WO2006082129A1 - Verwendung von tyrosinkinase-inhibitoren zur behandlung der chronischen rhinosinusitis - Google Patents
Verwendung von tyrosinkinase-inhibitoren zur behandlung der chronischen rhinosinusitis Download PDFInfo
- Publication number
- WO2006082129A1 WO2006082129A1 PCT/EP2006/050215 EP2006050215W WO2006082129A1 WO 2006082129 A1 WO2006082129 A1 WO 2006082129A1 EP 2006050215 W EP2006050215 W EP 2006050215W WO 2006082129 A1 WO2006082129 A1 WO 2006082129A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- amino
- quinazoline
- chloro
- phenyl
- fluoro
- Prior art date
Links
Classifications
-
- 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
-
- 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
- A61P11/02—Nasal agents, e.g. decongestants
Definitions
- the present invention is the use of selected EGf-R kinase inhibitors, in particular selected quinazolines, quinolines and pyrimido-pyrimidines, for the preparation of a medicament for the prevention and treatment, in particular for the treatment of nasal polyposis, rhinosinusitis, in particular chronic rhinosinusitis.
- Tautomers, racemates, stereoisomers, e.g. Enantiomers or diastereomers, solvates or hydrates, salts, in particular physiologically tolerable salts with inorganic or organic acids or bases, of the selected EGFR kinase inhibitors are likewise subject matter of the use according to the invention.
- Nasal polyposis is the cause of rhinosinusitis and chronic rhinosinusitis in many cases.
- Nasal polyps may be caused, for example, by allergic rhinitis, acute and chronic rhinitis or by viral or bacterial infections; caused by irritants, mist and vapors.
- the EGFR kinase inhibitors U. to 1.101 are preferred, in particular the EGFR kinase inhibitors 11 14,! ⁇ > 18 > Ii-IH, 1/17, 1/19, 121, 123, 124, 127, 128, 1.30. 1.34, 1.35, 1.37, 1.38, 1.40, 1.42, 1.43. 1.44, 1.48, 1.52, 1.55, 1.57, 1.59, 1.60, 1.63, 1.64, 1.66, 1.67, 1.69, 1.70, 1.71, 1.72, 1.78, 1.82, 1.83, 1.84, 1.8 » 1.90, 1.91, 194, and 1.95
- Physiologically acceptable acid addition salts of the compounds of group 1 are, for example, the hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonates, hydronitrate, hydromaleinates, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrates, hydrolactates, hydroxalates, hydrosuccinates, hydrobenzoates and hydro-p-toluenesulfonates ,
- Another object of the present invention is a method for the prevention and / or treatment of chronic rhinosinusitis, the nasal
- Polyposis and nasal polyposis chronic rhinosinusitis preferably chronic nasal polyposis rhinosinusitis comprising administering an effective amount of one or more of the foregoing
- Compounds (1.a) to (1.0 or (1.1) to (1.101) or, where appropriate, one of their physiologically acceptable salts to a patient in need of such treatment are administered in a suitable pharmaceutical form, preferably in one for nasal use suitable preparation, for example in the form of a solution, a suspension, an aerosol or a
- the monotherapy furthermore preferred is the method of treatment.
- prevention means a treatment for the purpose of reducing the risk of developing one of the mentioned indications, in particular in patients with an increased risk for these indications, in the case of existing history or appropriate history, for example in patients after conventional therapy has already taken place, such as surgical polypectomy.
- Statistically verifiable is the success of the preventive treatment by reduction of the occurrence of the relevant indications in a corresponding high-risk population compared with a high-risk population without preventive treatment.
- treatment is to be understood as a therapeutic treatment of patients with a manifest, acute or chronic indication, on the one hand the symptomatic (palliative) treatment for the alleviation of the disease symptoms and on the other hand the causal or curative treatment of the indication with the aim of the pathological condition to terminate the severity of the pathological
- the compounds mentioned are used in dosages of 0.001-500 mg per application, preferably at 0.01-50 mg, particularly preferably 0.02 to 10 mg, wherein the administration is expediently carried out 1 to 3 times a day.
- nasal administration of the active ingredients can be carried out, for example, by administering nasal drops or, using known dosing systems, in the form of nasal spray (solution or suspension), aqueous solutions or suspensions as aerosol or by powder for intranasal deposition.
- Part of the active ingredients La - 1.j and 1.1 - 1.101 contains a hydrolysis-sensitive ester or lactone group.
