WO2006051375A1 - Sel-tartrate de n-1-adamanthyl-2-{3-[(2r)- 2-({(2r)-2-hydroxy -2-[4-hydroxy- 3-(hydroxymethyl) phenyl]ethyl} amino)propyl] phenyl} acetamide - Google Patents

Sel-tartrate de n-1-adamanthyl-2-{3-[(2r)- 2-({(2r)-2-hydroxy -2-[4-hydroxy- 3-(hydroxymethyl) phenyl]ethyl} amino)propyl] phenyl} acetamide Download PDF

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Publication number
WO2006051375A1
WO2006051375A1 PCT/IB2005/003314 IB2005003314W WO2006051375A1 WO 2006051375 A1 WO2006051375 A1 WO 2006051375A1 IB 2005003314 W IB2005003314 W IB 2005003314W WO 2006051375 A1 WO2006051375 A1 WO 2006051375A1
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Prior art keywords
asthma
bronchitis
inhibitors
phenyl
bronchiectasis
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PCT/IB2005/003314
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English (en)
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Kim James
Stefan Colin John Taylor
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Pfizer Limited
Pfizer Inc.
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Publication of WO2006051375A1 publication Critical patent/WO2006051375A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • This invention relates to the L-tartrate salt of ⁇ /-1-Adamantyl-2- ⁇ 3-[(2fl)-2-( ⁇ (2fl)-2- hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl ⁇ amino)propyl] phenyljacetamide and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, said compound.
  • the invention also relates to the derived forms of the L-tartrate salt of ⁇ /-1-Adamantyl-2- ⁇ 3-[(2f?)- 2-( ⁇ (2/ : ?)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl) phenyl]ethyl ⁇ amino)propyl]phenyl ⁇ acetamide, including hydrates, solvates and polymorphs thereof.
  • Adrenoceptors are members of the large G-protein coupled receptor super-family.
  • the adrenoceptor subfamily is itself divided into the ⁇ and ⁇ subfamilies with the ⁇ sub-family being composed of at least 3 receptor sub-types: ⁇ 1 , ⁇ 2 and ⁇ 3. These receptors exhibit differential expression patterns in tissues of various systems and organs of mammals.
  • ⁇ 2 adrenergic ( ⁇ 2) receptors are mainly expressed in smooth muscle cells (e.g.
  • ⁇ 3 adrenergic receptors are mainly expressed in fat tissues (therefore ⁇ 3 agonists could potentially be useful in the treatment of obesity and diabetes) and ⁇ 1 adrenergic receptors are mainly expressed in cardiac tissues (therefore ⁇ 1 agonists are mainly used as cardiac stimulants).
  • Glucocorticosteroids, anti-leukotrienes, theophylline, cromones, anti-cholinergics and ⁇ 2 agonists constitute drug classes that are currently used to treat allergic and non-allergic airways diseases such as asthma and chronic obstructive airways disease (COPD). Treatment guidelines for these diseases include both short and long acting inhaled ⁇ 2 agonists. Short acting, rapid onset ⁇ 2 agonists are used for "rescue" bronchodilation, whereas, long-acting forms provide sustained relief and are used as maintenance therapy.
  • Bronchodilation is mediated via agonism of the ⁇ 2 adrenoceptor expressed on airway smooth muscle cells, which results in relaxation and hence bronchodilation.
  • ⁇ 2 agonists can prevent and reverse the effects of all bronchoconstrictor substances, including leukothene D4 (LTD4), acetylcholine, bradykinin, prostaglandins, histamine and endothelins.
  • LTD4 leukothene D4
  • acetylcholine acetylcholine
  • bradykinin prostaglandins
  • histamine and endothelins ⁇ 2 receptors are so widely distributed in the airway, ⁇ 2 agonists may also affect other types of cells that play a role in asthma. For example, it has been reported that ⁇ 2 agonists may stabilize mast cells.
