CA2543649A1 - Use of tyrosine kinase inhibitors for the treatment of inflammatory processes - Google Patents
Use of tyrosine kinase inhibitors for the treatment of inflammatory processes Download PDFInfo
- Publication number
- CA2543649A1 CA2543649A1 CA002543649A CA2543649A CA2543649A1 CA 2543649 A1 CA2543649 A1 CA 2543649A1 CA 002543649 A CA002543649 A CA 002543649A CA 2543649 A CA2543649 A CA 2543649A CA 2543649 A1 CA2543649 A1 CA 2543649A1
- Authority
- CA
- Canada
- Prior art keywords
- amino
- quinazoline
- yloxy
- phenyl
- methoxy
- 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.)
- Abandoned
Links
- 230000004054 inflammatory process Effects 0.000 title description 2
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 title description 2
- 239000005483 tyrosine kinase inhibitor Substances 0.000 title description 2
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 201000010099 disease Diseases 0.000 claims abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
- 210000004072 lung Anatomy 0.000 claims abstract description 11
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 7
- 150000007524 organic acids Chemical class 0.000 claims abstract description 7
- 235000005985 organic acids Nutrition 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims abstract 2
- -1 3-chloro-4-fluoro-phenyl Chemical group 0.000 claims description 29
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 9
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 8
- 208000006673 asthma Diseases 0.000 claims description 8
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 8
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 230000002757 inflammatory effect Effects 0.000 claims description 6
- 210000000936 intestine Anatomy 0.000 claims description 6
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 5
- 208000011231 Crohn disease Diseases 0.000 claims description 5
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 5
- 208000015768 polyposis Diseases 0.000 claims description 5
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- PDOSWZJDBOBQAN-BGYRXZFFSA-N C=12C=C(O[C@@H]3CC[C@@H](CC3)N(C)C(=O)N3CCN(C)CC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 Chemical compound C=12C=C(O[C@@H]3CC[C@@H](CC3)N(C)C(=O)N3CCN(C)CC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 PDOSWZJDBOBQAN-BGYRXZFFSA-N 0.000 claims description 4
- 206010057030 Pneumatosis intestinalis Diseases 0.000 claims description 4
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims description 4
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims description 4
- 206010056626 Pseudopolyp Diseases 0.000 claims description 4
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- KJGKVANCDSTYDH-UHFFFAOYSA-N 4-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]oxy-n-(3-methoxypropyl)piperidine-1-carboxamide Chemical compound C1CN(C(=O)NCCCOC)CCC1OC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=C(F)C(Cl)=C1 KJGKVANCDSTYDH-UHFFFAOYSA-N 0.000 claims description 3
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- 206010009137 Chronic sinusitis Diseases 0.000 claims description 3
- HGQSWGUVSJUFJD-UHFFFAOYSA-N [4-[4-(3-chloro-4-fluoroanilino)-7-(2-methoxyethoxy)quinazolin-6-yl]oxypiperidin-1-yl]-morpholin-4-ylmethanone Chemical compound C=12C=C(OC3CCN(CC3)C(=O)N3CCOCC3)C(OCCOC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 HGQSWGUVSJUFJD-UHFFFAOYSA-N 0.000 claims description 3
- SVUDIFNZJPBCOX-WMZOPIPTSA-N [4-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]-[(1s,4s)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]methanone Chemical compound C([C@]1(OC[C@]2([H])C1)[H])N2C(=O)N(CC1)CCC1OC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=C(F)C(Cl)=C1 SVUDIFNZJPBCOX-WMZOPIPTSA-N 0.000 claims description 3
- GCFQYHBVQUQWIX-UHFFFAOYSA-N [4-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]-piperidin-1-ylmethanone Chemical compound C=12C=C(OC3CCN(CC3)C(=O)N3CCCCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 GCFQYHBVQUQWIX-UHFFFAOYSA-N 0.000 claims description 3
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- 208000027157 chronic rhinosinusitis Diseases 0.000 claims description 3
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- 239000003381 stabilizer Substances 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Classifications
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A—HUMAN NECESSITIES
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- 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
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- 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
- A61P11/02—Nasal agents, e.g. decongestants
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- 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]
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- 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
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Abstract
The invention relates to the use of selected quinazoline, tautomers thereof, stereoisomers and salts thereof, particularly physiologically compatible salts thereof having inorganic or organic acids or bases, for the production of a medicament in order to prevent or treat diseases of the respiratory tracts or lungs, in addition to other inflammatory diseases.
