HK1189591B - HYDROCHLORIDE SALT OF 5-R3-F3-TIVDROXYPHENOXY)AZETIDIπ-1-Vπ-5-METHYL-2，2- DIPHENYLHEXANAMIDE - Google Patents

Description

Hydrochloride of 5- [3- (3-hydroxyphenoxy) azetidin-1-yl ] -5-methyl-2, 2-diphenylhexanamide

The application is a divisional application of a patent application with the name of 'hydrochloride of 5- [3- (3-hydroxyphenoxy) azetidin-1-yl ] -5-methyl-2, 2-diphenylhexanamide' with the application number of 200880008581.6, the application date of 2008, 3.6.3.

Technical Field

The present invention relates to hydrochloride salts of 5- [3- (3-hydroxyphenoxy) azetidin-1-yl ] -5-methyl-2, 2-diphenylhexanamide, processes for their preparation, intermediates used in the preparation of the compounds, compositions containing them and their use.

The invention also relates to derivative forms of the hydrochloride salt of 5- [3- (3-hydroxyphenoxy) azetidin-1-yl ] -5-methyl-2, 2-diphenylhexanamide, including hydrates, solvates and polymorphs thereof.

Background

Cholinergic muscarinic receptors are members of the superfamily of G-protein coupled receptors and are further divided into 5 subtypes, M₁To M₅. Muscarinic receptor subtypes are widely and differentially expressed in the body. All 5 subtypes of the gene have been cloned, where M₁、M₂And M₃The pharmacological properties of receptors have been well characterized in animal and human tissues. M₁Receptors are expressed in the brain (cortex and hippocampus), glands, and ganglia of the sympathetic and parasympathetic nerves. M₂Receptors in the heart, hindbrainSmooth muscle and in the synapses of the autonomic nervous system. M₃Receptors are expressed in the brain, glands and smooth muscle. In the airways, M is stimulated₃The receptor causes contraction of airway smooth muscle, resulting in bronchoconstriction, while in salivary glands, M₃Receptor stimulation increases fluid and mucus secretion, resulting in increased salivary secretion. M expressed on smooth muscle₂Receptors are thought to have a pro-contractile effect and presynaptic M₂The receptors modulate the release of acetylcholine from parasympathetic nerves. Stimulation of M expressed in the heart₂The receptor may produce bradycardia.

Use of short and long acting muscarinic antagonists in asthma and COPD management; these antagonists include short acting agents(ipratropium bromide) and(Oxotonium bromide) and long-acting agents(tiotropium bromide). These compounds cause bronchodilation after inhaled administration. In addition to improving spirometry, the use of antimuscarinic drugs in Chronic Obstructive Pulmonary Disease (COPD) leads to improved health status and increased quality of life scores. Due to the wide distribution of muscarinic receptors in the body, the large number of systemic muscarinic antagonists can lead to conditions such as dry mouth, constipation, mydriasis, urinary retention (all via blocking M, primarily)₃Receptor mediated) and tachycardia (by blocking M)₂Receptor-mediated) effect. The side effect commonly reported after inhaled administration of therapeutic doses of currently clinically used non-selective muscarinic antagonists is xerostomia, which, although only mild in intensity, does limit the dose of inhaled medicament administered.

Thus, there still exists a need for improved M₃There is a need for receptor antagonists having suitable pharmacological profilesE.g. in terms of potency, pharmacokinetics or duration of action. In this connection, the invention relates to novel M₃A receptor antagonist. There is a need for M having pharmacological properties suitable for administration by the inhalation route₃The need for receptor antagonists.

Disclosure of Invention

The present invention relates to hydrochloride salts of 5- [3- (3-hydroxyphenoxy) azetidin-1-yl ] -5-methyl-2, 2-diphenylhexanamide and derivatives thereof.

Preferably, the present invention relates to a crystalline form of the hydrochloride salt of 5- [3- (3-hydroxyphenoxy) azetidin-1-yl ] -5-methyl-2, 2-diphenylhexanamide.

Preferably, the present invention relates to a non-solvated crystalline form of the hydrochloride salt of 5- [3- (3-hydroxyphenoxy) azetidin-1-yl ] -5-methyl-2, 2-diphenylhexanamide.

Preferably, when Cu K.alpha.is used₁The hydrochloride salt of the present invention has an X-ray diffraction pattern characterized by the following major X-ray diffraction pattern peaks expressed in 2-theta angles when measured with radiation (wavelength =1.5406 angstroms):

2-theta angle °
	9.1
11.2
	13.7
18.3
	19.7

Preferably, when Cu K.alpha.is used₁The hydrochloride salt of the present invention has an X-ray diffraction pattern characterized by the following major X-ray diffraction pattern peaks expressed in 2-theta angles when measured with radiation (wavelength =1.5406 angstroms):

2-theta angle °
	7.5
9.1
	11.2
13.7
	14.8
18.3
	19.7

Preferably, when Cu K.alpha.is used₁The hydrochloride salt of the present invention has an X-ray diffraction pattern characterized by the following major X-ray diffraction pattern peaks expressed in 2-theta angles when measured with radiation (wavelength =1.5406 angstroms):

2-theta angle °
	7.5
9.1
	11.2
13.7
	14.8
18.3
	19.7
23.4
	28.3

It has now been found that the hydrochloride salt of the present invention is M₃Antagonists of the receptor, particularly useful in the treatment of M₃-mediated diseases and/or conditions and show good efficacy, especially when administered via the inhaled route. The hydrochloride salts of the present invention are particularly suitable for administration by the inhalation route. In particular, the hydrochloride salt of the present invention may be formulated for administration using a dry powder inhaler.

The hydrochloride salts of the present invention have properties including solid state stability and compatibility with the particular pharmaceutical product excipients, which make them superior to their corresponding free bases.

The hydrochloride salt of the present invention may be prepared from 5- [3- (3-hydroxyphenoxy) azetidin-1-yl ] -5-methyl-2, 2-diphenylhexanamide according to conventional procedures for preparing Salts such as those disclosed in "Handbook of Pharmaceutical Salts, Properties, Selection and use, published by Wiley-VCH, 2002, edited by P.Heinrich Stahl, Camile G Wermuth, ISBN 3-906390-26-8".

