WO2021014169A1 - Forme cristalline de 4-[[2-(5-chloro-2-hydroxy-phényl)acétyl]amino]-n-cyclohexyl-pyridine-2-carboxamide - Google Patents

Forme cristalline de 4-[[2-(5-chloro-2-hydroxy-phényl)acétyl]amino]-n-cyclohexyl-pyridine-2-carboxamide Download PDF

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Publication number
WO2021014169A1
WO2021014169A1 PCT/GB2020/051781 GB2020051781W WO2021014169A1 WO 2021014169 A1 WO2021014169 A1 WO 2021014169A1 GB 2020051781 W GB2020051781 W GB 2020051781W WO 2021014169 A1 WO2021014169 A1 WO 2021014169A1
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compound
amino
treatment
polymorph
conditions
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PCT/GB2020/051781
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English (en)
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Sarah ELLAM
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Enterprise Therapeutics Limited
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Publication of WO2021014169A1 publication Critical patent/WO2021014169A1/fr

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    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides

Definitions

  • the present invention relates to a novel crystalline form, of a compound which has activity as a positive modulator of the calcium-activated chloride channel (CaCC), TMEM16A.
  • the invention also relates to methods of preparing the novel crystalline form and to compositions containing it as well as to its use in treating diseases and conditions in which TMEM16A plays a role, particularly respiratory diseases and conditions.
  • Background of the invention is a novel crystalline form, of a compound which has activity as a positive modulator of the calcium-activated chloride channel (CaCC), TMEM16A.
  • the hydration of the mucus gel is critical to enable mucus clearance (Boucher 2007; Matsui et al, 1998).
  • the mucus gel In a normal, healthy airway, the mucus gel is typically 97% water and 3% w/v solids under which conditions the mucus is cleared by mucociliary action.
  • the hydration of the airway mucosa is regulated by the coordinated activity of a number of ion channels and transporters.
  • the % solids of the mucus gel is increased as the hydration is reduced and mucus clearance is reduced (Boucher, 2007).
  • cystic fibrosis where loss of function mutations in CFTR attenuates the ability of the airway to secrete fluid, the % solids can be increased to 15% which is believed to contribute towards the plugging of small airways and failure of mucus clearance.
  • Strategies to increase the hydration of the airway mucus include either the stimulation of anion secretion and thereby fluid secretion or the inhibition of Na + absorption. To this end, stimulating the activity of TMEM16A channels will increase anion secretion and therefore increase fluid accumulation in the airway mucosa, hydrate mucus and enhance mucus clearance mechanisms.
  • TMEM16A also referred to as Anoctamin-1 (Ano1), is the molecular identity of calcium- activated chloride channels (Caputo et al, 2008; Yang et al, 2008).
  • TMEM16A channels open in response to elevation of intracellular calcium levels and allow the bidirectional flux of chloride, bicarbonate and other anions across the cell membrane.
  • Functionally TMEM16A channels have been proposed to modulate transepithelial ion transport, gastrointestinal peristalsis, nociception and cell migration/proliferation (Pedemonte & Galietta, 2014).
  • TMEM16A channels are expressed by the epithelial cells of different organs including the lungs, liver, kidney, pancreas and salivary glands. In the airway epithelium TMEM16A is expressed at high levels in mucus producing goblet cells, ciliated cells and in submucosal glands. Physiologically TMEM16A is activated by stimuli which mobilise intracellular calcium, particularly purinergic agonists (ATP, UTP), which are released by the respiratory epithelium in response to cyclical shear stress caused by breathing and other mechanical stimuli such as cough. In addition to increasing anion secretion leading to enhanced hydration of the airways, activation of TMEM16A plays an important role in bicarbonate secretion. Bicarbonate secretion is reported to be an important regulator of mucus properties and in controlling airway lumen pH and hence the activity of native antimicrobials such as defensins (Pezzulo et al, 2012).
  • TMEM16A positive modulators have the potential to deliver clinical benefit to all CF patients and non-CF respiratory diseases characterised by mucus congestion including chronic bronchitis and severe asthma.
  • TMEM16A modulation has been implicated as a therapy for dry mouth (xerostomia), resultant from salivary gland dysfunction in Sjorgen's syndrome and radiation therapy, dry eye, cholestasis and gastrointestinal motility disorders.
  • TMEM16A positive modulators of TMEM16A and which are therefore of use in the treatment of diseases and conditions in which TMEM16A plays a role, particularly respiratory diseases and conditions.
  • WO2019/145726 discloses 4-[[2-(5-Chloro-2- hydroxy-phenyl)acetyl]amino]-N-cyclohexyl-pyridine-2-carboxamide (Compound 1), which has the following structural formula:
  • Figure 1 is an XRPD diffractogram of solid crystalline polymorphic Form 1 of Compound 1
  • FIG. 2 shows overlaid thermogravimetric analysis (TGA; upper line) and differential scanning calorimetry (DSC; lower line) thermograms of solid crystalline polymorphic Form 1 Compound 1.