  • the inhibition of the release of bronchoconstrictor substances may be how ⁇ 2 agonists block the bronchoconstriction induced by allergens, exercise and cold air. Furthermore, ⁇ 2 agonists inhibit cholinergic neurotransmission in the human airway, which can result in reduced cholinergic-reflex bronchoconstriction .
  • ⁇ 2 adrenoceptors are also expressed in other organs and tissues and thus ⁇ 2 agonists, such as those described in the present invention, may have application in the treatment of other diseases such as, but not limited to those of the nervous system, premature labor, congestive heart failure, depression, inflammatory and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma and in conditions where there is an advantage in lowering gastric acidity, particularly in gastric and peptic ulceration.
  • diseases such as, but not limited to those of the nervous system, premature labor, congestive heart failure, depression, inflammatory and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma and in conditions where there is an advantage in lowering gastric acidity, particularly in gastric and peptic ulceration.
  • ⁇ 2 agonists are limited in their use due to their low selectivity or adverse side-effects driven by high systemic exposure and mainly mediated through action at ⁇ 2 adrenoreceptors expressed outside the airways (muscle tremor, tachycardia, palpitations, restlessness). Therefore there is a need for improved agents in this class.
  • the present invention relates to a novel beta 2 agonist.
  • the invention relates to the L-tartrate salt of ⁇ /-1-Adamantyl-2- ⁇ 3-[(2fl)-2-( ⁇ (2fl)-2- hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl ⁇ amino)propyl] phenyljacetamide and its derived forms.
  • the L-tartrate salt of the invention is an agonist of the ⁇ 2 receptors, that is particularly useful for the treatment of ⁇ 2-mediated diseases and/or conditions, and show good potency, in particular when administered via the inhalation route.
  • the L-tartrate salt of the invention is particularly suitable for an administration by the inhalation route.
  • the L-tartrate salt of the invention can be formulated for an administration using a dry powder inhaler.
  • the L-tartrate salt of the invention exhibits properties including those of solid state stability and compatibility with certain drug product excipient that render it superior to its corresponding free base.
  • Figure 1 represents the observed X-ray diffraction pattern of the L-tartrate salt of ⁇ /-1- Adamantyl-2- ⁇ 3-[(2R)-2-( ⁇ (2f?)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl) phenyl]ethyl ⁇ amino)propyl] phenyljacetamide.
  • the L-tartrate salt of the invention may be prepared from ⁇ /-1 -Adamantyl-2- ⁇ 3-[(2fl)-2-
  • the L-tartrate salt of ⁇ /-1 -Adamantyl-2- ⁇ 3-[(2f?)-2-( ⁇ (2f?)-2-hydroxy-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl ⁇ amino)propyl]phenyl ⁇ acetamide may exist in both unsolvated and solvated forms.
  • the term 'solvate' is used herein to describe a molecular complex comprising the L-tartrate salt of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • the term 'hydrate' is employed when said solvent is water.
  • complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiomethc amounts.
  • complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiomethc amounts.
  • the resulting complexes may be ionised, partially ionised, or non- ionised.
  • L-tartrate salt of the invention include the L-tartrate salt of ⁇ /-1 -Adamantyl-2- ⁇ 3-[(2/ : ?)- 2-( ⁇ (2fl)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl] ethyljamino) propyl]phenyl ⁇ acetamide and its derived forms.
  • the L-tartrate salt of the invention is a valuable pharmaceutically active compound, which is suitable for the therapy and prophylaxis of numerous disorders in which the ⁇ 2 receptor is involved or in which agonism of this receptor may induce benefit, in particular the allergic and non-allergic airways diseases (e.g. asthma, COPD%) but also in the treatment of other diseases such as, but not limited to those of the nervous system, premature labor, congestive heart failure, depression, inflammatory and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma and in conditions where there is an advantage in lowering gastric acidity, particularly in gastric and peptic ulceration.
