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    • 专利摘要:
    DERIVATIVES FROM 2-AMINO-1-HYDROXYETHYL-8-HYDROXYQUINOLIN-2 (1H) -ONA HAVING BOTH ADRENERGIC RECEPTOR AGONIST BETA2 ACTIVITY AND M3 MUSCARINIC RECEPTOR ANTAGONIST ACTIVITY. The present invention relates to crystalline addition salts of (i) derivatives of 8-hydroxyquinolin-2 (1H) -one and (ii) a hydroxycarboxylic acid, a sulfonic acid or a sulfimide, or a pharmaceutically acceptable solvate thereof.
    公开号:BR112015020152B1
    申请号:R112015020152-0
    申请日:2014-02-27
    公开日:2021-01-26
    发明作者:Maria Prat Quinones；Montserrat JULIA JANE；Francesc Carrera Carrera；Carlos Puig Duran；Francesca Pajuelo Lorenzo；Juan Antonio Perez Andres
    申请人:Almirall, S.A.；
    IPC主号:
    专利说明:

    Field of the Invention
    [0001] The present invention relates to pharmaceutically acceptable crystalline addition salts of (i) 2-amino-1-hydroxyethyl8-hydroxyquinolin-2 (1H) -one derivatives and (ii) a hydroxycarboxylic acid, a sulfonic acid or a sulfimide derivative, or a pharmaceutically acceptable solvate thereof. The invention also relates to pharmaceutical compositions comprising salts, methods to be used to treat respiratory diseases associated with dual activities of beta2 adrenergic receptor agonist and activities of M3 muscarinic receptor antagonist, and processes and intermediates useful for the preparation of such salts. Background of the Invention
    [0002] WO 2011/141180 A1 discloses compounds which are known to have a dual activity of β2 adrenergic receptor agonist and M3 muscarinic receptor antagonist activity. However, many of these compounds cannot be formulated for effective delivery by inhalation as a dry powder. Delivery by inhalation as a dry powder is a challenge. It requires careful control of the particle size of the powder to be inhaled, and careful control of the particle size distribution. In addition, it is important to avoid particle agglomeration or aggregation. In addition, when preparing pharmaceutical compositions and formulations for use in such devices, it is highly desirable to have a crystalline form of a therapeutic agent that is neither hygroscopic nor deliquescent and has a relatively high melting point (that is, greater than than about 150 ° C) thereby allowing the material to be micronized without significant loss or decomposition of crystallinity.
    [0003] Although the 2-amino-1-hydroxyethyl-8-hydroxyquinolin2 (1H) -one derivatives disclosed in WO 2011/141180 A1 showed adequate pharmacological behavior, it was proved as difficult to obtain in the form of a salt that is crystalline, neither hygroscopic nor deliquescent and which has a relatively high melting point to allow micronization.
    [0004] So far no crystalline salt of any of the compounds disclosed in WO 2011/141180 having the desired properties has been reported.
    [0005] Correspondingly, a need exists for stable, non-deliquescent salt forms of at least some of those compounds having acceptable levels of hygroscopicity and relatively high melting points. Summary of the Invention
    [0006] The present invention provides pharmaceutically acceptable crystalline addition salts of (i) derivatives of 2-amino-1-hydroxyethyl-8hydroxyquinolin-2 (1H) -one and (ii) a hydroxycarboxylic acid, a sulfonic acid or a derivative of sulfimide, or a pharmaceutically acceptable solvate thereof, wherein the 2-amino-1-hydroxyethyl-8hydroxyquinolin-2 (1H) -one derivatives having the following formula (I):

    [0007] where:
    [0008] R1 represents a hydrogen atom or a C1-4 alkyl group,
    [0009] R2 and R3 independently represent a hydrogen atom, a halogen atom, a C1-4 alkyl group, a C1-4 alkoxy group and a cyano group,
    [00010] A represents a C1-4 alkylene group optionally substituted with one or more C1-2 alkyl groups,
    [00011] L represents a direct bond, group -NH (CO) -, (CO) NHor -NH (CO) O-, where in the case of -NH (CO) O-, the nitrogen atom is attached to the substituent of phenylene and the oxygen atom is attached to substituent A.
    [00012] and their pharmaceutically acceptable solvates.
    [00013] The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a salt of the invention and a pharmaceutically acceptable carrier.
    [00014] The invention subsequently provides a combination comprising a salt of the invention and one or more other therapeutic agents.
    [00015] The invention also provides a salt of the invention, a pharmaceutical composition of the invention or a combination of the invention, for use in the treatment of a disease or pathological condition associated with both β2 adrenergic receptor agonist activity and the antagonist activity of muscarinic receptor M3.
    [00016] The invention further provides for the use of a salt of the invention, a pharmaceutical composition of the invention or a combination of the invention, in the manufacture of a medicament or for the treatment of a disease or pathological condition associated with both β2 adrenergic receptor agonist activity regarding M3 muscarinic receptor antagonist activity.
    [00017] The invention also provides a method for treating an individual afflicted with a disease or pathological condition associated with both β2 adrenergic receptor agonist activity and M3 muscarinic receptor antagonist activity, which comprises administering to said individual an amount effectiveness of a salt of the invention, a pharmaceutical composition of the invention or a combination of the invention. Brief Description of the Figures
    [00018] Figure 1 shows the Fourier transformation infrared (FTIR) spectrum for trans-4 - (((3- (2-chloro-4 - ((((2R) -2-hydroxy-2- (8-hydroxy2- oxo-1,2-dihydroquinolin-5-yl) ethylamino) methyl) -5-methoxyphenylamino) -3oxopropyl) (methyl) amino) cyclohexyl hydroxy (di-2-thienyl) acetate.
    [00019] Figure 2 shows the powder X-ray diffraction pattern (PXRD) for trans-4 - ((3- (2-chloro-4 - ((((2R) -2-hydroxy-2- (8- hydroxy-2-oxo-1,2dihydroquinolin-5-yl) ethylamino) methyl) -5-methoxyphenylamino) -3-oxopropyl) (methyl) amino) cyclohexyl hydroxy (di-2-thienyl) acetate ethanedisulfonate.
    [00020] Figure 3 shows 1H-NMR (600 MHz, DMSO-d6) for trans4 - ((3- (2-chloro-4 - ((((2R) -2-hydroxy-2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5yl) ethylamino) methyl) -5-methoxyphenylamino) -3-oxopropyl) (methyl) amino) cyclohexyl hydroxy (di-2-thienyl) acetate ethanedisulfonate.
    [00021] Figure 4 shows the differential scanning calorimetry (DSC) analysis of trans-4 - (((3- (2-chloro-4 - (((2R) -2-hydroxy-2- (8-hydroxy- 2-oxo1,2-dihydroquinolin-5-yl) ethylamino) methyl) -5-methoxyphenylamino) -3-oxopropyl) (methyl) amino) cyclohexyl hydroxy (di-2-thienyl) acetate ethanedisulfonate.
    [00022] Figure 5 shows the thermogravimetric analysis (TG) of trans-4 ((3- (2-chloro-4 - (((2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1 , 2-dihydroquinolin-5yl) ethylamino) methyl) -5-methoxyphenylamino) -3-oxopropyl) (methyl) amino) cyclohexyl hydroxy (di-2-thienyl) acetate ethanedisulfonate.
    [00023] Figure 6 shows the transformation infrared (FTIR) spectrum for trans-4 - ((3- (2-chloro-4 - (((2R) -2-hydroxy-2- (8-hydroxy-2 -oxo1,2-dihydroquinolin-5-yl) ethylamino) methyl) -5-methoxyphenylamino) -3-oxopropyl) (methyl) amino) cyclohexyl hydroxy (di-2-thienyl) acetate ethanedisulfonate.
    [00024] Figure 7 shows the Fourier transformation infrared (FTIR) spectrum for trans-4 - ((2- (2-chloro-4 - ((((R) -2-hydroxy-2- (8-hydroxy2- oxo-1,2-dihydroquinolin-5-yl) ethylamino) methyl) -5-methoxyphenylcarbamoyloxy) ethyl) (methyl) amino) cyclohexyl 2-hydroxy-2,2-di (thiophen-2-yl) acetate .
    [00025] Figure 8 shows the powder X-ray diffraction pattern (PXRD) for trans-4 - ((2- (2-chloro-4 - ((((R) -2-hydroxy-2- (8- hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethylamino) methyl) -5-methoxyphenylcarbamoyloxy) ethyl) (methyl) amino) cyclohexyl 2-hydroxy-2,2-di (thiophen-2-yl ) disacarinate acetate.