  • DSC shows an endotherm with integral 32 J/g, onset 174.3 °C and peak at 180.7 °C; an exotherm with integral 4 J/g, onset 182.5 °C and peak at 183.5 °C and an endotherm with integral 48 J/g, onset 185.4 °C and peak at 189.3 °C.
  • Figure 3 is the XRPD diffractogram for the static stability test for the Form 1 polymorph of Compound 1 showing that Form 1 is stable after 7 days at 40°C and 75% relative humidity: Lower trace: initial sample
  • Figure 4 is an XRPD diffractogram of solid crystalline polymorphic Form 2 of Compound 1
  • Figure 5 shows overlaid TGA and DSC thermograms of solid crystalline polymorphic Form 2 Compound 1.
  • the DSC plot has an endotherm with integral 70 J/g, onset 186.7 °C and peak at 192.4 °C.
  • Figure 6 is the XRPD diffractogram for the static stability test for the Form 2 polymorph of Compound 1 showing that Form 2 is stable after 7 days at 40°C and 75% relative humidity: Lower trace: initial sample
  • references to “pharmaceutical use” refer to use for administration to a human or an animal, in particular a human or a mammal, for example a domesticated or livestock mammal, for the treatment or prophylaxis of a disease or medical condition.
  • pharmaceutical composition refers to a composition which is suitable for pharmaceutical use and“pharmaceutically acceptable” refers to an agent which is suitable for use in a pharmaceutical composition.
  • Other similar terms should be construed accordingly.
  • a volume of solvent per unit mass of Compound 1 this refers to mg of Compound 1 and mL of solvent such that 50 mg of Compound 1 in 20 volumes of solvent is a sample of 1 mL volume; 30 mg of Compound 1 in 60 volumes of solvent is a sample of 1.8 mL volume and 30 mg of Compound 1 in 70 volumes of solvent is sample 2.1 mL volume.
  • Compound 1 disclosed herein is 4-[[2-(5-Chloro-2-hydroxy-phenyl)acetyl]amino]-N- cyclohexyl-pyridine-2-carboxamide. This compound is exemplified in our earlier application WO2019/145726 and the method exemplified in that document results in the production of Compound 1 as its Form 2 crystalline polymorph.
  • the Form 2 crystalline polymorph is an anhydrous non-solvated form of Compound 1 and appears to be stable to exposure to elevated temperature and humidity with no evidence of a hydrated form of Compound 1 being observed.
  • Compound 1 in the form of its Form 1 anhydrous solid crystalline polymorph (the Form 1 polymorph), for example as characterised by an XRPD diffractogram substantially as shown in Figure 1 .
  • the XRPD diffractogram of the Form 1 polymorph has a major peak at 5.2 ( ⁇ 0.2 degrees, 2-theta value).
  • a major peak at 5.2 ( ⁇ 0.2 degrees, 2-theta value) and at least three peaks (for example three, four, five, six, seven, eight or all nine) at positions selected from 4.7, 10.4, 17.2, 18.8, 20.8, 23.0, 25.0, 29.1 and 31.3 ( ⁇ 0.2 degrees, 2-theta values) are observable in the XRPD diffractogram.
  • the Form 1 polymorph can be distinguished from the Form 2 polymorph because the XRPD diffractogram does not contain a peak at 11.5 ( ⁇ 0.2 degrees, 2-theta value), which is one of the major peaks in the XRPD diffractogram of the Form 2 polymorph.
  • a peak at 11.5 ( ⁇ 0.2 degrees, 2-theta value) is not observable in the XRPD diffractogram of the Form 1 polymorph.
  • a major peak at 5.2 ( ⁇ 0.2 degrees, 2-theta value) and at least three peaks (for example three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen or all fourteen) of the peaks at positions selected from 4.7, 10.4, 17.2, 17.8, 18.8, 20.8, 21.5, 23.0, 23.1 , 23.7, 24.8, 25.0, 29.1 and 31.3 ( ⁇ 0.2 degrees, 2-theta values) are observable in the XRPD diffractogram of the Form 2 polymorph of Compound 1. Still more suitably, no peak at 1 1.5 ( ⁇ 0.2 degrees, 2-theta value) is observable.
  • a major peak at 5.2 ( ⁇ 0.2 degrees, 2-theta value) and at least three peaks (for example three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen or all nineteen) of the peaks at positions selected from 4.7, 10.4, 15.6, 17.2, 17.8, 18.8, 19.3, 20.2, 20.8, 21.5, 23.0, 23.1 , 23.7, 24.3, 24.8, 25.0, 26.0, 29.1 and 31.3 ( ⁇ 0.2 degrees, 2-theta values) are observable. Still more suitably, no peak at 1 1.5 ( ⁇ 0.2 degrees, 2-theta value) is observable.
