WO2011083387A1 - Sel de chlorhydrate du biphényl-2-yl-carbamate de 1-{9-[(3-fluoro-4-hydroxy-benzoyl)-méthyl-amino]-nonyl}-pipéridin-4-yle - Google Patents

Sel de chlorhydrate du biphényl-2-yl-carbamate de 1-{9-[(3-fluoro-4-hydroxy-benzoyl)-méthyl-amino]-nonyl}-pipéridin-4-yle Download PDF

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WO2011083387A1
WO2011083387A1 PCT/IB2010/056018 IB2010056018W WO2011083387A1 WO 2011083387 A1 WO2011083387 A1 WO 2011083387A1 IB 2010056018 W IB2010056018 W IB 2010056018W WO 2011083387 A1 WO2011083387 A1 WO 2011083387A1
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asthma
inhibitors
bronchitis
antagonists
hydrochloride salt
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PCT/IB2010/056018
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English (en)
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Kim James
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Pfizer Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • 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
    • 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
    • A61P11/06—Antiasthmatics
    • 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
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to the hydrochloride salt of biphenyl-2-yl-carbamic acid 1 - ⁇ 9-[(3- fluoro-4-hydroxy-benzoyl)-methyl-amino]-nonyl ⁇ -piperidin-4-yl ester 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 hydrates, solvates and polymorphs of the hydrochloride salt of biphenyl-2-yl-carbamic acid 1 - ⁇ 9-[(3-fluoro-4-hydroxy-benzoyl)-methyl-amino]-nonyl ⁇ -piperidin-4-yl ester.
  • Cholinergic muscarinic receptors are members of the G-protein coupled receptor super-family and are further divided into 5 subtypes, M-i to M 5 . Muscarinic receptor sub-types are widely and differentially expressed in the body. Genes have been cloned for all 5 sub-types and of these, M-i , M 2 and M 3 receptors have been extensively pharmacologically characterized in animal and human tissue. M-i receptors are expressed in the brain (cortex and hippocampus), glands and in the ganglia of sympathetic and parasympathetic nerves. M 2 receptors are expressed in the heart, hindbrain, smooth muscle and in the synapses of the autonomic nervous system.
  • M 3 receptors are expressed in the brain, glands and smooth muscle. In the airways, stimulation of M 3 receptors evokes contraction of airway smooth muscle leading to bronchoconstriction, while in the salivary gland M 3 receptor stimulation increases fluid and mucus secretion leading to increased salivation.
  • M 2 receptors expressed on smooth muscle are understood to be pro-contractile while pre-synaptic M 2 receptors modulate acetylcholine release from parasympathetic nerves. Stimulation of M 2 receptors expressed in the heart produces bradycardia.
  • Short and long-acting muscarinic antagonists are used in the management of asthma and COPD; these include the short acting agents Atrovent® (ipratropium bromide) and Oxivent® (oxitropium bromide) and the long acting agent Spiriva® (tiotropium bromide). These compounds produce bronchodilation following inhaled administration.
  • Atrovent® ipratropium bromide
  • Oxivent® oxitropium bromide
  • Spiriva® tiotropium bromide
  • muscarinic antagonists As a conseq uence of the wide distribution of muscarinic receptors in the body, significant systemic exposure to muscarinic antagonists is associated with effects such as dry mouth, constipation, mydriasis, urinary retention (all predominantly mediated via blockade of M 3 receptors) and tachycardia (mediated by blockade of M 2 receptors).
  • a commonly reported side-effect following inhaled administration of therapeutic dose of the current, clinically used nonselective muscarinic antagonists is dry-mouth and while this is reported as only mild in intensity it does limit the dose of inhaled agent given.
  • M 3 receptor antagonists that would have an appropriate pharmacological profile, for example in term of potency, pharmacokinetics or duration of action and that would be particularly suitable for an administration by the inhalation route.
