrier.
29) Medicament combinations according to one of claims 1 to 6, characterised in that they also contain, in addition to therapeutically effective amounts of 1, therapeutically effective amounts of a PDEIV- inhibitor (2b) according to one of claims 16 and 17, as well as therapeutic amounts of an LTD4-antagonist (2d) according to one of claims 20 and 21, as well as optionally a pharmaceutically acceptable carrier.
30) Medicament combinations according to one of claims 1 to 6, characterised in that they also contain, in addition to therapeutically effective amounts of 1, therapeutically effective amounts of a PDEIV- inhibitor (2b) according to one of claims 16 and 17, as well as therapeutic amounts of an EGFR-inhibitor (2e) according to one of claims 22 and 23, as well as optionally a pharmaceutically acceptable carrier.
31) Medicament combinations according to one of claims 1 to 6, characterised in that they also contain, in addition to therapeutically effective amounts of 1, therapeutically effective amounts of a steroid (2c) according to one of claims 18 and 19, as well as therapeutic amounts of an LTD4-antagonist (2d) according to one of claims 20 and 21, as well as optionally a pharmaceutically acceptable carrier.
32) Medicament combinations according to one of claims 1 to 6, characterised in that they also contain, in addition to therapeutically effective amounts of 1, therapeutically effective amounts of a steroid (2c) according to one of claims 18 and 19, as well as therapeutic amounts of an EGFR-inhibitor (2e) according to one of claims 22 and 23, as well as optionally a pharmaceutically acceptable carrier.
33) Medicament combinations according to one of claims 1 to 6, characterised in that they also contain, in addition to therapeutically effective amounts of 1, therapeutically effective amounts of an LTD4-antagonist (2d) according to one of claims 20 and 21, as well as therapeutic amounts of an EGFR-inhibitor (2e) according to one of claims 22 and 23, as well as optionally a pharmaceutically acceptable carrier.
34) Medicament combinations according to one of claims 1 to 33, characterised in that they also contain, in addition to therapeutically effective amounts of 1 and 2, a pharmaceutically acceptable carrier.
35) Medicament combinations according to one of claims 1 to 33, characterised in that they do not contain, in addition to therapeutically effective amounts of 1 and 2, any pharmaceutically acceptable carrier.
36) Pharmaceutical combination according to one of claims 1 to 35, characterised in that it is in the form of a formulation suitable for inhalation.
37) Pharmaceutical combination according to claim 36, characterised in that it is a preparation selected from the group comprising inhalable powders, propellant-driven metered-dose aerosols and propellant-free inhalable solutions or suspensions.
38) Pharmaceutical combination according to claim 37, characterised in that the preparation is an inhalable powder which contains 1 and 2 in admixture with suitable physiologically acceptable excipients selected from the group comprising monosaccharides, disaccharides, oligo- and polysaccharides, polyalcohols, salts, or mixtures of these excipients with one another.
39) Pharmaceutical combination according to claim 37, characterised in that the preparation is a propellant-drive inhalable aerosol which contains 1 and 2 in dissolved or dispersed form.
40) Pharmaceutical combination according to claim 39, characterised in that the inhalable aerosol contains as the propellant gas hydrocarbons such as n-propane, n-butane or isobutane or halohydrocarbons such as chlorinated and/or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
41) Pharmaceutical combination according to claim 40, characterised in that the propellant gas is TG11, TG12, TG134a, TG227 or mixtures thereof, preferably TG134a, TG227 or a mixture thereof.
42) Pharmaceutical combination according to claim 37, characterised in that the preparation is a propellant-free inhalable solution or suspension which contains as solvent water, ethanol or a mixture of water and ethanol.
43) Use of a pharmaceutical combination according to one of claims 1 to 42 for preparing a pharmaceutical composition for the treatment of inflammatory and obstructive respiratory complaints, for inhibiting premature labour in midwifery (tocolysis), for restoring sinus rhythm in the heart in atrioventricular block, for correcting bradycardic heart rhythm disorders (antiarrhythmic), for treating circulatory shock (vasodilatation and increasing the heart volume) as well as for the treatment of skin irritations and inflammation.
44) Use according to claim 43, for preparing a pharmaceutical composition for the treatment of respiratory complaints selected from the group comprising obstructive pulmonary diseases of various origins, pulmonary emphysema of various origins, restrictive pulmonary diseases, interstitial pulmonary diseases, cystic fibrosis, bronchitis of various origins, bronchiectasis, ARDS (adult respiratory distress syndrome) and all forms of pulmonary oedema.
45) Use according to claim 44, for preparing a pharmaceutical composition for the treatment of obstructive pulmonary diseases selected from among bronchial asthma, paediatric asthma, severe asthma, acute asthma attacks, chronic bronchitis and COPD
(chronic obstructive pulmonary disease), while it is particularly preferable according to the invention to use them for preparing a pharmaceutical composition for the treatment of bronchial asthma and COPD.
46) Use according to claim 44, for preparing a pharmaceutical composition for the treatment of pulmonary emphysema which has its origins in COPD or .alpha.1-proteinase inhibitor deficiency.
47) Use according to claim 44, for preparing a pharmaceutical composition for the treatment of restrictive pulmonary diseases selected from among allergic alveolitis, restrictive pulmonary diseases triggered by work-related noxious substances, such as asbestosis or silicosis, and restriction caused by lung tumours, such as for example lymphangiosis carcinomatosa, bronchoalveolar carcinoma and lymphomas.
48) Use according to claim 44, for preparing a pharmaceutical composition for the treatment of interstitial pulmonary diseases selected from among pneumonia caused by infections, such as for example infection by viruses, bacteria, fungi, protozoa, helminths or other pathogens, pneumonitis caused by various factors, such as for example aspiration and left heart insufficiency, radiation-induced pneumonitis or fibrosis, collagenoses, such as for example lupus erythematodes, systemic sclerodermy or sarcoidosis, granulomatoses, such as for example Boeck's disease, idiopathic interstitial pneumonia or idiopathic pulmonary fibrosis (IPF).
49) Use according to claim 44, for preparing a pharmaceutical composition for the treatment of cystic fibrosis or mucoviscidosis.
50) Use according to claim 44, for preparing a pharmaceutical composition for the treatment of bronchitis, such as bronchitis caused by bacterial or viral infection, allergic bronchitis and toxic bronchitis.
51) Use according to claim 44, for preparing a pharmaceutical composition for the treatment of bronchiectasis.
52) Use according to claim 44, for preparing a pharmaceutical composition for the treatment of ARDS (adult respiratory distress syndrome).
53) Use according to claim 44, for preparing a pharmaceutical composition for the treatment of pulmonary oedema.
CA2559699A 2004-04-22 2005-04-18 Pharmaceutical combinations containing benzoxazine for treating respiratory diseases Expired - Fee Related CA2559699C (en)

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DE102004019540.4 2004-04-22
DE102004019540A DE102004019540A1 (en) 2004-04-22 2004-04-22 Composition, useful for treatment of e.g. inflammatory and obstructive respiratory complaint, sinus rhythm in heart in atrioventricular block and circulatory shock, comprises 6-hydroxy-4H-benzo1,4oxazin-3-one derivatives and other actives
DE102004052987.6 2004-11-03
DE102004052987A DE102004052987A1 (en) 2004-11-03 2004-11-03 Composition, useful for treatment of e.g. inflammatory and obstructive respiratory complaint, sinus rhythm in heart in atrioventricular block and circulatory shock, comprises 6-hydroxy-4H-benzo1,4oxazin-3-one derivatives and other actives
EP05002496.7 2005-02-07
EP05002496 2005-02-07
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