RS52636B - MESILATE IS 5- (2 - {[6- (2,2-DIFLUORO-2-PHENYLETOXY) HEXYL] AMINO} -1-HYDROXYETHYL) -8-HYDROXYCHINOLIN-2 (1H) -ONE AS AN ANTAGONIST OF BETA 2 ADRENERGY RECEPTOR - Google Patents

Abstract

The mesylate is 5- (2 - {[6- (2,2-difluoro-2-phenylethoxy) hexyl] amino} -1-hydroxyethyl) -8-hydroxyquinolin-2 (1H) -one and its pharmaceutically acceptable solvents. The application contains another 13 patent claims.

Description

FIELD OF INVENTION

[0001] This invention is directed to new water-soluble methanesulfonic acid salts (mesylates) of 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one, its enantiomers and its solutions (solvates). The present invention is also directed to pharmaceutical substances comprising salts, methods for their use in the treatment of respiratory diseases which can improve (32) adrenergic receptor activity, and processes and agents useful for obtaining such salts.

STATE OF THE ART

[0002] O 2 -adrenergic receptor antagonists are preferably administered directly into the respiratory tract by inhalation when used to treat pulmonary or respiratory disorders. Several types of pharmaceutical inhalation devices have been developed to administer therapeutic agents by inhalation including dry powder inhalers (DPIs), metered dose inhalers (MDIs), and nebulizer inhalers.

[0003] Liquid formulations, especially aqueous (aquatic) formulations, are easily administered because they are inhaled during normal breathing through a mouthpiece or face mask. They are especially suitable for young or elderly people who are most often patients who need such therapy and who have difficulty using other devices.

[0004] The protection sought for 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one is claimed and described in published patent application WO 2006/122788 A1. And its nadisylate salts are described in WO 2008/09570.

[0005] lako5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one shows appropriate pharmacological behavior, it has been shown that it is difficult to obtain it in the form of a salt that is soluble in water and especially very stable when it is in aqueous solutions.

[0006] So far there is no data that any water-soluble salt of 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-8-hydroxy-quinolin-2(1/-/)-one has the desired properties.

[0007] In this regard, there is a need for a water-soluble and stable salt of this compound that can be used in the preparation of aqueous solutions, especially for some patients such as children and elderly patients.

BRIEF DESCRIPTION OF THE INVENTION

[0008] It has been established that salts of methanesulfonic acid 5-(2-{[8-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one can be obtained in the form of a powder which is very soluble and has a very high stability in aqueous solutions and formulations and so that the appropriate use life on

shelf suitable for storage and sale in the market

[0009] The present invention provides the mesylate salt of 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one and pharmaceutically acceptable solvates thereof.

[0010] The present invention also provides a pharmaceutical substance comprising a salt of the present invention and a pharmaceutically acceptable carrier. The present invention also encompasses combinations comprising a salt of the present invention and one or more therapeutic agents and pharmaceutical substances comprising such combinations.

[0011] This invention also includes the synthetic processes and intermediates described herein, which are useful for obtaining the salts of this invention.

[0012] The present invention also provides a salt, pharmaceutical substance or combination of the present invention as described herein for use in the treatment of pulmonary diseases or conditions ameliorated by [32] adrenergic receptor activity such as asthma or chronic obstructive pulmonary disease in mammals. The present invention also provides the use of this salt, pharmaceutical substance or combination of the present invention in the manufacture of a medicament for the treatment of these diseases.

BRIEF DESCRIPTION OF THE PICTURES

Figure 1 shows the structure by DSC (differential scanning calorimetry) of 5-(-2-(6-(2,2-difluoro-2-phenylethoxy)hexylamino)-1(R)-hydroxyethyl)-8-hydroxyquinolin-2(1 H )-one mesylate.

DETAILED DESCRIPTION OF THE INVENTION

[0014] When describing these salts, substances and methods of the present invention, the following terms have the following meanings, unless otherwise indicated.

[0015] The term "therapeutically effective amount" refers to an amount sufficient to effect treatment when administered to a patient in need of treatment.

[0016] The term "therapy" as used herein refers to the treatment of a disease or medical condition in a human patient which includes. (a) prevention of disease or health condition, t. j. prophylactic treatment of the patient; (b) aggravation of a disease or medical condition, i.e., causing regression of the disease or medical condition in the patient; (c) aggravation of a disease or medical condition, i.e., slowing down the development of a patient's disease or medical condition; or

(d) alleviating symptoms of a disease or medical condition in a patient

[0017] The phrase "pulmonary disease or condition associated with 32 adrenergic receptor activity" includes all pulmonary diseases and/or conditions now known, or which in the future will be determined to be associated with p2 adrenergic receptor activity. Such disease states include, but are not limited to, asthma and chronic obstructive pulmonary disease (including chronic bronchitis and emphysema).

[0018] The term "solution" refers to a complex or aggregate formed by one or more molecules of a dissolved substance, i.e. a salt of the present invention or a pharmaceutically acceptable salt thereof, and one or more solvent molecules. Such solvents are most often crystalline solids that have a really stable molar ratio of solute to solvent. As representative solvents we mention only by way of example, water, ethanol, and isopropanol and the like. When the solvent is water, the resulting solution is a hydrate.

[0019] It is clear that the term "or a solution or a stereoisomer thereof" should include all permutations of solvates and stereoisomers, such as a solution of a stereoisomer of a salt according to formula (I).