Description
Boehringer Ingelheim International GmbH Case 1/1576-Ro D-55216 INGELHEIM foreign filing text 85563fft Use of tyrosine kinase inhibitors for the treatment of inflammatory processes The present invention relates to the use of quinazolines selected from the group comprising (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, (2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (3) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (4) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline, (5) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, (6) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy)-7-methoxy-quinazoline, (7) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, (8) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline, (9) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, (10) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline, (11) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline, (12) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, (13) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{traps-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, (14) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{traps-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, (15) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{traps-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (16) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-2o acetylamino-ethoxy)-quinazoline, (17) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline, (18) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, (19) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline, (20) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (21 ) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-ami no}-cycl ohexan-1-yloxy)-7-methoxy-q uinazol i ne, (22) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-ami no}-cyclohexan-1-yloxy)-7-methoxy-q uinazol i ne, (23) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (24) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline, (25) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, (26) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline, (27) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-2o methoxy-quinazoline, (28) 4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, (29) 4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline, (30) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (31) 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, (32) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, (33) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, (34) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-y1 oxy}-7-(2-meth oxy-ethoxy)-q a i nazol i ne, (35) 4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline, (36) 4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-rnethoxy-quinazoline, (37) 4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-1 s methoxy-quinazoline, (38) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, (39) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, (40) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (41) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, (42) 4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline, (43) 4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, (44) 4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, (45) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-((cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, (46) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, (47) 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, (48) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, (49) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline, (50) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-2o yloxy}-7-methoxy-quinazoline and (51) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, the tautomers, stereoisomers and salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, for preparing a pharmaceutical composition for the prevention and treatment of diseases of the airways and lungs which are accompanied by increased or altered so production of mucus, e.g. in inflammatory diseases of the airways such as acute bronchitis, chronic bronchitis, chronic obstructive bronchitis (COPD), asthma, bronchiectasias, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, a1-antitrypsin deficiency, or coughs, pulmonary emphysema, pulmonary fibrosis or hyperreactive airways.
The compounds are also suitable for treating inflammatory diseases of the gastrointestinal tract or bile duct and gall bladder which are associated with disrupted activity of the tyrosine kinases, such as may be found e.g. in acute or chronic s inflammatory changes such as cholecystitis, Crohn's disease, ulcerative colitis, and ulcers or polyposis in the gastrointestinal tract or such as may occur in diseases of the gastrointestinal tract which are associated with increased secretions, such as Menetrier's disease, secreting adenomas or protein loss syndromes, ~o and also for treating inflammatory diseases of the joints, such as rheumatoid arthritis, inflammatory diseases of the skin, the eyes, in inflammatory pseudopolyps, in colitis cystica profunda or pneumatosis cystoides intestinalis.
Preferred fields of application are inflammatory diseases of the respiratory organs or of the intestine, such as chronic bronchitis (COPD), chronic sinusitis, asthma, Crohn's disease, ulcerative colitis or polyposis of the intestines.
Particularly preferred fields of application are inflammatory diseases of the airways or lungs such as chronic bronchitis (COPD) or asthma.
zo The present invention further relates to a process for treating diseases of the airways and lungs which are accompanied by increased or altered production of mucus, e.g. in inflammatory diseases of the airways such as acute 2s bronchitis, chronic bronchitis, chronic obstructive bronchitis (COPD), asthma, bronchiectasias, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, a1-antitrypsin deficiency, or coughs, pulmonary emphysema, pulmonary fibrosis and hyperreactive airways, 3o for treating inflammatory diseases of the gastrointestinal tract and bile duct and gall bladder which are associated with disrupted activity of the tyrosine kinases, such as may be found e.g. in acute or chronic inflammatory changes such as cholecystitis, Crohn's disease, ulcerative colitis and ulcers or polyposis in the gastrointestinal tract or such as may occur in diseases of the gastrointestinal tract which are associated _7_ with increased secretions, such as Menetrier's disease, secreting adenomas and protein loss syndromes, and also for treating inflammatory diseases of the joints, such as rheumatoid arthritis, inflammatory diseases of the skin, the eyes, in inflammatory pseudopolyps, in colitis cystica profunda and pneumatosis cystoides intestinalis, comprising administering an effective amount of one or more of the above-mentioned compounds (1 ) to (8) or optionally one of the physiologically acceptable salts thereof 1o to a patient requiring such treatment.