- substantially anhydrous dosage forms and application forms are selected for these compounds.
- nasal administration is preferably as a powder for intranasal deposition.
- the powder formulations for nasal administration which can be used in the context of the use according to the invention may contain the active substance or the active substance combination either alone or in admixture with suitable, preferably physiologically acceptable excipients.
- the adjuvants used in nasal powders are carriers (which carry a finely micronized active), gelling agents (which promote the removal of the Slow down active agent from the nasal cavity), fillers (to bring low-dose drugs to a manageable volume) or enhancers (which improve the absorption of the drug), where an excipient can also perform several functions at the same time.
- Suitable carriers are, for example, the following auxiliaries, including mixtures thereof (part of these carriers having at the same time an action as enhancer):
- Cellulose or its ester and ether derivatives microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose;
- Disaccharides such as lactose or lactose monohydrate, sucrose, maltose;
- Starch starch microparticles, cross-linked starch, (cross-linked) starch derivatives
- Oligo- and polysaccharides such as dextran microparticles (Sephadex ®); Cyclodextrins, for example, ⁇ -cyclodextrin or dimethyl- ⁇ -cyclodextrin; (crosslinked) polyvinyl pyrollidone; Gelatin, chitin, chitosan, tragacanth, polyacrylates, alginic acid, polyethylene glycols (mol. Weight about 1000-8000 Da).
- suitable enhancers for the respective formulation routes are, for example, the following auxiliaries, including mixtures thereof:
- nonionic, ionic and amphoteric surfactants for example polyoxyethylene-9-lauryl ether, poloxamer 407, Brij 35, Brij 96, polysorbate 80, soybean-steryl glucoside (soybean-derived sterylglucoside);
- Bile salts or derivatives for example Na-deoxycholate, Na-glycocholate, sodium tauro-24,25-dihydrofusidate (sodium tauro-24,25-dihydrofusidate [STDHF]); Fatty acid derivatives, for example oleic acid, lauroylcarnitines, acylcarnitine, palmitoyl-DL-carnitines;
- Phospholipids for example didecanoyl-L-alpha-phosphatidylcholine, dimyristoylphosphatidylglycerol, lysophosphatidylcholine, semisynthetic lysophosphatidylcholine variants, dipalmitoylphosphatidylcholine;
- Cyclodextrins and derivatives for example ⁇ -, ⁇ - or ⁇ -cyclodextrin, dimethyl- ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin;
- Chitosan and derivatives for example poly-L-arginine-chitosan, hyaluronan chitosan;
- Mucolytics for example N-acetylcysteine or ambroxol, for reducing the viscosity of the mucus, whereby the diffusion and absorption of the active ingredient can be improved (described in WO 04078211);
- candidate excipients are: human serum albumin, polyalcohols (e.g., mannitol, sorbitol, xylitol), trehalose, amino acids, monosaccharides (e.g., glucose or arabinose), casein, salts (e.g., sodium chloride, calcium carbonate) or mixtures of these excipients with each other.
- polyalcohols e.g., mannitol, sorbitol, xylitol
- trehalose amino acids
- monosaccharides e.g., glucose or arabinose
- casein casein
- salts e.g., sodium chloride, calcium carbonate
- suitable for the nasal deposition particle sizes of the active ingredient and optionally used adjuvants are described in the prior art, as well as suitable techniques for setting appropriate particle size distributions, such as by grinding, micronization or by spray drying.
- EP 1124544 US 2005019411; EP 1 036 562; WO 95/05805; Farmacopea Europea, III Edition 1997, Paragraph 2.9.18., Page 143.
- Particle sizes or particle size distributions unless stated otherwise, always refer to the aerodynamic diameter determined for particle sizes smaller or equal to 10 ⁇ m by means of cascade impactor, for particle sizes greater than 10 ⁇ m by means of laser diffraction. Both methods of determination are described in the prior art.
- suitable particle sizes are in the range between about 10 and 200 microns. With particle sizes below 10 microns, especially below about 5 microns, the particles are inhaled and enter the lungs.
- the auxiliaries have an average particle size of up to 350 .mu.m, preferably between 10 and 150 .mu.m, particularly preferably between 15 and 80 .mu.m.
- the active ingredient is mixed with an average particle size of 0.1 to 200 .mu.m, preferably 5 to 25 .mu.m, particularly preferably 10 to 25 .mu.m, the excipient.