[0020] The salts of this invention contain a chiral center. Therefore, the invention includes racemic mixtures, enantiomers, and mixtures enriched in one of the enantiomers. The scope of this invention according to the description and claims includes racemic forms of salts as well as individual enantiomers and enantiomer-enriched mixtures.

Of particular interest are the salts: (R,S) 5-(2-{[6-(2,2-difluoro-2-phenyl)ethoxy)hexy)]amino}-1-hydroxyethyl)-8-hydroxyquinoline-2(1H;-o/i, mesylate

5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(R)-hydroxyethyl)-8-hydroxyquinolin-2(1/-y)-one, mesylate

and pharmaceutically acceptable salts thereof.

[0022] It is most preferable that the salt is 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(R)-hydroxy-ethyl)-8-hydroxyquinolin-2(1H)-one mesylate according to formula (I):

and pharmaceutically acceptable solvents thereof.

[0023] The present invention also encompasses pharmaceutical substances containing a therapeutically effective amount of a salt as defined above and a pharmaceutically acceptable carrier.

[0024] In an embodiment of the present invention, the pharmaceutical substance further comprises a therapeutically effective amount of one or more therapeutic agents.

[0025] One of the embodiments of this invention is that the pharmaceutical substance is formulated for oral or intravenous drug administration.

[0026] The salts of the present invention as defined above may also be combined with one or more other therapeutic agents, in particular one or more drugs selected from the group consisting of corticosteroids, anticholinergic agents and PDE4 inhibitors. The present invention is also directed to a combination comprising a salt of the present invention with one or more other therapeutic agents, in particular one or more drugs selected from the group consisting of corticosteroids, anticholinergic agents and PDE4 inhibitors.

[0027] The present invention is also directed to a salt according to formula (I) for use in the treatment of a pulmonary disease that can be improved by the action of the 02 adrenergic receptor such as asthma or chronic obstructive pulmonary disease.

[0028] This invention is also directed to a method for the treatment of a disease or condition in a mammal that is amenable to amelioration by means of a p2 adrenergic receptor, a method comprising administering to a mammal a drug, a therapeutically effective amount of a pharmaceutical substance containing an antagonist (32 adrenergic receptor according to this invention. Of particular importance is the method applied to the treatment of a disease or condition that is lung disease, preferably asthma or chronic obstructive pulmonary disease.

[0029] The present invention is also directed to the use of a salt of formula (I) in the manufacture of a medicament for the treatment of a pulmonary disease or condition in a mammal. A mammal is a desirable human being. Particularly relevant lung diseases or conditions are asthma or chronic obstructive pulmonary disease.

General synthetic procedures

[0030] The salts of this invention can be made using the methods and procedures described herein, or using similar methods and procedures. It is understood that where the most common or preferred process conditions are given (ie, reaction temperatures, times, reactant mass ratio OR REACTANT MOLE RATIO, solvents, pressure levels, etc.), other foreign processes may also be used unless otherwise noted. The best reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by those skilled in the art by routine optimization procedures.

[0031] Processes for obtaining the salts of this invention are provided as additional embodiments of this invention and are shown by means of the procedures below.

[0032] The salts of this invention can be synthesized from 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1/-/)-one and from methanesulfonic acid which is commercially available from, for example, Aldrich.

[0033] Suitable inert diluents for this reaction include, but are not limited to, acetone, ethyl acetate, dimethylformamide, chloroform, methanol, ethanol, isopropanol, 2-butanol and the like, and mixtures thereof, preferably containing water. For example, the free base can be contacted with methanesulfonic acid dissolved in 2-butanol.

[0034] Upon completion of any of the following reactions, the salt can be isolated from the reaction mixture by any of the standard means such as precipitation, concentration, centrifugation, and the like.

[0035] It is understood that although specific process conditions are given (ie, reaction temperatures, times, mole ratio of reactants, solvents, pressure levels, etc.), other process conditions may also be used unless otherwise noted.

[0036] The water-soluble mesylate salt of this invention usually contains between about 0.85 and 1.15 molar equivalents of methanesulfonic acid per molar equivalent of free base, most often about 1 molar equivalent of methanesulfonic acid per molar equivalent of free base.

[0037] The mole ratios described in the methods of the present invention can be readily determined by a variety of methods known to those skilled in the art. For example, such molar ratios can be readily determined by<1>H NMR. Alternatively, elemental analysis and HPLC procedures can be used to determine the molar ratio.

[0038] To make the mesylate salt according to this invention, the free base is most often dissolved in a solvent such as acetone, ethyl acetate, dimethylformamide, chloroform, methanol, ethanol, isopropanol, 2-butanol and their mixtures, especially 2-butanol to obtain a 0.20-0.25 M solution which is then heated to approximately 60-70°C. Then, a solution of 0.45-0.50 M methanesulfonic acid is diluted with a suitable solvent into the heating solution. The mixture is then stirred for 60 minutes at 70-75°C and then cooled to 20/25°C and gently stirred overnight. The resulting precipitate is isolated by filtration, washed with a suitable solvent and dried, for example, in a vacuum at 50°C.

EXAMPLES

[0039] General. Reagents, starting materials, and solvents were purchased commercially from suppliers and used as received.