  • the present invention relates to a novel M 3 receptor antagonist which is the hyd rochloride salt of biphenyl-2-yl-carbamic acid 1 - ⁇ 9-[(3-fluoro-4-hydroxy- benzoyl)-methyl-amino -nonyl ⁇ -piperidin-4-yl ester of formula:
  • the invention relates to a substantially crystalline form of the hydrochloride salt of biphenyl-2-yl-carbamic acid 1 - ⁇ 9-[(3-fluoro-4-hydroxy-benzoyl)-methyl-amino]- nonyl ⁇ -piperidin-4-yl ester.
  • the hydrochloride salt of the invention may also be characterized by a solid state 13 C NMR pattern having the following principal carbon chemical shifts referenced to external sample of solid phase adamantane at 29.5 ppm:
  • the hydrochloride salt of the invention may also be characterized by a solid state 19 F NMR pattern having the following principal fluorine chemical shifts referenced to an external standard of trifluoroacetic acid, 50% V/V in water, at -76.54 ppm:
  • the hydrochloride salt of the invention is an antagonist of the M 3 receptor, that is particularly useful for the treatment of M 3 -mediated diseases and/or conditions, and shows good potency.
  • the hydrochloride salt of the invention is substantially crystalline and thus exhibits properties including those of solid state stability and compatibility with certain drug product excipients, such as e.g. lactose, in particular a-lactose monohydrate, th at re n d er it s u pe ri o r to its corresponding free base which is not crystalline.
  • the hydrochloride salt of the invention is thus particularly suitable for an administration by the inhalation route e.g. using a dry powder inhaler.
  • substantially crystalline means that the hydrochloride salt of the present invention is at least 70% crystalline, more preferably at least 80% crystalline, still more preferably at least 85% crystalline, still more preferably at least 90% crystalline and even more preferably at least 95% crystalline.
  • the hydrochloride salt of the invention may be prepared from biphenyl-2-yl-carbamic a c i d 1 - ⁇ 9-[(3-fluoro-4-hydroxy-benzoyl)-methyl-amino]-nonyl ⁇ -piperidin-4-yl ester according to conventional processes for the preparation of salts such as those disclosed in "Handbook of Pharmaceutical Salts, Properties, Selection and Use. Published by Wiley-VCH , 2002. Edited by P. Heinrich Stahl, Camille G Wermuth. ISBN 3-906390-26-8".
  • the hydrochloride salt of the present invention may be prepared by addition of aqueous hydrochloric acid to biphenyl-2-yl- ca rba m ic aci d 1 - ⁇ 9-[(3-fluoro-4-hydroxy-benzoyl)-methyl-amino]-nonyl ⁇ -piperidin-4-yl ester as a free base in a suitable solvent.
  • the hyd roch loride salt of biphenyl-2-yl-carbamic acid 1 - ⁇ 9-[(3-fluoro-4-hydroxy- benzoyl)-methyl-amino]-nonyl ⁇ -piperidin-4-yl ester that is thus obtained may further be re-crystallised from other solvents such as e.g. acetone, to give higher crystallinity material.
  • the hydroch loride salt of biphenyl-2-yl-carbamic acid 1 - ⁇ 9-[(3-fluoro-4-hydroxy- benzoyl)-methyl-amino]-nonyl ⁇ -piperidin-4-yl ester according to the present invention may exist in both unsolvated and solvated forms.
  • the term 'solvate' is used herein to describe a molecular complex comprising the hydrochloride 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-stoichiometric amounts.
  • complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts.
  • the resulting complexes may be ionised, partially ionised, or non-ionised.
  • hydrochloride salt of the invention includes the hydrochloride salt of biphenyl-2-yl-carbam ic acid 1 - ⁇ 9-[(3-fluoro-4-hydroxy-benzoyl)-methyl-amino]-nonyl ⁇ - piperidin-4-yl ester as well as solvates and/or polymorphs thereof.