- Active ingredient having an average particle size of 0.1 to 5 microns is formulated with a carrier having a suitable for nasal deposition particle size spectrum.
- Active ingredient with an average particle size of 5 to 10 ⁇ m is preferably, but not necessarily, formulated with a carrier which has a particle size spectrum suitable for nasal deposition.
- the powders may e.g. from capsules with suitable inhalers described in the prior art.
- the propellant-containing aerosols which can be used in the context of the use according to the invention can dissolve the active substance or the active substance combination in the propellant gas or contain it in dispersed form.
- the propellant gases which can be used to produce the aerosols are known from the prior art. Suitable propellant gases are selected from the group consisting of hydrocarbons such as n-propane, n-butcine or isobutane and halohydrocarbons such as preferably fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
- the abovementioned propellant gases can be used alone or in mixtures thereof.
- Particularly preferred propellant gases are fluorinated alkane derivatives selected from TG134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,1,3,3,3,3-heptafluoropropane) and mixtures thereof.
- the propellant-containing aerosols which can be used in the context of the use according to the invention can also contain further constituents, such as co-solvents, stabilizers, surfactants, antioxidants, lubricants and agents for aerosols Adjustment of pH included. All of these ingredients are known in the art.
- the nasal application of the active ingredient according to the invention or the active ingredient combination in the form of propellant-free solutions or suspensions come as a solution or suspending aqueous, oily or alcoholic, for example ethanolic solutions into consideration.
- the solvent may be water only or it may be a mixture of water and ethanol.
- sterile aqueous solutions of the corresponding pharmaceutically acceptable salts may be used.
- solutions or suspensions of the active compounds in aqueous propylene glycol, in sesame or peanut oil into consideration.
- Aqueous solutions should be suitably buffered if necessary and the liquid diluent made isotonic with, for example, sufficient salt or glucose.
- the solutions or suspensions containing the active substance or the active compound can be adjusted to a pH of 2 to 9, preferably 2 to 7, in particular 2 to 5, with suitable physiologically tolerated acids or bases.
- acids selected from inorganic or organic acids can be used.
- inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid.
- particularly suitable organic acids are: ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid and others.
- Preferred inorganic acids are hydrochloric acid, sulfuric acid.
- organic acids ascorbic acid, fumaric acid and citric acid are preferable.
- mixtures of the abovementioned acids in particular in the case of acids which, in addition to their acidification properties, also possess other properties, for example as antioxidants or complexing agents, for example citric acid or ascorbic acid.
- Suitable bases are, for example, sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
- the compounds 1 and their salts have valuable properties, in particular they can be used for the treatment of nasal polyposis, rhinosinusitis, preferably chronic rhinosinusitis or chronic rhinosinusitis with nasal pooyposis.
- the formulations described in Examples 1-5 and 7 contain any active ingredient selected from Group 1.
- the formulation of Example 6 contains an active ingredient selected from Group 1 which has no hydrolysis-sensitive group, such as an ester or lactone group.
- Example 1 A) powder for intranasal administration: Example 1
- the active ingredient and any excipient present are each micronised using conventional techniques, optionally spheronised and sieved, and optionally then mixed in the desired ratio.
- an average particle size (aerodynamic diameter) lying between 5 and 200 ⁇ m is set, for example in the range between 10 to 25 ⁇ m, the average particle size of the excipient is expediently selected in the range 10 to 350 ⁇ m, for example between 15 to 80 ⁇ m.
- Method of preparation The active ingredient in the form of a physiologically acceptable salt and the excipients are dissolved in water and filled into a corresponding container.
- the active ingredient is dissolved in sesame oil and filled into a corresponding container.
