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
  • 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
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • 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
• • 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
• • 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
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/10—Expectorants
• • 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
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • 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
• • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to the use of quinazolines selected from the group consisting of
• a medicament for the prevention and treatment of Respiratory or lung disorders associated with increased or altered mucus production, such as inflammatory respiratory disorders such as acute bronchitis, chronic bronchitis, chronic obstructive bronchitis (COPD), asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis , ⁇ 1-antitrypsin deficiency, for cough, emphysema, pulmonary fibrosis or hyperreactive airways.
• inflammatory respiratory disorders such as acute bronchitis, chronic bronchitis, chronic obstructive bronchitis (COPD), asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis , ⁇ 1-antitrypsin deficiency, for cough, emphysema, pulmonary fibrosis or hyperreactive airways.
• COPD chronic o
• the compounds are also suitable for the treatment of inflammatory diseases of the gastrointestinal tract or of the bile ducts or gall bladder, which are associated with a disturbed activity of the tyrosine kinases, such as e.g. acute or chronic inflammatory changes such as cholecystitis, Crohn's disease, uitis ulcer, ulcers or polyposis in the gastrointestinal tract or how they occur in diseases of the gastrointestinal tract that are associated with increased secretion like M. Menetrier, secreting adenomas or protein loss syndromes,
• inflammatory diseases of the joints such as rheumatoid arthritis, inflammatory diseases of the skin, eyes, inflammatory pseudopolyps, colitis cystica profunda or Pneumatosis cystoides intestinales.
• COPD chronic bronchitis
• COPD chronic sinusitis
• asthma chronic bronchitis
• Crohn's disease chronic sinusitis
• colitis uicerosa or polyposis of the intestine.
• COPD chronic bronchitis
• Another object of the present invention is a method for the treatment of
• Respiratory and lung disorders associated with increased or altered mucus production such as inflammatory Respiratory disorders such as acute bronchitis, chronic bronchitis, chronic obstructive bronchitis (COPD), asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, 1-antitrypsin deficiency, or for cough, pulmonary emphysema, pulmonary fibrosis and hyperreactive respiratory tract,
• inflammatory Respiratory disorders such as acute bronchitis, chronic bronchitis, chronic obstructive bronchitis (COPD), asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, 1-antitrypsin deficiency, or for cough, pulmonary emphysema, pulmonary fibrosis and hyperreactive respiratory tract,
• COPD chronic obstructive bronchitis
• inflammatory diseases of the gastrointestinal tract and the bile ducts and gallbladder which are associated with a disturbed activity of the tyrosine kinases, such as e.g. acute or chronically inflammatory changes can be found, such as cholecystitis, Crohn's disease, uicerosa colitis and ulcers, and polyposis in the gastrointestinal tract or how they occur in diseases of the gastrointestinal tract that are associated with increased secretion like M. Menetrier, secreting adenomas and protein loss syndromes,
• inflammatory diseases of the joints such as rheumatoid arthritis, of inflammatory diseases of the skin, of the eyes, of inflammatory pseudopolyps and of colitis cystica profunda and of pneumatosis cystoides intestinales,
• the compounds mentioned are used in doses of 0.001-10 mg / kg of body weight, for example 0.5-0.7 mg / kg, preferably at 0.01-1.5 mg / kg, the administration advantageously being carried out 1 to 3 times a day.
• the active substances can be administered orally, buccally, parenterally, by inhalation-atomization, rectally or topically.
• Parenteral administration can include subcutaneous, intravenous, and intramuscular injections and infusion techniques.
• Customary dosage forms can be used for administration, for example those mentioned in those cited above for the active substances Dosage forms.
• the active ingredients optionally in combination with other active substances, together with one or more inert customary carriers and / or diluents, for example with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / Ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fat-containing substances such as hard fat or their suitable mixtures, in usual galenical preparations such as tablets, dragees, capsules, powders, suspensions or suppositories.
• the active ingredients can be administered orally in a wide variety of different dosage forms, for example together with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, cookies, hard candies, powders, atomizers, aqueous suspensions, elixirs, syrups and the like be formulated.
• Such carriers include, for example, solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents.
• such oral formulations can be sweetened and / or flavored in a suitable manner with the aid of various agents usually used for this purpose.
• the active ingredients are present in such oral dosage forms with concentration levels, the range of which, based on the total composition, ranges from about 0.5% by weight to about 90% by weight, in amounts sufficient to give the desired dosage units.
• concentration levels the range of which, based on the total composition, ranges from about 0.5% by weight to about 90% by weight, in amounts sufficient to give the desired dosage units.
• suitable dosage forms for the active ingredients include controlled release formulations and devices that are well known to those skilled in the art.