  • the hydrochloride salt of the invention is a valuable pharmaceutically active compound, which is suitable for the therapy and prophylaxis of numerous disorders in which the muscarinic receptor M 3 is involved or in which antagonism of this receptor may induce benefit.
  • the hydrochloride salt of the invention has the ability to interact with the M 3 receptor and thereby have a wide range of therapeutic applications, as described further below, because of the essential role which the hydrochloride salt plays in the physiology of all mammals.
  • references herein to "treatment” include references to curative, palliative and prophylactic treatment.
  • the hydrochloride salt of the invention is thus particularly useful in the the therapy and prophylaxis of the allergic and non-allergic airways diseases (e.g. asthma, COPD%) but also in the treatment of other diseases such as Inflammatory Bowel Disease, Irritable Bowel Disease, d iverticu lar disease, motion sickness, gastric ulcers, radiological examination of the bowel , symptomatic treatment of BP H (benign prostatic hyperplasia), NSAID induced gastric ulceration, urinary incontinence (including urgency, frequency, urge incontinence, overactive bladder, nocturia and lower urinary tract symptoms), cycloplegia, mydriatics and parkinsons disease.
  • BP H benign prostatic hyperplasia
  • NSAID induced gastric ulceration including urgency, frequency, urge incontinence, overactive bladder, nocturia and lower urinary tract symptoms
  • cycloplegia mydriatics and parkinsons disease.
  • the hydrochloride salt of the invention is suitable for use in the treatment of diseases, disorders, and conditions in which the M 3 receptor is involved . More specifically, the present invention also concerns the hydrochloride salt of the invention for use in the treatment of diseases, disorders, and conditions selected from the group consisting of:
  • obstructive or inflammatory airways diseases in particular chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COP D), CO P D 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;
  • COP D chronic obstructive pulmonary disease
  • CO P D 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
  • ARDS adult respiratory distress syndrome
  • bronchitis in particu lar 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;
  • asthma in particular 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;
  • bronchiectasis in particular cylindric bronchiectasis, sacculated bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis.
  • the present invention also concerns the hydrochloride salt of the invention for use in the treatment of diseases, disorders, and conditions selected from the group consisting of chronic or acute bronchoconstriction, emphysema, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), bronchitis, asthma, acute lung injury and bronchiectasis.
  • diseases, disorders, and conditions selected from the group consisting of chronic or acute bronchoconstriction, emphysema, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), bronchitis, asthma, acute lung injury and bronchiectasis.
  • a sti ll fu rther aspect of the present invention also relates to the use of the hydrochloride salt of the invention for the manufacture of a medicament having a M 3 antagonist activity.
  • the present inventions concerns the use of the hydrochloride salt of the invention, for the manufacture of a medicament for the treatment of M 3 recpetor-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 mam mal , i ncl ud i ng a h u m an bei ng , with an effective a mou nt of the hydrochloride salt of the invention. More precisely, the present invention provides a particularly interesting method for the treatment of a M 3 receptor-mediated diseases and/or conditions in a mammal, including a human being, in particular the diseases and/or conditions listed above, comprising administering said mammal with an effective amount of the hydrochloride salt of the invention.
  • the hydrochloride 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 hydrochloride salt of the invention, in addition to customary pharmaceutically innocuous excipients and/or additives.
  • the hydrochloride salt of th e i nvention 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 hydrochloride 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 hydrochloride salt of the invention. The choice of excipient will to a large extent depend on the particular mode of administration.
  • the hydrochloride salt of the invention may be administered directly into the blood stream , into muscle, or into an internal organ .
  • parenteral adm in istration i ncl ude intravenous, i ntraarterial , 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 nonaqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • a suitable vehicle such as sterile, pyrogen-free water.
  • the preparation of parenteral formulations under sterile conditions for example, by lyophilisation, 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 hydrochloride salt of the invention may be form u lated as a sol i d , sem i-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(c//-lactic-coglycolic)acid (PGLA) microspheres.