The hydrochloride salt of 5- [3- (3-hydroxyphenoxy) azetidin-1-yl ] -5-methyl-2, 2-diphenylhexanamide may exist in unsolvated as well as solvated forms. The term "solvate" as used herein describes a molecular complex comprising the hydrochloride salt of the present invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). When the solvent is water, the term "hydrate" is used. Complexes, such as clathrate, drug-matrix (drug-host) inclusion complexes, are contemplated within the scope of the present invention, wherein the drug and matrix are present in stoichiometric or non-stoichiometric amounts as compared to the solvates described above. Also included are complexes of drugs comprising two or more organic and/or inorganic components that may be present in stoichiometric or non-stoichiometric amounts. The resulting complex may be ionized, partially ionized or non-ionized. For an overview of these complexes, see Haleblian J Pharm Sci, 64(8), 1269-1288 (8/1975).

The polymorphic forms and the crystal/habit of the hydrochloride salt of the invention are also covered within the scope of the invention.

The term "hydrochloride salt of the invention" includes hydrochloride salts of 5- [3- (3-hydroxyphenoxy) azetidin-1-yl ] -5-methyl-2, 2-diphenylhexanamide and derivatives thereof.

The hydrochloride salts of the present invention are valuable pharmaceutically active compounds which are suitable for the treatment and prevention of a variety of diseases in which muscarinic receptors are involved or in which antagonism of such receptors may be of benefit, especially allergic and non-allergic airway diseases (e.g. asthma, copd.), and also for the treatment of other diseases such as inflammatory bowel disease, irritable bowel syndrome, diverticular disease, motion disease, gastric ulcers, intestinal radiological examinations, and symptomatic treatment of: BPH (benign prostatic hyperplasia), NSAID-induced gastric ulcers, urinary incontinence (including urgency, urinary frequency, urge incontinence, overactive bladder, nocturia and lower urinary tract symptoms), cycloplegia, mydriasis and parkinson's disease.

According to the invention, the hydrochloride salt of the invention can be administered to an animal, preferably a mammal, especially a human, as a medicament for therapy and/or prophylaxis. They can be administered as such, in a mixture with one another or in the form of a pharmaceutical preparation comprising an effective dose of the hydrochloride salt according to the invention as active ingredient together with customary pharmaceutically nontoxic excipients and/or additives.

The hydrochloride salt of the present invention may be freeze dried, spray dried or evaporation dried to provide a solid bulk, powder, or film form crystalline or amorphous material. Microwave or radio frequency drying may be used for this purpose.

The hydrochloride salts of the present invention may be administered alone or in combination with other drugs and are generally administered as a formulation in combination with one or more pharmaceutically acceptable excipients. The term "excipient" as used herein describes any ingredient other than the hydrochloride salt of the present invention. The choice of excipient will depend to a large extent on the particular mode of administration.

The hydrochloride salt of the invention may be administered directly into the bloodstream, muscle or internal organs. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous administration. Suitable devices for parenteral administration include needle (including microneedle) syringes, needle-free syringes and infusion techniques. Parenteral formulations are typically aqueous solutions which may contain excipients (e.g. salts, carbohydrates) and buffers (preferably to a pH of 3 to 9), but for some applications may be more suitably formulated as sterile non-aqueous solutions or as dry forms for use in combination with a suitable medium (e.g. sterile, pyrogen-free water).

Preparation of parenteral formulations under sterile conditions (e.g., by freeze-drying) can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

Formulations for parenteral administration may be formulated as immediate release and/or modified release formulations. Modified release formulations include sustained release, pulsatile release, controlled release, targeted release, and programmed release formulations. Thus, the hydrochloride salts of the present invention may be formulated as solid, semi-solid or thixotropic liquids for administration as an implanted depot formulation to provide a modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA poly (dl-lactic-co-glycolic acid) (PGLA) microspheres.

The hydrochloride salt of the present invention may also be administered topically, i.e. transdermally or transdermally, to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical carriers include ethanol, water, mineral oil, liquid paraffin, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may also be incorporated-see, for example, J Pharm Sci, 88(10), 955-958, Finnin and Morgan (10 months 1999).

Other topical means of administration include by electroporation, iontophoresis, phonophoresis (phonophoresis), sonophoresis (sonophoresis), and microneedles or needleless (e.g., Powderject)^TM、Bioject^TMEtc.) injection.

Formulations for topical administration may be formulated as immediate release and/or modified release formulations. Modified release formulations include sustained release, pulsatile release, controlled release, targeted release, and programmed release formulations.

The hydrochloride salts of the present invention may also be administered intranasally or by inhalation, in the typical form used for such administration: dry powders from dry powder inhalers (alone, as a mixture (e.g. a dry blend containing lactose, or as mixed component particles, e.g. mixed with a phospholipid such as phosphatidylcholine) or as an aerosol from a pressurised container, pump, nebuliser (preferably a nebuliser using electrohydrodynamics to generate a fine mist) or nebuliser, with or without the use of a suitable propellant, e.g. 1,1,1, 2-tetrafluoroethane or 1,1,1,2,3,3, 3-heptafluoropropane for intranasal use the powder may comprise a bioadhesive agent, e.g. chitosan or cyclodextrin.

Pressurized containers, pumps, sprayers, atomizers or sprayers contain solutions or suspensions of the compounds of the invention including, for example, ethanol, aqueous ethanol or other suitable agents for dispersion, solubilization or extended release of the active material, a propellant as a solvent, and optionally a surfactant (e.g., sorbitan trioleate, oleic acid or oligolactic acid).

Prior to use in dry powder or suspension formulations, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This can be accomplished by any suitable comminution method such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization or spray drying.

Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blister packs and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the hydrochloride salt of the invention, a suitable powder base (for example, lactose or starch) and a performance-modifying agent (for example, l-leucine, mannitol or magnesium stearate). Lactose can be anhydrous or in the form of a monohydrate, the latter being preferred. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

Solution formulations suitable for use in nebulizers that generate fine mist using electrohydrodynamic techniques may contain 1 microgram to 20 milligrams of the hydrochloride salt of the present invention per spray and the volume of spray may vary from 1 microliter to 100 microliters. A typical formulation may comprise the hydrochloride salt of the invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that may be used in place of propylene glycol include glycerol and polyethylene glycol.

Suitable flavoring agents (e.g., menthol and levomenthol) or sweetening agents (e.g., saccharin or saccharin sodium) may be added to those formulations of the present invention that are intended to be administered by inhalation/intranasal means.

Formulations for inhalation/intranasal administration may be formulated as immediate release and/or modified release formulations using, for example, PGLA. Modified release formulations include sustained release, pulsatile release, controlled release, targeted release, and programmed release formulations.