  • allergic and non-allergic airways diseases e.g. asthma, COPD
  • other diseases such as, but not limited to those of the nervous system, premature labor, congestive heart failure, depression, inflammatory and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma and in conditions where there is an advantage in lowering gastric acidity,
  • the L-tartrate salt of the invention can be administered according to the invention to animals, preferably to mammals, and in particular to humans, as pharmaceutical for therapy and/or prophylaxis. It can be administered per se, in mixtures with one another or in the form of pharmaceutical preparations which as active constituent contain an efficacious dose of the L- tartrate salt of the invention, in addition to customary pharmaceutically innocuous excipients and/or additives.
  • the L-tartrate salt of the invention may be freeze-dried, spray-dried, or evaporatively dried to provide a solid plug, powder, or film of crystalline or amorphous material. Microwave or radio frequency drying may be used for this purpose.
  • the L-tartrate salt of the invention may be administered alone or in combination with other drugs and will generally be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • excipient is used herein to describe any ingredient other than the L-tartrate salt of the invention. The choice of excipient will to a large extent depend on the particular mode of administration.
  • the L-tartrate salt of the invention may be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9)
  • a suitable vehicle such as sterile, pyrogen-free water.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the L-tartrate salt of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound.
  • examples of such formulations include drug-coated stents and PGLApoly(d/-lactic-coglycolic)acid (PGLA) microspheres.
  • the L-tartrate salt of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
  • Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999).
  • topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. PowderjectTM, BiojectTM, etc.) injection.
  • Formulations for topical administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the L-tartrate salt of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the L- tartrate salt of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 ⁇ g to 20mg of the L-tartrate salt of the invention per actuation and the actuation volume may vary from 1 ⁇ l to 100 ⁇ l.
  • a typical formulation may comprise the L- tartrate salt of the invention, propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
  • Suitable flavours such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the dosage unit is determined by means of a valve which delivers a metered amount.
  • Units in accordance with the invention are typically arranged to administer a metered dose or "puff" containing from 0.001 mg to 10mg of the L-tartrate salt of the invention.
  • the overall daily dose will typically be in the range 0.001 mg to 40mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
  • the L-tartrate salt of the invention is particularly suitable for an administration by inhalation.
  • the L-tartrate salt of the invention is suitable for a formulation with lactose as a dry powder and can thus be administered using a dry powder inhaler.
  • the L-tartrate salt of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the L-tartrate salt of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • a polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
  • a preservative such as benzalkonium chloride.
  • Such formulations may also be delivered by iontophoresis.
  • Formulations for ocular/aural administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.
  • the L-tartrate salt of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
  • soluble macromolecular entities such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers
  • Drug-cyclodextrin complexes are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.
  • two or more pharmaceutical compositions may conveniently be combined in the form of a kit suitable for coadministration of the compositions.
  • the kit of the invention comprises two or more separate pharmaceutical_compositions, at least one of which contains the L-tartrate salt of the invention in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • a container, divided bottle, or divided foil packet An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
  • the kit of the invention is particularly suitable for administering different dosage forms, for example parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit typically comprises directions for administration and may be provided with a so-called memory aid.
  • the total daily dose of the L-tartrate salt of the invention is typically in the range 0.001 mg to 5000mg depending, of course, on the mode of administration.
  • an intravenous daily dose may only require from 0.001 mg to 40mg.
  • the total daily dose may be administered in single or divided doses_and may, at the physician's discretion, fall outside of the typical range given herein.
  • These dosages are based on an average human subject having a weight of about 65kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
  • references herein to "treatment” include references to curative, palliative and prophylactic treatment.
  • the L-tartrate salt of the invention or compositions thereof can also be used as a combination with one or more additional therapeutic agents to be co-administered to a patient to obtain some particularly desired therapeutic end result such as the treatment of pathophysiologically-relevant disease processes including, but not limited to (i) bronchoconstriction, (ii) inflammation, (iii) allergy, (iv) tissue destruction, (v) signs and symptoms such as breathlessness, cough.
  • pathophysiologically-relevant disease processes including, but not limited to (i) bronchoconstriction, (ii) inflammation, (iii) allergy, (iv) tissue destruction, (v) signs and symptoms such as breathlessness, cough.