  • the XRPD peak positions and intensities in the Form 1 diffractogram pattern are as set out below.
  • the Form 1 polymorph is substantially free from other forms of Compound 1 , such that, for example, in a sample of Compound 1 , at least 97%, 98%, 99%, 99.5%, 99.6% 99.7%, 99.8% or 99.9% by weight of Compound 1 may be present as the Form 1 polymorph.
  • the Form 1 polymorph may be prepared by crystallisation from a suitable solvent, especially from n-heptane or water. Therefore, in a further aspect of the invention, there is provided a process for the preparation of the Form 1 crystalline polymorph of Compound 1 , the process comprising crystallising Compound 1 from n-heptane or water.
  • the process comprises the steps of:
  • step (ii) Subjecting the suspension from step (i) to a series of heat-cool cycles in which the minimum temperature is 15 to 25°C and the maximum temperature is 45 to 55°C and allowing crystallisation to take place; and
  • the amount of n-heptane or water used to suspend Compound 1 is suitably at least 20 volumes, for example 20 to 60 volumes, per unit mass of Compound 1.
  • each heat-cool cycle may take place over a period of about 8 hours and can be achieved by switching a heating element on or off about every 4 hours.
  • the suspension is shaken to assist crystallisation.
  • the suspension may be placed in a platform shaker incubator.
  • step (iii) the crystals are suitably isolated by filtration.
  • Compound 1 is a modulator of TMEM16A and therefore, in a further aspect of the invention, there is provided Compound 1 in the form of its Form 1 polymorph as defined above for use in the treatment or prophylaxis of diseases and conditions affected by modulation of TMEM16A.
  • Compound 1 in the form of its Form 1 polymorph as defined above in the manufacture of a medicament for the treatment or prophylaxis of diseases and conditions affected by modulation of TMEM16A.
  • a method for the treatment or prophylaxis of diseases and conditions affected by modulation of TMEM16A comprising administering to a patient in need of such treatment an effective amount of Compound 1 in the form of its Form 1 polymorph as defined above.
  • TMEM16A The diseases and conditions affected by modulation of TMEM16A include respiratory diseases and conditions, dry mouth (xerostomia), intestinal hypermobility, cholestasis and ocular conditions.
  • the invention also provides:
  • a method for the treatment or prophylaxis of respiratory diseases and conditions comprising administering to a patient in need of such treatment an effective amount of Compound 1 in the form of its Form 1 polymorph as defined above.
  • a method for the treatment or prophylaxis of intestinal hypermobility comprising administering to a patient in need of such treatment an effective amount of Compound 1 in the form of its Form 1 polymorph as defined above.
  • a method for the treatment or prophylaxis of cholestasis comprising administering to a patient in need of such treatment an effective amount of Compound 1 in the form of its Form 1 polymorph as defined above.
  • a method for the treatment or prophylaxis of ocular conditions comprising administering to a patient in need of such treatment an effective amount of Compound 1 in the form of its Form 1 polymorph as defined above.
  • Respiratory diseases and conditions which may be treated or prevented by Compound 1 in the form of its Form 1 polymorph include cystic fibrosis, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, bronchiectasis, including non-cystic fibrosis bronchiectasis, asthma and primary ciliary dyskinesia.
  • cystic fibrosis chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, bronchiectasis, including non-cystic fibrosis bronchiectasis, asthma and primary ciliary dyskinesia.
  • COPD chronic obstructive pulmonary disease
  • Dry mouth which may be treated or prevented by Compound 1 in the form of its Form 1 polymorph may result from Sjorgens syndrome, radiotherapy treatment and xerogenic drugs.
  • Compound 1 will generally be administered as part of a pharmaceutical composition and therefore the invention further provides a pharmaceutical composition comprising Compound 1 in the form of its Form 1 polymorph as defined above together with a pharmaceutically acceptable excipient.
  • the pharmaceutical composition may be formulated for oral, rectal, nasal, topical (including topical administration to the lung, dermal, transdermal, eye drops, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration and may be prepared by any methods well known in the art of pharmacy.
  • Compositions for oral administration or topical administration to the lung are particularly suitable.
  • the composition may be prepared by bringing into association the above defined active agent with the excipient.
  • the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • the invention extends to methods for preparing a pharmaceutical composition comprising bringing Compound 1 in the form of its Form 1 polymorph as defined above in conjunction or association with a pharmaceutically acceptable carrier or vehicle.