When using dry powder inhalers and aerosols, the dosage unit is determined by the valve which can deliver a metered amount. The units of the invention are generally set up to administer a metered dose or "spray" containing from 0.001 mg to 10 mg of the hydrochloride salt of the invention. The daily dose is usually between 0.001 mg and 40 mg, and may be given as a single dose or more often as divided doses administered throughout the day. The hydrochloride salt of the present invention is particularly suitable for administration by inhalation. In particular, the hydrochloride salt of the invention is suitable for formulation as a dry powder with lactose and can therefore be administered using a dry powder inhaler.

The hydrochloride salts of the present invention may be administered rectally or vaginally (e.g., in the form of suppositories, pessaries or enemas). Cocoa butter is a conventional suppository base, but various alternatives may be used as appropriate.

Formulations for rectal/vaginal administration may be formulated as immediate release and/or modified release formulations. Modified release formulations include sustained release, pulsatile release, controlled release, targeted release, and programmed release formulations.

The hydrochloride salt of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH adjusted sterile saline. Other formulations suitable for ocular and otic administration include ointments, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, wafers, lenses, and particulate or vesicular systems (e.g., niosomes) or liposomes. Polymers such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulosic polymers (e.g., hydroxypropyl methylcellulose, hydroxyethyl cellulose, or methyl cellulose), or heteropolysaccharide polymers (e.g., agarose gum) may be incorporated with a preservative (e.g., benzalkonium chloride). These formulations can also be delivered by iontophoresis.

Formulations for ocular/otic administration may be formulated as immediate release and/or modified release formulations. Modified release formulations include sustained release, pulsatile release, controlled release, targeted release, or programmed release formulations.

The hydrochloride salt of the present invention may be combined with a soluble macromolecular entity (e.g., cyclodextrin and suitable derivatives thereof or a polymer comprising polyethylene glycol) to improve its solubility, dissolution rate, taste masking, bioavailability and/or stability for use in any of the administration modes described above.

For example, drug-cyclodextrin complexes have been found to be generally useful in most dosage forms and routes of administration. Both inclusion and non-inclusion complexes may be used. In addition to direct complexation with the drug, cyclodextrins may also be used as auxiliary additives, i.e. as carriers, diluents or solubilisers. The most commonly used for these purposes are alpha-, beta-and gamma-cyclodextrins, examples of which can be found in International patent applications WO91/11172, WO94/02518 and WO 98/55148.

Since it may be desirable to administer a combination of active compounds, e.g. for the purpose of treating a particular disease or condition, the present invention encompasses: conveniently two or more pharmaceutical compositions, at least one of which comprises a hydrochloride salt of the invention, are combined in a kit (kit) form suitable for co-administration of these compositions.

Accordingly, the kit of the invention comprises two or more separate pharmaceutical compositions (at least one of which comprises a hydrochloride salt of the invention according to the invention) and means for separately storing the compositions (e.g. a container, a separate bottle or a separate foil package). Examples of such kits are the common blister packs used for the packaging of tablets, capsules and the like.

The kits of the invention are particularly useful for administering different dosage forms (e.g., parenterally), for administering separate compositions at different dosage intervals, or for titrating separate compositions against one another. To aid compliance, the kit usually contains instructions for administration and may be provided with a so-called memory aid.

For administration to a human patient, the total daily dosage of the hydrochloride salt of the invention will generally be between 0.001 mg and 5000 mg, depending of course on the mode of administration. For example, an intravenous daily dose may need only be between 0.001 mg and 40 mg. The total daily dose may be administered in a single dose or in divided doses and may be outside the typical ranges given herein at the discretion of the physician.

These doses are based on a typical human subject having a body weight of about 65 kg to 70 kg. A physician can readily determine dosages for subjects with weights outside this range, such as infants and the elderly.

For the avoidance of doubt, reference herein to "treatment" includes curative, palliative and prophylactic treatment.

According to another embodiment of the present invention, the hydrochloride salt of the present invention or a composition thereof may also be used as a combination with one or more other therapeutic agents that are simultaneously administered to a patient to achieve certain particularly desirable therapeutic end results, such as a method of treating pathophysiologically relevant disease processes, including but not limited to (i) bronchoconstriction, (ii) inflammation, (iii) allergy, (iv) tissue destruction, (v) signs and symptoms, such as apnea, cough.

As used herein, the terms "co-administration", "co-administration" and "in combination with …" when referring to the hydrochloride salt of the present invention and one or more other therapeutic agents are intended to mean and do mean and include the following meanings:

administering such a combination of a hydrochloride salt of the invention and a therapeutic agent simultaneously to a patient in need of treatment, when the components are formulated together in a single dosage form that releases the components to the patient substantially simultaneously,

administering such a combination of a hydrochloride salt of the invention and a therapeutic agent to a patient in need of treatment substantially simultaneously, when the components are formulated separately from each other into separate dosage forms, which dosage forms are taken substantially simultaneously by the patient, whereupon the components are released substantially simultaneously to the patient,

administering such combinations of a hydrochloride salt of the invention and a therapeutic agent sequentially to a patient in need of treatment, when the components are formulated separately from each other into separate dosage forms to be taken by the patient in successive times with a significant time interval between each administration, whereupon the components are released to the patient at substantially different times; and

administering such a combination of a hydrochloride salt of the invention and a therapeutic agent sequentially to a patient in need of treatment, when the components are formulated together in a single dosage form which releases the components in a controlled manner, according to which the components are administered simultaneously and/or at different times simultaneously, consecutively and/or overlappingly to the patient,

wherein each portion may be administered by the same or different routes.