  • co-administration As used herein, the terms “co-administration”, “co-administered” and “in combination with”, referring to the L-tartrate salt of the invention and one or more other therapeutic agents, is intended to mean, and does refer to and include the following:
  • each part may be administered by either the same or different route.
  • Suitable examples of other therapeutic agents which may be used in combination with the L-tartrate salt of the invention, or pharmaceutically acceptable salts, derived forms or compositions thereof, include, but are by no means limited to:
  • LTRAs Leukotriene antagonists
  • Histamine receptor antagonists including H1 and H3 antagonists
  • PDE inhibitors e.g. PDE3, PDE4 and PDE5 inhibitors
  • Anti-tumor necrosis factor (anti-TNF- ⁇ ) agents (m) Adhesion molecule inhibitors including VLA-4 antagonists,
  • Kinin-B, - and B 2 -receptor antagonists (o) Immunosuppressive agents, (p) Inhibitors of matrix metalloproteases (MMPs), (q) Tachykinin NK 1 , NK 2 and NK 3 receptor antagonists, (r) Elastase inhibitors, (s) Adenosine A2a receptor agonists, (t) Inhibitors of urokinase,
  • (w) modulators of cytokine signalling pathways such as p38 MAP kinase, syk kinase or JAK kinase inhibitor,
  • cytokine signalling pathyways such as p38 MAP kinase or syk kinase, or,
  • LTRAs Leukotriene antagonists
  • glucocorticosteroids in particular inhaled glucocorticosteroids with reduced systemic side effects, including prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide, and mometasone furoate, or
  • ipratropium salts namely bromide, tiotropium salts, namely bromide, oxitropium salts, namely bromide, perenzepine, and telenzepine
  • ipratropium salts namely bromide
  • tiotropium salts namely bromide
  • oxitropium salts namely bromide, perenzepine, and telenzepine
  • the L-tartrate salt of the invention has the ability to interact with the ⁇ 2 receptor and thereby have a wide range of therapeutic applications, as described further below, because of the essential role which the ⁇ 2 receptor plays in the physiology of all mammals.
  • a further aspect of the present invention relates to the L-tartrate salt of the invention or compositions thereof, for use in the treatment of diseases, disorders, and conditions in which the ⁇ 2 receptor is involved. More specifically, the present invention also concerns the L- tartrate salt of the invention or compositions thereof, for use in the treatment of diseases, disorders, and conditions selected from the group consisting of :
  • asthma of whatever type, etiology, or pathogenesis in particular asthma that is a member selected from the group consisting of atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiologic disturbances, extrinsic asthma caused by environmental factors, essential asthma of unknown or inapparent cause, non-atopic asthma, bronchitic asthma, emphysematous asthma, exercise-induced asthma, allergen induced asthma, cold air induced asthma, occupational asthma, infective asthma caused by bacterial, fungal, protozoal, or viral infection, non-allergic asthma, incipient asthma, whez infant syndrome and bronchiolytis,
  • obstructive or inflammatory airways diseases of whatever type, etiology, or pathogenesis in particular an obstructive or inflammatory airways disease that is a member selected from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated or not associated with COPD, COPD that is characterized by irreversible, progressive airways obstruction, adult respiratory distress syndrome (ARDS), exacerbation of airways hyper-reactivity consequent to other drug therapy and airways disease that is associated with pulmonary hypertension,
  • COPD chronic osinophilic pneumonia
  • COPD chronic obstructive pulmonary disease
  • COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated or not associated with COPD
  • COPD that is characterized by irreversible, progressive airways obstruction, adult respiratory distress syndrome (ARDS), exacerb
  • bronchitis of whatever type, etiology, or pathogenesis in particular bronchitis that is a member selected from the group consisting of acute bronchitis, acute laryngotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphylococcus or streptococcal bronchitis and vesicular bronchitis,
  • bronchiectasis of whatever type, etiology, or pathogenesis, in particular bronchiectasis that is a member selected from the group consisting of cylindric bronchiectasis, sacculated bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis.
  • a still further aspect of the present invention also relates to the use of the L-tartrate salt of the invention or compositions thereof, for the manufacture of a drug having a ⁇ 2 agonist activity.