  • Formulations for oral administration in the present invention may be presented as: discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active agent; as a powder or granules; as a solution or a suspension of the active agent in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water in oil liquid emulsion; or as a bolus etc.
  • the term“acceptable carrier” includes vehicles such as common excipients e.g. binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate, sodium stearate and other metallic stearates, glycerol stearate, stearic acid, silicone fluid, talc waxes, oils and colloidal silica.
  • Flavouring agents such as peppermint, oil of wintergreen, cherry flavouring and the like can also be used. It may be desirable
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active agent in a free flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active agent.
  • compositions suitable for oral administration include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier.
  • compositions for oral administration comprise aqueous suspensions of Compound 1 in the form of its Form 1 polmorph.
  • the Form 1 polymorph of Compound 1 may be suspended in aqueous solvent immediately before administration to a patient.
  • the Form 1 polymorph of Compound 1 may be suspended in an aqueous solvent and the aqueous suspension may be stored for an extended period of time (e.g. 1-2 days, 1-7 days, 1-2 weeks, 1-5 weeks, 1-15 weeks or 1-30 weeks) before administration to a patient.
  • Compound 1 in the form of its Form 1 polymorph may be made up into a cream, ointment, jelly, solution or suspension etc.
  • Cream or ointment formulations that may be used for the drug are conventional formulations well known in the art, for example, as described in standard text books of pharmaceutics such as the British Pharmacopoeia.
  • Aerosol formulations typically comprise the active ingredient suspended or dissolved in a suitable aerosol propellant, such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC).
  • a suitable aerosol propellant such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC).
  • CFC propellants include trichloromonofluoromethane (propellant 11), dichlorotetrafluoromethane (propellant 114), and dichlorodifluoromethane (propellant 12).
  • Suitable HFC propellants include tetrafluoroethane (HFC-134a) and heptafluoropropane (HFC-227).
  • the propellant typically comprises 40%-99.5% e.g.
  • the formulation may comprise excipients including co solvents (e.g. ethanol) and surfactants (e.g. lecithin, sorbitan trioleate and the like).
  • excipients include polyethylene glycol, polyvinylpyrrolidone, glycerine and the like. Aerosol formulations are packaged in canisters and a suitable dose is delivered by means of a metering valve (e.g. as supplied by Bespak, Valois or 3M or alternatively by Aptar, Coster or Vari).
  • Topical administration to the lung may also be achieved by use of a non-pressurised formulation such as an aqueous solution or suspension.
  • a non-pressurised formulation such as an aqueous solution or suspension.
  • a nebuliser e.g. one that can be hand-held and portable or for home or hospital use (ie non-portable).
  • the formulation may comprise excipients such as water, buffers, tonicity adjusting agents, pH adjusting agents, surfactants and co-solvents.
  • Suspension liquid and aerosol formulations (whether pressurised or unpressurised) will typically contain the compound of the invention in finely divided form, for example with a D 50 of 0.5- 10 mm e.g. around 1-5 mm.
  • Particle size distributions may be represented using D 1 0 , D 50 and D 90 values.
  • the D 50 median value of particle size distributions is defined as the particle size in microns that divides the distribution in half.
  • the measurement derived from laser diffraction is more accurately described as a volume distribution, and consequently the D 50 value obtained using this procedure is more meaningfully referred to as a Dv 50 value (median for a volume distribution).
  • Dv values refer to particle size distributions measured using laser diffraction.
  • D 1 0 and D 90 values used in the context of laser diffraction, are taken to mean Dv 10 and Dv 90 values and refer to the particle size whereby 10% of the distribution lies below the D 1 0 value, and 90% of the distribution lies below the D 90 value, respectively.
  • An aqueous suspension for topical administration to the lung may be prepared by suspending the Form 1 polymorph of Compound 1 in aqueous solvent immediately before administration to a patient.
  • the Form 1 polymorph of Compound 1 may be suspended in an aqueous solvent and the aqueous suspension may be stored for an extended period of time (e.g. 1-2 days, 1-7 days, 1-2 weeks, 1-5 weeks, 1-15 weeks or 1- 30 weeks) before administration to a patient.
  • Topical administration to the lung may also be achieved by use of a dry-powder formulation.
  • a dry powder formulation will contain the compound of the disclosure in finely divided form, typically with a mass mean diameter (MMAD) of 1-10 mm or a D 50 of 0.5-10 mm e.g. around 1-5 mm.
  • Powders of the compound of the invention in finely divided form may be prepared by a micronization process or similar size reduction process. Micronization may be performed using a jet mill such as those manufactured by Hosokawa Alpine. The resultant particle size distribution may be measured using laser diffraction (e.g. with a Malvern Mastersizer 2000S instrument).
