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WO2014071512A1 - Polythérapie et méthodes pour le traitement de maladies respiratoires - Google Patents

Polythérapie et méthodes pour le traitement de maladies respiratoires Download PDF

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Publication number
WO2014071512A1
WO2014071512A1 PCT/CA2013/050559 CA2013050559W WO2014071512A1 WO 2014071512 A1 WO2014071512 A1 WO 2014071512A1 CA 2013050559 W CA2013050559 W CA 2013050559W WO 2014071512 A1 WO2014071512 A1 WO 2014071512A1
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Prior art keywords
compound
formula
asm
homopiperazinium
asthma
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PCT/CA2013/050559
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English (en)
Inventor
Yvon Cormier
Evelyne ISRAEL ASSAYAG
Pierre Lavallée
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Universite Laval
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Publication of WO2014071512A1 publication Critical patent/WO2014071512A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/037—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements with quaternary ring nitrogen atoms

Definitions

  • the present disclosure relates to novel combination, use and method for the treatment or prevention of respiratory diseases.
  • the disclosure also relates to novel compounds and intermediates as well as processes for preparing same.
  • Chronic treatment of asthma often requires increasingly higher doses of the inhaled corticosteroids (ICS) and long-acting beta-agonists (LABAs), however this has caused concerns to attending physicians.
  • Chronic use of certain LABAs can increase airway hyperresponsiveness (AHR) and reduce response to short-acting beta-agonists when needed for acute use (Deborah H et al. Effect of regular salmeterol treatment on albuterol-induced bronchoprotection in mild asthma. Am J Respir Crit Care Med 1997, 156: 988-991 ).
  • COPD chronic obstructive pulmonary disease
  • Corticosteroids are potent anti-inflammatory drugs used, for example, in the treatment of asthma and COPD. Their systemic use at high doses causes major side effects that preclude their long-term uses whenever possible. Inhaled poorly absorbed steroids are useful to treat airway inflammation. At low doses these drugs have little or no side effects. However, higher doses increase the risks for oral candidasis, vocal cords paralysis, cataracts and osteoporosis. Inhaled steroids have no effects on lung interstitium and have no anti-fibrotic properties (Boulet LP et al. Airway hyperresponsiveness, inflammation, and subepithelial collagen deposition in recently diagnosed versus long-standing mild asthma. Influence of inhaled corticosteroids. Am J Respir Crit Care Med 2000, 162: 1308-1313).
  • More recent drugs such as anti-leukotrienes, are useful in some asthmatics but have no effects in COPD and other lung diseases. These drugs have anti-inflammatory properties limited to the components of inflammation caused by leukotrienes.
  • interstitial lung disease such as IPF, Sarcoidosis, HP, and BOOP basically rests on the use of systemic corticosteroids. This treatment is effective in controlling some of the inflammation but induces serious side effects and does not reverse underlying fibrotic changes.
  • Immunosupressive agents such as cyclophosphamide and azathioprine are sometimes tried in severe IPF but their therapeutic values are unproven and at most, very limited (Zisman D et al. Cyclophosphamide in the treatment of idiopathic pulmonary fibrosis: a prospective study in patients who failed to respond to corticosteroids. Chest 2000, 1 17: 1619- 1626). In essence, lung fibrosis is usually progressive and untreatable, with most IPF patients dying of this condition.
  • a method for treating or preventing diseases selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), interstitial pulmonary fibrosis (IPF), sarcoidosis, hypersensitivity pneumonitis (HP) and bronchiolitis obliterans with organizing pneumonitis (BOOP), comprising administering an effective amount of : i) a homopiperazinium compound having the formula:
  • J is a counter ion; and ii) one or more agents for treating or preventing the pulmonary diseases: beta2 agonists, muscarinic antagonists, leukotriene modulators and phosphodiesterase (PDE) inhibitors or a combination thereof.
  • PDE phosphodiesterase
  • a combination for treating or preventing disease selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), interstitial pulmonary fibrosis (IPF), sarcoidosis, hypersensitivity pneumonitis (HP) and bronchiolitis obliterans with organizing pneumonitis (BOOP), comprising an effective amount of i) a homopiperazinium compound as defined herein and ii) one or more agents for treating or preventing the pulmonary diseases: beta2 agonists, muscarinic antagonists, leukotriene modulators and phosphodiesterase (PDE) inhibitors or a combination thereof.
  • COPD chronic obstructive pulmonary disease
  • IPF interstitial pulmonary fibrosis
  • HP hypersensitivity pneumonitis
  • BOOP bronchiolitis obliterans with organizing pneumonitis
  • a method for treating or preventing pulmonary inflammation, inducing airway smooth muscle relaxation and improving airway hyperresponsiveness in an asthma or COPD patient which comprises administering an effective amount of i) a homopiperazinium compound as defined herein and ii) one or more agents for treating or preventing the pulmonary diseases: beta2 agonists, muscarinic antagonists, leukotriene modulators and phosphodiesterase (PDE) inhibitors or a combination thereof.