    [00026] Figure 9 is the spectrum of 1H-NMR (500 MHz, d4-methanol) for trans-4 - ((2- (2-chloro-4 ((((R) -2hydroxy -2 (8hydroxy -2oxo - 1,2-dihydroquinolin-5-yl) ethylamino) methyl) -5-methoxyphenylcarbamoyloxy) ethyl) - (methyl) amino) cyclohexyl 2-hydroxy-2,2-di (thiophen-2-yl) acetate disacarinate.
    [00027] Figure 10 shows the DSC analysis for trans-4 - ((2- (2-chloro4 - ((((R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl) ethylamino) methyl) -5-methoxyphenylcarbamoyloxy) ethyl) - (methyl) amino) cyclohexyl 2-hydroxy-2,2di (thiophen-2-yl) acetate disacarinate.
    [00028] Figure 11 shows the analysis of TG for trans-4 - ((2- (2-chloro-4 ((((R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2 -dihydroquinolin-5-yl) ethylamino) methyl) -5methoxyphenylcarbamoyloxy) ethyl) - (methyl) amino) cyclohexyl 2-hydroxy-2,2-di (thiophen2-yl) acetate disacarinate.
    [00029] Figure 12 shows the FTIR spectrum for trans-4 - ((2- (2-chloro-4 - ((((R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl) ethylamino) methyl) -5-methoxyphenylcarbamoyl-oxy) ethyl) (methyl) amino) cyclohexyl 2-hydroxy2,2-di (thiophen-2-yl) acetate disacarinate.
    [00030] Figure 13 shows the powder X-ray diffraction pattern (PXRD) for trans-4 - ((2- (2-chloro-4 - ((((R) -2-hydroxy-2- (8- hydroxy-2-oxo1,2-dihydroquinolin-5-yl) ethylamino) methyl) -5-methoxyphenylcarbamoyloxy) ethyl) (methyl) amino) cyclohexyl 2-hydroxy-2,2-di (thiophen-2-yl ) L-tartrate acetate.
    [00031] Figure 14 is the 1H-NMR (500 MHz, d6-DMSO) spectrum of trans-4 - ((2- (2-chloro-4 - ((((R) -2-hydroxy-2- ( 8-hydroxy-2-oxo-1,2-dihydroquinolin5-yl) ethylamino) methyl) -5-methoxyphenylcarbamoyloxy) ethyl) - (methyl) amino) cyclohexyl 2-hydroxy-2,2-di (thiophen- 2-yl) L-tartrate acetate.
    [00032] Figure 15 shows the DSC analysis for trans-4 - ((2- (2-chloro4 - ((((R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl) ethylamino) methyl) 5-methoxyphenylcarbamoyloxy) ethyl) - (methyl) amino) cyclohexyl 2-hydroxy-2,2-di (thiophen-2-yl) acetate L-tartrate.
    [00033] Figure 16 shows the analysis of TG for trans-4 - ((2- (2-chloro-4 ((((R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2 -dihydroquinolin-5-yl) ethylamino) methyl) -5methoxyphenylcarbamoyloxy) ethyl) - (methyl) amino) cyclohexyl 2-hydroxy-2,2-di (thiophen2-yl) acetate L-tartrate.
    [00034] Figure 17 shows the FTIR spectrum for trans-4 - ((2- (2-chloro-4 - ((((R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl) ethylamino) methyl) -5-methoxyphenylcarbamoyl-oxy) ethyl) (methyl) amino) cyclohexyl 2-hydroxy-2,2di (thiophen-2-yl) acetate L-tartrate. Detailed Description of the Invention
    [00035] When describing the salts, compositions and methods of the invention, the following terms have the meanings, unless otherwise indicated.
    [00036] The term "therapeutically effective amount" refers to an amount sufficient to effect treatment when administered to a patient in need of treatment.
    [00037] The term "treatment" as used here refers to the treatment of a medical condition or disease in a human patient which includes: (a) prevention of the disease or medical condition from occurring, that is, prophylactic treatment of a patient; (b) improvement of the disease or medical condition, that is, that causes regression of the disease or medical condition in a patient; (c) suppression of the disease or medical condition, that is, slowing the development of the disease or medical condition in a patient; or (d) relieving symptoms of the disease or medical condition in a patient.
    [00038] The phrase "disease or condition associated with β2 adrenergic receptor agonist activities and M3 muscarinic receptor antagonist activities" includes all disease states and / or conditions that are now recognized, or that are found in the future, to be associated with both β2 adrenergic receptor agonist activity and M3 muscarinic receptor antagonist activity. Such disease states include, but are not limited to, lung diseases, such as asthma and chronic obstructive pulmonary disease (including chronic bronchitis and emphysema), as well as neurological disorders and cardiac disorders. Β2 adrenergic receptor activity is also known to be associated with preterm labor (see International Patent Application Publication Number WO 98/09632), glaucoma and some types of inflammation (see International Patent Application Publication Number WO 99/30703 and Patent Application Publication Number EP 1 078 629).
    [00039] On the other hand M3 receptor activity is associated with disorders of the gastrointestinal tract such as irritable bowel syndrome (IBS) (see, for example, US 5397800), GI ulcers, spastic colitis (see, for example, US 4556653) ; disorders of the urinary tract such as urinary incontinence (see, for example, J. Med. Chem., 2005, 48, 6597-6606), polyaquiauria; vaguely induced locomotion disease and sinus bradycardia.
    [00040] The term "solvate" refers to a complex or aggregate formed by one or more molecules of a solute, that is, a salt of the invention or a pharmaceutically acceptable salt thereof, and one or more molecules of a solvent. Such solvates are typically crystalline solids having a substantially fixed molar ratio of solute and solvent. Representative solvents include, for example, water, ethanol, isopropanol and the like. The preferred solvate is a hydrate.
    [00041] As used herein the term C1-4 alkyl includes linear or branched radicals having 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl or t-butyl.
    [00042] As used herein, the term C1-4 alkylene includes divalent alkyl moieties typically having 1 to 4 carbon atoms. Examples of C 1-4 alkylene radicals include methylene, ethylene, propylene and butylene radicals.
    [00043] As used herein, the term C1-4 alkoxy (or alkyloxy) includes radicals containing linear or branched oxides, optionally substituted each having alkyl portions of 1 to 4 carbon atoms. Examples of C1-4 alkoxy radicals include methoxy, ethoxy, n-propoxy, ipropoxy, n-butoxy, sec-butoxy and t-butoxy.
    [00044] As used herein, the term halogen atom includes chlorine, fluorine, bromine or iodine atoms typically a fluorine, chlorine or bromine atom. The term halo when used as a prefix has the same meaning.
    [00045] Typically, in the compound of formula (I), R1 represents a hydrogen atom or a methyl group, preferably a methyl group.
    [00046] Typically, in the compound of formula (I), R2 and R3 independently represent a halogen atom or a C1-4 alkoxy group, preferably a C1-2 alkoxy group. More preferably R2 and R3 independently represent a chlorine atom or a methoxy group, more preferably R2 represents a methoxy group and R3 represents a chlorine atom.
    [00047] Typically, in the compound of formula (I), A represents a C1-2 alkylene group optionally substituted with one or two methyl groups, preferably A represents an ethylene group optionally substituted with a methyl group, more preferably a group unsubstituted ethylene.
    [00048] Typically, in the compound of the formula (I), L represents a group -NH (CO) -, - (CO) NHor -NH (CO) O-, more preferably L represents a group -NH (CO) or -NH (CO) O-.
    [00049] Preferably, in the compound of formula (I), R1 represents a methyl group, R2 represents a methoxy group, R3 represents a chlorine atom, A represents an ethylene group and L represents an -NH (CO) or - group NH (CO) O-.
    [00050] Typically, hydroxycarboxylic acid is selected from the group consisting of citric acid, lactic acid, musclic acid, tartaric acid, pantothenic acid, glucuronic acid, lactobionic acid, gluconic acid, 1-hydroxy-2-naphthoic acid, mandelic acid , malic acid.
    [00051] Typically, sulfonic acid is selected from the group consisting of methanesulfonic acid, ethanedisulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid and (1S) -phorphonic acid 10sulfonic.
    [00052] Typically, the sulfimide derivative is selected from the group consisting of benzoic sulfimide (also known as saccharin), thieno [2,3-d] isothiazole-3 (2H) -one 1,1-dioxide and isothiazole-3 (2H) on 1,1-dioxide.