  • the formulation will typically contain a topically acceptable diluent such as lactose, glucose or mannitol (preferably lactose), usually of comparatively large particle size e.g. a mass mean diameter (MMAD) of 50 mm or more, e.g. 100 mm or more or a D 50 of 40-150 mm.
  • a topically acceptable diluent such as lactose, glucose or mannitol (preferably lactose)
  • MMAD mass mean diameter
  • lactose refers to a lactose-containing component, including a-lactose monohydrate, b-lactose monohydrate, a-lactose anhydrous, b-lactose anhydrous and amorphous lactose.
  • Lactose components may be processed by micronization, sieving, milling, compression, agglomeration or spray drying.
  • Commercially available forms of lactose in various forms are also encompassed, for example Lactohale ® (inhalation grade lactose; DFE Pharma), lnhaLac ® 70 (sieved lactose for dry powder inhaler; Meggle), Pharmatose ® (DFE Pharma) and Respitose ® (sieved inhalation grade lactose; DFE Pharma) products.
  • the lactose component is selected from the group consisting of a-lactose monohydrate, a-lactose anhydrous and amorphous lactose.
  • the lactose is a- lactose monohydrate.
  • Dry powder formulations may also contain other excipients.
  • a dry powder formulation according the present disclosure comprises magnesium or calcium stearate.
  • Such formulations may have superior chemical and/or physical stability especially when such formulations also contain lactose.
  • a dry powder formulation is typically delivered using a dry powder inhaler (DPI) device.
  • DPI dry powder inhaler
  • Example dry powder delivery systems include SPINHALER®, DISKHALER®, TURBOHALER®, DISKUS®, SKYEHALER®, ACCUHALER® and CLICKHALER®.
  • dry powder delivery systems include ECLIPSE, NEXT, ROTAHALER, HANDIHALER, AEROLISER, CYCLOHALER, BREEZHALER/NEOHALER, MONODOSE, FLOWCAPS, TWINCAPS, X-CAPS, TURBOSPIN, ELPENHALER, MIATHALER, TWISTHALER, NOVOLIZER, PRESSAIR, ELLIPTA, ORIEL dry powder inhaler, MICRODOSE, PULVINAL, EASYHALER, ULTRAHALER, TAIFUN, PULMOJET, OMNIHALER, GYROHALER, TAPER, CONIX, XCELOVAIR and PROHALER.
  • Compound 1 in the form of its Form 1 polymorph as defined above is provided as a micronized dry powder formulation, for example comprising lactose of a suitable grade.
  • composition comprising Compound 1 in the form of its Form 1 polymorph as defined above in particulate form in combination with particulate lactose, said composition optionally comprising magnesium stearate.
  • Compound 1 in the form of its Form 1 polymorph as defined above is provided as a micronized dry powder formulation, comprising lactose of a suitable grade and magnesium stearate, filled into a device such as DISKUS.
  • a device such as DISKUS.
  • a device is a multidose device, for example the formulation is filled into blisters for use in a multi-unit dose device such as DISKUS.
  • Compound 1 in the form of its Form 1 polymorph as defined above is provided as a micronized dry powder formulation, for example comprising lactose of a suitable grade, filled into hard shell capsules for use in a single dose device such as AEROLISER.
  • Compound 1 in the form of its Form 1 polymorph as defined above is provided as a micronized dry powder formulation, comprising lactose of a suitable grade and magnesium stearate, filled into hard shell capsules for use in a single dose device such as AEROLISER.
  • Compound 1 in the form of its Form 1 polymorph as defined above is provided as a fine powder for use in an inhalation dosage form wherein the powder is in fine particles with a D 50 of 0.5-10 mm e.g. around 1-5 mm, that have been produced by a size reduction process other than jet mill micronisation e.g. spray drying, spray freezing, microfluidisation, high pressure homogenisation, super critical fluid crystallisation, ultrasonic crystallisation or combinations of these methods thereof, or other suitable particle formation methods known in the art that are used to produce fine particles with an aerodynamic particle size of 0.5-10 mm.
  • the resultant particle size distribution may be measured using laser diffraction (e.g. with a Malvern Mastersizer 2000S instrument).
  • the particles may either comprise the compound alone or in combination with suitable other excipients that may aid the processing.
  • the resultant fine particles may form the final formulation for delivery to humans or may optionally be further formulated with other suitable excipients to facilitate delivery in an acceptable dosage form.
  • the compound of the invention may also be administered rectally, for example in the form of suppositories or enemas, which include aqueous or oily solutions as well as suspensions and emulsions and foams.
  • suppositories can be prepared by mixing the active ingredient with a conventional suppository base such as cocoa butter or other glycerides.
  • the drug is mixed with a suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • a suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • the total amount of Compound 1 in the form of its Form 1 polymorph will be about 0.0001 to less than 4.0% (w/w).