  • PDE phosphodiesterase
  • a method of decreasing the risk of recurrence of symptoms associated with a disease selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), interstitial pulmonary fibrosis (IPF), sarcoidosis, hypersensitivity pneumonitis (HP) and bronchiolitis obliterans with organizing pneumonitis (BOOP), comprising administering an effective amount of i) a homopiperazinium compound as defined herein and ii) one or more agents for treating or preventing the pulmonary diseases: beta2 agonists, muscarinic antagonists, leukotriene modulators and phosphodiesterase (PDE) inhibitors or a combination thereof.
  • COPD chronic obstructive pulmonary disease
  • IPF interstitial pulmonary fibrosis
  • HP hypersensitivity pneumonitis
  • BOOP bronchiolitis obliterans with organizing pneumonitis
  • a method for reducing the side effects associated with one or more agents for treating or preventing the pulmonary diseases beta2 agonists, muscarinic antagonists, leukotriene modulators and phosphodiesterase (PDE) inhibitors or a combination thereof in a patient suffering from a disease selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), interstitial pulmonary fibrosis (IPF), sarcoidosis, hypersensitivity pneumonitis (HP) and bronchiolitis obliterans with organizing pneumonitis (BOOP), said patient, the method comprising administering a homopiperazinium compound as defined herein.
  • COPD chronic obstructive pulmonary disease
  • IPF interstitial pulmonary fibrosis
  • HP hypersensitivity pneumonitis
  • BOOP bronchiolitis obliterans with organizing pneumonitis
  • COPD chronic obstructive pulmonary disease
  • IPF interstitial pulmonary fibrosis
  • HP hypersensitivity pneumonitis
  • BOOP bronchiolitis obliterans with organizing pneumonitis
  • a method for reducing airflow obstruction, preventing bronchospasm and reducing exacerbations in patients with asthma and COPD comprising administering an effective amount of i) a homopiperazinium compound as defined herein and ii) one or more agents for treating or preventing the pulmonary diseases: beta2 agonists, muscarinic antagonists, leukotriene modulators and phosphodiesterase (PDE) inhibitors or a combination thereof.
  • a homopiperazinium compound as defined herein and ii) one or more agents for treating or preventing the pulmonary diseases: beta2 agonists, muscarinic antagonists, leukotriene modulators and phosphodiesterase (PDE) inhibitors or a combination thereof.
  • PDE phosphodiesterase
  • a pharmaceutical composition comprising an effective amount of i) a homopiperazinium compound as defined herein and ii) one or more agents for treating or preventing the pulmonary diseases: beta2 agonists, muscarinic antagonists, leukotriene modulators and phosphodiesterase (PDE) inhibitors or a combination thereof.
  • a homopiperazinium compound as defined herein and ii) one or more agents for treating or preventing the pulmonary diseases: beta2 agonists, muscarinic antagonists, leukotriene modulators and phosphodiesterase (PDE) inhibitors or a combination thereof.
  • a pharmaceutical composition comprising an effective amount of a homopiperazinium compound as defined herein and a pharmaceutically acceptable carrier, said composition is for use in the treatment or prevention of pulmonary disease together with one or more agents for treating or preventing the pulmonary diseases: beta2 agonists, muscarinic antagonists, leukotriene modulators and phosphodiesterase (PDE) inhibitors or a combination thereof.
  • a pharmaceutically acceptable carrier comprising an effective amount of a homopiperazinium compound as defined herein and a pharmaceutically acceptable carrier, said composition is for use in the treatment or prevention of pulmonary disease together with one or more agents for treating or preventing the pulmonary diseases: beta2 agonists, muscarinic antagonists, leukotriene modulators and phosphodiesterase (PDE) inhibitors or a combination thereof.
  • PDE phosphodiesterase
  • J " is a counter ion; as well as the synthesis of intermediates useful in the synthesis of same.
  • Fig. 1 shows the effect of ASM-024 in in vitro relaxation response to maximally effective concentration of short-acting beta-2 agonists in dog bronchi;
  • Fig. 2 shows the effect of ASM-024 in in vitro relaxation response to maximally effective concentration of short-acting beta-2 agonists in human bronchi;
  • Fig. 3 is a bar graph representing guinea pig trachea unresponsiveness to salbutamol following adrenoreceptor desensitization;
  • Fig. 4 shows the effect of ASM-024 on guinea pig trachea responsiveness following salbutamol-induced beta2-adrenoreceptor desensitization
  • Fig. 5 is a bar graph representing guinea pig trachea unresponsiveness to salbutamol following salmeterol -induced beta2-adrenoreceptor desensitization
  • Fig. 6 shows the effect of ASM-024 on guinea pig trachea responsiveness following salmeterol-induced beta2-adrenoreceptor desensitization
  • Fig. 7 is a bar graph representing guinea pig trachea unresponsiveness to salbutamol following formoterol -induced beta2-adrenoreceptor desensitization
  • Fig. 8 shows the effect of ASM-024 on guinea pig trachea responsiveness following formoterol-induced beta2-adrenoreceptor desensitization
  • Fig. 9 shows the effect of ASM-024 over ipratropium resistance to histamine-induced contraction
  • Fig. 10 shows the effect of ASM-024 over tiotropium resistance to histamine-induced contraction
  • Fig. 1 1 shows the additive effect of ASM-024 and ipratropium on the relaxation response to methacholine
  • Fig. 12 shows the additive effect of ASM-024 and tiotropium_on the relaxation response to methacholine
  • Fig. 13 is a XRD diffraction of ASM-024. DESCRIPTION OF THE EMBODIMENTS
  • one or more of the following agents can be used: beta2 agonists, muscarinic antagonists, leukotriene modulators and phosphodiesterase (PDE) inhibitors.