    [00053] Particular salt compounds of the invention include:
    [00054] trans-4 - ((3- (2-chloro-4 - ((((2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethylamino ) methyl) -5-methoxyphenylamino) -3-oxopropyl) (methyl) amino) -cyclohexyl hydroxy (di-2-thienyl) acetate ethanedisulfonate,
    [00055] trans-4 - ((2- (2-chloro-4 - ((((R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethylamino ) -methyl) -5-methoxyphenylcarbamoyloxy) ethyl) - (methyl) amino) -cyclohexyl 2-hydroxy-2,2-di (thiophen-2-yl) acetate disacarinate, and
    [00056] L-tartrate salt of trans-4 - ((2- (2-chloro-4 - ((((R) -2-hydroxy-2- (8hydroxy -2oxo1,2di -hydroquinolin -5yl) ethylamino) methyl) ) -5methoxyphenylcarbamoyloxy) ethyl) - (methyl) amino) cyclohexyl 2-hydroxy-2,2-di (thiophen2-yl) acetate, General Synthetic Procedures
    [00057] The salts of the invention can be prepared using the methods and procedures described here, or using similar methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, ratios in moles of reagents, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise affirmed way. Optimal reaction conditions may vary with the particular reagents or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
    [00058] Processes for preparing salts of the invention are provided as other embodiments of the invention and are illustrated by the procedures below.
    [00059] The salts of the invention can be synthesized from compounds of the formula (I) and from the appropriate hydroxycarboxylic acid, sulfonic acid or sulfimide derivatives, which in general will be commercially available from, for example, Aldrich.
    [00060] Solvents suitable for carrying out the reaction can be selected by a skilled chemist and may depend on the specific salt to be formed. Mixtures of appropriate solvents can be used, optionally containing water. For example, the appropriate solvents can be selected from methanol, ethanol, dichloromethane, tetrahydrofuran, water or a mixture thereof.
    [00061] Upon completion of any of the above reactions, the salt can be isolated from the reaction mixture by any conventional means such as precipitation, concentration, centrifugation and the like.
    [00062] It will be appreciated that although specific process conditions (ie reaction temperatures, times, ratios in moles of reagents, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise otherwise stated.
    [00063] To prepare the salts of the present invention, the free base is typically dissolved in an appropriate solvent which in some instances is heated to about 60-80 ° C. Then a solution of hydroxycarboxylic acid or sulfonic acid or an appropriate sulfimide in a suitable solvent, preferably the same solvent as that in which the free base is dissolved, is typically added to the heated solution. The mixture is then optionally stirred for 15300 minutes at 60-80 ° C or at room temperature. The mixture is then typically cooled, for example, reduced to 20-25 ° C or 0-5 ° C. The precipitate formed is isolated by filtration, washed with an appropriate solvent and dried, for example, in vacuo. Pharmaceutical Compositions
    [00064] The invention also includes pharmaceutical compositions comprising a therapeutically effective amount of a salt of the invention or an enantiomer or its pharmaceutically acceptable solvate and a pharmaceutically acceptable carrier.
    [00065] Typically the pharmaceutical composition is formulated for administration by inhalation, preferably as a dry powder.
    [00066] Typically, the pharmaceutical composition further comprises a therapeutically effective amount of one or more other therapeutic agents.
    [00067] Pharmaceutical formulations can conveniently be presented in unit dosage form and can be prepared by any of the methods well known in the pharmacy art. All methods include the step of putting the active ingredient (s) in association with the vehicle. In general the formulations are prepared by uniformly and intimately putting the active ingredient in association with liquid vehicles or finely divided solid vehicles or both and then, if necessary, forming the product to give the desired formulation.
    [00068] Dry powder compositions for topical delivery to the lung by inhalation can, for example, be presented in capsules and cartridges of, for example, gelatin or blisters of, for example, laminated aluminum foil, for use in an inhaler or insufflator. Formulations in general comprise a mixture of powder for inhaling the salt of the invention and a suitable powder base (carrier substance) such as lactose or starch. Use of lactose is preferred. The powder base may include additional components such as preservatives, stabilizing agents, absorption enhancers or aerodynamic modifiers.
    [00069] Each capsule or cartridge can generally contain between 0.1 μg and 9000 μg of each therapeutically active ingredient. Alternatively, the active ingredient (s) can be presented without excipients.
    [00070] Formulation packaging may be suitable for delivery of multiple doses or unit dose. In the case of multiple dose delivery, the formulation can be pre-measured or measured in use. Dry powder inhalers are thus classified into three groups: (a) single dose devices, (b) multiple unit doses and (c) multiple doses.
    [00071] For inhalers of the first type, single doses were weighed by the manufacturer in small containers, which are mainly cartridges or hard gelatin capsules. In the case of a cartridge, the single dose inhaler thus consists of a cartridge containing the powder for inhalation and measurement of individual dosages. The inhalation powder is permanently located at the bottom of the cartridge, in a reservoir with a measuring slider at the bottom and a top at the top. When a capsule is used as a container, the capsule must be taken out of a separate box or container and inserted into a receptacle area of the inhaler. Then, the capsule must be opened or perforated with pins or cutting blades to allow part of the inspiratory air stream to pass through the capsule to drag powder or discharge the powder from the capsule through these perforations by means of centrifugal force during inhalation. After inhalation, the empty capsule must be removed from the inhaler again. Mainly, disassembly of the inhaler is necessary for the insertion and removal of the capsule, which is an operation that can be difficult and costly for some patients.
    [00072] Other disadvantages related to the use of hard gelatin capsules for inhalation of powders are (a) poor protection against absorption of moisture from ambient air, (b) problems with opening or perforation after the capsules have been previously exposed extreme relative humidity, which causes fragmentation or indentation, and (c) possible inhalation of capsule fragments. Furthermore, for numerous capsule inhalers, incomplete expulsion has been reported (for example, Nielsen et al, 1997).
    [00073] Some capsule inhalers have a tank from which individual capsules can be transferred to a receiving chamber, in which puncture and emptying take place, as described in WO 92/03175. Other capsule inhalers have rotating tanks with capsule chambers that can be placed in line with the air duct for dose discharge (eg WO91 / 02558 and GB 2242134). They comprise the type of multiple unit dose inhalers together with blister inhalers, which have a limited number of unit doses in supply on a disc or on a strip.
    [00074] Blister inhalers provide better protection against drug moisture than capsule inhalers. Access to dust is obtained by perforating the cover as well as the blister sheet, or by peeling off the cover sheet. When a blister strip is used instead of a disc, the number of doses can be increased, but it is inconvenient for the patient to replace an empty strip. Therefore, such devices are often available with the built-in dose system, including the technique used to carry the strip and open the blister pockets.
    [00075] Multiple dose inhalers do not contain pre-measured amounts of the powder formulation. They consist of a relatively large container and dose measurement principle that must be operated by the patient. The container holds multiple doses that are individually isolated from the powder mass by volumetric displacement. There are several principles of dose measurement, including viable membranes (for example, EP0069715) or discs (for example, GB 2041763; EP 0424790; DE 4239402 and EP 0674533), viable cylinders (for example, EP 0166294; GB 2165159 and WO 92 / 09322) and viable trunks (for example, WO 92/00771), all having cavities that have to be filled with powder from the container. Other multi-dose devices have measuring pistons with a local or circumferential recess to move a certain volume of powder from the container to a supply chamber or air duct (eg EP 0505321, WO 92/04068 and WO 92 / 04928), or measurement slides such as the Genuair® device (known as Novolizer SD2FL) which is described in the following patent applications: WO 97/000703, WO 03/000325 and WO 2006/008027 Additional therapeutic agents
    [00076] The salts of the present invention can also be used in combination with other drugs known to be effective in the treatment of the diseases or disorders indicated above. For example, the salts of the present invention can be combined with (a) corticosteroids, or gluococorticoids, (b) antihistamines (c) chemokine receptor antagonists, such as maraviroc or enfuvirtide, (e) CRth2 antagonists, (f) ) leukotriene receptor antagonists, (g) JAK inhibitors such as tofacitinib or INCB018424, (h) Syk inhibitors (i) phosdiesterase IV inhibitors, (j) p38 inhibitors such as ARRY-797, (k) inhibitors of PKCs such as NVP-AEB071, (l) 5-lipoxygenase activating protein inhibitors, such as veliflapon, (m) 5lipoxygenase inhibitors, (n) CYSLTR1 antagonists, (o) CYSLTR2 antagonists, (p) antagonists of BLT1, (q) BLT2 antagonists, (r) thromboxane A2 antagonists such as ramatroban, DP1 receptor antagonists, such as laropiprant, (t) DP1 receptor agonists, such as BW-245C, (u ) IP receptor agonists, such as RO-1138452, (v) Anti-IgE, such as omalizumab, (w) IL5 antibody, such as such as mepolizumab, (x) leukotriene formation inhibitors, (y) decongestants, such as ephedrine, levo-methamphetamine, naphazoline, oxymetazoline, phenylephrine, phenylpropanolamine, propylexedrine, pseudoephedrine, synephrine or tetrahydrozoline; (z) mucolytics such as acetylcysteine, ambroxol, bromohexine, carbocysteine, domiodol, eprazinone, erdosteine, letosteine, neltenexine, soberol, estepronin or thiopronine; (aa) antitussives, such as dextromethorphan, (bb) analgesics such as aspirin, paracetamol, rofecoxid, celecoxib, morphine, codeine, oxycodone, hydrocodone, dihydromorphine or flupirtine; and (cc) expectorants such as antimony pentasulfide, guaiacol sulfonate, guaifenesin, potassium iodide or tiloxapol.