  • the present inventions concerns the use of the L-tartrate salt of the invention, or pharmaceutically acceptable salts, derived forms or compositions thereof, for the manufacture of a drug for the treatment of ⁇ 2-mediated diseases and/or conditions, in particular the diseases and/or conditions listed above.
  • the present invention provides a particularly interesting method to treat a mammal, including a human being, with an effective amount of the L-tartrate salt of the invention, or a composition thereof. More precisely, the present invention provides a particularly interesting method for the treatment of a ⁇ 2-mediated diseases and/or conditions in a mammal, including a human being, in particular the diseases and/or conditions listed above, comprising admidministering said mammal with an effective amount of the L-tartrate salt of the invention.
  • Example 1 The melting point of example 1 was determined by Differential Scanning Calorimetry (DSC) using a Perkin Elmer DSC7. The sample of example 1 (2.940 mg) was heated from 30-300 0 C at 20°C/min in a nitrogen atmosphere. The material was sealed into a vented aluminium pan. The melting point was evidenced by a strong endotherm at 194°C (onset at 187°C). Post-melt endothermic degradation events were also observed.
  • DSC Differential Scanning Calorimetry
  • reaction mixture was cooled to room temperature and purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (98:2:0.2 changing to 97:3:0.3, by volume) to give the title compound (12.1g) as a white oil.
  • Tributyltin methoxide 28.3 ml, 98mmol
  • preparation 10 15.Og, 65mmol
  • isopropenyl acetate (10.8ml, 98mmol)
  • palladium(ll)acetate 750mg, 3.30mmol
  • tri-ortfto-tolylphosphine (2.Og, 6.5mmol) were stirred together in toluene (75ml) at 100 0 C under nitrogen for 5 hours.
  • the reaction was diluted with ethyl acetate (150ml) and 4M aqueous potassium fluoride solution (90ml) and stirred for 15 minutes.
  • the mixture was filtered through arbocel and the organic phase separated and reduced In vacuo.
  • Acetyl chloride (0.7ml, 9.3mmol) was slowly added to a solution of (3-bromo-phenyl)-acetic acid (20.Og, 93mmol) in methanol (500ml) at O 0 C under nitrogen and the reaction was allowed to warm gradually to room temperature over a period of 5 hours. The solvent was removed in vacuo and the residual oil was redissolved in dichloromethane, dried (sodium sulfate) and concentrated in vacuo to give the title compound as a colourless oil (20.6g).
  • TBDMS fert-butyl(dimethyl)silyl
  • the ability of the L-tartrate salt of the invention to act as potent ⁇ 2 agonists therefore mediating smooth muscle relaxation may be determined by the measure of the effect of beta-2 adrenergic receptor stimulation on electrical field stimulated-contraction of guinea pig trachea strips.
  • the strips are equilibrated, un-tensioned, for 20 minutes in a modified Krebs Ringer buffer (Sigma K0507) containing 3 ⁇ M lndomethacin (Sigma I7378), 10 ⁇ M Guanethidine (Sigma G8520) and 10 ⁇ M Atenolol (Sigma A7655), heated at 37 0 C and gassed with 95% O 2 /5% CO 2 , before applying an initial tension of 1 g.
  • the preparations are allowed to equilibrate for a further 30-45 minutes, during which time they are re-tensioned (to 1 g) twice at 15-minute intervals.
  • the organ baths are constantly perfused with the above-described Krebs Ringer buffer by means of a peristaltic pump system (pump flow rate 7.5 ml / minute) throughout the experiment, with the exception of when a beta-2 agonist according to the present invention is added, the pump is then stopped for the time of the cumulative dosing to the bath and started again after maximal response is reached for the wash-out period.
  • a peristaltic pump system pump flow rate 7.5 ml / minute
  • isoprenaline (Sigma 15627) to establish a maximal response in terms of inhibition of the contractile EFS response.
  • the isoprenaline is then washed out over a period of 40 minutes.