In the process according to the invention the above-mentioned compounds are used in doses from 0.001-10 mg/kg body weight, preferably 0.01-1.5 mg/kg, expediently administered 1 to 3 times a day.
The active substances may be administered by oral, buccal or parenteral route, by atomisation for inhalation, rectally or topically. They may be administered parenterally by subcutaneous, intravenous and intramuscular injections and infusion techniques.
2o Conventional formulations may be used for administering them, such as the formulations mentioned above with regard to the active substances. For example, the active substances may be formulated, optionally together with other active substances, with one or more inert conventional carriers and/or diluents, e.g.
with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, cetyl stearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.
The active substances may be given orally in a variety of different dosage forms, i.e.
they may be prepared with various pharmaceutically acceptable inert carriers to form tablets, capsules, pastilles, lozenges, sweets, powders, sprays, aqueous suspensions, elixirs, syrups and the like. Such carriers include solid diluents or fillers, _$_ sterile aqueous media and various non-toxic organic solvents. In addition, oral pharmaceutical preparations of this kind may be suitably sweetened or flavoured, using various agents conventionally used for this purpose. In general the active substances are present in oral formulations of this kind in concentrations ranging from about 0.5 to about 90 wt.%, based on the total composition, in amounts sufficient to produce the desired dosage units. Other suitable dosage forms for the active substances include preparations and devices with controlled release, with which the skilled man will be familiar.
~o For parenteral administration solutions of the active substances in sesame or groundnut oil or in aqueous propyleneglycol as well as sterile aqueous solutions of the corresponding pharmaceutically acceptable salts may be used. Aqueous solutions of this kind should be suitably buffered as necessary and the liquid diluent may optionally be made isotonic with sufficient salt or glucose. These specific ~s aqueous solutions are particularly suitable for intravenous, intramuscular and subcutaneous injection. In this context, the sterile aqueous media used may easily be obtained by conventional methods well known to the skilled man. For example, distilled water is normally used as a liquid diluent, and the finished preparation is passed through a suitable bacterial filter, e.g. a filter made of sintered glass, 2o kieselguhr or unglazed porcelain. Preferred filters of this type include Berkefeld, Chamberland and asbestos disc metal Seitz filters, the liquid being aspirated into a sterile container using a suction pump. Throughout the entire process of preparing these injectable solutions the necessary steps should always be carried out in such a way as to obtain the end products in a sterile state. For transdermal administration 2s the formulations of the particular compound or compounds include for example solutions, lotions, ointments, creams, gels, suppositories, formulations for long-lasting speed-limited release preparations and devices therefor. These formulations comprise the particular compounds) and may contain ethanol, water, penetration promoters and inert carriers, e.g. gel-forming materials, mineral oil, emulsifiers, so benzyl alcohol and the like.
The substances may be administered by inhalation in the form of powder formulations with lactose and other excipients or in the form of aqueous solutions as an aerosol.
_g_ The inhalable powders which may be used according to the invention may contain the active substance or combination of active substances either on its own or in admixture with suitable physiologically acceptable excipients. If the active substance or combination of active substances is present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients may be used to prepare these inhalable powders according to the invention:
monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g. dextran), polyalcohols (e.g.
1o sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients with one another. Preferably, mono- or disaccharides are used, while the use of lactose or glucose is preferred, particularly, but not exclusively, in the form of their hydrates. For the purposes of the invention, lactose is the particularly preferred excipient, while lactose monohydrate is most particularly preferred.
Inhalation aerosols containing propellant gas which may be used according to the invention may contain the active substance or combination of active substances dissolved in the propellant gas or in dispersed form. The propellant gases which may be used to prepare the inhalation aerosols according to the invention are known from 2o the prior art. Suitable propellant gases are selected from among 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 propellant gases mentioned above may be used on their own or in mixtures thereof. Particularly preferred propellant gases are fluorinated alkane derivatives selected from TG134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof.
The propellant-driven inhalation aerosols which may be used according to the invention may also contain other ingredients such as co-solvents, stabilisers, surface-3o active agents (surfactants), antioxidants, lubricants and pH adjusters. All these ingredients are known in the art, If the active substance or combination of active substances according to the invention is administered by inhalation in the form of propellant-free solutions or suspensions, aqueous or alcoholic, preferably ethanolic solutions may be used as the solvent. The solvent may be exclusively water or a mixture of water and ethanol.