Suitable examples of other therapeutic agents that may be used in combination with a compound of formula (I) or a pharmaceutically acceptable salt, derivative form or composition thereof include, but are in no way limited to:

(a) 5-lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists,

(b) leukotriene antagonists (LTRA) comprising LTB₄、LTC₄、LTD₄And LTE₄An antagonist of the activity of a compound of formula (I),

(c) histamine receptor antagonists including H1 and H3 antagonists,

(d) alpha for decongestant use₁-and a₂-an adrenoceptor agonist vasoconstrictor sympathomimetic agent,

(e) short or long acting beta₂An agonist, which is a compound of formula (I),

(f) PDE inhibitors, such as PDE3, PDE4 and PDE5 inhibitors,

(g) the content of the theophylline is determined,

(h) the content of the sodium cromoglycate is as follows,

(i) COX inhibitors, non-selective COX-1 or COX-2 inhibitors (NSAIDs) and selective COX-1 or COX-2 inhibitors (NSAIDs),

(j) glucocorticoids for oral use and for inhalation,

(k) monoclonal antibodies active against endogenous inflammatory entities,

(l) Anti-tumor necrosis factor (anti-TNF-alpha) agents,

(m) adhesion molecule inhibitors comprising VLA-4 antagonists,

(n) kinin-B₁-and B₂-an antagonist of a receptor,

(o) an immunosuppressive agent, wherein,

(p) inhibitors of Matrix Metalloproteinases (MMP),

(q) tachykinin NK₁、NK₂And NK₃(ii) an antagonist of a receptor,

(r) an inhibitor of an elastase,

(s) adenosine A2a receptor agonists,

(t) an inhibitor of urokinase,

(u) compounds acting at dopamine receptors, such as D2 agonists,

(v) modulators of the NF κ B pathway, such as IKK inhibitors,

(w) modulators of cytokine signaling pathways, such as p38MAP kinase or syk kinase,

(x) Agents that can be classified as mucolytics or antitussives,

(y) an antibiotic, wherein the antibiotic is selected from the group consisting of,

(z) an HDAC inhibitor and (z),

(aa) PI3 kinase inhibitors, and,

(bb) CXCR2 antagonists.

According to the invention, preference is given to the combination of a compound of the formula (I) with the following agents:

-an antagonist of H3, and,

-β₂an agonist, which is a compound of formula (I),

-a PDE4 inhibitor which is,

-steroids, in particular glucocorticoids,

-an adenosine A2a receptor agonist,

a modulator of a cytokine signalling pathway, such as p38MAP kinase or syk kinase, or,

leukotriene antagonists (LTRA), which include LTB₄、LTC₄、LTD₄And LTE₄An antagonist of (1).

According to the invention, more preferred are the combinations of compounds of formula (I) with the following agents:

glucocorticoids, especially inhaled glucocorticoids with reduced systemic side effects, which include prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide and mometasone furoate, or

-beta 2 agonists, including, inter alia, salbutamol, terbutaline, bambuterol, fenoterol, salmeterol, formoterol, tulobuterol and salts thereof.

It is to be understood that all references herein to treatment include curative, palliative and prophylactic treatment. The following description relates to therapeutic applications contemplated by the hydrochloride salt of the present invention.

As further illustrated below, the hydrochloride salt of the present invention has the ability to interact with the M3 receptor and thus has a wide range of therapeutic applications, since it plays an important role in the physiology of all mammals.

Accordingly, a further aspect of the present invention relates to the hydrochloride salt of the present invention or compositions thereof for use in the treatment of diseases, disorders and conditions in which the M3 receptor is involved. More particularly, the invention also relates to the hydrochloride salt of the invention for use in the treatment of a disease, disorder or condition selected from the group consisting of:

chronic or acute bronchoconstriction, chronic bronchitis, obstruction of the small airways and emphysema,

obstructive or inflammatory airways diseases of any type, etiology or pathogenesis, in particular selected from: chronic eosinophilic pneumonia, Chronic Obstructive Pulmonary Disease (COPD), COPD including chronic bronchitis, emphysema or dyspnea associated or not with COPD, COPD characterized by irreversible progressive airway obstruction, Adult Respiratory Distress Syndrome (ARDS), highly reactive exacerbations of airways resulting from other drug therapy and airway diseases associated with pulmonary hypertension,

bronchitis of any type, etiology or pathogenesis, in particular bronchitis selected from: acute bronchitis, acute laryngotracheobronchitis, arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, proliferative bronchitis, staphylococcal or streptococcal bronchitis, and alveolar bronchitis,

asthma of any type, etiology or pathogenesis, in particular asthma selected from: atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, idiopathic asthma, true asthma, endogenous asthma due to a pathophysiological disorder, exogenous asthma due to an environmental factor, idiopathic asthma of unknown or recessive cause, non-atopic asthma, bronchial asthma, emphysema-suffering asthma, exercise-suffering asthma, allergen-suffering asthma, cold air-suffering asthma, occupational asthma, infectious asthma due to bacterial, fungal, protozoal or viral infection, non-allergic asthma, incipient asthma, wheezy infant syndrome and bronchiolitis,

the risk of acute lung injury is high,

bronchiectasis of any type, etiology or pathogenesis, in particular a bronchiectasis selected from: columnar bronchiectasis, cystic bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis, and follicular bronchiectasis.

Yet another aspect of the present invention also relates to the use of a hydrochloride salt of the present invention for the preparation of a medicament having M3 antagonist activity. In particular, the invention relates to the use of the hydrochloride salt of the invention or a derivative form thereof for the manufacture of a medicament for the treatment of diseases and/or conditions mediated by the M3 receptor, in particular the diseases and/or conditions listed above.

As a result, the present invention provides a particularly interesting method of treating mammals, including humans, with an effective amount of the hydrochloride salt of the invention or a composition thereof. More precisely, the present invention provides a method of particular interest for the treatment of diseases and/or conditions mediated by the M3 receptor (especially the diseases and/or conditions listed above) in a mammal, including a human, comprising administering to the mammal an effective amount of a hydrochloride salt of the invention.

Brief description of the drawings

FIG. 1 shows the X-ray diffraction pattern of the powder obtained by the measurement.

Fig. 2 shows a PXRD pattern (top: measured pattern of single crystal structure, bottom: calculated pattern of single crystal structure) of example 1.

Fig. 3 shows the DSC curve of example 1.

Detailed Description

Example 1: 5- [3- (3-hydroxy-phenoxy) -azetidin-1-yl]-5-methyl-2, 2-diphenyl Hydrochloride of hexyl amide

To a solution of 5- [3- (3-hydroxy-phenoxy) -azetidin-1-yl ] -5-methyl-2, 2-diphenyl-hexanamide (3.5 g, 7.8 mmol) in methanol (30 ml) was added a 1.25M solution of HCl in methanol (6.3 ml, 7.8 mmol). The solution was stirred at room temperature for 3 hours and then placed in an ice bath for 6 hours. Since no precipitate was observed, the solution was concentrated under reduced pressure to remove some of the solvent (17 ml), and the resulting solution was stirred at room temperature for 16 hours to obtain a precipitate. The suspension was filtered, washed with methanol (10 ml) and dried in a vacuum oven at 40 ℃ to give 2.55 g (67%) of the hydrochloride salt of 5- [3- (3-hydroxy-phenoxy) -azetidin-1-yl ] -5-methyl-2, 2-diphenyl-hexanamide as a white solid.