  • compositions comprising Compound 1 in the form of its Form 1 polymorph will be formulated as solutions, suspensions, emulsions and other dosage forms.
  • Aqueous solutions are generally preferred, based on ease of formulation, as well as a patient's ability to administer such compositions easily by means of instilling one to two drops of the solutions in the affected eyes.
  • the compositions may also be suspensions, viscous or semi-viscous gels, or other types of solid or semi-solid compositions. Suspensions may be preferred for compounds that are sparingly soluble in water.
  • Compound 1 in the form of its Form 1 polymorph may also be introduced by means of ocular implants or inserts.
  • compositions comprising Compound 1 in the form of its Form 1 polymorph may also include various other ingredients, including, but not limited to, tonicity agents, buffers, surfactants, stabilizing polymer, preservatives, co-solvents and viscosity building agents.
  • Suitable pharmaceutical compositions of of the invention include Compound 1 in the form of its Form 1 polymorph formulated with a tonicity agent and a buffer.
  • the pharmaceutical compositions of Compound 1 in the form of its Form 1 polymorph may further optionally include a surfactant and/or a palliative agent and/or a stabilizing polymer.
  • tonicity agents may be employed to adjust the tonicity of the composition, preferably to that of natural tears for ophthalmic compositions.
  • sodium chloride, potassium chloride, magnesium chloride, calcium chloride, simple sugars such as dextrose, fructose, galactose, and/or simply polyols such as the sugar alcohols mannitol, sorbitol, xylitol, lactitol, isomaltitol, maltitol, and hydrogenated starch hydrolysates may be added to the composition to approximate physiological tonicity.
  • Such an amount of tonicity agent will vary, depending on the particular agent to be added.
  • compositions will have a tonicity agent in an amount sufficient to cause the final composition to have an ophthalmically acceptable osmolality (generally about 150-450 mOsm, preferably 250-350 mOsm and most preferably at approximately 290 mOsm).
  • ophthalmically acceptable osmolality generally about 150-450 mOsm, preferably 250-350 mOsm and most preferably at approximately 290 mOsm.
  • the tonicity agents of the invention will be present in the range of 2 to 4% w/w.
  • Preferred tonicity agents of the invention include the simple sugars or the sugar alcohols, such as D-mannitol.
  • An appropriate buffer system e.g. sodium phosphate, sodium acetate, sodium citrate, sodium borate or boric acid
  • the particular concentration will vary, depending on the agent employed.
  • the buffer will be chosen to maintain a target pH within the range of pH 5 to 8, and more preferably to a target pH of pH 5 to 7.
  • Surfactants may optionally be employed to deliver higher concentrations of Compound 1 in the form of its Form 1 polymorph.
  • the surfactants function to solubilise the compound and stabilise colloid dispersion, such as micellar solution, microemulsion, emulsion and suspension.
  • examples of surfactants which may optionally be used include polysorbate, poloxamer, polyosyl 40 stearate, polyoxyl castor oil, tyloxapol, Triton, and sorbitan monolaurate.
  • Preferred surfactants to be employed in the invention have a hydrophile/lipophile/balance "HLB" in the range of 12.4 to 13.2 and are acceptable for ophthalmic use, such as TritonX114 and tyloxapol.
  • Additional agents that may be added to the ophthalmic compositions of Compound 1 in the form of its Form 1 polymorph are demulcents which function as a stabilising polymer.
  • the stabilizing polymer should be an ionic/charged example with precedence for topical ocular use, more specifically, a polymer that carries negative charge on its surface that can exhibit a zeta-potential of (-)10-50 mV for physical stability and capable of making a dispersion in water (i.e. water soluble).
  • a preferred stabilising polymer of the invention would be polyelectrolyte, or polyelectrolytes if more than one, from the family of cross- linked polyacrylates, such as carbomers and Pemulen(R), specifically Carbomer 974p (polyacrylic acid), at 0.1-0.5% w/w.
  • viscosity enhancing agents include, but are not limited to: polysaccharides, such as hyaluronic acid and its salts, chondroitin sulfate and its salts, dextrans, various polymers of the cellulose family; vinyl polymers; and acrylic acid polymers.
  • Topical ophthalmic products are typically packaged in multidose form. Preservatives are thus required to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, chlorobutanol, benzododecinium bromide, methyl paraben, propyl paraben, phenylethyl alcohol, edentate disodium, sorbic acid, polyquaternium-1 , or other agents known to those skilled in the art. Such preservatives are typically employed at a level of from 0.001 to 1.0% w/v. Unit dose compositions of Compound 1 in the form of its Form 1 polymorph will be sterile, but typically unpreserved. Such compositions, therefore, generally will not contain preservatives.
  • Parenteral formulations will generally be sterile.
