WO2005011701A1

WO2005011701A1 - Use of quinazoline tyrosine kinase inhibitors in the treatment of inflammatory processes

Info

Publication number: WO2005011701A1
Application number: PCT/EP2004/008185
Authority: WO
Inventors: Birgit Jung; Hubert Pueschner
Original assignee: Boehringer Ingelheim International Gmbh; Boehringer Ingelheim Pharma Gmbh & Co. Kg
Priority date: 2003-07-28
Filing date: 2004-07-22
Publication date: 2005-02-10
Also published as: CA2533752A1; DE10334226A1; JP2007500156A; EP1651228A1

Abstract

The invention relates to the use of selected quinazolines, tautomers, stereoisomeres and salts thereof, especially the physiologically compatible salts thereof with inorganic or organic acids or bases, in the production of a medicament for the prophylaxis or treatment of illnesses of the respiratory tracts or lungs and additional inflammatory illnesses.

Description

USE OF CHINAZOLIN TYROSINKINASE INHIBITORS FOR TREATING INFLAMMATORY PROCESSES

The present invention relates to the use of quinazolines selected from the group consisting of

(1) 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,

(2) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] - amino} -7- [(tetrahydrofuran-2-yl) methoxy] -quinazoline,

(3) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N, N-bis (2-methoxyethyl) amino] -1-oxo-2-butene 1-yl} amino) -7 - [(tetrahydrofuran-2-yl) methoxy] -quinazoline,

(4) 4 - [(3-ethynylphenyl) amino] -6 - {[4- (5,5-dimethyl-2-oxomorpholin-4-yl) -1-oxo-2-buten-1 - yl] amino} -quinazoline,

(5) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) - ethoxy] -7-methoxy- quinazoline,

(6) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) - ethoxy] -7 - [( R) - (tetrahydrofuran-2-yl) methoxy] -quinazoline,

(7) 4 - [(3-chloro-4-fluorophenyl) amino] -7- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) - ethoxy] -6 - [( S) - (tetrahydrofuran-2-yl) methoxy] -quinazoline,

(8) 4 - [(3-chloro-4-fluorophenyl) amino] -6- {2- [4- (2-oxo-morpholin-4-yl) piperidin-1-yl] - ethoxy} - 7-methoxy-quinazoline,

(9) 4 - [(3-Chloro-4-fluorophenyl) amino] -6- [cis-4- (N-methanesulfonyl-N-methylamino) cyclohexan-1-yloxy] -7-methoxy- quinazoline, (10) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [cis-4- (N-acetyl-N-methylamino) - cyclohexan-1-yloxy] -7-methoxy- in chinazo!,

(11) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (trans-4-methylamino-cyclohexan-1-yloxy) - 7-methoxy-quinazoline,

(12) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [trans-4- (N-methanesulfonyl-N-methylamino) cyclohexane-1-yloxy] -7-methoxy- quinazoline,

(13) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (trans-4-dimethylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline.

(14) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (trans-4- {N - [(morpholin-4-yl) carbonyl] -N-methylamino} cyclohexane 1-yloxy) -7-methoxy-quinazoline,

(15) 4 - [(3-chloro-4-fluorophenyl) amino] -6- {1 - [2- (2-oxo-3-methylimidazolidin-1 - yl) ethyl] piperidine-4- yloxy} -7-methoxy-quinazoline,

(16) 4 - [(3-Chloro-4-fluorophenyl) amino] -6- {1 - [2- (2-oxo-hexahydropyrimidin-1-yl) ethyl] - piperidin-4-yloxy} -7 methoxy-quinazoline,

(17) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) - ethoxy] -7 - [( S) - (tetrahydrofuran-2-yl) methoxy] -quinazoline,

(18) 4 - [(3-Chloro-4-fluorophenyl) amino] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline and

(19) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (1-cyano-piperidin-4-yloxy) -7-methoxyquinazoline,

their tautomers, their stereoisomers and their salts, in particular their physiologically tolerable salts with inorganic or organic acids or bases, for the manufacture 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 , α1-antitrypsin deficiency, for cough, emphysema, pulmonary fibrosis or hyperreactive airways.

Furthermore, 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,

also for the treatment of inflammatory diseases of the joints, such as rheumatoid arthritis, inflammatory diseases of the skin, eyes, inflammatory pseudopolyps, colitis cystica profunda or Pneumatosis cystoides intestinales.

Inflammatory diseases of the respiratory organs or the intestine are mentioned as preferred areas of application, such as chronic bronchitis (COPD), chronic sinusitis, asthma, Crohn's disease, colitis uicerosa or polyposis of the intestine.