  • beta2 agonists beta2 agonists
  • muscarinic antagonists beta2 agonists
  • leukotriene modulators phosphodiesterase (PDE) inhibitors.
  • PDE phosphodiesterase
  • Beta2 agonists can be separated in three classes: ultra-long-acting beta2 agonist (such as indacaterol, carmoterol, vilanterol, olodaterol, milveterol, Abediterol, PF-610355; AZD-3199 and phenethanolamine derivatives), long acting beta2 agonist (LABA) (such as formoterol, salmeterol, bambuterol and bedoradrine) and short acting beta2-agonist (SABA) (such as salbutamol, carbuterol, clenbuterol, fenoterol, metaproterenol, terbutaline, pirbuterol, albuterol, levalbuterol, reprotenol and bitolterol.
  • LAA long acting beta2 agonist
  • SABA short acting beta2-agonist
  • Muscarinic antagonists may be separated in two classes: long acting muscarinic antagonist (LAMA) (such as tiotropium, aclidinium, glycopyrronium, GSK656398, umeclidinium, vilanterol, CHF5407, QAT370, EP-101 , TD4208 and glycopyrrolate) and short acting muscarinic antagonist (SAMA) (such as ipratropium, oxitropium and atropine).
  • LAMA long acting muscarinic antagonist
  • SAMA short acting muscarinic antagonist
  • a subclass includes also muscarinic antagonist/beta2 agonist (MABA) such as GSK961081 , THRX- 200495, AZD21 15, PF3429281 , PF4348235 and LAS190792.
  • Leukotriene modulators may be separated in two classes: leukotriene antagonists (such as zafirlukast, montelukast and pranlukast) and Inhibitors of leukotriene synthesis (such as zileuton, GSK2190915 and Setileuton).
  • leukotriene antagonists such as zafirlukast, montelukast and pranlukast
  • Inhibitors of leukotriene synthesis such as zileuton, GSK2190915 and Setileuton.
  • PDE inhibitors may be separated in two classes: PDE4 inhibitors (such as roflumilast, cilomilast, rolipram, GSK256066, apremilast and CHF6001 ) and PDE4/PDE3 inhibitors (such as RPL554).
  • PDE4 inhibitors such as roflumilast, cilomilast, rolipram, GSK256066, apremilast and CHF6001
  • PDE4/PDE3 inhibitors such as RPL554
  • the methods or combinations use a homopiperazinium compound as defined herein and one or more of beta2 agonists. In one embodiment, the methods or combinations use a homopiperazinium compound as defined herein and one or more of muscarinic antagonists. In one embodiment, the methods or combinations use a homopiperazinium compound as defined herein and one or more of leukotriene modulators. I n one embodiment, the methods or combinations use a homopiperazinium compound as defined herein and one or more phosphodiesterase (PDE) inhibitors.
  • PDE phosphodiesterase
  • COPD chronic obstructive pulmonary disease
  • IPF interstitial pulmonary fibrosis
  • HP hypersensitivity pneumonitis
  • BOOP bronchiolitis obliterans with organizing pneumonitis
  • the disease is asthma. In one embodiment, the disease is COPD. In one embodiment, the disease is IPF. In one embodiment, the disease is sarcoidosis. I n one embodiment, the disease is HP. In one embodiment, the disease is BOOP.
  • the combinations and methods as defined herein can be useful for treating one or more of asthma, including bronchial, allergic, intrinsic, extrinsic, exercise- induced, drug-induced (including aspirin and NSAID-induced) and occupational asthma, both intermittent and persistent and of all severities, and other causes of airway hyper- responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy.
  • COPD chronic obstructive pulmonary disease
  • bronchitis including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cyst
  • Asthma can be classified according to severity and/or control of the condition.
  • the combinations and methods as defined herein can be useful for treating one or more of Intermittent asthma, Persistent mild asthma, Persistent moderate asthma and Persistent severe asthma. In one embodiment, the combinations and methods as defined herein can be useful for treating Persistent moderate asthma and/or Persistent severe asthma.