  • the hydrochloride 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).
  • Oth er m ea n s of topi ca l a d m i n i stration 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 hydrochloride 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 hydrochloride 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.
  • hydrochloride 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 I nternational Patent Applications Nos. WO 91/1 1 172, WO 94/02518 and WO 98/55148.
  • the hydrochloride 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, preferably a-lactose monohydrate, 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 for example 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 hydrochloride 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.
  • Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • 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 total daily dose of the hydrochloride salt of the invention is typically in the range 0.001 mg to 5000 mg depending, of course, on the mode of administration.
  • the present invention also relates to pharmaceutical compositions comprising from 0.001 mg to 5000 mg of the hydrochloride salt of the present invention together with one or more pharmaceutically acceptable excipients.
  • these pharmaceutical compositions may further comprise one or more other therapeutic agent(s).
  • 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.
  • a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 ⁇ g to 20 mg of the hydrochloride salt of the invention per actuation and the actuation volume may vary from 1 ⁇ to 1 00 ⁇ .
  • a typical formulation may comprise the hydrochloride 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.
  • the dosage unit is determined by a prefilled capsule, blister or pocket or by a system that utilises gravimetrically fed dosing chamber.
  • Units in accordance with the invention are typically arranged to administer a metered dose or "puff" containing from 0.001 mg to 1 0 mg of the hydrochloride salt of the invention.
  • the overall daily dose will typically be in the range 0.001 mg to 40 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
  • the hydrochloride salt of the invention is particularly suitable for an administration by inhalation.
  • the hydrochloride salt of the invention is suitable for a formulation with lactose, preferably lactose monohydrate, as a dry powder and can thus be administered using a dry powder inhaler, e.g. the dry powder inhaler described in WO 2005/002654.
  • the present invention also relates to pharmaceutical dry powders comprising 0.001 mg to 40 mg of the hydrochloride salt of biphenyl-2-yl-carbamic acid 1- ⁇ 9-[(3-fluoro-4-hydroxy-benzoyl)-methyl-amino]- nonyl ⁇ -piperidin-4-yl ester blended with lactose monohydrate.
  • these pharmaceutical formulations may further comprise one or more other therapeutic agent(s).
  • These dosages are based on an average human subject having a weight of about 65 to 70 kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
  • the hydrochloride 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.
  • hydrochloride 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 hydrochloride salt of the invention include, but are by no means limited to:
  • LTRAs Leukotriene antagonists
  • Histamine receptor antagonists including H 1 and H3 antagonists
  • PDE inhibitors including PDE3, PDE4 and PDE5 inhibitors
  • COX i nh ibitors both non-selective and selective COX-1 or COX-2 inhibitors (NSAIDs);
  • Anti-tumor necrosis factor (anti-TNF-a) agents (n) Anti-tumor necrosis factor (anti-TNF-a) agents; (o) Adhesion molecule inhibitors including VLA-4 antagonists;
  • MMPs matrix metalloproteases
  • (y) modulators of cytokine signalling pathyways such as p38 MAP kinase, PI3 kinase,
  • JAK kinase JAK kinase, syk kinase, EGFR or MK-2;
  • Adhesion factors including VLAM, ICAM, and ELAM.
  • composition comprising the hydrochloride salt of the invention in combination with H3 antagonists, ⁇ 2 agonists including long-acting ⁇ 2 agonists, PDE4 inhibitors, steroids including inhaled glucocorticosteroids, adenosine A2a receptor agonists, modulators of cytokine signalling pathyways including p38 MAP kinase or syk kinase, and/or leukotriene antagonists (LTRAs) including antagonists of LTB 4 , LTC 4 , LTD 4 , and LTE 4 , are preferred.