  • a standard curve to isoprenaline is carried out on all tissues (Isoprenaline Curve 1) by means of cumulative, bolus addition to the bath using half log increments in concentration. The concentration range used is 1 e"9 to 1 ⁇ /3 e"6 M.
  • Beta-2 agonist responses are expressed as percentage inhibition of the EFS response.
  • Data for beta-2 agonist are normalised by expressing inhibition as a percentage of the maximal inhibition induced by isoprenaline in Curve 1.
  • the EC 50 value for beta-2 agonist according to the present invention refers to the concentration of compound required to produce half maximal effect.
  • Data for beta-2 agonists according to the present invention are then expressed as relative potency to isoprenaline defined by the ratio (EC 50 beta- 2 agonist)/(EC50 Isoprenaline).
  • Beta-2 agonist activity of test compounds is confirmed using the protocol above, however, prior to constructing the curve to beta-2 agonist according to the present invention, the preparations are pre-incubated (for a minimum of 45 minutes) with 300 nM ICI 118551 (a selective ⁇ 2 antagonist) which results in the case of a beta-2 mediated effect in a rightward-shift of the test compound dose response curve.
  • the agonist potency for the ⁇ 2 receptor of the L-tartrate salt of the invention may also be determined by the measure of the concentration of compound according to the present invention required to produce half maximal effect (EC 50 ) for the ⁇ 2 receptor.
  • CHO Choinese Hamster Ovary cells recombinantly expressing the human ⁇ 2 adrenergic receptor (from Kobilka et al., PNAS 84: 46-50, 1987 and Bouvier et al., MoI Pharmacol 33: 133- 139 1988 CH0h ⁇ 2) were grown in Dulbeccos MEM/ NUT MIX F12 (Gibco, 21331-020) supplemented with 10 % foetal bovine serum (Sigma, F4135, Lot 90K8404 Exp 09/04), 2 mM glutamine (Sigma, G7513), 500 ⁇ g/ml geneticin (Sigma, G7034) and 10 ⁇ g/ml puromycin (Sigma, P8833). Cells were seeded to give about 90 % confluency for testing.

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Abstract

L'invention concerne le sel L-tartrate de N-1-adamantyl-2- {3-[(2R)-2-({(2R)- 2-hydroxy-2- [4-hydroxy-3- (hydroxyméthyl) phényl]éthyl}amino) propyl} acétamide et son utilisation en tant que médicament.
PCT/IB2005/003314 2004-11-12 2005-10-31 Sel-tartrate de n-1-adamanthyl-2-{3-[(2r)- 2-({(2r)-2-hydroxy -2-[4-hydroxy- 3-(hydroxymethyl) phenyl]ethyl} amino)propyl] phenyl} acetamide WO2006051375A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0425057A GB0425057D0 (en) 2004-11-12 2004-11-12 L-tartrate salt of N-1-adamantyl-2-{3-[(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]eth yl}amino)propyl]phenyl}acetamide
GB0425057.7 2004-11-12

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WO2006051375A1 true WO2006051375A1 (fr) 2006-05-18

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TW (1) TW200630324A (fr)
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009068177A1 (fr) * 2007-11-28 2009-06-04 Almirall, S.A. Dérivés de 4-(2-amino-1-hydroxyéthyl)phénol comme agonistes du récepteur β2-adrénergique
EP2196465A1 (fr) 2008-12-15 2010-06-16 Almirall, S.A. Dérivés de (3-oxo)pyridazin-4-ylurée comme inhibiteurs de PDE4
WO2011061527A1 (fr) 2009-11-17 2011-05-26 Astrazeneca Ab Combinaisons qui comprennent un modulateur du récepteur glucocorticoïde, destinées au traitement de maladies respiratoires
EP2394998A1 (fr) 2010-05-31 2011-12-14 Almirall, S.A. Dérivés de 3-(5-Amino-6-oxo-1,6-dihydropyridazin-3-yl)-biphenyl en tant qu'inhibiteurs de la PDE4
WO2012046050A1 (fr) 2010-10-07 2012-04-12 Astrazeneca Ab Nouvelles combinaisons