The melting point of example 1 was determined by Differential Scanning Calorimetry (DSC) using a Perkin Elmer Diamond differential scanning calorimeter. The sample was heated from room temperature to 300 ℃ at 20 ℃/min in a 50 microliter vented aluminum pan. The DSC curve is shown in figure 3. The melting point was confirmed by a strong endotherm at 218.7 ℃ (starting at 215.3 ℃).

Powder X-ray diffraction method

Powder X-ray diffraction images were measured using a Bruker-AXS Ltd. D4 powder X-ray diffractometer equipped with an autosampler, theta-theta goniometer, an automatic beam divergence slit, and a PSDVantec-1 detector. The sample was prepared to be analyzed by placing it on a low background silicon wafer sample holder. The sample was rotated while being irradiated with Cu ka 1X-ray (wavelength =1.5406 a) using an X-ray tube operating at 40 kv/35 ma. The analysis was carried out in the 2 theta range of 2 deg. to 55 deg. using an goniometer set to 0.2 second counts per 0.018 deg. step running in continuous mode. The measured pattern is shown in fig. 1. The resulting powder X-ray diffraction images with intensity and peak position (angular 2 θ error +/-0.1 degrees) are shown in Table 1:

TABLE 1

Determination of the Crystal Structure by Single Crystal X-ray diffraction

The crystal structure of example 1 was measured by single crystal X-ray diffraction method at room temperature using Bruker SMART APEX single crystal X-ray diffractometer and MoK α radiation. Integrating intensities from several exposure series¹Where each exposure covers ω 0.3 °, the exposure time is 30 seconds and the total data set exceeds a hemisphere. Using multiple scanning methods²And correcting the absorbed data. The crystal structure has passed through the Space Group P2₁2₁2₁Using SHELXS-97³Can be successfully obtained by the direct method of (1), and can use SHELXL-97⁴The correction is performed by a least squares method.

SMART v5.622 (control) and SAINT v6.02 (integration) software, Brukeraxs, Madison, Wis 1994.

SADABS, procedure for scaling and correcting the flat panel detector data, g.m. sheldrick,university, 1997 (based on the method of R.H.Blesseng, Acta Crystal.1995, A51, 33-38).

SHELXS-97, Crystal Structure resolution procedure. Sheldrick, germanyUniversity, 1997, version 97-2.

SHELXL-97, Crystal Structure modification program. Sheldrick, germanyUniversity, 1997, version 97-2.

Calculation of powder X-ray diffraction patterns from the Crystal Structure of example 1

Using Accelrys MS modeling^TM[3.0 edition]The "Reflex powder diffraction" module of (1) calculates the 2 theta angle and relative intensity of the single crystal structure of example 1. The relevant simulation parameters were:

wavelength =1.5406 angstroms (Cu K α)

Polarization factor =0.5

Pseudo-Woedt (Pseudo-Voigt) curve (U =0.01, V = -0.001, W =0.002)

The calculated pattern represents the pure phase pattern of example 1 because it is derived from a single crystal structure. A comparison of the measured pattern with the calculated pattern is shown in fig. 2 and demonstrates that the host is a single crystal structure. The subtle difference between the peak intensities can be attributed to the preferred orientation effect in the measurement pattern. Fig. 2 shows a PXRD pattern (top: measured pattern of single crystal structure, bottom: calculated pattern of single crystal structure) of example 1.

Preparation example 1: 5- [3- (3-hydroxyphenoxy) azetidin-1-yl]-5-methyl-2, 2-diphenyl Aminocaproamide

A suspension of 5- [3- (3-hydroxyphenoxy) azetidin-1-yl ] -5-methyl-2, 2-diphenyl-hexanenitrile (0.16 g, 0.38 mmol, 1 eq), tert-amyl alcohol (1.8 ml, 12 ml/g) and KOH (0.41 g, 7.26 mmol, 20 eq) was heated to 80 ℃ for 2 days whereupon HPLC showed the reaction to be complete. The reaction was cooled to ambient temperature and then partitioned between water and TBME, the aqueous layer was acidified to pH8 using aqueous HCl, the layers were separated and the organic layer was concentrated to provide 0.11 g (68%) of 5- [3- (3-hydroxyphenoxy) azetidin-1-yl ] -5-methyl-2, 2-diphenylhexanamide as a colorless oil.

¹H NMR(400MHz,CDCl₃):1.10(s,6H),1.22-1.34(m,2H),2.42-2.55(m,2H),3.28-3.40(m,2H),3.65-3.88(m,2H),4.70-4.80(m,1H),5.55-5.70(brs,2H),6.23-6.36(m,2H),6.45-6.53(m,1H),7.03-7.12(m,1H),7.19-7.39(m,10H);LRMS ESI m/z445[M+H]⁺

Preparation example 2: 5- [3- (3-hydroxyphenoxy) azetidin-1-yl]-5-methyl-2, 2-diphenyl Cyano-capronitriles

To methanesulfonic acid (200 ml, 5 ml/g) was added 5- [3- (3-methoxyphenoxy) azetidin-1-yl ] -5-methyl-2, 2-diphenyl-hexanenitrile (40 g, 90.8 mmol, 1 eq) at ambient temperature under a nitrogen atmosphere, followed by DL-methionine (40.6 g, 272 mmol, 3 eq) to produce a solution. The solution was stirred at ambient temperature for 3 days and at 30 ℃ for 1 day, after which additional DL methionine (5.42 g, 36 mmol, 0.4 eq) was added and maintained at 30 ℃ for an additional 2 days, whereupon HPLC showed the reaction to be complete (<5% SM).

The mixture was diluted with i-PrOAc (400 ml) and then carefully diluted with water (400 ml). The resulting layers were mixed for 15 minutes and then separated. The organic layer was washed with 1M NaOH (400 ml), then water (2 × 200 ml), then MgSO₄Dried and concentrated under reduced pressure at 40 ℃ to a white solid. The solid was resuspended in toluene (160 ml, 4 ml/g) at about 5 ℃ for 1 hour, then filtered, washed with cold toluene (80 ml, 2 ml/g) and dried in a vacuum oven at 50 ℃ for 2 days to obtain 5- [3- (3-hydroxyphenoxy) azetidin-1-yl as a white solid]29.3 g (76%) of 5-methyl-2, 2-diphenyl-hexanenitrile. HPLC analysis shows>98% area.