    [00077] Correspondingly, another embodiment of the invention is a combination product comprising (i) at least one salt compound as defined previously, and (ii) one or more active ingredients as described above, for simultaneous, separate or sequential use in the treatment of the human or animal body.
    [00078] A preferred embodiment of the invention is a combination product as defined above for the treatment or prevention of pathological conditions, diseases and disorders associated with both β2 adrenergic receptor activity and M3 antimuscarinic activity, in particular where the pathological condition or disease is selected from asthma, acute bronchitis or chronic bronchitis, emphysema, or chronic obstructive pulmonary disease (COPD), preferably asthma and COPD, as well as a method for treating an individual afflicted with a disease or pathological condition associated with both activity β2 adrenergic receptor for M3 antimuscarinic activity, in particular in which disease or pathological condition is as described above; which comprises administering to said individual an effective amount of a combination product as defined above.
    [00079] As indicated above, the salts according to the invention can also be used in combination with another therapeutically active agent as defined above.
    [00080] The amount of each asset that is necessary to achieve a therapeutic effect will, of course, vary with the particular asset, the route of administration, the individual being treated, and the particular disorder or disease being treated.
    [00081] The active ingredient can be administered from 1 to 6 times a day, enough to exhibit the desired activity. Preferably, the active ingredients are administered once or twice a day.
    [00082] Examples of suitable PDE4 inhibitors that can be combined with salt compounds of the present invention are benafentrine dimaleate, etazolate, denbufilin, rolipram, cipamfiline, zardaverine, arophylline, filaminaste, tipelukast, tofimilasto, piclamylate, tolafentine, tolafentine, tolafentin, tolafentin of drotaverine, lirimilasto, roflumilasto, cilomilasto, oglemilasto, apremilasto, tetomilasto, filaminasto, (R) - (+) - 4- [2- (3cyclopentyloxy-4-methoxyphenyl) -2-phenylethyl] pyridine (CDP-840), N - (3,5-dichloro-4pyridinyl) -2- [1- (4-fluorobenzyl) -5-hydroxy-1H-indol-3-yl] -2-oxoacetamide (GSK842470), 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-3Hpurine (V-11294A), 6- [3- (N, N-Dimethylcarbamoyl) phenylsulfonyl] -4 (3-methoxyphenylamino) hydrochloride - 8-methylquinoline-3-carboxamide (GSK-256066), 4 [6,7-Dietoxy-2,3-bis (hydroxymethyl) naphthalen-1-yl] -1- (2-methoxyethyl) pyridin-2 (1H) one (T-440), acid (-) - trans-2- [3 '- [3- (N-Cyclopropylcarbamoyl) -4-oxo-1,4 -dihydro-1,8-naphthyridin-1-yl] -3-fluorobiphenyl-4-yl] cyclopropanecarboxylic (MK0873), CDC-801, UK-500001, BLX-914, 2-carbomethoxy-4-cyano-4- ( 3cyclopropylmethoxy-4-difluroromethoxyphenyl) cyclohexane1-one, cis [4-cyano-4 (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol, CDC-801 and 5 (S) [3- (Cyclopentyloxy)) -4-methoxyphenyl] -3 (S) - (3-methylbenzyl) piperidin-2-one (IPL455903).
    [00083] Examples of suitable corticosteroids and glucocorticoids that can be combined with the salt compound of the present invention are prednisolone, methylprednisolone, dexamethasone, dexamethasone cipecylate, naflocort, deflazacort, halopredone acetate, budesonide, becpropionate, acetone, hydronocetone, hydronocetone, hydronehydrone, acetone, hydrochloride, acetone, hydrochloride. fluocinolone acetonide, fluocinonide, clocortolone pivalate, methylprednisolone aceponate, dexamethasone palmitoate, tipredan, hydrocortisone aceponate, prednicarbate, alclomethasone dipropionate, halomethasone, methylprednisolate, methopretone, hematoxylate, momoprednisolate, methylprednisolone butixocort, RPR-106541, deprodone propionate, fluticasone, fluticasone propionate, fluticasone furoate, halobetasol propionate, loteprednol etabonate, betamethasone propionate, flunisolide, prednisone, dexamethasone 17-valiam, triamyramone sodium phosphate, triamine triamine, valiam bet ametasone, betamethasone, betamethasone dipropionate, 21-Chloro-11betahydroxy-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.
    [00084] Examples of suitable antihistamines that can be combined with the salts of the invention are metapyrene, mequitazine, azelastine hydrochloride, acrivastine, emedastine difumarate, emedastine fumarate, loratadine, cyproheptadine hydrochloride, diphenhydramine hydrochloride, hydrochloride dehydronepine hydrochloride , promethazine hydrochloride, levocabastine hydrochloride, desloratadine, cinnarizine, setastine hydrochloride, mizolastine, ebastine, cetirizine hydrochloride, epinastine hydrochloride, olopatadine hydrochloride, triprolidine hydrochloride, bepotastine hydrochloride, fumarate hydrochloride, triprolidine hydrochloride, fumarate levocetirizine, ketotifen, azatadine maleate, dimethindene maleate, clemastine fumarate, alcaftadine, bilastine, vapitadine hydrochloride, AZD-1744, GSK-1004723D, GSK-835726 or SUN1334H.
    [00085] Examples of suitable leukotriene antagonists that can be combined with the salts of the present invention are CYSLTR1 antagonists, such as montelukast, pranlukast or zafirlukast; or CYSLTR2 antagonists, such as pranlukast, zafirlukast or tipylukast.
    [00086] Examples of suitable CRTH2 antagonists that can be combined with the salts of the present invention are ramatroban, AMG-009, OC-000459).
    [00087] Examples of suitable Syk kinase inhibitors that can be combined with the salts of the present invention are phosphatamatinib (from Rigel), R-348 (from Rigel), R-343 (from Rigel), R-112 (from Rigel) , piceatanol, 2 (2Aminoethylamino) -4 [3 (trifluoromethyl) phenylamino] pyrimidine-5carboxamide, R-091 (from Rigel), 6- [5-Fluoro-2- (3,4,5-trimethoxyphenylamino) pyrimidine-4- ylamino] -2,2-dimethyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-3ona benzenesulfonate (R-406 from Rigel), 1- (2,4 , 6-Trihydroxyphenyl) -2- (4methoxyphenyl) ethan-1-one, N- [4- [6- (Cyclobutylamino) -9H-purin-2-ylamino] phenyl] N-methylacetamide (QAB-205 from Novartis ), CI-1002 (from Pfizer), VRT750018 (from Vertex), PRT-062607, 2- [7- (3,4-Dimethoxyphenyl) imidazo [1,2c] pyrimidine-5-ylamino] pyridine-3-carboxamide dihydrochloride (BAY-61-3606 from Bayer) and AVE-0950 (from Sanofi-Aventis). Treatment of pathological conditions or diseases associated with both β2 adrenergic receptor activity and M3 antimuscarinic activity.