The relative proportion of ethanol to water is not restricted, but the maximum limit is up to 70 percent by volume, more particularly up to 60 percent by volume and most preferably up to 30 percent by volume. The remainder of the volume is made up of water. The solutions or suspensions containing the active substance or combination of active substances are optionally adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. The pH may be adjusted using acids selected from inorganic or organic acids. Examples of particularly suitable inorganic acids include hydrochloric 1o acid, hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid.
Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, malefic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid etc. Preferred inorganic acids are hydrochloric acid and sulphuric acid. Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If desired, mixtures of the above acids may also be used, particularly in the case of acids which have other properties in addition to their acidifying qualities, e.g. as flavourings, antioxidants or complexing agents, such as citric acid or ascorbic acid, for example. According to the invention, it is particularly preferred to use hydrochloric acid to adjust the pH.
As already mentioned hereinbefore, the compounds of general formula (I) and the salts thereof have valuable properties, particularly an anti-inflammatory activity.
For example, the compounds (A) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, (B) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-so yloxy}-7-methoxy-quinazoline, (C) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, (D) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (E) 4-((3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (F) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (G) 4-((3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, (H) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (I) 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, (K) 4-[(3-chloro-4-fluoro-phenyl)aminoJ-6-{cis-4-[(morpholin-4-yl)carbonylamino]-2o cyclohexan-1-yloxy}-7-methoxy-quinazoline, (L) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline and (M) 4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline were tested as follows to investigate their anti-inflammatory activity:
Test 1: Inhibition of the smoke-induced accumulation of granulocytes in the lung tissue Luna indications: Inhibition of the cigarette smoke-induced influx of neutrophilic granulocytes into the lung tissue by the above-mentioned EGF-receptor kinase inhibitor.
Method:
1o Male rats (strain: Sprague-Dawley) weighing from 250-300 g were exposed for days to the smoke from 8 cigarettes per day. The animals in the group treated with compound A, anaesthetised with isofluran, were given an intratracheal dose of 0.03 or 0.1 mg/kg of compound A in a volume of 0.05 ml each day 30 min before the start of the exposure to smoke. On the last day of the test the animals were killed 4 hours 1 s after the last exposure to smoke and the lung tissue was removed. A sample of 70 -200 mg was taken from each lung and placed in a test tube prepared with 1 ml of 0.5% hexadecyltrimethylammonium bromide. The samples were homogenised for 15 sec using an Ultraturrax. The homogenised samples were centrifuged at 15700 g in an Eppendorf bench centrifuge for 5 min at ambient temperature. 50 ml of the 2o supernatant was removed and mixed with 250 ml of phosphate buffer (50mmolll) containing 0.197 mg/ml of O-dianisidine dihydrochloride. After 10 minutes' incubation at ambient temperature the absorption was measured with a spectral photometer at a wavelength of 450 nm.
The dosage which led to a 50% inhibition of the MPO activity (= ID50) was z5 determined by linear regression.
Results:
Exposure to cigarette smoke in rats led to an influx of neutrophilic granulocytes into the lung tissue, measured by the content of myeloperoxidase in the tissues, which is so specific for neutrophilic granulocytes. Intratracheal treatment of the animals with the EGFR kinase inhibitor A resulted in a significant (p<0.005) inhibition of the smoke-induced accumulation of granulocytes and thus produced an anti-inflammatory activity.
Further results are shown in the following Table:
active substanceID50 [mg/kg]
A 0.100 B 0.010 C 0.030 D 0.020 E 0.400 F 0.015 G 0.010 H 0.150 I 0.150 K 0.130 L 0.400 M 0.070
The compounds are also suitable for treating inflammatory diseases of the gastrointestinal tract or bile duct and gall bladder which are associated with disrupted activity of the tyrosine kinases, such as may be found e.g. in acute or chronic s inflammatory changes such as cholecystitis, Crohn's disease, ulcerative colitis, and ulcers or polyposis in the gastrointestinal tract or such as may occur in diseases of the gastrointestinal tract which are associated with increased secretions, such as Menetrier's disease, secreting adenomas or protein loss syndromes, ~o and also for treating inflammatory diseases of the joints, such as rheumatoid arthritis, inflammatory diseases of the skin, the eyes, in inflammatory pseudopolyps, in colitis cystica profunda or pneumatosis cystoides intestinalis.
Preferred fields of application are inflammatory diseases of the respiratory organs or of the intestine, such as chronic bronchitis (COPD), chronic sinusitis, asthma, Crohn's disease, ulcerative colitis or polyposis of the intestines.