  • H3 antagonists ⁇ 2 agonists including long-acting ⁇ 2 agonists
  • PDE4 inhibitors steroids including inhaled glucocorticosteroids
  • adenosine A2a receptor agonists include modulators of cytokine signalling pathyways including p38 MAP kinase or syk kinase
  • LTRAs leukotriene antagonists
  • compositions comprising the hydrochloride salt of the invention in combination with a glucocorticosteroid, in particular an inhaled glucocorticosteroid with reduced systemic side effects and/or a ⁇ 2 agonist, are further preferred.
  • glucocorticosteroids include, but is not limited to, prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone, budesonide, fluticasone, ciclesonide, mometasone and their salts.
  • Suitable ⁇ 2 agonists include, but is not limited to, salbutamol, terbutaline, bambuterol, fenoterol, salmeterol, formoterol, tulobuterol and their salts.
  • compositions of the present invention comprise the hydrochloride salt of the invention in combination with a glucocorticosteroid, e.g. those listed above, and a ⁇ 2 agonist, e.g. those listed above, so as to form a 'triple combination' together with one or more pharmaceutically acceptable excipient.
  • the pharmaceutical compositions of the present invention include the dry powders comprising the hydrochloride salt of the invention, a glucocorticosteroid and a ⁇ 2 agonists, including long-acting ⁇ 2 agonists, together with lactose monohydrate.
  • compositions may conveniently be combined in the form of a kit suitable for coadministration of the compositions.
  • kit of the invention com prises two or more separate pharmaceutical compositions, at least one of which contains the hydrochloride 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 pockets.
  • a container, divided bottle, or divided foil pockets 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.
  • Figure 2/4 PXRD pattern of example 1 .
  • Biphenyl-2-yl-carbamic acid 1 -[9-(tert-butoxycarbonyl-methyl-amino)-nonyl]-piperidin- 4-yl ester (Preparation 4, 1 8.5g) was stirred in a solution of hydrochloric acid in dioxane (85ml, 4M) at room temperature for 18 hours. The solvent and excess acid were removed in vacuo and the residue azeotroped twice with dichloromethane (100ml) to give the title compound as a white solid, 18.0g.
  • Example 1 hydrochloride salt of biphenyl-2-yl-carbamic acid 1 -f9-f(3-fluoro-4- hvdroxy-benzoyl)-methyl-amino1-nonyl)-piperidin-4-yl ester
  • the seed crystal was prepared as follows:
  • the melting point of the material obtained in example 1 was determined by Differential Scanning Calorimetry (DSC) using a TA instruments Q1000 differential scanning calorimeter. The sample was heated at 20°C/minute, from 10 °C to 250° C, in a standard aluminium pan. The DSC thermogram obtained trace is shown in Figure 1 with flat baselines and sharp endotherms corresponding to the melt. The melting point for 2.072 mg of the material obtained in example 1 was evidenced by a strong endotherm with onset temperature at 1 1 1 .2 °C.
  • the powder X-ray diffraction pattern of example 1 was determined using a Bruker- AXS Ltd. D4 ENDEAVOR powder X-ray diffractometer fitted with an automatic sample changer, a theta-theta goniometer geometry, automatic beam divergence slit and a PSD Vantec-1 detector.
  • Table 1 Characteristic diffraction peaks of example 1 ( ⁇ 0.1 ° 2 ⁇ ) with relative intensity cut-off ⁇ 15%
  • Example 2 re-crystallisation of the compound of example 1 from acetone
  • the melting point of 2.027 mg of the material obtained in example 2 was determined using the same method as described for example 1 and was evidenced by a strong endotherm with onset temperature at 1 18.1 °C.
  • the DSC thermogram obtained trace is shown in Figure 2 with flat baselines and sharp endotherms corresponding to the melt. This higher melting point of acetone produced material can be attributed to a higher level of crystallinity and larger particle size.