  • the combinations and methods as defined herein can be useful for treating one or more of Controlled asthma, Partly controlled asthma, Uncontrolled asthma and asthma Exacerbation. In one embodiment, the combinations and methods as defined herein can be useful for treating Partly controlled asthma, Uncontrolled asthma and/or asthma Exacerbation.
  • the homopiperazinium compound is a compound wherein J " is a halogen, a sulphate, acetate or a sulfonate.
  • the homopiperazinium compound is a compound wherein J " is a halogen or a sulfonate.
  • the homopiperazinium compound is a compound wherein J " is a halogen.
  • the halogen is iodide, chloride or bromide. In one embodiment, the halogen is iodide. I n one embodiment, the halogen is chloride. In one embodiment, the halogen is bromide.
  • the homopiperazinium compound is a compound wherein J " is a sulfonate.
  • the sulfonate is 4-toluenesulfonate, phenylsulfonate or methanesulfonate.
  • the sulfonate is 4-toluenesulfonate.
  • the sulfonate is phenylsulfonate.
  • the sulfonate is methanesulfonate.
  • the methods or combinations are useful for asthma or COPD
  • the homopiperazinium compound is as defined herein wherein J " is a sulfonate and one or more agents is, beta2 agonists, muscarinic antagonists, leukotriene modulators, phosphodiesterase (PDE) inhibitors.
  • the methods or combinations are useful for asthma.
  • the methods or combinations are useful for COPD.
  • the homopiperazinium compound is as defined herein wherein J " is a 4-toluenesulfonate.
  • the one or more agents is beta2 agonists, muscarinic antagonists, leukotriene modulators, phosphodiesterase (PDE) inhibitors.
  • ASM-024 mechanism of action appears to involve a direct action on airway smooth muscle cells (SMC) by a mechanism independent of cGMP or cAMP pathways.
  • SMC airway smooth muscle cells
  • ASM-024 had no relaxant effect on LTD4-induced contraction suggesting a mechanism of action independent from the leukotriene pathway.
  • treatment refers to at least i) controlling or ameliorating at least one disease described herein or associated symptoms, at least for the duration of said treatment, ii) reduce one or more side effects caused by agents used in the combination or iii) reduce the amount or dosage regimen of other agents of a patient.
  • prevention or “prophylaxis” treatment is expected to be particularly useful to the treatment of patients who have suffered a previous episode associated with diseases described herein, or are otherwise considered to be at increased risk of said diseases.
  • a successful preventive treatment would normally be expected to i) reduce the occurrences of a further episode, ii) reduce its severity or iii) prevent occurrences of further episodes, at least for the duration of the therapy.
  • the amounts and/or ratios of therapeutic agents for use in treatment will vary not only with the particular agent selected but also with the route of administration, the nature of the condition for which treatment is required and the age and condition of the patient and will be ultimately at the discretion of the attendant physician.
  • the homopiperazinium compounds defined herein can be administered concurrently to the one or more agents used herein in the methods and combinations.
  • the desired doses may conveniently be presented in a single dose or as divided dose administered at appropriate intervals, for example as two, three, four or more doses per day.
  • the compound can be administered on a dosage regimen distinct to the one or more agents used herein in the methods and combinations. Alternatively, the compound can be administered sequentially or concurrently in distinct formulations or in a common formulation.
  • therapeutic agents or combination of the invention may be administered as the raw chemical it may be preferable to present the active ingredient as a pharmaceutical composition.
  • compositions may comprise pharmaceutically acceptable carriers.
  • Compositions include those suitable for oral, nasal, topical (including buccal and sub-lingual), transdermal, or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation.
  • the formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • compositions suitable for oral administration may conveniently be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution, a suspension or as an emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents.
  • the tablets may be coated according to methods well known in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservatives.
  • the compounds and combinations according to the invention may also be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing an/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • compositions suitable for topical administration in the mouth include lozenges comprising active ingredient in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • the compounds and combinations according to the invention are conveniently delivered from an insufflator, nebulizer or a pressurized pack or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the compounds and combinations according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form in, for example, capsules or cartridges or e.g. gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • homopiperazine derivatives such as N-methyl-homopiperazine and N-isopropyl- homopiperazine may also be available however these do not have the required chemical functions for the synthesis of the compounds defined herein.
  • homopiperazine is available from various commercial sources at a reasonable price however one concern with homopiperazine is that the molecule has two reactive NH groups. A skilled organic chemist will recognize that these groups can both get involved in successive and/or simultaneous chemical reactions. In case a single NH must react with a given reagent, a classical method to reduce undesired reactions of the NH groups is to use a smaller molar amount of the reagent however this is susceptible to unacceptably reduce the yield of the desired monoreacted product and nevertheless still lead to a mixture of unreacted, mono as well as bis-reacted products.