[0040] A particularly good solvent used to obtain the mesylate salt of 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]-amino}-1(/:?)-hydroxyethyl)-8-hydroxyquinolin-2(1/-/)-one was 2-butanol. The reaction involved dissolving 11.4 g (24.8 mmols) of the free base in 104 ml of 2-butanol to form a 0.24 M solution that was heated to approximately 75°C. Then, a solution of 2.37 g (24.6 mmol) of methylsulfonic acid in 52 ml of 2-butanol was added dropwise over 30 minutes to the heated solution. When the addition was complete, the mixture was then stirred for 1 hour at 70-75°C and then cooled to room temperature and gently stirred at this temperature overnight. The formed precipitate was isolated by filtration, washed with 2-butanol (15 ml) and dried under vacuum at 50°C. 10.93 g (yield: 79%) of a white solid was then obtained with a purity of 97.5% by HPLC (high performance liquid chromatography).

[0041] Differential scanning corimetry (DSC) analysis was obtained using a DSC-821 Mettler-Toledo, serial number 5117423874. Samples were measured in an aluminum shallow dish (pan), an aluminum lid was placed on top of the sample and pressed with a brass rod. The samples were equilibrated at 30°C and heated at 10°C/min to 300°C. The instrument was calibrated using indium and zinc standards.

Figure 1 shows the DSC structure of 5-(-2-(6-(2,2-difluoro-2-phenylethoxy)hexyl-amino)-1(R)-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one mesylate salt. The sample exhibits a broad and small endotherm starting at about 62°C, and a characteristic high endotherm starting at 183.04°C corresponding to the melting or decomposition of the salt. This indicates that the sample does not convert to any other polymorphs and does not undergo decomposition thus confirming its high stability.

Water solubility test:

[0043] The solubility of various salts of 5-(-2-(6-(2,2-difluoro-2-phenylethoxy)hexyl-amino)-1(R)-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one in water at room temperature was determined together with the solubility of formoterol fumarate and salmeterol xinafoate. The results are shown in Table 1 below.

[0044] As can be seen for the table, the mesylate salt of this invention shows a higher degree of solubility compared to the corresponding hydrogensulfonate or nadisylate salt. In addition, the mesylate of the present invention exhibits a higher degree of solubility when compared to formoterol fumarate and salmeterol xinafoate, two commercially available long-acting O2 antagonists.

Stability testing:

[0045] The stability of the mesylate salt of the present invention was evaluated under conditions of accelerated stability. About 5 mg of the mesylate salt of this invention was introduced into each of the 10 ml amber glass vials. These vials were stored at 40°C for 30 days and at 80°C for 15 and 30 days. After the stress condition, the samples were dissolved in 5 ml of the appropriate solvent. The increase in impurity was determined using HPLC (high performance liquid chromatography) analysis and calculation of relative areas. The results are shown in Table 2.

[0046] 15-day stability at 80°C indicates identity longer than 1 year at 30°C. Stability of 30 days at 80°C Purity for more than 1 year at 40°C. The percentage of impurities observed in all forcing conditions is less than 5%, thus indicating that there was no significant salt degradation.

Pharmaceutical substances

[0047] Pharmaceutical substances according to this invention include a therapeutically effective amount of mesylate salt 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one or enantiomer or its pharmaceutically acceptable solution and pharmaceutically acceptable carrier.

[0048] Pharmaceutical formulations may conveniently be presented in unit dose form and may be prepared by any method known in the art of pharmacy. All procedures include the step of bringing the active ingredient(s) into contact with the carrier. In general, formulations are obtained by uniformly and intimately bringing the active ingredient into contact with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

[0049] Dry powder substances for topical application to the lungs by inhalation can, for example, be in capsules and cartridges of, for example, gelatin or blisters of, for example, laminated aluminum foil, for use in an inhaler or insufflator. Formulations generally contain a powder mixture of the inhalation salts of the present invention and a suitable powder base (carrier) such as lactose and starch. Preference is given to the use of lactose. The powder base may include additional components such as preservatives, stabilizers, absorption enhancers or an aerodynamic modifier.

[0050] Each capsule or cartridge may generally contain between 0.1 mg and 150 mg of each therapeutically active ingredient. Alternatively, the active ingredient/(s) may be formulated without excipients.

[0051] The packaging of the formulation may be suitable for administration as a unit dose or multiple doses. In the case of multi-dose administration, the formulation may be pre-measured or measured during use. Dry powder inhalers are thus classified into three groups: (a) single dose, (b) multi-unit dose (c) multi-dose devices.

[0052] For inhalers of this type, individual doses are measured by the manufacturer into small containers, which are generally hard gelatin capsules. The capsule is taken from the individual box or container and inserted into the area of the inhaler where the container is. Furthermore, the capsule must be opened or punctured with needles or cutting knives to allow a portion of the inspiratory airflow to pass through the capsule for withdrawal or to discharge the powder from the capsule through these perforations by centrifugal force during inhalation. After inhalation, the empty capsule must be removed from the inhaler again. Generally, disassembling the inhaler is necessary to insert or remove the capsule, which can be difficult and troublesome for some patients.

[0053] Other disadvantages related to the use of hard gelatin capsules for inhalation powders are (a) poor protection against the uptake of moisture from the ambient air, (b) problems with opening or perforation since the capsules are exposed to previously extreme relative humidity, which causes fragmentation or indentation, and (c) possible inhalation of capsule fragments. In addition, a number of capsule inhalers have been found to exhibit incomplete expulsion (eg, Nielsen et al. 1997).