    [00088] The salts of the invention, pharmaceutical compositions and combinations of the invention can be used in the treatment of pathological conditions or diseases associated with both β2 adrenergic receptor activity and M3 antimuscarinic activity, typically respiratory diseases. Respiratory disease is preferably one in which the use of bronchodilator agents is expected to have a beneficial effect, for example, asthma, acute or chronic bronchitis, emphysema, or chronic obstructive pulmonary disease (COPD). Asthma or chronic obstructive pulmonary disease is more preferred.
    [00089] The active compounds in the combination and the second therapeutic agent as defined above can be administered together in the same pharmaceutical composition or in different compositions for separate, simultaneous, concomitant or sequential administration by the same route or by different routes.
    [00090] It is contemplated that all active agents would be administered at the same or very close times. Alternatively, one or two assets could be taken in the morning and the other (s) later in the day. Or in another scenario, one or two actives could be taken twice a day and the other (s) once a day, or at the same time that the dosage in one of the two times-aodia occurred, or separately. Preferably at least two of, and most preferably all, assets would be taken together at the same time. Preferably, at least two, and more preferably all of the assets would be administered as a mixture.
    [00091] The active substance compositions according to the invention are preferably administered in the form of compositions for inhalation supplied with the help of inhalers, especially dry powder inhalers, however, any other form of application or parenteral or oral is possible . Here, the application of inhaled compositions embodies the preferred form of application, especially in the therapy of obstructive lung diseases or for the treatment of asthma.
    [00092] Active compound (s) formulations in general contain a suitable vehicle that can be either a propellant for administering MDI or water for administration through a nebulizer. The formulation can comprise additional components such as preservatives (for example, benzalkonium chloride, potassium sorbate, benzyl alcohol); pH stabilizers (for example, acidic agents, alkaline agents, buffer systems); isotonic stabilizers (eg, sodium chloride); surfactant and wetting agents (for example, polysorbates, sorbitan esters); and / or absorption enhancers (eg, chitosan, hyaluronic acid, surfactants). The formulation can also contain additives to the solubility of other active compounds when mixed with the salt of the invention. Solubility enhancers can comprise components such as cyclodextrins, liposomes or cosolvents such as ethanol, glycerol and propylene glycol.
    [00093] Additional suitable vehicles for formulations of the active salts of the present invention can be found in Remington: The Science and Practice of Pharmacy, 20th edition, Lippincott Williams & Wilkins, Philadelphia, Pa., 2000.
    [00094] The vehicle for a pharmaceutical composition in the form of a dry powder is typically chosen from starch or a pharmaceutically acceptable sugar, such as lactose or glucose. The amount of the active ingredient for the vehicle in general will vary from 0.001% to 99%.
    [00095] The invention subsequently includes a method of treating diseases or conditions associated with both a β2 adrenergic receptor and M3 antimuscarinic activity, typically respiratory diseases, such as asthma or chronic obstructive pulmonary disease, in a mammal, the method comprising administration to the mammal, of a therapeutically effective amount of a salt, pharmaceutical composition or combination of the invention. The mammal is preferably a human being. EXAMPLES
    [00096] Reagents, starting materials, and solvents were purchased from commercial suppliers and used as received.
    [00097] Salt crystallization test of compounds of formula (I) with a wide range of pharmaceutically acceptable acids (comprising, among other fumaric, succinic, sulfuric, 1-hydroxy-2-naphthoic, L-tartaric, hydrobromic, 4-acetamidobenzoic acids, sober, hydrochloric, oxalic, triphenylacetic, methanesulfonic, ethanedisulfonic, p-toluenesulfonic, naphthalene-2-sulfonic, sarcarine, Lmandelic, maleic, 1S-camphor-10-sulfonic, L-malic, L-pyroglutamic and naphthalene-1,5-1,5 disulfonic) in a range of pharmaceutically acceptable solvents (including but not limited to acetone, ethyl acetate, isopropanol, 2-butanol, ethanol, chloroform, methanol, tetrahydrofuran and water or mixtures thereof).
    [00098] Salts from 4-acetamidobenzoic acid and sorbic acid rendered or amorphous solids or oils. The salt from sulfuric acid was obtained as a solid, but with very low crystallinity. On the other hand, the salts from hydrochloric acid and hydrobromic acid were unstable.
    [00099] Only the salts of the invention were very crystalline. In addition, these crystalline salts were neither hygroscopic nor deliquescent and had a relatively high melting point allowing them to be micronized and have long-term stability.
    [000100] Particularly good methods for preparing addition salts of the invention are illustrated in the following examples.
    [000101] FTIR spectra were recorded using either a Bruker Alpha spectrometer, equipped with a Bruker Diamond single reflection ATR system, a moderate infrared source as an excitation source and a DTGS detector, or using a Perking Elmer, Spectrum a spectrometer, equipped with a Diamond single reflection ATR system, a moderate infrared source as the excitation source and a DTGS detector. The spectra were acquired in 32 scans at a resolution of 4 cm-1 in the range of 4000-400 cm-1.
    [000102] DSC analyzes were recorded either on a Mettler Toledo DSC822e or using a Mettler-Toledo DSC-821, serial number 5117423874. In the case of a Mettler Toledo DSC822e equipment, samples of 1-3 mg were weighed (using the MX5 microscale, Mettler) in 40 μL aluminum crucibles with a pinhole lid, and were heated, under nitrogen flow (50mL / min), from 30 to 300 ° C at a rate heating temperature of 10 ° C / min. Data collection and evaluation were performed using STARe software. In the case of a Mettler-Toledo DSC-821 equipment, serial number 5117423874, samples were placed heavily in an aluminum pan, an aluminum pinhole lid placed on top of the sample and compressed with a dipstick. brass. Samples were equilibrated at 25 ° C and heated at 10 ° C / min to 300 ° C. The instrument was calibrated using Indian and zinc standards.
    [000103] Thermogravimetic analyzes were recorded on a Mettler Toledo SDTA851e. Samples of 1-3 mg were weighed (using an MX5 microscale, Mettler) into 40 μL aluminum crucibles with a bore cap, and were heated to 10 ° C / min between 30 and 300 ° C, under nitrogen flow (50 mL / min). Data collection and evaluation were performed using STARe software.
    [000104] Proton nuclear magnetic resonance analyzes were recorded in deuterated dimethyl sulfoxide (DMSO-d6) on a Bruker Avance 500 Ultrashield NMR spectrometer and a 600 MHz Varian VRMNS with cold probe. Spectra were acquired by dissolving 8-10 mg of sample in 0.5 ml of deuterated solvent.
    [000105] In order to acquire a powder diffraction pattern of the obtained solid, about 20 mg of the unhandled samples were prepared on standard sample holders using polyacetate sheets.
    [000106] Powder diffraction patterns were acquired on a Bruker D8 Advance Series 2Theta / Theta powder diffraction system using CuKα1 radiation (1.54060 A) in the transmission geometry. The system is equipped with a simple photon counting PSD VANTEC-1, a germanium monochromator, a sample platform, self-modifying, with ninety positions, fixed divergence slits and radial "soller". Programs used: Data collection with DIFFRAC plus XRD Commander V.2.4.1 and evaluation with EVA V.12.0.
    [000107] Powder diffraction patterns were also performed on a Brucker X-ray powder diffractometer, model D2 Phaser with a Cu X-ray source. The method runs from 5 to 40 degrees 2-Theta with a step size of 2-Theta of degree 0.01 and a second collection time of 0.4 in each step using a Lynxeye detector. Example 1 Preparation of trans-4 - ((3- (2-chloro-4 - ((((2R) -2-hydroxy-2- (8hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethylamino) methyl) -5-methoxyphenylamino) 3-oxopropyl) (methyl) amino) -cyclohexyl hydroxy (di-2-thienyl) acetate ethanedisulfonate.
    [000108] 1.1 Preparation of trans-4 - ((3- (2-chloro-4 ((((2R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-di- hydroquinolin -5-yl) ethylamino) methyl) -5-methoxyphenyl-amino) -3-oxopropyl) (methyl) -amino) cyclohexyl hydroxy (di-2-thienyl) acetate from its fluorhydrate salt.
    [000109] To a suspension of 1.15 g of trans-4 - ((3- (2-chloro-4 - ((((2R) 2-hydroxy-2- (8-hydroxy-2-oxo-1,2 -di-hydroquinolin-5-yl) ethylamino) methyl) -5methoxyphenylamino) -3-oxopropyl) - (methyl) amino) cyclohexyl hydroxy (di-2-thienyl) acetate fluoride (Example 9 of WO 2011/141180) in 50 ml of CHCl3, excess saturated aqueous NaHCO3 solution was added. The mixture was stirred for five minutes at room temperature. The solid became an oil and a CHCl3 / MeOH solution (10: 1) was added until dissolution was observed. The phases were separated and the aqueous phase was extracted again with 30 ml of CHCl3 / MeOH solution (10: 1). The organic phases were combined, dried over MgSO4, filtered and solvents were concentrated under reduced pressure to obtain 1.09 g of the free base as a yellow dry foam. (Yield: 97.17%).