Particularly preferred areas of application are inflammatory diseases of the respiratory tract or lungs, such as chronic bronchitis (COPD) or asthma.

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,

for the treatment of 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,

furthermore for the treatment of 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,

comprising administering to a patient in need of such treatment an effective amount of one or more of the aforementioned compounds (1) to (19) or, optionally, one of their physiologically acceptable salts.

In the process according to the invention, 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. For example, 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. In addition, such oral formulations can be sweetened and / or flavored in a suitable manner with the aid of various agents usually used for this purpose. In general, 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. Other suitable dosage forms for the active ingredients include controlled release formulations and devices that are well known to those skilled in the art.

For parenteral administration, 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. Such 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. In this together The sterile aqueous media used are easy to obtain using standard techniques which are well known to those skilled in the art. For example, distilled water is commonly used as the liquid diluent and the final preparation is passed through a suitable bacterial filter such as a sintered glass or diatomaceous earth or unglazed porcelain filter. Preferred filters of this type include the Berkefeld, Chamberland and asbestos disk metal Seitz filters, in which the fluid is sucked into a sterile container with the aid of a suction pump. Throughout the preparation of these injectable solutions, the necessary procedural steps should be taken to ensure that the end products are obtained in a sterile state. For transdermal administration purposes, 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. Such 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.

Inhaled administration takes the form of powder formulations with lactose and other auxiliaries or in the form of aqueous solutions as an aerosol. The inhalable powders which can be used in the context of the use according to the invention can contain the active ingredient or combination of active ingredients either alone or in a mixture with suitable physiologically acceptable auxiliaries. If the active ingredient or combination of active ingredients is contained in a mixture with physiologically acceptable excipients, the following physiologically acceptable excipients can be used to prepare these inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, sucrose, maltose), oligo- and Polysaccharides (e.g. dextrans), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these auxiliaries with one another. Mono- or disaccharides are preferably used, the use of lactose or glucose being preferred, in particular, but not exclusively, in the form of their hydrates. Lactose, most preferably lactose monohydrate, is used as an auxiliary as particularly preferred in the sense of the invention. The 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. The 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. 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.

If the active ingredient according to the invention or the active ingredient combination is administered by inhalation in the form of propellant-free solutions or suspensions, 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. If desired, 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. According to the invention particularly preferably hydrochloric acid to adjust the pH Value used.

As already mentioned at the beginning, the compounds of the general formula (I) and their salts have valuable properties, in particular an anti-inflammatory effect.

For example, the connections

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,

B = 4 - [(3-chloro-4-fluorophenyl) amino] -6 - ({4- [N, N-bis (2-methoxyethyl) amino] -1-oxo-2-buten-1 -yl} amino) -7 - [(tetrahydrofuran-2-yl) methoxy] -quinazoline,

C = 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) ethoxy] -7-methoxy-quinazoline .

D = 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) - ethoxy] -7 - [(R. ) - (tetrahydrofuran-2-yl) methoxy] -quinazoline and

E = 4 - [(3-chloro-4-fluorophenyl) amino] -7- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) - ethoxy] -6 - [(S ) - (tetrahydrofuran-2-yl) methoxy] -quinazoline

subjected to the following test to investigate the anti-inflammatory effect: 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).

Method:

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. 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. The homogenates were centrifuged at 15700 g in an Eppendorf table centrifuge for 5 min at room temperature. 50 ml of the supernatant were removed and mixed with 250 ml of phosphate buffer (50 mmol / l) which contained 0.197 mg / ml of O-dianisidine dihydrochloride. After a 10 minute incubation at room temperature, the absorption was measured with a spectrophotometer at a wavelength of 450 nm. The dose was determined by linear regression, which led to an inhibition of MPO activity by 50% (= ID50).

Result:

Exposure to cigarette smoke in rats caused neutrophil granulocytes to enter lung tissue as measured by the tissue content of myeloperoxidase, which is specific for neutrophil granulocytes. Intratracheal treatment of the animals with the EGFR kinase inhibitor A caused a significant (p <0.005) inhibition of smoke-related accumulation of granulocytes and thus produced an anti-inflammatory effect.