• solutions of the active ingredients in sesame or peanut oil or in aqueous propylene glycol can be used, as well as sterile aqueous solutions of the corresponding pharmaceutically acceptable salts.
• aqueous solutions should, if necessary, be suitably buffered and the liquid diluent made isotonic with sufficient salt or glucose.
• these certain aqueous solutions are particularly suitable for the purpose of intravenous, intramuscular and subcutaneous injections.
• the sterile aqueous media used are easy to obtain using standard techniques which are well known to those skilled in the art.
• the dosage form of the particular compound or compounds may include, for example, solutions, lotions, ointments, creams, gels, suppositories, permanent rate release formulations and devices therefor.
• dosage forms include the particular compound or compounds and may include ethanol, water, penetrants and inert carriers such as gel generators, mineral oil, emulsifiers, benzyl alcohol and the like.
• inhalable aerosols containing propellant gas which can be used in the context of the use according to the invention can contain the active ingredient or combination of active ingredients dissolved in the propellant gas or in dispersed form.
• propellant gases which can be used to produce the inhalation aerosols are known from the prior art.
• Suitable propellants are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halogenated hydrocarbons such as preferably fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
• hydrocarbons such as n-propane, n-butane or isobutane
• halogenated hydrocarbons such as preferably fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
• the above-mentioned propellant gases can be used alone or in mixtures thereof.
• Particularly preferred propellants 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 inhalable aerosols containing propellant gas which can be used in the context of the use according to the invention can furthermore contain further constituents such as cosolvents, stabilizers, surface-active agents (surfactants), antioxidants, lubricants and agents for adjusting the pH. All of these components are known in the art.
• aqueous or alcoholic, preferably ethanolic solutions are suitable as solvents.
• the solvent can only be water or it is a mixture of water and ethanol.
• the relative proportion of ethanol to water is not limited, but the maximum limit is preferably up to 70 volume percent, in particular up to 60 volume percent and particularly preferably up to 30 volume percent.
• the remaining volume percentages are filled up with water.
• the solutions or suspensions containing the active ingredient or combination of active ingredients are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. Acids selected from inorganic or organic acids can be used to adjust this pH.
• Examples of particularly suitable inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid.
• Examples of particularly suitable organic acids are: Ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid and others.
• Preferred inorganic acids are hydrochloric acid, sulfuric acid.
• Ascorbic acid, fumaric acid and citric acid are preferred among the organic acids.
• mixtures of the above acids may be used, in particular in the case of acids, in addition to their acidifying other properties, such as flavorings, antioxidants or complexing agents, "such as citric acid or ascorbic acid.
• hydrochloric acid to adjust the pH Value used.
• the compounds of the general formula (I) and their salts have valuable properties, in particular an anti-inflammatory effect.
• A 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,
• Test 1 Inhibition of smoke-induced accumulation of granulocytes in the lung tissue
• Indications of lunches Inhibition of the cigarette smoke-induced influx of neutrophils into the lung tissue by the EGF receptor kinase inhibitor 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 (compound A).
• mice Male rats (strain: Sprague-Dawley) weighing 250-300 g were exposed to the smoke of 8 cigarettes a day for 5 days.
• the animals in the compound A-treated group received intratracheal administration of 0.03 or 0.1 mg / kg of the compound A in a volume of 0.05 ml daily under anesthesia with isoflurane 30 minutes before the start of smoking exposure.
• the animals On the last day of the experiment, the animals were sacrificed 4 hours after the last smoke exposure and the lung tissue was removed.
• a sample of 70-200 mg was taken from each lung and placed in a reaction vessel prepared with 1 ml of 0.5% hexadecyltrimethylammonium bromide. The samples were homogenized with an Ultraturrax for 15 seconds.

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• Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Chemical & Material Sciences (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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• Chemical Kinetics & Catalysis (AREA)
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• Pulmonology (AREA)
• Rheumatology (AREA)
• Epidemiology (AREA)
• Ophthalmology & Optometry (AREA)
• Pain & Pain Management (AREA)
• Otolaryngology (AREA)
• Immunology (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Physical Education & Sports Medicine (AREA)
• Dermatology (AREA)
• Gastroenterology & Hepatology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)

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Citations (9)

• 2003
  • 2003-07-28 DE DE10334226A patent/DE10334226A1/de not_active Withdrawn
• 2004
  • 2004-07-22 WO PCT/EP2004/008185 patent/WO2005011701A1/de not_active Application Discontinuation
  • 2004-07-22 JP JP2006521478A patent/JP2007500156A/ja active Pending
  • 2004-07-22 EP EP04763394A patent/EP1651228A1/de not_active Withdrawn
  • 2004-07-22 CA CA002533752A patent/CA2533752A1/en not_active Abandoned

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