    [000110] Figure 1 shows the FTIR spectrum for free base of trans-4 - ((3- (2-chloro-4 - ((((2R) -2-hydroxy-2- (8-hydroxy-2-oxo -1,2-dihydroquinolin-5-yl) ethylamino) methyl) -5-methoxyphenylamino) -3-oxopropyl) (methyl) amino) cyclohexyl hydroxy (di-2-thienyl) acetate. Significant sign for a free base compound appears at: 2939, 1728, 1652, 1588, 1524, 1448, 1397, 1224, 1163, 1042, 833 and 700 cm-1.
    [000111] 1.2 Direct preparation of crystalline ethanedisulfonate salt from trans-4 - ((3- (2-chloro-4 - ((((2R) -2-hydroxy-2- (8-hydroxy-2- oxo-1,2-dihydroquinolin-5-yl) ethylamino) -methyl) -5-methoxyphenylamino) -3-oxopropyl) (methyl) amino) -cyclohexyl hydroxyl- (di-2-thienyl) acetate.
    [000112] 1.2.1 Using methanol as a solvent.
    [000113] 105 mg of the free base (0.132 mmol) were dissolved in 14 ml of methanol under magnetic stirring and using occasional sonication. The solution was filtered through a 0.45 μm syringe filter to eliminate some light yellow turbidity and then, while maintaining moderate agitation, a solution of 27.6 mg (0.145 mmol) of ethanedisulfonic acid in 1 ml of methanol was added drop by drop. A clear solution was obtained after the addition. The formation of a white turbidity started several minutes later and then the amount of precipitate gradually increased. Stirring was continued for 1 hour and then the mixture was allowed to stand at room temperature for 24 hours. The white solid was filtered, washed once with methanol / isopropyl ether solution (1: 1) and three times with ethyl ether to give, after drying, 76 mg of the title salt. (Yield: 58.5%).
    [000114] 1.2.2 Using CH2Cl2 / EtOH as a solvent
    [000115] Under magnetic stirring 105 mg of the free base (0.132 mmol) were dissolved in 3 ml of dichloromethane and 3 ml of ethanol were added. The solution was filtered through a 0.45 μ syringe filter to eliminate a very slight yellow turbidity and then, maintaining moderate agitation, a solution of 27.6 mg (0.145 mmol) of ethanedisulfonic acid in 1 ml of ethanol was added dropwise. The formation of a white cloudiness started immediately after adding the first drops of the acid solution and then the precipitate gradually increased. Stirring was continued for 1 hour and then the mixture was allowed to stand at room temperature for 24 hours. The white solid was filtered, washed once with ethanol / isopropyl ether solution (3: 1) and three times with ethyl ether to give, after drying, 99 mg of the title salt. (Yield: 76.1%).
    [000116] Figure 2 shows the powder X-ray diffraction pattern (PXRD) for the ethanedisulfonate salt. A large number of peaks were observed thus confirming the crystallinity of the salt. The summary of XRPD angles and relative intensity is given in Table 1.


    [000117] As can be seen from Table 1, the ethanedisulfonate salt of trans-4 - ((3- (2-chloro-4 - (((2R) -2-hydroxy-2- (8-hydroxy- 2-oxo-1,2-dihydroquinolin-5-yl) ethylamino) -methyl) -5-methoxyphenylamino) -3-oxopropyl) (methyl) amino) -cyclohexyl hydroxyl- (di-2-thienyl) acetate is characterized by an X-ray powder diffraction pattern (XRPD) having a significant peak at 2θ values of 19.95 ± 0.2, preferably a significant peak at 2θ values of 14.53 ± 0.2, 19, 83 ± 0.2 and 19.95 ± 0.2.
    [000118] Figure 3 corresponds to the 1 H-NMR spectrum of the ethanedisulfonate salt. It clearly shows a stoichiometric ratio of 1: 1 free base / ethanedisulfonic acid, when the infrared comes from the comparison between the integral values of the protons that correspond to the ethylene group of the acid and that of a simple proton of the quinolone portion of the original structure. 1H NMR (600 MHz, DMSO-d6) δ ppm 1.42 1.51 (m, 2 H), 1.59 1.79 (m, 2 H), 1.99 2.07 (m, 4 H) , 2.61 (s, 4 H), 2.74 (d, 3 H), 2.93-2.98 (m, 2 H), 3.00 3.08 (m, 2 H), 3, 22 3.33 (m, 2 H), 3.46 3.53 (m, 1 H), 3.79 (s, 3 H), 4.12 4.25 (m, 2 H), 4.74 4.81 (m, 1 H), 5.31 5.36 (m, 1 H), 6.18 (d, 1 H), 6.57 (d, J = 10.0 Hz, 1 H), 6.95 7.00 (m, 3 H), 7.07 (d, 2 H), 7.14 (d, 1 H), 7.31 (s, 1 H), 7.48 (d, 2 H), 7.55 (s, 1 H), 7.61 (s, 1 H), 8.08 (d, J = 10.0 Hz, 1 H), 8.78 (s, 2 H), 9.21 (s, 1 H), 9.85 (s, 1 H), 10.46 (s, 1 H), 10.56 (s, 1 H).
    [000119] Figure 4 shows the DSC analysis for the ethanedisulfonate salt which shows only an intense endothermic curve with a maximum at 206 ° C, indicating a possible melting / decomposition of the salt.
    [000120] Figure 5 shows the TG analysis for the ethanedisulfonate salt. The spectrum shows a slight loss of mass between 40 and 90 ° C. No significant changes are observed until about 250 ° C, at which the salt decomposes.
    [000121] Figure 6 shows the FTIR spectrum for the ethanedisulfonate salt. Significant sign for the ethanedisulfonate salt appears at: 3046, 1738, 1689, 1652, 1607, 1526, 1450, 1409, 1332, 1293, 1221, 1164, 1103, 1051, 1024, 994, 908, 841, 768 and 708 cm- 1. Example 2 Preparation of trans -4 ((2 (2 chloro -4 ((((R) -2hydroxy -2 (8hydroxy -2oxo1,2dihydroquinolin -5yl) ethylamino) methyl) -5methoxyphenylcarbamoyloxy) -ethyl) (methyl) amino) cyclohexyl 2-hydroxy-2,2-di (thiophen-2-yl) acetate disacarinate
    [000122] 2.1 Preparation of trans-4 - ((2- (2-chloro-4 ((((R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-di- hydroquinolin-5-yl) ethylamino) methyl) 5-methoxyphenylcarbamoyloxy) -ethyl) (methyl) amino) cyclohexyl 2-hydroxy-2,2-di (thiophen-2-yl) acetate from fluorhydrate.
    [000123] To a suspension of 1.26 g of trans-4 - ((2- (2-chloro-4 - ((((R) -2hydroxy-2- (8-hydroxy-2-oxo-1,2- dihydroquinolin-5-yl) ethylamino) methyl) -5methoxyphenylcarbamoyloxy) ethyl) - (methyl) amino) cyclohexyl 2-hydroxy-2,2-di (thiophen2-yl) acetate fluorhydrate (Example 12 of WO 2011/141180 ) in 58 ml CHCl3, excess saturated aqueous NaHCO3 solution was added. The mixture was stirred for 1 hour at room temperature. The aqueous layer was extracted twice with chloroform. The combined organic phases were dried over Na2SO4, filtered and solvents were concentrated under reduced pressure to obtain 1.2 g of a free base as a yellow dry foam. (Yield: 97.58%)
    [000124] Figure 7 shows the Fourier transformation infrared (FTIR) spectrum for trans-4 - ((2- (2-chloro-4 - (((R) -2hydroxy-2- (8- hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethylamino) methyl) -5methoxyphenylcarbamoyloxy) ethyl) (methyl) amino) cyclohexyl 2-hydroxy-2,2-di (thiophen 2-yl) acetate . Significant sign for a free base compound appears at: 2939, 1729, 1651, 1589, 1520, 1448, 1402, 1206, 1040, 985, 891, 833, 699, 624, 533 and 452 cm-1.