  • Compound 1 in the form of its Form 1 polymorph may be used in combination with one or more other active agents which are useful in the treatment or prophylaxis of respiratory diseases and conditions.
  • An additional active agent of this type may be included in the pharmaceutical composition described above but alternatively it may be administered separately, either at the same time as Compound 1 in the form of its Form 1 polymorph or at an earlier or later time.
  • a product comprising Compound 1 in the form of its Form 1 polymorph as defined above and an additional agent useful in the treatment or prevention of respiratory conditions as a combined preparation for simultaneous, sequential or separate use in the treatment of a disease or condition affected by modulation of TMEM16A and especially a respiratory disease or condition, for example one of the diseases and conditions mentioned above.
  • additional active agents which may be included in a pharmaceutical composition or a combined preparation with Compound 1 in the form of its Form A polymorph or Form B polymorph, especially its Form B(l) pseudopolymorph, as defined above or in amorphous form include:
  • b2 adrenoreceptor agonists such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, indacaterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol, olodaterol, vilanterol and abediterol;
  • antihistamines for example histamine Hi receptor antagonists such as loratadine, cetirizine, desloratadine, levocetirizine, fexofenadine, astemizole, azelastine and chlorpheniramine or H 4 receptor antagonists;
  • corticosteroids such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate mometasone furoate and fluticasone furoate;
  • Leukotriene antagonists such as montelukast and zafirlukast
  • anticholinergic compounds particularly muscarinic antagonists such as ipratropium, tiotropium, glycopyrrolate, aclidinium and umeclidinium;
  • CFTR repair therapies e.g. CFTR potentiators, correctors or amplifiers
  • Ivacaftor QBW251 , Bamacaftor (VX659), Elexacaftor (VX445), VX561/CPT-656, VX152, VX440, GLP2737, GLP2222, GLP2451 , PTI438, PTI801 , PTI808, FDL-169 and FDL-176 and CFTR correctors
  • Lumacaftor and Tezacaftor or combinations thereof for example a combination of Ivacaftor, Tezacaftor and Elexacaftor
  • ENaC modulators particularly ENaC inhibitors
  • Antivirals such as ribavirin and neuraminidase inhibitors such as zanamivir;
  • Antifungals such as PUR1900;
  • Airway hydrating agents such as hypertonic saline and mannitol (Bronchitol®); and
  • Mucolytic agents such as N-acetyl cysteine.
  • the additional active agent when it is an ENaC modulator, it may be an ENaC inhibitor such as amiloride, VX-371 , AZD5634, QBW276, SPX-101 , BI443651 , BI265162 and ETD001.
  • ENaC blockers are disclosed in our applications WO 2017/221008, WO 2018/096325, WO2019/077340 and WO 2019/220147 and any of the example compounds of those applications may be used in combination with the compounds of general formula (I).
  • Particularly suitable compounds for use in combination with the compounds of general formula (I) include compounds having a cation selected from: 2-[( ⁇ 3-amino-5H-pyrrolo[2,3-b]pyrazin-2-yl ⁇ formamido) ethyl]-6-(4- ⁇ bis[(2S,3R,4R,5R)-
  • a suitable anion for example halide, sulfate, nitrate, phosphate, formate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methane sulfonate or p-toluene sulfonate.
  • the starting materials and intermediates and Compound 1 may be isolated and purified using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Unless otherwise stated, all starting materials are obtained from commercial suppliers and used without further purification. Salts may be prepared from compounds by known salt-forming procedures. MS
  • Mass spectra were run on LC-MS systems using electrospray ionization. These were run using either a Waters Acquity uPLC system with Waters PDA and ELS detectors or Shimadzu LCMS-2010EV systems. [M+H]+ refers to mono-isotopic molecular weights.
  • NMR spectra were recorded on a Bruker Avance III HD 500 MHz or a Bruker Avance III HD 250 MHz using the solvent as internal deuterium lock. Spectra were recorded at room temperature unless otherwise stated and were referenced using the solvent peak.
  • the analytical HPLC conditions are as follows:
  • XRPD diffractograms were collected on a Bruker D8 diffractometer using Cu Ka radiation (40 kV, 40 mA) and a q-2q goniometer fitted with a Ge monochromator.
  • the incident beam passes through a 2.0 mm divergence slit followed by a 0.2 mm antiscatter slit and knife edge.
  • the diffracted beam passes through an 8.0 mm receiving slit with 2.5° Soller slits followed by the Lynxeye Detector.
  • the software used for data collection and analysis was Diffrac Plus XRD Commander and Diffrac Plus EVA respectively.
  • Samples were run under ambient conditions as flat plate specimens using powder as received.
  • the sample was prepared on a polished, zero-background (510) silicon wafer by gently pressing onto the flat surface or packed into a cut cavity. The sample was rotated in its own plane.