[0054] Some capsule inhalers have a storage space from which individual capsules can be transferred to a receiving chamber, where perforation and discharge occur, as described in WO 92/03175. Other capsule inhalers have a pivotable storage compartment with capsule chambers that can be aligned with air water to discharge the dose (eg VVO91/02558 and GB 2242134). These include this type of multi-dose inhaler along with bubble inhalers, which have a limited number of individual doses in stock on a disc or tablet.

[0055] Bubble inhalers provide better moisture protection to the drug than capsule inhalers. Access to the powder is obtained by piercing the wrapper as well as the bubble wrap, or by peeling off the covering foil. When using a strip compress instead of a disc, the number of doses can be increased, but it is not convenient for the patient to replace an empty compress. Therefore, such devices often exist with a built-in dosing system,

including the technique used to transport the tape and open the bubble pockets.

[0056] Multi-dose inhalers do not contain pre-measured amounts of burst formulation. They consist of a relatively large container and a dose measuring principle that the patient has to handle. The container carries multiple doses that are isolated individually from a bulk powder by volume suppression. Various dose measurement principles exist, including rotatable membranes (eg EP0069715) or discs (eg GB 2041763; EP 0424790; DE 4239402 and EP 0674533), rotatable cylinders (eg EP 0166294; GB 2165159 and WO 92/09322) and rotatable frustrums (eg WO 92/00771), all have cavities that must be filled with powder from a container. Other multi-dose devices have metering pistons with indentations on the local or peripheral indentation to push a quantity of powder from the container into the delivery chamber or air line (eg EP 0505321, WO 92/04068 and WO 92/04928), or metering sides such as the Genuair® invention (formerly known as the Novolizer SD2FL) described in the following patent applications: WO 97/000703, WO 03/000325 and WO 03/061742.

[0057] A preferred embodiment of the present invention is the use of a liquid formulation comprising a salt of the present invention in a device or system suitable for aerosol administration, such as nebulizers or pressurized metered dose inhalers (MDIs). Aerosols can be made using gases as propellants, engine-driven propellants or so-called atomizers, through which pharmaceutical active substances can be sprayed under high pressure so that, as a result, a mist is formed in the form of aerosols that are inhaled. Suitable atomizers may be, for example, the Respimat® described, for example, in WO 91/14468 and WO 97/12687. In the case of nebulizers, special nozzles can be used to nebulize solutions such as that described, for example, in WO 94/07607. Nebulizers most often use compressed air, ultrasonic waves, or a vibrating mesh to form aerosolized mist droplets and may also have protection to remove larger mist droplets by impact. Various nebulizers can be used for this purpose such as ultrasonic nebulizers, jet nebulizers, and inhalation-activated nebulizers.

[0058] The substances of the present invention may optionally comprise a therapeutically effective amount of one or more therapeutic agents known to be useful in the treatment of respiratory disorders, such as PDE4 inhibitors, corticosteroids and/or anticholinergics.

[0059] The amount of each active agent required to achieve a therapeutic effect will, of course, vary depending on the active agent used, the route of administration of the drug, the patient being treated, the particular disorder or disease being treated.

[0060] The active ingredients can be administered from 1 to 6 times a day, enough to show the desired activity. Preferably, the active ingredients are administered once or twice a week, most preferably once a day.

[0061] Examples of suitable PDE4 inhibitors that can be combined with 32-agonists are benafentrine dimaleate, etazolate, denbuphylline, rolipram, cipamphylline, zardaverine, arophylline, filaminast, tipelukast, tofimilast, piclamilast, tolafenthrine, mesopram, drotaverine hydrochloride, lirimilast, roflumilast, cilomilast, oglemilast, apremilast, tetomilast, Filaminast, (R)-(+)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine (CDP-840), N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide (GSK-842470), 9-(2-fluorobenzyl)-N6-methyl-2-(trifluoromethyl)adenine (NCS-613), N-(3,5-dichloro-4-pyridinyl)-8-methoxyquinoline-5-carboxamide (D-4418), 3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine hydrochloride (V-11294A). 6-[3-(N,N-dimethyl-carbamoyl)phenylsulfonyl]-4-(3-methoxyphenylamino)-8-methylquinoline-3-carboxamide hydrochloride (GSK-256066), 4-[6,7-diethoxy-2,3-bis(hydroxymethyl)naphthalen-1-yl]-1-(2-methoxyethyl)pyridin-2(1H)-one (T-440), (-)-trans-2-[3'-[3-(N-cyclopropylcarbamoyl)-4-oxo-1,4-dihydro-1,8-naphthyridin-1-yl]-3-fluorobiphenyl-4-yl]cyclopropanecarboxylic acid (MK-0873), CDC-801, UK-500001, BLX-914, 2-carbomethoxy-4-(3-cyclopropylmethoxy-4-difluoro) romethoxyphenyl)cyclohexane1-one,c/s[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol, CDC-801, 5(S)-[3-(cyclopentyloxy)-4-methoxyphenyl]-3(S)-(3-methylbenzyl)piperidin-2-one (IPL-455903), ONO-6126 (Eur Respir J 2003, 22(Suppl. 45): Abst 2557) and salts for which protection is sought in PCT patent application No. VVO03/097613, VV02004/058729, WO 2005/049581, WO 2005/123693 and WO 2005/123692.