¹H NMR(300MHz,CDCl₃):0.98(s,6H),1.35-1.44(m,2H),2.41-2.52(m,2H),3.18-3.26(m,2H),3.48-3.57(m,2H),4.65-4.74(m,1H),6.26-6.29(m,1H),6.32-6.37(m,1H),6.43-6.47(m,1H),7.12(t,J8.2Hz,1H),7.25-7.44(m,10H)

Preparation example 3: 5- [3- (3-methoxyphenoxy) azetidin-1-yl]-5-methyl-2, 2-bis Phenyl-hexanenitrile

In N₂Under atmosphere, ZrCl was added portionwise to ice-cooled THF (700 mL)₄(80.4 g, 0.35 mol, 2.1 eq.) while maintaining the temperature below 15 ℃ gives a brown suspension. The mixture was then further cooled in an ice/MeOH bath, followed by addition of MeMgCl (3M in THF, 493 ml, 1.48 mol, 9 eq.) over 1 hour while maintaining the temperature below 0 ℃. Slowly adding the pre-made 5- [3- (3-methoxyphenoxy) azetidin-1-yl group to the Zr/Grignard solution]-5-oxo-2, 2-diphenyl-valeronitrile (70 g, 0.164 mol, 1 eq) dissolved in THF (210 ml, 3 ml/g) with controlled exotherm to temperature below 0 ℃. The resulting brown suspension was maintained at 0 ℃ for 6.5 hours, after which Me-THF (700 ml) was added, followed by careful use of NH₄Aqueous Cl solution (400 ml of saturated NH were used₄Cl +500 ml water prepared beforehand) quench the reaction. After separation, the organic layer was washed with water (3 × 350 ml), MgSO₄Drying and exchange of the solvent to EtOH at 40 ℃ and reduced pressure gave a precipitate with a final volume of 210 ml (3 ml/g). The suspension was stirred at ambient temperature for 18 hours, then cooled in an ice bath for 1 hour, filtered, washed with EtOH (140 ml, 2 ml/g) and dried in a vacuum oven at 45 ℃ for 5 hours to obtain 5- [3- (3-methoxyphenoxy) azetidin-1-yl as a white solid]43.1 g (60%) of 5-methyl-2, 2-diphenyl-hexanenitrile. HPLC analysis shows>99% area.

¹H NMR(400MHz,CDCl₃):0.90-1.03(m,6H),1.31-1.44(m,2H),2.41-2.56(m,2H),3.07-3.24(m,2H),3.42-3.54(m,2H),3.77(s,3H),4.63-4.74(m,1H),6.28-6.38(m,2H),6.48-6.55(m,1H),7.26-7.49(m,11H);LRMS APCl m/z441[M+H]⁺

Preparation example 4: 5- [3- (3-methoxyphenoxy) azetidin-1-yl]-5-oxo-2, 2-bis Phenyl-valeronitrile

To a suspension of 4-cyano-4, 4-diphenyl-butyric acid (300 g, 1.13 mol, 1 eq) in EtCN (3.0 l, 3 ml/g) was added DMAP (13.82 g, 0.11 mol, 0.1 eq), 3- (3-methoxyphenoxy) azetidine hemi-oxalate (253.5 g, 1.13 mol, 1 eq) at room temperature followed by WSCDI (325.2 g, 1.68 mol, 1.5 eq) giving a slight bubbling phenomenon with an exotherm of 10 ℃ and dissolution into a solution. After 2 hours, the reaction was deemed complete by HPLC (no amine detected). 2M HCl (1.2L, 4 mL/g) was added and the biphasic mixture was stirred for 10 min before separation and the organic layer was washed with 2M NaOH (1.5L, 5 mL/g) and water (2X 1.5L).

The solution was concentrated to dryness under reduced pressure at 40 ℃ and replaced with MeOH. This operation was repeated to remove all the EtCN and the resulting hot methanol solution (8.33 ml/g) with a volume of 2.5 l was allowed to cool, yielding a viscous suspension. The suspension was cooled in an ice bath for 2 h, then filtered, washed with MeOH (600 ml, 2 ml/g) and the solid was dried under vacuum at 45 ℃ for 18 h to obtain 347 g (72%) of 5- [3- (3-methoxyphenoxy) azetidin-1-yl ] -5-oxo-2, 2-diphenyl-valeronitrile as a white solid. HPLC analysis showed >98% area.

¹H NMR(300MHz,d₆-dmso):2.07-2.16(m,2H),2.69-2.77(m,2H),3.70-3.78(m,1H),3.72(s,3H),3.94-4.00(m,1H),4.21-4.29(m,1H),4.42-4.45(m,1H),4.92-5.00(m,1H),6.36-6.42(m,2H),6.54-6.59(m,1H),7.16-7.23(m,1H),7.30-7.40(m,2H),7.41-7.46(m,8H)

Preparation example 5: 3- (3-methoxyphenoxy) azetidine semi-oxalate

To a suitable hydrogenation vessel was added 1-benzhydryl-3- (3-methoxyphenoxy) azetidine (300 g, 0.87 mol, 1 eq.), Pd (OH)₂(20 wt% on carbon) (60 g, 20 wt%) and EtOH (6 l, 20 ml/g). The mixture was placed in 60psi H₂Stirred at room temperature until the reaction was complete after 48 hours (HPLC,<5%SM)。

the reaction mixture was filtered over Arbocel and washed with copious EtOH, then concentrated to a volume of 1.2 l (4 ml/g) at 40 ℃ and reduced pressure. To the resulting solution was added oxalic acid (39.11 g, 0.43 mmol, 0.5 eq) in portions at ambient temperature to give a viscous suspension and an exotherm of 15 ℃ and the mixture was stirred at room temperature for 3 days.

The suspension was cooled in an ice bath for 2 hours, then filtered, washed with EtOH (600 ml, 2 ml/g) and the solid was dried under vacuum at 50 ℃ for 18 hours to give 165 g (85%) of 3- (3-methoxyphenoxy) azetidine hemi-oxalate as a white solid. HPLC analysis showed >96% area.

Preparation example 6: 1-benzhydryl-3- (3-methoxyphenoxy) azetidines

To a solution of 1-benzhydryl-azetidin-3-yl methanesulfonate (1169 g, 3.68 mol, 1 eq) in EtCN (2.33L, 2 mL/g) was added K at room temperature₂CO₃(610.6 g, 4.42 mol, 1.2 eq). Adding a pre-prepared slurry to the obtained slurryIn EtCN (3.50L, 3 mL/g) and in N₂The mixture was heated to 80 ℃ under an atmosphere for 18 hours, whereupon completion of the reaction was observed (HPLC showed,<5% methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester).