Particularly preferred fields of application are inflammatory diseases of the airways or lungs such as chronic bronchitis (COPD) or asthma.
zo The present invention further relates to a process for treating diseases of the airways and lungs which are accompanied by increased or altered production of mucus, e.g. in inflammatory diseases of the airways such as acute 2s bronchitis, chronic bronchitis, chronic obstructive bronchitis (COPD), asthma, bronchiectasias, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, a1-antitrypsin deficiency, or coughs, pulmonary emphysema, pulmonary fibrosis and hyperreactive airways, 3o for treating inflammatory diseases of the gastrointestinal tract and bile duct and gall bladder which are associated with disrupted activity of the tyrosine kinases, such as may be found e.g. in acute or chronic inflammatory changes such as cholecystitis, Crohn's disease, ulcerative colitis and ulcers or polyposis in the gastrointestinal tract or such as may occur in diseases of the gastrointestinal tract which are associated _7_ with increased secretions, such as Menetrier's disease, secreting adenomas and protein loss syndromes, and also for treating inflammatory diseases of the joints, such as rheumatoid arthritis, inflammatory diseases of the skin, the eyes, in inflammatory pseudopolyps, in colitis cystica profunda and pneumatosis cystoides intestinalis, comprising administering an effective amount of one or more of the above-mentioned compounds (1 ) to (8) or optionally one of the physiologically acceptable salts thereof 1o to a patient requiring such treatment.
In the process according to the invention the above-mentioned compounds are used in doses from 0.001-10 mg/kg body weight, preferably 0.01-1.5 mg/kg, expediently administered 1 to 3 times a day.
The active substances may be administered by oral, buccal or parenteral route, by atomisation for inhalation, rectally or topically. They may be administered parenterally by subcutaneous, intravenous and intramuscular injections and infusion techniques.
2o Conventional formulations may be used for administering them, such as the formulations mentioned above with regard to the active substances. For example, the active substances may be formulated, optionally together with other active substances, with one or more inert conventional carriers and/or diluents, e.g.
with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, cetyl stearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.
The active substances may be given orally in a variety of different dosage forms, i.e.
they may be prepared with various pharmaceutically acceptable inert carriers to form tablets, capsules, pastilles, lozenges, sweets, powders, sprays, aqueous suspensions, elixirs, syrups and the like. Such carriers include solid diluents or fillers, _$_ sterile aqueous media and various non-toxic organic solvents. In addition, oral pharmaceutical preparations of this kind may be suitably sweetened or flavoured, using various agents conventionally used for this purpose. In general the active substances are present in oral formulations of this kind in concentrations ranging from about 0.5 to about 90 wt.%, based on the total composition, in amounts sufficient to produce the desired dosage units. Other suitable dosage forms for the active substances include preparations and devices with controlled release, with which the skilled man will be familiar.
~o For parenteral administration solutions of the active substances in sesame or groundnut oil or in aqueous propyleneglycol as well as sterile aqueous solutions of the corresponding pharmaceutically acceptable salts may be used. Aqueous solutions of this kind should be suitably buffered as necessary and the liquid diluent may optionally be made isotonic with sufficient salt or glucose. These specific ~s aqueous solutions are particularly suitable for intravenous, intramuscular and subcutaneous injection. In this context, the sterile aqueous media used may easily be obtained by conventional methods well known to the skilled man. For example, distilled water is normally used as a liquid diluent, and the finished preparation is passed through a suitable bacterial filter, e.g. a filter made of sintered glass, 2o kieselguhr or unglazed porcelain. Preferred filters of this type include Berkefeld, Chamberland and asbestos disc metal Seitz filters, the liquid being aspirated into a sterile container using a suction pump. Throughout the entire process of preparing these injectable solutions the necessary steps should always be carried out in such a way as to obtain the end products in a sterile state. For transdermal administration 2s the formulations of the particular compound or compounds include for example solutions, lotions, ointments, creams, gels, suppositories, formulations for long-lasting speed-limited release preparations and devices therefor. These formulations comprise the particular compounds) and may contain ethanol, water, penetration promoters and inert carriers, e.g. gel-forming materials, mineral oil, emulsifiers, so benzyl alcohol and the like.
The substances may be administered by inhalation in the form of powder formulations with lactose and other excipients or in the form of aqueous solutions as an aerosol.
_g_ The inhalable powders which may be used according to the invention may contain the active substance or combination of active substances either on its own or in admixture with suitable physiologically acceptable excipients. If the active substance or combination of active substances is present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients may be used to prepare these inhalable powders according to the invention:
monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g. dextran), polyalcohols (e.g.