[0062] Examples of suitable corticosteroids and glucocorticoids that can be combined with 02-agonists are prednisolone, methylprednisolone, dexamethasone, dexamethasone cipecilate, naflocort, deflazacort, halopredone acetate, budesonide, beclomethasone dipropionate, hydrocortisone, triamcinolone acetonide, fluocinolone acetonide, fluocinonide, clocortolone pivalate, methylprednisolone aceponate, dexamethasone palmitoate, tipredane, hydrocortisone aceponate, prednicarbate, alclomethasone dipropionate, halomethasone, methylprednisolone suleptanate, mometasone furoate, rimexolone, prednisolone farnesylate, ciclesonide, butixocort propionate, RPR-106541, deprodone propionate, fluticasone propionate, fluticasone furoate, halobetasol propionate, loteprednol etabonate, betamethasone butyrate propionate, flunizolid, prednisone, dexamethasone sodium phosphate, triamcinolone, betamethasone 17-valerate, betamethasone, betamethasone dipropionate, 21-chloro-11beta-hydroxy-17alpha-[2-(methylsulfanyl)acetoxy]-4-pregnene-3,20-dione, Desisobutyryl ciclesonide, hydrocortisone acetate, hydrocortisone sodium succinate, NS-126, prednisolone sodium phosphate and hydrocortisone probutate, prednisolone sodium methanesulfobenzoate and clobetasol propionate

[0063] Examples of suitable M3 antagonists (anticholinergics) that can be combined with O2-agonists are tiotropium salts, oxitropium salts, flutropium salts, ipratropium salts, glycopyrronium salts, trospium salts, zamifenacin, revatropate, espatropate, NPC-14695, BEA-2108, 3-[2-Hyroxy-2,2-bis(2-thienitol)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo [2.2.2]octane salts (especially aclidinium salts, more preferably aclidinium bromide), 1-(2-phenylethyl)-3-(9H-xanthen-9-ylcarbonyloxy)-1-azoniabicyclo[2.2.2]octane salts, 2-oxo-1,2,3,4-tetrahydroquinazoline-3-carboxylic acids endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester salt (DAU-5884), 3-(4-benzyl)piperazin-1-yl)-1-cyclobutyl-1-hydroxy-1-phenylpropan-2-one (NPC-14695), N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2(R)-[3,3-difluoro-1(R)-cyclopentyl]-2-hydroxy-2-phenylacetamide (J-104135), 2(R)-cyclopentyl-2-hydroxy-N-[1-[4(S)-methylhexyl]piperidin-4-yl]-2-phenylacetamide (J-106366), 2(R)-cyclopentyl-2-hydroxy-N-[1-(4-methyl-3-pentenyl)-4-piperidinyl]-2-phenylacetamide (J-104129), 1 -[4-(2-aminoethyl)piperidin-1 -yl]-2(R)-[3,3-difluorocyclopent-1 (R)-yl]-2-hydroxy-2-phenylethan-1-one (Banyu-280634), N-[N-[2-[N-[1-(cyclohexylmethyl)piperidin-3(R)-ylmethyl]carbamoyl]-3,3,3-triphenylpropionamide (Banyu CPTP), 2(R)-cyclopentyl-2-hydroxy-2-phenylacetic acid 4-(3-azabicyclo[3.1.0]hex-3-yl)-2-butynyl ester (Ranbaxy 364057), 3(R)-[4,4-bis(4-fluorophenyl)-2-oxoimidazolidin-1-yl]-1-methyl-1-[2-oxo-2-(3-thienyl)ethyl]pyrrolidinium iodide, N-[1-(3-hydroxybenzyl)-1-methylpiperidinium-3(S)-yl]-N-[N-[4-(isopropoxycarbonyl)phenyl]carbamoyl]-L-tyrosinamide trifluoroacetate, UCB-101333, Merkova OrM3, 7-endo-(2-hydroxy-2,2-diphenylacetoxy)-9,9- dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0(2,4)]nonane salts, 3(R)-[4,4-bis(4-fluorophenyl)-2-oxoimidazolidin-1-yl]-1-methyl-1-(2-phenylethyl)pyrrolidinium iodide, trans-4-[2-[hydroxy-2,2-(dithien-2-yl)acetoxy]-1-methyl-1-(2-phenoxyethyl)piperidinium salts bromide from Novartis (412682), 7-(2.2-diphenylpropionyloxy)-7,9,9-trimethyl-3-oxa-9-azoniatricyclo[3.3.1.0<*>2,4<*>]nonane salt, 7-hydroxy-7,9,9-trimethyl-3-oxa-9-azoniatricyclo[3.3.1.0<*>2,4<*>]nonane 9-methyl-9H-fluorene-9-carboxylic acid ester salts, all optionally in the form of their racemates, enantiomers and mixtures thereof, and optionally in the form of salts of their pharmaceutically compatible acid addition. Among the salts, preference is given to chlorides, bromides, iodides and methanesulfonates.