US8524908B2 (en) 2009-03-12 2013-09-03 Almirall, S.A. Process for manufacturing 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one
US9108918B2 (en) 2011-10-07 2015-08-18 Almirall, S.A. Process for preparing 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(R)-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one via a novel intermediate
US9346759B2 (en) 2012-03-20 2016-05-24 Almirall, S.A. Polymorphic crystal forms of 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-(R)-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one, heminapadisytlate as agonist of the β2 adrenergic receptor
US10342786B2 (en) 2017-10-05 2019-07-09 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US11291659B2 (en) 2017-10-05 2022-04-05 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD

Citations (3)

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Publication number Priority date Publication date Assignee Title
WO2003091204A1 (fr) * 2002-04-25 2003-11-06 Glaxo Group Limited Derives de la phenethanolamine
EP1460064A1 (fr) * 2003-03-14 2004-09-22 Pfizer Limited Derivés de Indole-2-carboxamide comme beta-2 agonistes
EP1577291A1 (fr) * 2004-03-17 2005-09-21 Pfizer Limited Dérivés béta-2 agonistes de la phényléthanolamine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003091204A1 (fr) * 2002-04-25 2003-11-06 Glaxo Group Limited Derives de la phenethanolamine
EP1460064A1 (fr) * 2003-03-14 2004-09-22 Pfizer Limited Derivés de Indole-2-carboxamide comme beta-2 agonistes
EP1577291A1 (fr) * 2004-03-17 2005-09-21 Pfizer Limited Dérivés béta-2 agonistes de la phényléthanolamine

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101815700A (zh) * 2007-11-28 2010-08-25 奥米罗有限公司 作为β2肾上腺素受体的促效剂的4-(2-氨基-1-羟基乙基)苯酚衍生物
WO2009068177A1 (fr) * 2007-11-28 2009-06-04 Almirall, S.A. Dérivés de 4-(2-amino-1-hydroxyéthyl)phénol comme agonistes du récepteur β2-adrénergique
EP2196465A1 (fr) 2008-12-15 2010-06-16 Almirall, S.A. Dérivés de (3-oxo)pyridazin-4-ylurée comme inhibiteurs de PDE4
US8524908B2 (en) 2009-03-12 2013-09-03 Almirall, S.A. Process for manufacturing 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one
WO2011061527A1 (fr) 2009-11-17 2011-05-26 Astrazeneca Ab Combinaisons qui comprennent un modulateur du récepteur glucocorticoïde, destinées au traitement de maladies respiratoires
EP2394998A1 (fr) 2010-05-31 2011-12-14 Almirall, S.A. Dérivés de 3-(5-Amino-6-oxo-1,6-dihydropyridazin-3-yl)-biphenyl en tant qu'inhibiteurs de la PDE4
WO2012046050A1 (fr) 2010-10-07 2012-04-12 Astrazeneca Ab Nouvelles combinaisons
US9108918B2 (en) 2011-10-07 2015-08-18 Almirall, S.A. Process for preparing 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(R)-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one via a novel intermediate
US9346759B2 (en) 2012-03-20 2016-05-24 Almirall, S.A. Polymorphic crystal forms of 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-(R)-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one, heminapadisytlate as agonist of the β2 adrenergic receptor
US10342786B2 (en) 2017-10-05 2019-07-09 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US10537560B2 (en) 2017-10-05 2020-01-21 Fulcrum Therapeutics. Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US11291659B2 (en) 2017-10-05 2022-04-05 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US11479770B2 (en) 2017-10-05 2022-10-25 Fulcrum Therapeutics, Inc. Use of p38 inhibitors to reduce expression of DUX4

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GB0425057D0 (en) 2004-12-15
AR055282A1 (es) 2007-08-15
NL1030405C2 (nl) 2006-12-12
PE20061131A1 (es) 2006-10-20
TW200630324A (en) 2006-09-01
GT200500328A (es) 2006-06-02
UY29207A1 (es) 2006-06-30

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