After cooling to ambient temperature, 1M NaOH (5.85 l, 5 ml/g) was added and the resulting solution was stirred for about 15 minutes before separation. The resulting layers were partitioned and the organic layer was washed with 1M NaOH (3.51L, 3 mL/g) and brine (116 g NaCl in 5.58L water, 5 mL/g). The organic layer was subjected to atmospheric distillation and the solvent was exchanged for MeOH by concentration to a low volume (2 ml/g) and then MeOH was added in sequence to give a suspension of 4 ml/g,¹HNMR detected no EtCN.

The suspension was cooled to 0 ℃, held for 3 hours, then filtered, washed with MeOH (2.5 l) and the solid was dried under vacuum at 50 ℃ for 18 hours to obtain 944 g (74%) of PF1261660 as a white solid. HPLC analysis showed >99% area.

Abbreviations

rt = room temperature

Me = methyl group

Ph = phenyl

SM = raw Material

h = hour

mins = min

d = day

In vitro Activity of the hydrochloride salt of the invention

Potency assay

M determination in CHO-K1 cells transfected with NFAT-beta-lactamase Gene₃And (4) the efficiency. Transfection of recombinant expression of human muscarinic M with NFAT-. beta. -Lac Zeo plasmid₃CHO (Chinese hamster ovary) cells of the recipient. Cells were grown in DMEM with Glutamax-1 supplemented with 25mM HEPES (C: (M))Life Technologies32430-027), which contains 10% FCS (fetal calf serum; sigma F-7524), 1nM sodium pyruvate (Sigma S-8636), NEAA (non-essential amino acids; invitrogen11140-035) and 200. mu.g/ml Zeocin (Invitrogen R250-01).

hM₃beta-Lac assay protocol

When the cells reached 80-90% confluence, at 37 ℃ and in the presence of 5% CO₂The enzyme-free cell dissociation solution (Life technologies13151-014) was incubated with the cells for 5 minutes, and the cells were harvested for analysis. The isolated cells were collected in warm growth medium and centrifuged at 2000rpm for 10 minutes, washed in PBS (phosphate buffered saline; Life technologies14190-094) and centrifuged again as just before. In growth medium (composition as described above), at 2 × 10⁵The cells were resuspended per ml. To each well of 384-well black clear plates (Greiner Bio One781091-PFI) 20. mu.l of the cell suspension was added. The assay buffer used was PBS supplemented with 0.05% Pluronic F-127(Sigma9003-11-6) and 2.5% DMSO. At 37 deg.C/5% CO₂Next, 80nM carbamoylcholine (Aldrich N240-9) was used to stimulate muscarinic M by incubation with cells for 4 hours₃Receptor signal and was monitored at the end of the incubation period using a Tecan spectra fluor + plate reader (λ -excitation wavelength 405 nm, emission wavelength 450 nm and 503 nm). At the beginning of the 4 hour incubation period, the compound to be tested was added to the analyte and the compound activity was measured as concentration-dependent inhibition of the carbamoylcholine-induced signal. Plotting inhibition curves and generating IC using 4-parameter sigmoidal curve fitting₅₀Values, which were converted to Ki values using Cheng-Prusoff calibration and to K for carbamoylcholine in this assay_DThe value is obtained.

Tracheal analysis of guinea pigs

At elevated concentration of CO₂Male Dunkin-Hartley guinea pigs weighing 350-450 g were picked and then bled for the vena cava. The trachea is removed from the larynx at room temperature to the point of entry into the thorax and then placed in a fresh and oxygenated modified Krebs buffer (Krebs contains 10. mu.M propranolol, 10. mu.M guanethidine and 3. mu.M indomethacin). The trachea is opened by cutting the cartilage opposite the tracheal muscle. Cut into strips of about 3-5 cartilage rings wide. At one end of the strip, cotton thread was attached to the cartilage for connection to the force transducer, and at the other end a loop of cotton thread was made to anchor the tissue in the organ bath. These strips were placed in a5 ml organ bath filled with air-filled warm (37 ℃) modified Krebs. The pump flow rate was set to 1.0 ml/min and the tissue was washed continuously. The tissue was placed under an initial tension of 1000 mg. The tissue was re-tensioned after 15 and 30 minutes and then allowed to equilibrate for 30-45 minutes.

Subjecting the tissue to Electric Field Stimulation (EFS) of the following parameters: 10 second burst/2 min, 0.1 ms pulse width, 10 hz and 10-30 v. Within the specified range, the voltage was increased by 5 volts every 10 minutes until the maximum contractile response for each tissue was observed. This exact maximum voltage for each tissue was then used throughout the remainder of the experiment. After 20 minutes of equilibration for the EFS, the pump was stopped and control readings (4-5 reactions) were taken after 15 minutes over a period of 8-10 minutes. Then at 30xKi, compound (human M expressed in CHO cells in a filter binding assay) was added to each tissue in large doses₃On-receptor assay) and incubated for 2 hours. The compounds were then washed from the tissue using a quick wash method with modified Krebs for 1 minute and the flow rate was restored to 1 ml/min in the remainder of the experiment. At the end of the experiment, tissues were challenged with histamine (1 μ M) to determine viability. Use ofThe software automatically collected the readings taken during the experiment. The raw data was converted to a percent response taking into account the measure of suppression of the EFS response. After the onset of washout, the time required for the tissue to recover 25% from the induced inhibition state was recorded and used as a measure of the duration of action of the compound. Tissue viability limited the duration of the experiment to 16 hours after compound washout. Compounds are typically tested at n =2 to 5 to assess duration of action.