  • a proton decoupling field of approximately 85 kHz was applied. 4096 scans were collected with a 8.5 second recycle delay. The carbon spectrum was referenced using an external standard of crystalline adamantane, setting its upfield resonance to 29.5 ppm. The fluorine solid state spectrum was collected using a proton decoupled magic angle spinning experiment (MAS). A proton decoupling field of approximately 85 kHz was applied. 8 scans were collected with recycle delay of 420 seconds. The fluorine spectrum was referenced using an external standard of trifluoroacetic acid (50% VA in H20), setting its resonance to -76.54 ppm.
  • Membranes (5Dg/well) were incubated with 3 H-NMS (at a concentration 5 x K D ) plus/minus test compound for 24hr at RT (room temperature) in a 1 ml polystyrene 96- wel l deep well block.
  • the final assay vol u me was 200DI, comprising of: 20 ⁇ plus/minus test compound; 20 ⁇ 3 H-NMS (Perkin Elmer NEN 636) and 160 ⁇ membrane solution.
  • Total Binding was defined with 0.1 % DMSO; Non-Specific Binding was defined with 1 ⁇ Atropine.
  • Assay buffer was 20mM Hepes (pH 7.4). Once all assay components were added, plates were covered and incubated at room temperature for 24 hrs with shaking.
  • the assay was terminated by rapidly filtering through GF/B Unifilter plates pre-soaked with 0.5% polyethylenimine, using a Packard filtermate harvester, the filter plate was then washed with 3x1 ml 4°C assay buffer. The filter plates were dried at 45°C for 1 hour. The bottoms of the filter plates were sealed and 50 ⁇ / ⁇ of Microscint ⁇ ' added, the top of the plates were sealed with a Topseal. Following 90 minutes, the plates were read on an NXT Topcount (1 minute read time per well).
  • IC 50 is the concentration of unlabelled drug which inhibits by 50% the specific radioligand binding.
  • [L] is the free radioligand concentrations and K D and K, are the equilibrium dissociation constants of the radioligand and unlabelled drug respectively.
  • hydrochloride salt of biphenyl-2-yl-carbamic acid 1 - ⁇ 9- [(3-fluoro-4-hydroxy-benzoyl)-methyl-amino]-nonyl ⁇ -piperidin-4-yl ester that has been tested in the above assay show hM 3 receptor antagonist activity of 0.615 nM.
  • a cotton thread is attached to the cartilage at one end of the strip for attachment to the force transducer and a cotton loop made at the other end to anchor the tissue in the organ bath.
  • the strips are mounted in 5ml organ baths filled with warm (37°C) aerated modified Krebs.
  • the pump flow rate is set to 1 .0 ml/ min and the tissues washed continuously. Tissues are placed under an initial tension of 1000mg. Tissues are re-tensioned after 15 and 30 minutes, then allowed to equilibrate for a further 30-45 minutes.
  • Tissues are subjected to electrical field stimulation (EFS) of the following parameters: 10 secondes trains every 2 minutes, 0.1 ms pulse width , 1 0Hz and 1 0-30V. The voltage is raised 5V every 1 0 minutes within the stated range until a maximum contractile response for each tissue is observed. This just maximum voltage for each tissue is then used th rou ghout th e remai n der of the experi ment. Fol lowi ng equilibration to EFS for 20 minutes, the pump is stopped and after 15 minutes control readings are taken over a 8-10 minutes period (4-5 responses).
  • EFS electrical field stimulation
  • the compound is then added to each tissue as a bolus dose at 30xKi (determined at the human M 3 receptor expressed in CHO cells in a filtration binding assay), and left to incubate for 2 hours.
  • the compound is then washed from tissues using a rapid wash with modified Krebs for 1 minutes and flow is restored to 1 ml/min for the remainder of the experiment.
  • Guinea Pig Trachea assay can also be used:
  • Trachea are removed from male Dunkin-Hartley guinea-pigs (wt 350-450g) and following removal of adherent connective tissue, an incision is made through the cartilage opposite the trachealis muscle and tracheal strips 3-5 cartilage rings wide prepared.