    [000125] 2.2 Preparation of amorphous form of trans-4 - ((2- (2-chloro-4 ((((R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-di- hydroquinolin-5-yl) ethylamino) methyl) -5methoxyphenylcarbamoyl-oxy) ethyl) (methyl) -amino) cyclohexyl 2-hydroxy-2,2-di (thiophen2-yl) acetate disacarinate.
    [000126] A solution of saccharin (18 mg, 0.1 mmol) in THF (2 mL) is added over a solution of trans-4 - ((2- (2-chloro-4 - (((R) -2 -hydroxy-2 (8-hydroxy -2oxo-1,2-dihydroquinolin-5-yl) ethylamino) methyl) -5methoxyphenylcarbamoyl-oxy) ethyl) (methyl) -amino) cyclohexyl 2-hydroxy-2,2di (thiophen-2 -yl) acetate (40 mg, 0.5 mmol) in THF (2mL) at room temperature. The mixture was stirred for 1 hour, and the precipitate obtained was filtered off and dried in vacuo providing 95 mg of the title product (Yield 75%).
    [000127] 2.3 Preparation of crystalline salt of trans-4 - ((2- (2-chloro-4 ((((R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-di- hydroquinolin-5-yl) ethylamino) methyl) -5methoxyphenyl-carbamoyloxy) ethyl) (methyl) -amino) cyclohexyl 2-hydroxy-2,2-di (thiophen2-yl) acetate disacarinate from the amorphous form.
    [000128] The non-crystalline disaccharate salt of trans-4 - ((2- (2-chloro-4 ((((R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-di -hydroquinolin-5-yl) ethylamino) methyl) 5-methoxyphenylcarbamoyloxy) ethyl) (methyl) -amino) cyclohexyl 2-hydroxy-2,2di (thiophen-2-yl) acetate (25 mg, 0.031 mmol) was suspended in ethanol (0.5 mL) and was stirred at 70 ° C for 2 hours. The suspension was allowed to cool to room temperature, and the off-white powder obtained was filtered off and dried overnight under vacuum at 60 ° C. Yield 10 mg (40%).
    [000129] 2.4 Direct preparation of crystalline salt of trans-4 - ((2- (2-chloro-4 - ((((R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-di- hydroquinolin-5-yl) ethylamino) methyl) -5-methoxyphenylcarbamoyloxy) ethyl) (methyl) -amino) cyclohexyl 2-hydroxy2,2-di (thiophen-2-yl) acetate disacarinate.
    [000130] 225 mg of saccharin are added directly over a hot ethanolic solution (70 ° C) of trans-4 - ((2- (2-chloro-4 - ((((R) -2-hydroxy-2 (8- hydroxy2oxo1,2dihydroquinolin -5-yl) ethylamino) -methyl) -5methoxyphenylcarbamoyl-oxy) ethyl) (methyl) -amino) cyclohexyl 2-hydroxy-2,2-di (thiophen2-yl) acetate (500 mg in 3, 7 mL of ethanol). The solution was vigorously stirred for 1 hour, transforming into a thick, almost white suspension. The walls of the flask were scratched with a spatula and the suspension was stirred for 15 more minutes. The solid was then filtered off and washed twice with ethanol (2 x 2 ml), providing 500 mg (70% yield) of a yellowish solid. This saccharin salt is optionally made into mud for 30 minutes in 6 mL of water.
    [000131] Figure 8 shows the powder X-ray diffraction pattern (PXRD) for the disacarinate salt. A large number of peaks were observed thus confirming the crystallinity of the salt. The summary of XRPD angles and relative intensities are given in table 2.


    [000132] As can be seen from Table 2, the disacarinate salt of trans-4 - ((2 (2-chloro -4 ((((R) -2hydroxy -2 (8hydroxy -2oxo -1,2-dihydroquinolin-5 -yl) ethylamino) methyl) -5-methoxyphenylcarbamoyloxy) ethyl) (methyl) amino) cyclohexyl 2-hydroxy-2,2-di (thiophen-2-yl) acetate is characterized by a powder diffraction pattern X (XRPD) having a significant peak at 2 values of 16.94 ± 0.2, preferably a significant peak at 2 values of 16.41 ± 0.2, 16.94 ± 0.2 and 23 , 89 ± 0.2.
    [000133] Figure 9 corresponds to the 1 H-NMR spectrum of the disacarinate salt. It clearly shows a stoichiometric ratio of 1: 2 free base / saccharin, when the infrared comes from the comparison between the integral values of the protons that correspond to the aromatic ring of the saccharin molecule and that of a simple proton of the hydroxyl radical of the original structure. 1H NMR (500 MHz, MeOD-d4) δppm): 1.67 (m, 2H), 1.81 (m, 2H), 1.95 (m, 2H), 2.24 (m, 4H), 3 .00 (s, 3H), 3.26 (dd, 1H), 3.34 (dd, 1H), 3.52 (m, 1H), 3.62 (m, 2H), 3.81 (m, 2H), 3.94 (s, 3H), 4.34 (m, 2H), 4.65 (m, 2H), 5.50 (dd, 1H), 6.68 (d, 1H), 7, 04 (dd, 2H), 7.11 (d, 1H), 7.20 (dd, 2H), 7.36 (d, 1H), 7.44 (dd, 2H), 7.50 (s, 1H ), 7.75 (m, 4H), 7.807.86 (m, 5H), 8.25 (d, 1H).
    [000134] Figure 10 shows the DSC analysis for the disacarinate salt which shows only an intense endothermic curve with a maximum of 197 ° C, indicating a possible melting / decomposition of the salt.
    [000135] Figure 11 shows the TG analysis for the disacarinate salt. The spectrum shows a very slight loss of mass between 40 and 80 ° C. No significant changes are observed until about 160 ° C, at which the salt decomposes.
    [000136] Figure 12 shows the FTIR spectrum for the disacarinate salt. When compared to the free base compound, the infrared spectrum of disacarinate has significant differences. A comparison between both spectra is also included in figure 12. Significant sign for disacarinate appears at: 3106, 2954, 1742, 1636, 1600, 1530, 1456, 1328, 1259, 1210, 1136, 1117, 946, 831, 770 , 751, 631, 603 and 527 cm -1. Example 3 Preparation of trans-4 - ((2- (2-chloro-4 - ((((R) -2-hydroxy-2- (8hydroxy -2oxo1,2dihydroquinolin -5-yl) ethylamino) methyl) -5methoxyphenylcarbamoyloxy) - ethyl) (methyl) amino) cyclohexyl 2-hydroxy-2,2-di (thiophen2-yl) acetate L-tartrate
    [000137] To a solution of 115 mg of L-tartaric acid in 15 mL of methanol was added a solution of 600 mg of trans4 - free base ((2- (2-chloro-4 - (((R) -2 -hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5yl) ethylamino) methyl) -5-methoxyphenylcarbamoyloxy) ethyl) - (methyl) amino) cyclohexyl 2-hydroxy-2,2- di (thiophen-2-yl) acetate (see preparation 2.1 above) in 20 ml of methanol. The mixture was stirred for 4 hours at room temperature. The resulting precipitate was filtered and dried under vacuum at 40 ° C overnight. Yield 80%.
    [000138] Figure 13 shows the powder X-ray diffraction pattern (PXRD) for the L-tartrate salt. A large number of peaks were observed thus confirming the crystallinity of the salt. The summary of XRPD angles and relative intensities are given in table 3.

    [000139] As can be seen from Table 3, the L-tartrate salt of trans4 - ((2- (2-chloro-4 - ((((R) -2-hydroxy-2- (8-hydroxy-2- oxo-1,2-dihydroquinolin-5yl) ethylamino) methyl) -5-methoxyphenylcarbamoyloxy) ethyl) (methyl) -amino) cyclohexyl 2-hydroxy-2,2-di (thiophen-2-yl) acetate is characterized by X-ray powder diffraction pattern (XRPD) having a significant peak at 2θ values of 11.10 ± 0.2, preferably a significant peak at 2θ values of 11.10 ± 0.2 and 24.01 ± 0.2
    [000140] Figure 14 corresponds to the 1 H-NMR spectrum of the L-tartrate salt. It clearly shows a stoichiometric ratio of 1: 1 free base / L-tartaric acid, when the infrared comes from the comparison between the integral values of the protons that correspond to the hydroxyl radical of the L-tartaric acid molecule and that of a simple proton of the hydroxyl radical of the original structure. 1H NMR (500 MHz, DMSO-d6) δ (ppm): 1.38 (m, 4H), 1.74 (m, 2H), 1.92 (m, 2H), 2.24 (s, 3H) , 2.37 (q, 1H), 2.47 (m, 3H), 2.55 (m, 1H), 2.64 (q, 1H), 2.67 (t, 2H), 2.85 ( m, 2H), 3.76 (s, 3H), 3.90 (bs, 2H), 4.04 (bs, 2H), 4.12 (t, 2H), 4.70 (m, 1H), 5.18 (t, 1H), 6.53 (d, 2H), 6.94 (d, 1H), 6.98 (dd, 2H), 7.08 (dd, 2H), 7.10 (d , 1H), 7.27 (bs, 1H), 7.43 (bs, 1H), 7.47 (dd, 2H), 8.11 (d, 1H), 9.02 (s, 1H), 10 , 40 (bs, 1H).