Alternatively, the following guinea pig tracheal analysis may also be used:

trachea was removed from male Dunkin-Hartley guinea pigs (weighing 350-. The tracheal strip was suspended between an isometric strain gauge and a fixed tissue hook (with muscle in the horizontal plane) in a5 ml tissue bath under an initial tension of 1 gram and warmed (37 ℃) and inflated (95% O) containing 3 μ M indomethacin and 10 μ M guanethidine₂/5%CO₂) Soaking in Krebs solution. The tissue was placed between parallel platinum wire electrodes (approximately 1 cm gap). A constant flow rate of 1 ml/min of fresh Krebs solution (with the above-described components) was maintained in the tissue bath using a peristaltic pump. The tissue was allowed to equilibrate for 1 hour, and the tissue was re-tensioned to 1 gram from 15 and 30 minutes after the beginning of the equilibration period. At the end of the equilibration, the following parameters were used to Electrical Field Stimulate (EFS) the tissue: 10 volts, 10 hertz, 0.1 millisecond pulse width, 10 second burst/2 minutes. In each tissue, a voltage response curve was constructed (all other stimulation parameters were held constant) in the range of 10-30 volts to determine just the maximum stimulation. Using these stimulation parameters, EFS responses were 100% neuro-mediated and 100% cholinergic as evidenced by blockade by 1 μ M tetrodotoxin or 1 μ M atropine. The tissue stimulation was then repeated at 2 minute intervals until the response was reproducible. The peristaltic pump was stopped 20 minutes before the addition of study compound and the mean tic contraction over the last 10 minutes was scored as a control response. Study compounds were added to the tissue bath, where each tissue received a single concentration of compound and allowed to equilibrate for 2 hours. 2 hours after addition, inhibition of EFS response was recorded and IC was generated using a range of compound concentrations on tracheal strips from the same animals₅₀Curve line. The tissue was then washed rapidly and perfusion was reestablished using 1 ml/min of Krebs solution. These tissues were restimulated for 16 hours and recovery of EFS response was recorded. At the end of 16 hours, 10 μ M histamine was added to the bath to confirm tissue viability. self-IC₅₀The curve identifies the exact maximum concentration of antagonist (the concentration tested shows the response>70% inhibition but less than 100%) And the time required for 25% recovery of the induced inhibition (T) was calculated in the tissues receiving this concentration₂₅). Compounds are typically tested at n =2 to 5 to assess duration of action.

Claims (8)

1. Hydrochloride salt of 5- [3- (3-hydroxyphenoxy) azetidin-1-yl ] -5-methyl-2, 2-diphenylhexanamide.
2. 2.5- [3- (3-hydroxyphenoxy) azetidin-1-yl]Non-solvated crystalline form of hydrochloride salt of (E) -5-methyl-2, 2-diphenylhexanamide when Cu K.alpha.is used₁Measured in radiation (wavelength of 1.5406 angstroms), it has an X-ray diffraction pattern characterized by the following major X-ray diffraction pattern peaks expressed in 2-theta angles

   2-theta angle (+/-0.1 degree) 9.1 11.2 13.7 18.3 19.7

   。
3. 3. A pharmaceutical composition comprising at least an effective amount of a compound according to claim 1 or 2.
4. 4. Use of a compound of claim 1 or 2 in the preparation of a medicament having M₃Use in medicine of antagonist activity.
5. 5. Use of a compound according to claim 1 or 2 in the manufacture of a medicament for the treatment of a disease, disorder or condition selected from the group consisting of:

   chronic or acute bronchoconstriction;

   obstructive or inflammatory airways diseases of any type, etiology or pathogenesis;

   bronchitis of any type, etiology or pathogenesis;

   asthma of any type, etiology or pathogenesis;

   acute lung injury; and

   any type, etiology or pathogenesis of bronchodilation.
6. 6. The use according to claim 5, wherein the diseases, disorders and conditions are selected from the group consisting of:

   chronic eosinophilic pneumonia, chronic obstructive pulmonary disease, adult respiratory distress syndrome, exacerbation of airway hyperreactivity resulting from other drug treatments, and airway diseases associated with pulmonary hypertension;

   acute bronchitis, acute laryngotracheobronchitis, arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, proliferative bronchitis, staphylococcal or streptococcal bronchitis, and alveolar bronchitis;

   atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, idiopathic asthma, true asthma, endogenous asthma due to a pathophysiological disorder, exogenous asthma due to an environmental factor, idiopathic asthma of unknown or recessive cause, bronchitic asthma, emphysema-suffering asthma, exercise-induced asthma, allergen-induced asthma, cold air-induced asthma, occupational asthma, infectious asthma due to bacterial, fungal, protozoal or viral infection, non-allergic asthma, incipient asthma, wheezy infant syndrome, and bronchiolitis;

   chronic bronchitis, small airway obstruction and emphysema; and

   columnar bronchiectasis, cystic bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis, and follicular bronchiectasis.
7. 7. A combination of a compound according to claim 1 or 2 and a therapeutic agent selected from:

   (a) 5-lipoxygenase inhibitors or antagonists of 5-lipoxygenase activating protein,

   (b) (ii) a leukotriene antagonist,

   (c) a histamine receptor antagonist which is selected from the group consisting of,

   (d) used for relieving congestionAlpha of medicine₁-and α₂-an adrenoceptor agonist vasoconstrictor sympathomimetic agent,

   (e) short or long acting beta₂An agonist, which is a compound of formula (I),

   (f) a PDE inhibitor which is capable of inhibiting the activity of a compound,

   (g) the content of the theophylline is determined,

   (h) the content of the sodium cromoglycate is as follows,

   (i) a COX inhibitor is used in the treatment of,

   (j) glucocorticoids of the oral and inhaled type,

   (k) monoclonal antibodies active against endogenous inflammatory entities,

   (l) An anti-tumor necrosis factor agent which is a pharmaceutically acceptable agent,

   (m) an adhesion molecule inhibitor, wherein,

   (n) kinin-B₁-and B₂-an antagonist of a receptor,

   (o) an immunosuppressive agent, wherein,

   (p) inhibitors of matrix metalloproteinases,

   (q) tachykinin NK₁、NK₂And NK₃(ii) an antagonist of a receptor,

   (r) an inhibitor of an elastase,

   (s) adenosine A2a receptor agonists,

   (t) an inhibitor of urokinase,

   (u) compounds which act on dopamine receptors,

   (v)NF_Κa modulator of the B pathway, a compound of the formula,

   (w) modulators of cytokine signaling pathways,

   (x) Agents that can be classified as mucolytics or antitussives,

   (y) an antibiotic, wherein the antibiotic is selected from the group consisting of,

   (z) an HDAC inhibitor and (z),

   (aa) PI3 kinase inhibitors, and,

   (bb) CXCR2 antagonists.
8. 8. The composition of claim 7, wherein the leukotriene antagonist is LTB₄、LTC₄、LTD₄And LTE₄An antagonist; the histamine receptor antagonists are H1 and H3 antagonists; the PDE inhibitors are PDE3, PDE4 and PDE5 inhibitors; what is needed isThe adhesion molecule inhibitor is a VLA-4 antagonist; the compound acting on dopamine receptor is a D2 agonist; the NF_ΚModulators of the B pathway are IKK inhibitors; the modulator of the cytokine signaling pathway is p38MAP kinase or syk kinase.