Abstract
Description
Claims
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2007553578A JP2009523700A (ja) | 2005-02-04 | 2006-01-16 | 慢性鼻副鼻腔炎の治療のためのチロシンキナーゼ抑制剤の使用 |
MX2007009265A MX2007009265A (es) | 2005-02-04 | 2006-01-16 | Uso de inhibidores de tirosina quinasa para el tratamiento de rinosinusitis cronica. |
CA002601740A CA2601740A1 (en) | 2005-02-04 | 2006-01-16 | Use of tyrosine kinase inhibitors for the treatment of chronic rhinosinusitis |
EP06707722A EP1845992A1 (de) | 2005-02-04 | 2006-01-16 | Verwendung von tyrosinkinase-inhibitoren zur behandlung der chronischen rhinosinusitis |
BRPI0607358-1A BRPI0607358A2 (pt) | 2005-02-04 | 2006-01-16 | uso de inibidores de tirosina quinase para o tratamento da rinossinusite crÈnica, bem como medicamento |
AU2006210175A AU2006210175A1 (en) | 2005-02-04 | 2006-01-16 | Use of tyrosine kinase inhibitors for the treatment of chronic rhinosinusitis |
EA200701619A EA200701619A1 (ru) | 2005-02-04 | 2006-01-16 | Применение ингибиторов тирозинкиназы для лечения хронического риносинусита |
NO20073097A NO20073097L (no) | 2005-02-04 | 2007-06-18 | Anvendelse av tyrosin kinase inhibitorer for behandling av kronisk rinosinusit |
IL184997A IL184997A0 (en) | 2005-02-04 | 2007-08-02 | Use of tyrosine kinase inhibitors for the treatment of chronic rhinosinusitis |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE102005005505.2 | 2005-02-04 | ||
DE102005005505A DE102005005505A1 (de) | 2005-02-04 | 2005-02-04 | Verwendung von Tyrosinkinase-Inhibitoren zur Behandlung der chronischen Rhinosinusitis |
DE102005036216A DE102005036216A1 (de) | 2005-08-02 | 2005-08-02 | Verwendung von Tyrosinkinase-Inhibitoren zur Behandlung der chronischen Rhinosinusitis |
DE102005036216.8 | 2005-08-02 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2006082129A1 true WO2006082129A1 (de) | 2006-08-10 |
Family
ID=36228798
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2006/050215 WO2006082129A1 (de) | 2005-02-04 | 2006-01-16 | Verwendung von tyrosinkinase-inhibitoren zur behandlung der chronischen rhinosinusitis |
Country Status (14)
Country | Link |
---|---|
US (1) | US20060178364A1 (de) |
EP (1) | EP1845992A1 (de) |
JP (1) | JP2009523700A (de) |
KR (1) | KR20070108889A (de) |
AR (1) | AR055029A1 (de) |
AU (1) | AU2006210175A1 (de) |
BR (1) | BRPI0607358A2 (de) |
CA (1) | CA2601740A1 (de) |
EA (1) | EA200701619A1 (de) |
IL (1) | IL184997A0 (de) |
MX (1) | MX2007009265A (de) |
NO (1) | NO20073097L (de) |
TW (1) | TW200638937A (de) |
WO (1) | WO2006082129A1 (de) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010026029A1 (en) * | 2008-09-03 | 2010-03-11 | Boehringer Ingelheim International Gmbh | Use of quinazoline derivatives for the treatment of viral diseases |
US8507502B2 (en) | 2008-11-10 | 2013-08-13 | National Health Research Institutes | Fused bicyclic and tricyclic pyrimidine compounds as tyrosine kinase inhibitors |
CN104844580A (zh) * | 2015-04-17 | 2015-08-19 | 中国药科大学 | 嘧啶类化合物、其制备方法及医药用途 |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110104166A1 (en) | 2008-01-18 | 2011-05-05 | Stankovic Konstantina M | Methods and Compositions for Treating Polyps |
US20170007704A1 (en) * | 2015-07-09 | 2017-01-12 | David Ram | Carrier and pharmaceutical compositions for intrasinal delivery and uses thereof |
CN110291104B (zh) | 2016-11-17 | 2023-11-03 | 得克萨斯州大学系统董事会 | 具有针对携带egfr或her2外显子20突变之癌细胞的抗肿瘤活性的化合物 |
RU2646806C1 (ru) * | 2017-05-05 | 2018-03-07 | Дмитрий Александрович Щербаков | Способ лечения хронического полипозного риносинусита |
KR20220057993A (ko) | 2020-10-30 | 2022-05-09 | 오창민 | 코막힘, 콧물 등 알레르기 비염을 포함한 부비동 질환의 증상 개선을 위한 식품 조성물 |
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WO2002018376A1 (de) * | 2000-08-26 | 2002-03-07 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Bicyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung |
US20030149062A1 (en) * | 2002-02-05 | 2003-08-07 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Use of tyrosine kinase inhibitors for the treatment of inflammatory processes |