1o sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients with one another. Preferably, mono- or disaccharides are used, while the use of lactose or glucose is preferred, particularly, but not exclusively, in the form of their hydrates. For the purposes of the invention, lactose is the particularly preferred excipient, while lactose monohydrate is most particularly preferred.
Inhalation aerosols containing propellant gas which may be used according to the invention may contain the active substance or combination of active substances dissolved in the propellant gas or in dispersed form. The propellant gases which may be used to prepare the inhalation aerosols according to the invention are known from 2o the prior art. Suitable propellant gases are selected from among 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 propellant gases mentioned above may be used on their own or in mixtures thereof. Particularly preferred propellant gases are fluorinated alkane derivatives selected from TG134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof.
The propellant-driven inhalation aerosols which may be used according to the invention may also contain other ingredients such as co-solvents, stabilisers, surface-3o active agents (surfactants), antioxidants, lubricants and pH adjusters. All these ingredients are known in the art, If the active substance or combination of active substances according to the invention is administered by inhalation in the form of propellant-free solutions or suspensions, aqueous or alcoholic, preferably ethanolic solutions may be used as the solvent. The solvent may be exclusively water or a mixture of water and ethanol.
The relative proportion of ethanol to water is not restricted, but the maximum limit is up to 70 percent by volume, more particularly up to 60 percent by volume and most preferably up to 30 percent by volume. The remainder of the volume is made up of water. The solutions or suspensions containing the active substance or combination of active substances are optionally adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. The pH may be adjusted using acids selected from inorganic or organic acids. Examples of particularly suitable inorganic acids include hydrochloric 1o acid, hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid.
Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, malefic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid etc. Preferred inorganic acids are hydrochloric acid and sulphuric acid. Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If desired, mixtures of the above acids may also be used, particularly in the case of acids which have other properties in addition to their acidifying qualities, e.g. as flavourings, antioxidants or complexing agents, such as citric acid or ascorbic acid, for example. According to the invention, it is particularly preferred to use hydrochloric acid to adjust the pH.
As already mentioned hereinbefore, the compounds of general formula (I) and the salts thereof have valuable properties, particularly an anti-inflammatory activity.
For example, the compounds (A) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, (B) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-so yloxy}-7-methoxy-quinazoline, (C) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, (D) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (E) 4-((3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (F) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (G) 4-((3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, (H) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (I) 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, (K) 4-[(3-chloro-4-fluoro-phenyl)aminoJ-6-{cis-4-[(morpholin-4-yl)carbonylamino]-2o cyclohexan-1-yloxy}-7-methoxy-quinazoline, (L) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline and (M) 4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline were tested as follows to investigate their anti-inflammatory activity:
Test 1: Inhibition of the smoke-induced accumulation of granulocytes in the lung tissue Luna indications: Inhibition of the cigarette smoke-induced influx of neutrophilic granulocytes into the lung tissue by the above-mentioned EGF-receptor kinase inhibitor.
Method:
1o Male rats (strain: Sprague-Dawley) weighing from 250-300 g were exposed for days to the smoke from 8 cigarettes per day. The animals in the group treated with compound A, anaesthetised with isofluran, were given an intratracheal dose of 0.03 or 0.1 mg/kg of compound A in a volume of 0.05 ml each day 30 min before the start of the exposure to smoke. On the last day of the test the animals were killed 4 hours 1 s after the last exposure to smoke and the lung tissue was removed. A sample of 70 -200 mg was taken from each lung and placed in a test tube prepared with 1 ml of 0.5% hexadecyltrimethylammonium bromide. The samples were homogenised for 15 sec using an Ultraturrax. The homogenised samples were centrifuged at 15700 g in an Eppendorf bench centrifuge for 5 min at ambient temperature. 50 ml of the 2o supernatant was removed and mixed with 250 ml of phosphate buffer (50mmolll) containing 0.197 mg/ml of O-dianisidine dihydrochloride. After 10 minutes' incubation at ambient temperature the absorption was measured with a spectral photometer at a wavelength of 450 nm.
The dosage which led to a 50% inhibition of the MPO activity (= ID50) was z5 determined by linear regression.