[0064] A particularly recommended pharmaceutical substance according to the present invention contains a salt according to formula (I) and a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of mometasone furoate, ciclesonide, budesonide, fluticasone propionate, fluticasone furoate, tiotropium salt, glycopyrronium salt, 3-[2-hydroxy-2.2-bis(2-thienyl)acetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane salts (especially aclidinium salts, preferably aclidinium bromide), 1-(2-phenylethyl)-3-(9H-xanthen-9-ylcarbonyloxy)-1-azoniabicyclo[2.2.2]octane salts, rolipram, roflumilast, cilomilast and compounds for which patent protection is sought in patent applications PCT number VVO03/097613, WO2004/058729, WO 2005/049581, WO 2005/123693 and WO 2005/123692.

[0065] A further particularly preferred pharmaceutical substance according to the present invention comprises a salt according to formula (I) and therapeutically effective amounts of one or more additional therapeutic agents selected from the group consisting of mometasone furoate, ciclesonide, budesonide, fluticasone propionate, fluticasone furoate, tiotropium salts, glycopyrronium salts, 3-[2-hydroxy-2,2-bis(2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane salts (especially aclidinium salts, preferably aclidinium bromide), 1-(2-phenylethyl)-3-(9H-xanthen-9-ylcarbonyloxy)-1-azoniabicyclo[2.2.2]octane salts, rolipram, roflumilast and cylo-loving

[0066] Thus, in one embodiment of the present invention, the substance comprises a salt according to formula (I) and a corticosteroid. Particularly preferred corticosteroids are those selected from the group consisting of mometasone furoate, ciclesonide, budesonide, fluticasone furoate and fluticasone propionate.

[0067] In another embodiment of the present invention, the substance contains a salt according to formula (I) and an anticholinergic agent. Particularly preferred anticholinergic agents are those selected from the group consisting of tiotropium salts, glycopyrronium salts, 3-[2-hydroxy-2,2-bis(2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane salts and 1-(2-Phenylethyl)-3-(9H-xanthen-9-ylcarbonyloxy)-1-azoniabicyclo[2.2.2]octane salts. The substance may also contain a corticosteroid selected from the group consisting of mometasone furoate, ciclesonide, budesonide, fluticasone furoate and fluticasone propionate.

[0068] In another embodiment of the present invention, the substance comprises a salt according to formula (I) and a PDE4 inhibitor. Particularly preferred PDE4 inhibitors are those selected from the group consisting of rolipram, roflumilast, cilomilast and the compounds claimed in PCT Patent Applications No. VVO03/097613, VV02004/058729, WO 2005/049581, WO 2005/123693 and WO 2005/123692. The substance may also contain a corticosteroid selected from the group consisting of mometasone furoate, ciclesonide, budesonide, fluticasone furoate and fluticasone propionate. In addition to the salts of the present invention and the PDE4 inhibitor, the substance may further contain an anticholinergic agent selected from the group consisting of tiotropium salts, glycopyrronium salts, 3-[2-hydroxy-2,2-bis(2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2] octane salts and 1-(2-Phenylethyl)-3-(9H-xanthen-9-ylcarbonyloxy)-1-azoniabicyclo[2.2.2] octane salts.

[0069] In a particularly recommended embodiment of this invention, the substance contains a salt according to formula (I) and a therapeutically effective amount of 3-[2-hydroxy-2,2-bis(2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo [2.2.2]octane salt. Optionally, the substance further also contains a corticosteroid and/or a PDE4 inhibitor.

[0070] In another particularly recommended embodiment of the present invention, the substance contains a salt according to formula (I) and a therapeutically effective amount of mometasone furoate. Optionally, this substance also contains an anticholinergic and/or PDE4 inhibitor.

[0071] In another embodiment of the present invention, the substance comprises a salt according to formula (I) and a corticosteroid, an anticholinergic agent and a PDE4 inhibitor.

[0072] Salts according to formula (I) and combinations according to this invention can be used in the treatment of respiratory diseases, in which the use of bronchodilating agents is expected to have a beneficial effect, for example, for asthma, acute or chronic bronchitis, emphysema, or chronic obstructive pulmonary disease.

(COPD).

[0073] Active compounds and salts in this combination, ie. (32-agonist of this invention and PDE4 inhibitors, corticosteroid and or glucocorticoids and/or anticholinergics can be administered together with the same pharmaceutical substance or in different substances intended for separate, simultaneous, simultaneous with or sequential administration of the drug in the same or different way.

[0074] It is understood that all active agents should be administered at the same time, or within a very close time period. Alternatively, one or two active substances can be taken in the morning and the others later in the day. Or in another scenario, one or two active components can be taken twice daily and the other(s) once daily, either at the same time as one of the two daily doses, or separately. It is recommended that at least two, and preferably all, active substances be taken together at the same time. Preferably, at least two, and more preferably all active substances should be taken as a mixture.

[0075] The substances that make up the active substance according to the present invention are preferably given in the form of inhalable substances that are given with the help of inhalers, especially nebulizers and metered dose inhalers, however, any form of topical, parenteral or oral administration is possible. Here, the administration of inhaled substances represents the implementation of the recommended form of administration, especially in the therapy of obstructive pulmonary disease or for the treatment of asthma.

[0076] The active compounds of the formulation generally contain a suitable carrier which can be either a propellant for MDI administration or water for administration through a nebulizer. The formulation may include additional components such as preservatives (eg, benzalkonium chloride, potassium sorbate, benzyl alcohol); pH stabilizers (eg, acidic agents, alkaline agents, buffer systems); isotonic stabilizers (for example, sodium chloride); surfactants and wetting agents (eg, polysorbates, sorbitan esters); and/or absorption enhancers (eg chitosan, hyaluronic acid, surfactants). The formulation may also contain additives to improve the solubility of other active compounds when mixed with the salt of this invention. Solubility enhancers can include components such as cyclodextrins, liposomes or co-solvents such as ethanol, glycerol and propylene glycol.