  • a suitable reagent for introducing the phenyl ring is phenyl iodide, however other agents such asphenyl bromide alone or in the presence of sodium or potassium iodide in order to exchange the bromide on phenyl bromide to form phenyl iodide in situ may also be used.
  • Compound (2) is acylated, using for example acetic anhydride or an acyl halide to produce compound (3).
  • Compound (3) is reduced to compound of formula (4) using a suitable reducing agent, for example a hydride reducing agent such as LiAIH 4 or a borane reagent like BH 3 or a complexed borane reagent like BH 3 -Me 2 S.
  • a suitable reducing agent for example a hydride reducing agent such as LiAIH 4 or a borane reagent like BH 3 or a complexed borane reagent like BH 3 -Me 2 S.
  • the steps from homopiperazine (1 ) to crude compound (4) can be conducted without purifying intermediate compounds (2) and (3). From a commercial standpoint, avoiding purification of intermediates while maintaining an acceptable yield is an advantage when conducting large scale synthesis.
  • Compound (4) is in turn reacted with a suitable reagent of general formula Et-J, wherein Et is ethyl and J is a leaving group that will provide a counterion J " , for introducing the second ethyl group to produce compound (5) having a quaternary ammonium functionality wherein J " is a counterion.
  • J is I, Br, CI, tosyl, mesyl, bezyl; most preferably a tosyl.
  • Compounds 5 may also be formed using a reagent Et-J wherein J is other than I, Br, CI, tosyl, mesyl, bezyl, for example to form a synthetically suitable salt for the purpose of isolation or purification.
  • a "synthetically suitable salt” is a salt that may or may not be a pharmaceutically acceptable salt and that is used in the process to obtain a desired intermediate.
  • J " is other than I " , Br “ , CI " , tosylate, mesylate, bezylate
  • the desired salt is obtained by methods known in the art such as by ion exchanged.
  • Compound 5 can optionally be purified using techniques known in the art such as crystallization or chromatography.
  • J " is a counterion, preferably, J " is I “ , Br “ , CI “ , tosylate, mesylate, bezylate; most preferably a tosylate comprising the steps as defined in scheme 1.
  • J " is a counterion, preferably, J is I, Br, CI, tosyl, mesyl, bezyl; preferably tosyl, mesyl, bezyl, most preferably a tosyl.
  • the layers were separated, and the aqueous phase was extracted with TBME (3 x 150 ml_). The organic layers were combined and washed with brine (2 x 150 ml_), dried over Na 2 S0 4 , filtered and evaporated. The crude product was purified by chromatography on silica gel using 100% hexanes and a gradient of 0% to 20% MeOH in CH 2 CI 2 .
  • Example 1 1 , 1 -Diethyl-4-phenyl-homopiperazinium Iodide (ASM-009)
  • Example 2 1 , 1 -Diethyl-4-phenyl-homopiperazinium Bromide (ASM-021 )
  • the resin Amberlite ® IRA-400(CI) (100 mL) was treated with 2N KBr (250 mL), and then washed with 200 mL H 2 0.
  • the compound ASM-009 (FG1 -62, 2.286 g, 6.35 mmol) was dissolved in H 2 0 (50 mL) by heating slightly and put down on the resin.
  • the product was eluted with water (500 mL) and the solvent was evaporated.
  • the residue was analyzed by MS and a signal at m/e 127 was present. So, the resin was retreated with 2N KBr and the residue dissolved in 100 mL H 2 0. By MS, always one signal at m/e 127.
  • the resin was washed with deionized water and treated with 2N HBr (500mL), washed with deionized water (350 mL), the residue dissolved in deionized water (100 mL) was passed through the resin. But by MS, 12.5% of I " were still present. So, a new resin was used: Amberlite ® IRA-410(CI) (100 mL), treated with 2N HBr (2 x 250 mL), washed with deionized water (250 mL). The residue was dissolved in deionized water (50 mL) and eluted from the resin with deionized water.
  • ASM-021 was obtained and coevaporated with Et 2 0/acetone to afford ASM-021 as a solid (1.616 g).
  • the compound was dried by heating at 40°C under vacuum for 24 h, but traces of acetone (5%) were detected by H NMR at 2.22 ppm.
  • the product was analyzed by ES negative ion mode MS and signals at m/e 125 and 127 were present.
  • Example 3 1 , 1 -Diethyl-4-phenyl-homopiperazinium Chloride (ASM-022)
  • Example 4 1 , 1 -Diethyl-4-phenyl-homopiperazinium Acetate (ASM-023)
  • Example 5 1 , 1 -Diethyl-4-phenyl-homopiperazinium Tosylate (ASM-024)
  • Example 6 1 , 1 -Diethyl-4-phenyl-homopiperazinium Mesylate (ASM-025)
  • the resin Amberlite ® IRA-400(CI) (150-170 mL) was treated with 2N HCI (250 mL), and then washed with 250 mL of distilled water. Then the resin was washed with 2N NaOH (250 mL), treated with 2N NaOH (50 mL) in an ultrasonic bath for 20 minutes, washed with 2N NaOH (200 mL). It was washed with a 2N solution of methane sulfonic acid (250 mL), treated with this 2N solution of methane sulfonic acid (50mL) in an ultrasonic bath for 30 minutes and washed again with this 2N of methane sulfonic acid (200 mL).