Results:
Exposure to cigarette smoke in rats led to an influx of neutrophilic granulocytes into the lung tissue, measured by the content of myeloperoxidase in the tissues, which is so specific for neutrophilic granulocytes. Intratracheal treatment of the animals with the EGFR kinase inhibitor A resulted in a significant (p<0.005) inhibition of the smoke-induced accumulation of granulocytes and thus produced an anti-inflammatory activity.
Further results are shown in the following Table:
active substanceID50 [mg/kg]
A 0.100 B 0.010 C 0.030 D 0.020 E 0.400 F 0.015 G 0.010 H 0.150 I 0.150 K 0.130 L 0.400 M 0.070
Claims (8)
1. Use of quinazolines selected from the group comprising (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, (2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (3) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (4) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline, (5) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, (6) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, (7) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, (8) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline, (9) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, (10) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline, (11) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline, (12) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, (13) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, (14) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, (15) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, (16) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline, (17) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline, (18) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, (19) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline, (20) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (21) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (22) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (23) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (24) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline, (25) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, (26) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline, (27) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (28) 4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, (29) 4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline, (30) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (31) 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, (32) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, (33) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, (34) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline, (35) 4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline, (36) 4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, (37) 4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, (38) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, (39) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, (40) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (41 ) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, (42) 4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline, (43) 4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, (44) 4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, (45) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, (46) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, (47) 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, (48) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, (49) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline, (50) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline and (51) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, the tautomers, stereoisomers and salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, for preparing a pharmaceutical composition for the prevention and treatment of diseases of the airways or lungs which are accompanied by increased or altered production of mucus, inflammatory diseases of the gastrointestinal tract or bile duct or gall bladder which are associated with disrupted activity of the tyrosine kinases, inflammatory diseases of the joints, inflammatory diseases of the skin, the eyes, inflammatory pseudopolyps, colitis cystica profunda or pneumatosis cystoides intestinalis.
2. Use according to claim 1, characterised in that it is a treatment of the upper and lower respiratory organs or of the intestines.
3. Use according to claim 2, characterised in that the diseases are COPD, chronic sinusitis, asthma, cystic fibrosis, Crohn's disease, ulcerative colitis or polyposis of the intestine.
4. Use according to claim 3, characterised in that the diseases are COPD, asthma or cystic fibrosis.
5. Method of treating diseases of the airways and lungs which are accompanied by increased or altered production of mucus, inflammatory diseases of the gastrointestinal tract or bile duct or gall bladder which are associated with disrupted activity of the tyrosine kinases, inflammatory diseases of the joints, inflammatory diseases of the skin, the eyes, inflammatory pseudopolyps, colitis cystica profunda or pneumatosis cystoides intestinalis, comprising administering an effective amount of a quinazoline selected from the group consisting of (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, (2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (3) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (4) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline, (5) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, (6) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, (7) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, (8) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline, (9) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, (10) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline, (11) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline, (12) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, (13) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, (14) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, (15) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, (16) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline, (17) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline, (18) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, (19) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline, (20) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (21) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (22) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (23) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (24) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline, (25) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, (26) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline, (27) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (28) 4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, (29) 4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline, (30) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (31) 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, (32) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, (33) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, (34) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline, (35) 4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline, (36) 4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, (37) 4-((3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, (38) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, (39) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, (40) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (41) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, (42) 4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline, (43) 4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, (44) 4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, (45) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, (46) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-((2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, (47) 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, (48) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, (49) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline, (50) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline and (51) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, the tautomers, stereoisomers and salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, to a patient requiring such treatment.
6. Method according to claim 5, characterised in that it is a treatment of the upper and lower respiratory organs or of the intestines.
7. Method according to claim 6, characterised in that the diseases are COPD, chronic sinusitis, asthma, cystic fibrosis, Crohn's disease, ulcerative colitis or polyposis of the intestine.