  • the tracheal strips are suspended between an isometric strain gauge and a fixed tissue hook with the muscle in the horizontal plane in 5ml tissue baths under an initial tension of 1 g and bathed in warmed (37°C) aerated (95%0 2 /5%C0 2 ) Krebs solution containing 3 ⁇ indomethacin and 10 ⁇ guanethidine.
  • the tissues are positioned between parallel platinum wire electrodes ( ⁇ 1 cm gap).
  • a constant 1 ml/min flow of fresh Krebs solution (of the above composition) is maintained through the tissue baths using peristaltic pumps.
  • the tissues are allowed to equilibrate for an hour with re-tensioning to 1 g at 15 minutes a nd 30 minutes from the start of the equilibration period.
  • tissues are electrically field stimulated (EFS) using the following parameters: 10V, 10Hz 0.1 ms pulse width with 10 seconds trains every 2 minutes.
  • EFS electrically field stimulated
  • EFS responses are 100% nerve mediated and 100% cholinergic as confirmed by blockade by 1 ⁇ tetrodotoxin or 1 ⁇ atropine. Tissues are then repeatedly stimulated at 2 minutes intervals until the responses were reproducible. The peristaltic pump is stopped 20 minutes prior to the addition of the study compound and the average twitch contraction over the last 10 minutes recorded as the control response. The study compound is added to the tissue baths, with each tissue receiving a single concentration of compound and allowed to equilibrate for 2 hours. At 2 hours post addition the inhibition of the EFS response is recorded and IC 50 curves generated using a range of compound concentrations over tracheal strips from the same animal.
  • the tissues are then rapidly washed and the 1 ml/minute perfusion with Krebs solution re-established. Tissues are stimulated for a further 16 hours and recovery of the EFS response recorded. At the end of the 16 hours, 10 ⁇ histamine is added to the baths to confirm tissue viability.
  • the just max concentration (tested concentration giving a response > 70% inhibition but less than 100%) of antagonist is identified from the IC 50 curve and the time to 25% recovery of the induced inhibition (T 25 ) calculated in tissues receiving this concentration.

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Abstract

La présente invention concerne le sel de chlorhydrate du biphényl-2-yl-carbamate de 1-{9-[(3-fluoro-4-hydroxy-benzoyl)-méthyl-amino]-nonyl}-pipéridin-4-yle ainsi que ses procédés de synthèse, les intermédiaires utilisés dans sa synthèse, les compositions l'incluant et ses applications. La présente invention concerne également les hydrates, solvates et formes polymorphiques du sel de chlorhydrate du biphényl-2-yl-carbamate de 1-{9-[(3-fluoro-4-hydroxy-benzoyl)-méthyl-amino]-nonyl}-pipéridin-4-yle.
PCT/IB2010/056018 2010-01-07 2010-12-22 Sel de chlorhydrate du biphényl-2-yl-carbamate de 1-{9-[(3-fluoro-4-hydroxy-benzoyl)-méthyl-amino]-nonyl}-pipéridin-4-yle WO2011083387A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
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US9642799B2 (en) 2012-03-13 2017-05-09 Respivert, Ltd. Crystalline 6-(2-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-D]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-0X0-3,4-dihydroquinazolin-5-yl)-N,N-bis(2-methoxyethyl)hex-5-ynamide
CN109843297A (zh) * 2016-10-20 2019-06-04 辉瑞大药厂 治疗pah的抗增殖剂
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

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9642799B2 (en) 2012-03-13 2017-05-09 Respivert, Ltd. Crystalline 6-(2-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-D]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-0X0-3,4-dihydroquinazolin-5-yl)-N,N-bis(2-methoxyethyl)hex-5-ynamide
CN109843297A (zh) * 2016-10-20 2019-06-04 辉瑞大药厂 治疗pah的抗增殖剂
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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