  • Example 7 1 , 1 -Diethyl-4-phenyl-homopiperazinium Bezylate (ASM-033)
  • Example 8 1 , 1 -Diethyl-4-(2-pyridyl)-homopiperazinium Tosylate (ASM-037)
  • Example 9 1 , 1 -Diethyl-4-(phenyl-4-hydroxy)-homopiperazinium tosylate (ASM -073) step 1
  • the organic phase was washed once with H 2 0 (25 ml_).
  • the combined aqueous phases were back extracted with EtOAc (25 ml_).
  • the resulting combined organic phases were extracted with a 2N HCI solution (3 x 20 ml_).
  • the aqueous phases were combined, cooled down with an ice bath and basified up to pH 10 with a 5N NaOH solution.
  • the residue was coevaporated with DCM, and dissolved in DCM (90 mL), 10% Pd/C (700 mg) was added, the mixture was filled, vented, and filled 3 times with hydrogen and was heated at 40°C for an additional 7 h. However, there was some material left, the catalyst was filtered on Celite®, washed with MeOH, and the filtrate and washings were evaporated.
  • the residue was coevaporated with DCM, and dissolved in DCM (90 mL), 10% Pd/C (700 mg) was added. The mixture was filled, vented, and filled 3 times with hydrogen and stirred at 40°C under H 2 atmosphere for an additional 15 h.
  • Example 10 EC ⁇ TNF (Inflammation) and the EC 50 isometric studies of selected compounds.
  • Human mononuclear cells were isolated on Lymphocyte Separation Media (VVisent, Canada) gradient. Cells were let to adhere on tissue culture plates for 2 hours at 37C in culture medium. Plates were washed and adherent monocytes were stimulated with LPS (100 ng/mL) (E.coli 026:B6) for 18 hours at 37°C with or without increasing concentrations of the various compounds. The production of TNF in the supernatant was measured by ELISA (R&D Systems, Minneapolis, MN) according to the manufacturer's instructions.
  • mice tracheas were isolated, adherent connective tissue removed and tracheal preparations were suspended in organ baths containing Krebs bicarbonate solution at 37°C, and bubbled with 95% 0 2 -5% C0 2 . A passive tension of 0.5g was applied followed by a 30-60 min equilibration period. Tissues were then contracted with methacholine (10-5M) which was maintained during addition of cumulative concentrations of the relaxant compounds and changes of tension recorded. The results are expressed as a percentage of maximal methacholine or histamine-induced contraction.
  • the table below provides for illustrative examples for the EC50 for TNF production, a marker of inflammation) and the EC50 for the relaxant responses in mouse isolated tracheas for several claimed analogs.
  • TX effect on cell viability, no conclusion were drawn on the EC50's because the tested concentration was detrimental to the cultured cells.
  • Example 11 Characterization of compound of Example 5 (ASM-024)
  • DSC testing was performed using a Perkin Elmer Jade DSC. Approximately 2mg of ASM-024 was loaded into an aluminum sample pan and non-hermetically sealed. The sample was heated to 300°C at a rate of 10°C/minute, and heat flow response was monitored and recorded. The DSC thermogram supports the STA result above, only showing a melt at onset 166°C.
  • XRPD testing was performed using a PANalytical X'pert PRO XRPD. Approximately 20mg of sample was placed onto a low background XRPD sample holder. The sample was then loaded into the instrument and diffraction patterns recorded using the following experimental conditions:
  • Fig. 13 shows a typical diffractogram of dry ASM-024 obtained from example 5.
  • the API was seen to be crystalline with sharp peaks.
  • the crystalline form is designated anhydrous Form I for the purpose of the description herein.
  • Table 1 summarizes the list of peaks of the crystalline ASM-024.
  • the XRD pattern of ASM-024 Form I is characterized by 16 peaks. Table 2 represents the positions of these peaks according to the solid state form.
  • the XRP pattern of ASM-024 Form I could be further characterised and classified by the intensity of the peaks relative to each other. Two % of peaks relative intensity patterns were determined according the highest value of the peak # 7 or 8 (Table 3 and 4).
  • the compound having a 4-(2-piridyl) i.e.ASM-0307
  • ASM-009 is reported to have an EC50 (TNF) as low as about 2uM.
  • ASM-073 bearing a 4-hydroxyphenyl residue which may be considered an analogue closely related to the 4-phenyl substituent, showed a negative effect on cell viability in the EC50 (TNF) assay and no conclusion were drawn on the EC50's because the tested concentration was detrimental to the cultured cells.