WO2003082290A1 (de) * | 2002-03-30 | 2003-10-09 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 4- ( n-phenylamino ) -chinazoline/chinoline als tyrosinkinaseinhibitoren |
WO2005011701A1 (de) * | 2003-07-28 | 2005-02-10 | Boehringer Ingelheim International Gmbh | Verwendung von chinazolin tyrosinkinase-inhibitoren zur behandlung inflammatorischer prozesse |
WO2005041973A1 (de) * | 2003-10-30 | 2005-05-12 | Boehringer Ingelheim International Gmbh | Verwendung von tyrosinkinase-inhibitoren zur behandlung inflammatorischer prozesse |
-
2006
- 2006-01-16 AU AU2006210175A patent/AU2006210175A1/en not_active Abandoned
- 2006-01-16 BR BRPI0607358-1A patent/BRPI0607358A2/pt not_active IP Right Cessation
- 2006-01-16 JP JP2007553578A patent/JP2009523700A/ja active Pending
- 2006-01-16 KR KR1020077020172A patent/KR20070108889A/ko not_active Application Discontinuation
- 2006-01-16 EP EP06707722A patent/EP1845992A1/de not_active Withdrawn
- 2006-01-16 WO PCT/EP2006/050215 patent/WO2006082129A1/de active Application Filing
- 2006-01-16 MX MX2007009265A patent/MX2007009265A/es not_active Application Discontinuation
- 2006-01-16 EA EA200701619A patent/EA200701619A1/ru unknown
- 2006-01-16 CA CA002601740A patent/CA2601740A1/en not_active Abandoned
- 2006-02-02 US US11/275,903 patent/US20060178364A1/en not_active Abandoned
- 2006-02-03 AR ARP060100386A patent/AR055029A1/es unknown
- 2006-02-03 TW TW095103840A patent/TW200638937A/zh unknown
-
2007
- 2007-06-18 NO NO20073097A patent/NO20073097L/no not_active Application Discontinuation
- 2007-08-02 IL IL184997A patent/IL184997A0/en unknown
Patent Citations (5)
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WO2002018376A1 (de) * | 2000-08-26 | 2002-03-07 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Bicyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung |
US20030149062A1 (en) * | 2002-02-05 | 2003-08-07 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Use of tyrosine kinase inhibitors for the treatment of inflammatory processes |
WO2003082290A1 (de) * | 2002-03-30 | 2003-10-09 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 4- ( n-phenylamino ) -chinazoline/chinoline als tyrosinkinaseinhibitoren |
WO2005011701A1 (de) * | 2003-07-28 | 2005-02-10 | Boehringer Ingelheim International Gmbh | Verwendung von chinazolin tyrosinkinase-inhibitoren zur behandlung inflammatorischer prozesse |
WO2005041973A1 (de) * | 2003-10-30 | 2005-05-12 | Boehringer Ingelheim International Gmbh | Verwendung von tyrosinkinase-inhibitoren zur behandlung inflammatorischer prozesse |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010026029A1 (en) * | 2008-09-03 | 2010-03-11 | Boehringer Ingelheim International Gmbh | Use of quinazoline derivatives for the treatment of viral diseases |
JP2012501991A (ja) * | 2008-09-03 | 2012-01-26 | 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 | ウイルス性疾患の治療のためのキナゾリン誘導体の使用 |
US8629153B2 (en) | 2008-09-03 | 2014-01-14 | Boehringer Ingelheim International Gmbh | Use of quinazoline derivatives for the treatment of viral diseases |
US8507502B2 (en) | 2008-11-10 | 2013-08-13 | National Health Research Institutes | Fused bicyclic and tricyclic pyrimidine compounds as tyrosine kinase inhibitors |
CN104844580A (zh) * | 2015-04-17 | 2015-08-19 | 中国药科大学 | 嘧啶类化合物、其制备方法及医药用途 |
Also Published As
Publication number | Publication date |
---|---|
EA200701619A1 (ru) | 2008-02-28 |
TW200638937A (en) | 2006-11-16 |
JP2009523700A (ja) | 2009-06-25 |
BRPI0607358A2 (pt) | 2009-09-01 |
CA2601740A1 (en) | 2006-08-10 |
MX2007009265A (es) | 2007-09-07 |
AU2006210175A1 (en) | 2006-08-10 |
NO20073097L (no) | 2007-07-12 |
US20060178364A1 (en) | 2006-08-10 |
AR055029A1 (es) | 2007-08-01 |
IL184997A0 (en) | 2007-12-03 |
KR20070108889A (ko) | 2007-11-13 |
EP1845992A1 (de) | 2007-10-24 |
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