[0077] Additional suitable carriers for active salt formulations of the present invention are found in the manual Remington: The Science and Practice of Pharmacv, 20th Edition, Lippincott Williams & Wilkins, Philadelphia, Pa., 2000. The following non-limiting examples illustrate representative pharmaceutical substances of the present invention.

[0078] The invention further includes a method for treating a pulmonary disease or condition, such as asthma or chronic obstructive pulmonary disease in a mammal associated with (32) adrenergic receptor activity, the method comprising administering to the mammal a therapeutically effective amount of a pharmaceutical substance as described above. The mammal is preferably a human being.

[0079] In particular, the method for treating a pulmonary disease or condition comprises administering to a mammal, which is preferably a human being, a therapeutically effective amount of a mesylate salt of a compound according to formula (I) and a therapeutically effective amount of one or more therapeutic agents, such as a corticosteroid, an anticholinergic agent, or a PDE4 inhibitor.

1. Example of formulation (Formulation for nebulizer).

[0080] 2nd example of formulation (Formulation for nebulizer).

[0081] 3rd example of formulation (Formulation for MDI).

[0082] 4th example of formulation (Formulation for MDI).

[0083]

Claims (14)

1. Mesylate salt 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one and its pharmaceutically acceptable solvents. 2. Salt according to patent claim 1 selected from the group comprising: (R,S) 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl}amino}-1-hydroxy-ethyl)-8-hydroxyquinolin-2(1H)-one, mesylate 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl}amino}-1 (R)-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one, mesylate and pharmaceutically acceptable solvents thereof. 3. A pharmaceutical substance comprising a therapeutically effective amount of a salt according to any claim 1 or 2 and a pharmaceutically acceptable carrier. 4. The pharmaceutical substance according to claim 3, wherein the substance is formulated for administration by inhalation. 5. Pharmaceutical substance from patent claim 3 or 4, where the substance also includes a therapeutically effective amount of one or more therapeutic agents. 6. The pharmaceutical substance of claim 5 wherein the second therapeutic agent is a corticosteroid, an anticholinergic agent, and/or a PDE4 inhibitor. 7. The pharmaceutical substance of claim 5 or 6 where the second therapeutic agent is a corticosteroid selected from the group comprising prednisolone, methylprednisolone, dexamethasone, dexamethasone cipecilate, naflocort, deflazacort, halopredone acetate, budesonide, beclomethasone dipropionate, hydrocortisone, triamcinolone acetonide, fluocinolone acetonide, fluocinonide, clocortolone pivalate, methylprednisolone aceponate, dexamethasone palmitoate, tipredane, hydrocortisone aceponate, prednicarbate, alclomethasone dipropionate, halomethasone, methylprednisolone suleptanate, mometasone furoate, rimexolone, prednisolone farnesylate, ciclesonide, butixocort propionate, RPR-106541, deprodone propionate, fluticasone propionate, fluticasone furoate, halobetasol propionate, loteteprednol etabonate, betamethasone butyrate propionate, flunizolid, prednisone, dexamethasone sodium phosphate, triamcinolone, betamethasone 17-valerate, betamethasone, betamethasone dipropionate, 21-chloro-11beta-hydroxy-17alpha-[2-(methylsulfanyl)acetoxy]-4-pregnene-3,20-dione, desisobutyrylciclesonide, hydrocortisone acetate, hydrocortisone sodium succinate, NS-126, prednisolone sodium phosphate and hydrocortisone probutate, prednisolone sodium metasulfobenzoate and clobetasol propionate 8. The pharmaceutical substance of claim 5 or 6 wherein the second therapeutic agent is selected from the group consisting of tiotropium salts, oxitropium salts, flutropium salts, ipratropium salts, glycopyrronium salts, trospium salts, zamifenacin, revatropate, espatropate, NPC-14695, BEA-2108, 3-[2-hydroxy-2,2- bis(2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane salt, 1-(2-phenylethyl)-3-(9H-xanthen-9-ylcarbonyloxy)-1-azoniabicyclo[2.2.2]octane salt, 2-oxo-1,2,3,4-tetrahydroquinazoline-3-carboxylic acid endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester salt (DAU-5884), 3-(4-benzylpiperazin-1-yl)-1-cyclobutyl-1-hydroxy-1-phenylpropan-2-one (NPC-14695), N-[1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl]-2(R)-[3,3-difluoro-1 (R)-cyclopentyl]-2-hydroxy-2-phenylacetamide (J-104135), 2(R)-Cyclopentyl-2-hydroxy-N-[1-[4(S)-methylhexyl]piperidin-4-yl]-2-phenylacetamide (J-106366), 2(R)-cyclopentyl-2-hydroxy-N-[1-(4-methyl-3-pentenyl)-4-piperidinyl]-2-phenylacetamide (J-104129), 1-[4-(2-aminoethyl)piperidine-1-ii]-2(R)-[3,3-difluorocyclopent-1 (R)-yl]-2-hydroxy-2-phenylethan-1-one (Banyu-280634), N-[N-[2-[N-[1-(cyclohexylmethyl)piperidin-3(R)-ylmethyl]carbamoyl]ethyl]carbamoylmethyl]-3,3,3-triphenylpropionamide (Banyu CPTP), 2(R)-cyclopentyl-2-hydroxy-2-phenylacetate. 