  • the EC50 relaxant responses of ASM-073 was higher than 2000uM which is from about 29-57 times higher than most 4- phenyl compounds in the table.
  • BBB blood- brain barrier
  • solubility (in deionized water) of certain compounds is provided below:
  • ASM-067) about 12mg/ml_;
  • ASM-071 diethyl-4-(phenyl-4-trifluoromethyl)-homopiperazinium iodide
  • ASM-002 1 -diethyl-4-(phenyl)-homopiperazinium iodide
  • ASM-024 1 -diethyl-4-(phenyl)-homopiperazinium tosylate
  • homopiperazinium of ASM-067 provides much lower water solubility than that obtained for ASM-024 despite the fact that they both have a tosyl counterion. Also, the trifluoromethyl phenyl homopiperazinium compounds ASM-071 has a water solubility of almost 3 times less than the phenyl homopiperazinium ASM-002, both compounds having the same counterion.
  • Another desirable feature of a compound to be developed is the avoidance of a chiral center in the molecule, which at the same time avoids the formation of enantiomers. Since it is desired that active pharmaceutical ingredients be preferably provided as a single enantiomer, the development of chiral compounds will require either the development of asymmetric synthetic processes or enantiomeric purifications. The compounds described herein avoid this unnecessary burden since they are symmetrical.
  • Example 12 In vitro evaluation of ASM-024 mediated smooth muscle relaxation.
  • a passive tension of 0.5 g was applied to mouse tracheas and dog bronchi and 1.0 g to human bronchi, followed by a 30-60 min equilibration period. Tissues were then contracted with methacholine (10 "5 M) or histamine (10 "5 M) which was maintained during addition of cumulative concentrations of the relaxant compounds and changes of tension recorded. The results are expressed as a percentage of maximal methacholine or histamine- induced contraction.
  • ASM-024 additive effects of ASM-024 on beta2 -agonists airway smooth muscle relaxation in dog and human bronchi. i) ASM-024 increased in vitro relaxation response to maximally effective concentration of short-acting beta-2 agonists in dog bronchi.
  • Dog bronchial preparations were contracted with 10 "5 M methacholine and cumulative concentrations of ASM-024 or salbutamol added.
  • ASM-024 increased in vitro relaxation response to maximally effective concentration of short-acting beta-2 agonists in human bronchi.
  • beta2-agonists bronchodilators widely used in the respiratory diseases of asthma and COPD, induces functional desensitization of the beta2-adrenoreceptors (Davies AO et al. Regulation of beta-adrenergic receptors by steroid hormones. Annu Rev Physiol 1984, 46: 1 19-130), potentially leading to reduced responsiveness to to the short-acting ⁇ - agonist rescue medication, salbutamol, when used acutely (Lipworth BJ. Airway subsensitivity with long-acting beta2-agonists. Is there cause for concern? Drug Saf 1997, 16: 295-308).
  • tracheal preparations were exposed to submaximal concentrations of the short-acting beta agonist (SABA) salbutamol (5X10 "8 M) for 4 hours. Relaxation response to salbutamol was measured before and after prolonged exposure to the drug. Reduced relaxation response is observed after a 4 hour exposure to salbutamol (6% relaxation response as measured 10 minutes after application of the drug compared to 57% initial relaxation) (see Fig. 3).
  • SABA short-acting beta agonist
  • tracheal preparations were exposed to submaximal concentrations of the long-acting ⁇ agonist (LABA) salmeterol (5X10 "8 M) for 4 hours.
  • Initial relaxant response to salmeterol was measured before exposure to the drug, relaxant response following the desensitization process was measured using salbutamol.
  • Reduced relaxation response is observed after 4 hour exposure to salmeterol (1 % relaxation compared to 66% relaxation response as measured 10 minutes after application of salbutamol) (see Fig. 5).
  • tracheal preparations were exposed to submaximal concentrations of the lond-acting ⁇ 2 agonist (LABA) formoterol (5X10 "8 M) for 18 hours.
  • Initial relaxant response to formoterol was measured before exposure to the drug, relaxant response following the desensitization process was measured using salbutamol (2% initial relaxation compared to 95% relaxation response as measured 10 minutes after application of salbutamol) (see Fig. 7).
  • ASM-024 was able to maintain its relaxation capacity on beta2- adrenoreceptor desensitized tracheal preparations.
  • Muscarinic acetylcholine receptors (mAChR) antagonists are bronchodilators drugs used in COPD and in acute asthma exacerbations to reduce the enhanced cholinergic activity. These pharmaceutical agents are effective for their indicated uses but have limitations. They are however less effective on histamine-induced bronchoconstriction. Moreover the maximal approved therapeutic dose of these compounds, 18 ⁇ g, was selected to limit systemic side effects rather than to induce maximal bronchodilation at these tolerable doses. A series of experiments were designed to explore and differentiate the pharmacological functionality of ASM-024 to the muscarinic antagonists and examine the potential additive benefits of ASM- 024 to this class of compounds.