Further results are summarized in the following table:

Claims

claims

1. Use of quinazolines selected from the group consisting of

(2) 4 - [(3-Chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] - amine no} -7 - [(tetrahydroof u ran-2-y I) methoxy] -ch i nazoli n,

(4) 4 - [(3-ethynylphenyl) amino] -6 - {[4- (5,5-dimethyl-2-oxo-morpholin-4-yl) -1-oxo-2-buten-1 - yl] amino} -quinazoline,

(9) 4 - [(3-Chloro-4-fluorophenyl) amino] -6- [cis-4- (N-methanesulfonyl-N-methylamino) cyclohexan-1-yloxy] -7-methoxy- quinazoline, (10) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [cis-4- (N-acetyl-N-methyl-amino) - cyclohexan-1-yloxy] -7-methoxy- quinazoline,

(12) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [trans-4- (N-methanesulfonyl-N-methylamino) cyclohexan-1-yloxy] -7-methoxy- quinazoline,

(13) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (trans-4-dimethylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline,

(15) 4 - [(3-chloro-4-fluorophenyl) amino] -6- {1- [2- (2-oxo-3-methylimidazolidin-1 - yl) ethyl] piperidine-4- yloxy} -7-methoxy-quinazoline,

(16) 4 - [(3-Chloro-4-fluorophenyl) amino] -6- {1- [2- (2-oxo-hexahydropyrimidin-1-yl) ethyl] - piperidin-4-yloxy} -7 methoxy-quinazoline,

their tautomers, their stereoisomers and their salts, in particular their physiologically tolerable salts with inorganic or organic acids or bases, for the manufacture of a medicament for the prevention and treatment of Diseases of the respiratory tract or lungs associated with an increased or changed production of mucus,

inflammatory diseases of the gastrointestinal tract or bile ducts or gall bladder, which are associated with impaired activity of the tyrosine kinases,

inflammatory diseases of the joints, inflammatory diseases of the skin, eyes, inflammatory pseudopolyps, colitis cystica profunda or Pneumatosis cystoides intestinales.

2. Use according to claim 1, characterized in that it is a treatment of the upper and lower respiratory organs or the intestine.

3. Use according to claim 2, characterized in that the diseases are COPD, chronic sinusitis, asthma, cystic fibrosis, Crohn's disease, uitis colitis or polyposis of the intestine.

4. Use according to claim 3, characterized in that the diseases are COPD, asthma or cystic fibrosis.

5.Procedures for the treatment of diseases of the respiratory tract or lungs which are associated with an increased or changed production of mucus,

inflammatory diseases of the joints, inflammatory diseases of the skin, eyes, inflammatory pseudopolyps, colitis cystica profunda or Pneumatosis cystoides intestinales, comprising the administration of an effective amount of a quinazoline selected from the group consisting of

(1) 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, (2) 4 - [(3-chloro-4-fluorophenyl) amino] -6 - {[4- (morpholin-4-yl) -1-oxo-2-buten-1-yl] - amino} -7- [(tetrahydrofuran-2-yl) methoxy] -quinazoline,

(4) 4 - [(3-ethynylphenyl) amino] -6 - {[4- (5,5-dimethyl-2-oxo-morpholin-4-yl) -1-oxo-2-buten-1 - yljaminoj-quinazoline,

(5) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (2,2-dimethyl-6-oxo-morpholin-4-yl) ethoxy] -7-methoxy- quinazoline,

(9) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [cis-4- (N-methanesulfonyI-N-methyl-amino) -cyclohexan-1-yloxy] -7-methoxy- quinazoline,

(10) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [cis-4- (N-acetyl-N-methylamino) - cyclohexan-1-yloxy] -7-methoxy- quinazoline,

(12) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [trans-4- (N-methanesulfonyl-N-methylamino) cyclohexan-1-yloxy] -7-methoxy- quinazoline, (13) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (trans-4-dimethylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline,

(14) 4 - [(3-chloro-4-fluorophenyl) amino] -6- (trans-4- {N - [(morpholin-4-yl) carbonyI] -N-methylamino} cyclohexane 1-yloxy) -7-methoxy-quinazoline,

(17) 4 - [(3-chloro-4-fluorophenyl) amino] -6- [2- (2,2-dimethyl-6-oxo-morpholin-4-yI) - ethoxy] -7 - [( S) - (tetrahy drof u ran-2-yl) methoxy] -ch i nazol in,

their tautomers, their stereoisomers and their salts, in particular their physiologically tolerable salts with inorganic or organic acids or bases, to a patient in need of such treatment.

6. The method according to claim 5, characterized in that it is a treatment of the upper and lower respiratory organs or the intestine.

7. The method according to claim 6, characterized in that the diseases are COPD, chronic sinusitis, asthma, cystic fibrosis, Crohn's disease, uitis colitis or polyposis of the intestine.

8. The method according to claim 7, characterized in that the diseases are COPD, asthma or cystic fibrosis.