8. Method according to claim 7, characterised in that the diseases are COPD, asthma or cystic fibrosis.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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DE10350717.5 | 2003-10-30 | ||
DE10350717A DE10350717A1 (en) | 2003-10-30 | 2003-10-30 | Use of tyrosine kinase inhibitors for the treatment of inflammatory processes |
PCT/EP2004/011989 WO2005041973A1 (en) | 2003-10-30 | 2004-10-23 | Use of tyrosine kinase inhibitors for the treatment of inflammatory processes |
Publications (1)
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CA2543649A1 true CA2543649A1 (en) | 2005-05-12 |
Family
ID=34529925
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CA002543649A Abandoned CA2543649A1 (en) | 2003-10-30 | 2004-10-23 | Use of tyrosine kinase inhibitors for the treatment of inflammatory processes |
Country Status (6)
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EP (1) | EP1682147B1 (en) |
JP (1) | JP2007509875A (en) |
AT (1) | ATE444754T1 (en) |
CA (1) | CA2543649A1 (en) |
DE (2) | DE10350717A1 (en) |
WO (1) | WO2005041973A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7625908B2 (en) | 2003-11-13 | 2009-12-01 | Astrazeneca Ab | Quinazoline derivatives |
US7820683B2 (en) | 2005-09-20 | 2010-10-26 | Astrazeneca Ab | 4-(1H-indazol-5-yl-amino)-quinazoline compounds as erbB receptor tyrosine kinase inhibitors for the treatment of cancer |
US7947676B2 (en) | 2004-12-14 | 2011-05-24 | Astrazeneca Ab | Pyrazolo[3,4-d]pyrimidine compounds as antitumor agents |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
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US6924285B2 (en) | 2002-03-30 | 2005-08-02 | Boehringer Ingelheim Pharma Gmbh & Co. | Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them |
BRPI0607358A2 (en) * | 2005-02-04 | 2009-09-01 | Boeringer Ingelheim Internat Gmbh | use of tyrosine kinase inhibitors for the treatment of chronic rhinosinusitis as well as |
EP1921070A1 (en) | 2006-11-10 | 2008-05-14 | Boehringer Ingelheim Pharma GmbH & Co. KG | Bicyclic heterocycles, medicaments comprising them, their use and process for their preparation |
JP5377332B2 (en) | 2007-02-06 | 2013-12-25 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Bicyclic heterocycles, drugs containing these compounds, their use and their preparation |
PL2245026T3 (en) | 2008-02-07 | 2013-01-31 | Boehringer Ingelheim Int | Spirocyclic heterocycles, medicaments containing said compounds, use thereof and method for their production |
CA2733153C (en) | 2008-08-08 | 2016-11-08 | Boehringer Ingelheim International Gmbh | Cyclohexyloxy substituted heterocycles, pharmaceutical compositions containing these compounds and processes for preparing them |
Family Cites Families (4)
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US6797706B1 (en) * | 1999-06-09 | 2004-09-28 | Yamanouchi Pharmaceutical Co., Ltd. | Heterocyclecarboxamide derivative |
DE10042059A1 (en) * | 2000-08-26 | 2002-03-07 | Boehringer Ingelheim Pharma | Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation |
DE10042058A1 (en) * | 2000-08-26 | 2002-03-07 | Boehringer Ingelheim Pharma | Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation |
IL164167A0 (en) * | 2002-03-30 | 2005-12-18 | Boehringer Ingelheim Pharma | 4-(N-phenylamino)-quinazolines/ quinolines as tyrosine kinase inhibitors |
-
2003
- 2003-10-30 DE DE10350717A patent/DE10350717A1/en not_active Withdrawn
-
2004
- 2004-10-23 JP JP2006537144A patent/JP2007509875A/en active Pending
- 2004-10-23 WO PCT/EP2004/011989 patent/WO2005041973A1/en active Application Filing
- 2004-10-23 DE DE502004010212T patent/DE502004010212D1/en not_active Expired - Fee Related
- 2004-10-23 CA CA002543649A patent/CA2543649A1/en not_active Abandoned
- 2004-10-23 AT AT04790780T patent/ATE444754T1/en not_active IP Right Cessation
- 2004-10-23 EP EP04790780A patent/EP1682147B1/en not_active Not-in-force
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7625908B2 (en) | 2003-11-13 | 2009-12-01 | Astrazeneca Ab | Quinazoline derivatives |
US7947676B2 (en) | 2004-12-14 | 2011-05-24 | Astrazeneca Ab | Pyrazolo[3,4-d]pyrimidine compounds as antitumor agents |
US7820683B2 (en) | 2005-09-20 | 2010-10-26 | Astrazeneca Ab | 4-(1H-indazol-5-yl-amino)-quinazoline compounds as erbB receptor tyrosine kinase inhibitors for the treatment of cancer |
Also Published As
Publication number | Publication date |
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EP1682147A1 (en) | 2006-07-26 |
JP2007509875A (en) | 2007-04-19 |
WO2005041973A1 (en) | 2005-05-12 |
DE502004010212D1 (en) | 2009-11-19 |
DE10350717A1 (en) | 2005-06-02 |
ATE444754T1 (en) | 2009-10-15 |
EP1682147B1 (en) | 2009-10-07 |
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