    [000141] Figure 15 shows the DSC analysis for the Ltartarate salt that shows only an intense endothermic curve with a maximum of 173 ° C, indicating a possible melting / decomposition of the salt.
    [000142] Figure 16 shows the TG analysis for the Ltartarate salt. The spectrum shows a slight loss of mass between 37 and 90 ° C probably corresponding to the water molecule. No significant changes are observed until about 173 ° C, at which the salt decomposes.
    [000143] Figure 17 shows the FTIR spectrum for Ltartarate salt. Significant sign for the L-tartrate salt appears at: 3213, 2949, 2868, 1729, 1658, 1592, 1530, 1338, 1292, 1212, 1171, 1068, 1041, 841, 702, 623 and 524 cm-1.
    [000144] Examples of composition (formulation) are reported in the following preparation forms: EXAMPLE OF COMPOSITION 1 Example of formulation 1 (Formulation for inhalation with a DPI)

    权利要求:
    Claims (7)
    [0001]
    1. Pharmaceutically acceptable crystalline addition salt, characterized by the fact that it is one of the trans-4 - ((3- (2-chloro-4 - ((((2R) -2-hydroxy-2- (8-hydroxy -2-oxo-1,2dihydroquinolin-5-yl) ethylamino) methyl) -5-methoxyphenylamino) -3-oxopropyl) (methyl) amino) -cyclohexyl hydroxy (di-2-thienyl) acetate ethanedisulfonate, trans -4 - ((2- (2-chloro-4 - ((((R) -2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethylamino) -methyl) -5-methoxyphenylcarbamoyloxy) ethyl) (methyl) amino) -cyclohexyl 2-hydroxy-2,2-di (thiophen-2-yl) acetate disacarinate, and trans-4 - ((2- (2 -chloro-4 - ((((R) -2-hydroxy-2- (8-hydroxy2-oxo-1,2-dihydroquinolin-5-yl) ethylamino) -methyl) -5-methoxyphenylcarbamoyloxy) ethyl) - ( methyl) amino) cyclohexyl 2-hydroxy-2,2-di (thiophen-2-yl) acetate.
    [0002]
    2. Pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of a salt as defined in claim 1, and a pharmaceutically acceptable carrier.
    [0003]
    Pharmaceutical composition according to claim 2, characterized in that it is formulated for administration by inhalation as a dry powder.
    [0004]
    Pharmaceutical composition according to claim 2 or 3, characterized in that it further comprises a therapeutically effective amount of one or more other therapeutic agents.
    [0005]
    5. Pharmaceutical composition according to claim 4, characterized by the fact that the other therapeutic agent is selected from: (a) corticosteroids, or glucocorticoids, (b) antihistamines, (c) chemokine receptor antagonists, such as maraviroc or enfuvirtide, (e) CRth2 antagonists, (f) leukotriene receptor antagonists, (g) JAK inhibitors such as tofacitinib or INCB018424, (h) Syk inhibitors such as R-343, (i) phosphodiesterase IV inhibitors , (j) p38 inhibitors such as ARRY-797, (k) PKC inhibitors such as NVP-AEB071, (l) 5-lipoxygenase-activating protein inhibitors, such as veliflapon, (m) 5-lipoxygenase inhibitors , (h) CYSLTR1 antagonists, (o) CYSLTR2 antagonists, (p) BLT1 antagonists, (q) BLT2 antagonists, (r) thromboxane A2 antagonists such as ramatroban, DP1 receptor antagonists, such as such as laropiprant, (t) DP1 receptor agonists, such as BW-245C, (u) I receptor agonists P, such as RO-1138452, (v) Anti-IgE, such as omalizumab, (w) IL5 antibody, such as mepolizumab, (x) leukotriene formation inhibitors, (y) decongestants, such as ephedrine, levo- methamphetamine, naphazoline, oxymetazoline, phenylephrine, phenylpropanolamine, propylexedrine, pseudoephedrine, synephrine or tetrahydrozoline; (z) mucolytics such as acetylcysteine, ambroxol, bromhexine, carbocysteine, domiodol, eprazinone, erdosteine, letosteine, neltenexine, soberol, estepronin or thiopronine; (aa) antitussives, such as dextromethorphan, (bb) analgesics such as aspirin, paracetamol, rofecoxib, celecoxib, morphine, codeine, oxycodone, hydrocodone, dihydromorphine or flupirtine; and (cc) expectorants such as antimony pentasulfide, guaiacol sulfonate, guaifenesin, potassium iodide or tiloxapol.
    [0006]
    (6) Use of a salt as defined in claim 1, characterized by the fact that it is in the manufacture of a medicine for the treatment of a disease or pathological condition, in which the pathological condition or disease is asthma, acute or chronic bronchitis, emphysema, or chronic obstructive pulmonary disease (COPD).
    [0007]
    (7) Use of a pharmaceutical composition as defined in any of claims 2 to 5, characterized by the fact that it is in the manufacture of a medicament for the treatment of a disease or pathological condition, in which the pathological condition or disease is asthma, bronchitis acute or chronic, emphysema, or chronic obstructive pulmonary disease (COPD).
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    同族专利:
    公开号 | 公开日
    KR20150123245A|2015-11-03|
    AU2014222645B2|2017-11-30|
    DK2961407T3|2018-05-28|
    CA2901865A1|2014-09-04|
    EA201500875A1|2016-06-30|
    US9562039B2|2017-02-07|
    HK1212246A1|2016-06-10|
    WO2014131851A1|2014-09-04|
    PH12015501754A1|2015-11-09|
    RS57297B1|2018-08-31|
    BR112015020152A2|2017-07-18|
    ES2674085T3|2018-06-27|
    AU2014222645A1|2015-08-13|
    PL2961407T3|2018-10-31|
    CR20150427A|2015-11-18|
    DOP2015000197A|2015-09-30|
    MX358624B|2018-08-28|
    PT2961407T|2018-05-18|
    MX2015010680A|2017-09-08|
    ZA201505374B|2016-07-27|
    SG11201505868QA|2015-09-29|
    CN105025897B|2018-03-23|
    EP2961407B1|2018-04-11|
    IL240278A|2019-08-29|
    SI2961407T1|2018-07-31|
    CA2901865C|2020-04-21|
    CN105025897A|2015-11-04|
    JP6364429B2|2018-07-25|
    US20160009698A1|2016-01-14|
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    AR094911A1|2015-09-09|
    HUE039303T2|2018-12-28|
    EA028566B1|2017-12-29|
    IL240278D0|2015-09-24|
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    TW201443043A|2014-11-16|
    PE20151602A1|2015-11-04|
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    HRP20181097T1|2018-09-07|
    EP2961407A1|2016-01-06|
    MX2015010679A|2016-05-31|
    JP2016510011A|2016-04-04|
    PH12015501754B1|2015-11-09|
    AR094910A1|2015-09-09|
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    法律状态:
    2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2018-02-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-05-21| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |
    2019-08-27| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2020-07-07| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|
    2020-12-01| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-01-26| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 27/02/2014, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    EP13382060|2013-02-27|
    EP13382060.5|2013-02-27|
    US201361804558P| true| 2013-03-22|2013-03-22|
    US61/804,558|2013-03-22|
    PCT/EP2014/053871|WO2014131851A1|2013-02-27|2014-02-27|SALTS OF 2-AMINO-1-HYDROXYETHYL-8-HYDROXYQUINOLIN-2-ONE DERIVATIVES HAVING BOTH β2 ADRENERGIC RECEPTOR AGONIST AND M3 MUSCARINIC RECEPTOR ANTAGONIST ACTIVITIES|
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