4-(3-azabicyclo[3.1.0]hex-3-yl)-2-butynyl ester (Ranbaxy 364057), 3(R)-[4,4-bis(4-fluorophenyl)-2-oxoimidazolidin-1-yl]-1-methyl-1-[2-oxo-2-(3-thienyl)ethyl]pyrrolidinium iodide, N-[1-(3-hydroxybenzyl)-1-methylpiperidinium-3(S)-yl]-N- [N-[4-(isopropoxycarbonyl)phenyl]carbamoyl]-L-tyrosinamide trifluoroacetate, UCB-101333, Merkova OrM3, 7-endo-(2-hydroxy-2,2-diphenylacetoxy)-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0(2,4)]nonane salt, 3(R)-[4,4-Bis(4-5)] fluorophenyl)-2-oxoimidazolidin-1-yl]-1-methyl-1-(2-phenylethyl)pyrrolidinium iodide, trans-4-[2-[hydroxy-2,2-(di-ien-2-yl)acetoxy]-1-methyl-1-(2-phenoxyethyl) piperidinium bromide from Novartis (412682), 7-(2,2-diphenylpropio-2-diphenyl) nyloxy)-7,9,9-trimethyl-3-oxa-9-azoniatricyclo[3.3.1.0<*>2,4<*>]nonane salts, 7-hydroxy-7,9,9-trimethyl-3-oxa-9-azonia-tricyclo[3.3.1.0<*>2,4<*>]nonane 9-methyl-9H-fluorene-9-carboxylic acid ester salts, all optional in the form of racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally in the form of salts of their pharmaceutically compatible acid addition. 9. Pharmaceutical substance according to patent claim 5 or 6 where the second therapeutic agent is a PDE4 inhibitor selected from the group containing benafenthrine dimaleate, etazolate, denbuphylline, rolipram, cipamphylline, zardaverine, arophylline, filaminast, tipelukast, tofimilast, piclamilast, tolafenthrine, mesopram, drotaverine hydrochloride, lirimilast, roflumilast, cilomilast, oglemilast, apremilast, tetomilast, filaminast, (R)-(+)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine (CDP-840), N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide (GSK-842470), 9-(2-fluorobenzyl)-N6-methyl-2-(trifluoromethyl)adenine (NCS-613), N-(3,5-dichloro-4-pyridinyl)-8-methoxyquinoline-5-carboxamide (D-4418), N-[9-Methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydro-pyrrolo[3,2,1-jk][1,4]benzodiazepine-3(R)-yl]pyridin-4-carboxamide, 3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine hydrochloride (V-11294A). 6-[3-(N,N-dimethylcarbamoyl)phenylsulfonyl]-4-(3- methoxyphenylamino)-8-methylquinoline-3-carboxamide hydrochloride (GSK-256066), 4-[6,7-diethoxy-2,3-bis(hydroxymethyl)naphthalen-1-yl]-1-(2-methoxyethyl)pyridin-2(1H)-one (T-440), (-)-trans-2-[3'-[3-(N-cyclopropylcarbamoyl)-4-oxo-1,4-dihydro-1,8-naphthyridin-1-yl]-3- fluorobiphenyl-4-yl]cyclopropanecarboxylic acid (MK-0873), CDC-801, UK-500001, BLX-914,, 2-carbomethoxy-4-cyano-4-(3-cyclopropimethoxy-4-difluoromethoxyphenyl)-cyclohexan1-one, cis [4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-cyclohexan-1-ol, CDC-801, 5 (S)-[3-(cyclopentyloxy)-4-methoxyphenyl]-3(S)-(3-methylbenzyl)piperidin-2-one (IPL-455903) and ONO-6126 (Eur Respir J 2003, 22(Suppl. 45): Abst 2557). 10. A pharmaceutical substance according to any of claims 5 to 9 wherein the second therapeutic agent is selected from the group comprising mometasone, furoate, ciclesonide, budesonide, fluticasone propionate, fluticasone furoate, tiotropium salts, glycopyrrolate salts, 3-[2-hydroxy-2,2-bis(2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoni-abicyclo[2.2.2]octane salts, 1-(2-phenylethyl)-3-(9H-xanthen-9-ylcarbonyloxy)-1-azoniabicyclo[2.2.2]octane salts, rolipram, roflumilast and cilomilast. 11. A combination comprising a salt as defined in any of claims 1 or 2 and one or more therapeutic agents as defined in any of claims 5 to 10. 12. A salt according to any of claims 1 or 2, a pharmaceutical substance according to any of claims 3 to 10 or a combination according to claim 11, for use in the treatment of a pathological condition or disease associated with the activity of (32) adrenergic receptors. 13. The salt of claim 12, wherein the pathological condition or disease is asthma or chronic obstructive pulmonary disease. 14. Use of a salt as defined in claim 1 or 2, a pharmaceutical substance according to any of claims 3 to 10 or a combination according to claim 11, in the production of a drug for the treatment of a pathological condition or disease as defined in claim 12 or 13.