  • mAChR Muscarinic acetylcholine receptors
  • ASM-024 overcomes ipratropium resistance to histamine-induced contraction.
  • Guinea pig tracheal preparations were contracted in vitro with histamine (10 "5 M), cumulative concentrations of ipratropium (10 "8 M to 10 “4 M) were added, and changes of tension recorded. Once equilibration was reached after addition of the highest concentration of the cholinergic antagonist, ASM-024 (10 "4 M to 10 “3 M) was applied to the organ baths.
  • ASM-024 overcomes tiotropium resistance to histamine-induced contraction.
  • Guinea pig tracheal preparations were contracted in vitro with histamine (10 "5 M), cumulative concentrations of tiotropium (10 "8 M to 10 “4 M) were added, and changes of tension recorded. Once equilibration was reached after addition of the highest concentration of the cholinergic antagonist, ASM-024 (10 "4 M to 10 “3 M) was applied to the organ baths.
  • Ipratropium is an effective and potent relaxant compound on contraction induced by muscarinic agonists such as methacholine or acetylcholine.
  • the approved therapeutic dose for ipratropium is 18 ⁇ g, yet this dose level is well below the maximal bronchodilation dose.
  • a lower therapeutic dose was chosen for regulatory approval due to the increase in anticholinergic side effects associated with the dose level required for maximal bronchodilatory effect. The potential for a greater bronchodilator effect when given in combination with ASM-024 was assessed.
  • Tiotropium is structurally related to ipratropium but has a significantly higher affinity for muscarinic receptors.
  • the affinity of tiotropium for all muscarinic receptor subtypes is similar but tiotropium dissociates from the M2 receptors 10 times faster than it does from the M3 receptors making it more selective for the M3 receptors than ipratropium.
  • the submaximal dose 18 ⁇ g was selected to limit systemic side effects and not to induce maximal bronchodilation, (Littner et al. , 2000) and there is also a potential for underdosing with tiotropium.
  • Guinea-pig tracheal rings were exposed to a suboptimal concentration of tiotropium (9x10 "7 M) for 10 minutes, giving about 30% relaxation, followed by cumulative additions of ASM-024 (10 "6 M to 10 3 M).
  • ASM-024 a suboptimal dose of tiotropium improved the relaxation response.

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Abstract

La présente invention concerne une nouvelle combinaison comprenant un composé d'homopipérazinium présentant une formule (I): J étant un contre-ion; et un ou plusieurs agents pour traiter ou prévenir les maladies pulmonaires, et pour une utilisation pour le traitement ou la prévention de maladies respiratoires. L'invention concerne également de nouveaux composés et de nouveaux intermédiaires ainsi que des procédés de préparation de ceux-ci. N N Et Et
PCT/CA2013/050559 2012-11-06 2013-07-18 Polythérapie et méthodes pour le traitement de maladies respiratoires WO2014071512A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2023141376A3 (fr) * 2022-01-20 2023-09-28 Mahana Therapeutics, Inc. Méthodes et systèmes de traitement d'affections respiratoires à l'aide d'agents thérapeutiques numériques en combinaison avec d'autres thérapies

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050130990A1 (en) * 2001-03-23 2005-06-16 Universite Laval Nicotinic receptor agonists for the treatment of inflammatory diseases
CA2410237C (fr) * 2000-05-26 2008-01-08 Schering Corporation Antagonistes du recepteur adenosine a2a
US20080221085A1 (en) * 2004-07-15 2008-09-11 Universite Laval Nicotinic Receptor Agonists for the Treatment of Inflammatory Diseases
US20100331307A1 (en) * 2009-06-29 2010-12-30 Salituro Francesco G Therapeutic compounds and compositions
CA2445159C (fr) * 2001-04-24 2012-09-11 Massachusetts Institute Of Technology Formation par catalyse de cuivre de liaisons carbone-heteroatome et carbone-carbone

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2410237C (fr) * 2000-05-26 2008-01-08 Schering Corporation Antagonistes du recepteur adenosine a2a
US20050130990A1 (en) * 2001-03-23 2005-06-16 Universite Laval Nicotinic receptor agonists for the treatment of inflammatory diseases
CA2445159C (fr) * 2001-04-24 2012-09-11 Massachusetts Institute Of Technology Formation par catalyse de cuivre de liaisons carbone-heteroatome et carbone-carbone
US20080221085A1 (en) * 2004-07-15 2008-09-11 Universite Laval Nicotinic Receptor Agonists for the Treatment of Inflammatory Diseases
US20100331307A1 (en) * 2009-06-29 2010-12-30 Salituro Francesco G Therapeutic compounds and compositions

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023141376A3 (fr) * 2022-01-20 2023-09-28 Mahana Therapeutics, Inc. Méthodes et systèmes de traitement d'affections respiratoires à l'aide d'agents thérapeutiques numériques en combinaison avec d'autres thérapies

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