  • XRPD d iff ractog rams were collected on a PANalytical Empyrean diffractometer using Cu Ka radiation (45 kV, 40 mA) in transmission geometry.
  • a 0.5° slit, 4 mm mask and 0.04 rad Soller slits with a focusing mirror were used on the incident beam.
  • the software used for data collection was X'Pert Data Collector using X'Pert Operator Interface. The data were analysed and presented using Diffrac Plus EVA or HighScore Plus.
  • Samples were prepared and analysed in either a metal or Millipore 96 well-plate in transmission mode. X-ray transparent film was used between the metal sheets on the metal well-plate and powders (approximately 1 - 2 mg) were used as received.
  • the Millipore plate was used to isolate and analyse solids from suspensions by adding a small amount of suspension directly to the plate before filtration under a light vacuum.
  • the scan mode for the metal plate used the gonio scan axis, whereas a 2q scan was utilised for the Millipore plate.
  • DSC data were collected on a TA Instruments Q2000 equipped with a 50 position auto sampler. Typically, 0.5 - 3 mg of each sample, in a pin-holed aluminium pan, was heated at 10 °C/min from 25 °C to 250 °C. A purge of dry nitrogen at 50 ml/min was maintained over the sample.
  • TGA data were collected on a TA Instruments Discovery TGA, equipped with a 25 position auto-sampler. Typically, 5 - 10 mg of each sample was loaded onto a pre-tared aluminium DSC pan and heated at 10 °C/min from ambient temperature to 350 °C. A nitrogen purge at 25 ml/min was maintained over the sample.
  • the instrument control software was TRIOS and the data were analysed using Universal Analysis.
  • Step 1 Methyl 4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylate
  • Step 2 4-[[2-(5-Chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid
  • step 1 To a solution of methyl 4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2- carboxylate (step 1) (95%, 38.09 g, 108.1 mmol) in THF (200 mL ) was added a 2M aqueous solution of lithium hydroxide hydrate (162.15 mL , 324.29 mmol) and the resulting mixture was stirred at room temperature for 1 hour. The volatile organics were removed in vacuo and the aqueous residue cooled (ice-bath) and treated with the gradual addition of 3M aqueous HCI (150 mL ).
  • the resulting suspension was filtered, washed with water (3 x 200 mL ), diethyl ether (2 x 250 mL ), dried under suction and then further dried in a high vacuum oven at 40 °C to afford the titled compound as a beige solid.
  • Step 3 4-[[2-(5-Chloro-2-methoxy-phenyl)acetyl]amino]-N-cyclohexyl-pyridine-2- carboxamide
  • step 2 A solution of 4-[[2-(5-chloro-2-methoxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (step 2) (3.0 g, 9.07 mmol), cyclohexanamine (1.25 mL , 10.89 mmol), EDCI (2.09 g, 10.89 mmol), HOAt (1.48 g, 10.89 mmol) and DIPEA (3.17 mL , 18.15 mmol) in DMF (30 mL ) was stirred at room temperature for 19.5 hours. The resulting mixture was concentrated in vacuo and the residue partitioned between EtOAc (200 mL ) and water (200 mL ).
  • the product was crystalline and was designated the Form 2 crystalline polymorph.
  • the material is a non-solvated form of Compound 1 which contains a small amount of residual solvent.
  • XRPD diffractogram and TGA and DSC thermograms for this polymorph are shown in Figures 4 and 5 and the XRPD peaks are listed in Table 1.
  • the DSC data has only a single sharp endothermic event, likely to be a melt (see Figure 5).
  • Form 2 was stored at 40 °C/75 %RH, in an open vial. After 2 weeks, the residue was analysed by XRPD and no change in form was detected (see Figure 6). Therefore, Form 2 is stable to exposure to elevated temperature and humidity for up to 2 weeks
  • Form 1 A repeated crystallisation yielded an alternative crystalline form (designated Form 1).
  • the XRPD diffractogram of the Form 1 crystalline polymorph is shown in Figure 1 and this form was used in subsequent polymorphism studies.
  • the XRPD peaks and intensities for Form 1 are shown in Table 2.
  • Form 1 was stored at 40 °C/75 %RH for 7 days, after which the residue was analysed by XRPD.
  • the resulting diffractogram remained consistent with Form 1 , confirming that this form is stable to exposure to elevated temperature and humidity (see Figure 3).
  • Form 1 was stored at 40 °C/75 %RH, in an open vial. After 2 weeks, the residue was analysed by XRPD and no change in form was detected (see Figure 3). Therefore, Form 1 is stable to exposure to elevated temperature and humidity for up to 2 weeks and no evidence of a hydrated form was observed.
  • Compound 1 (Form 1 , approximately 30 mg) was weighed into 2 ml glass vials and was treated with aliquots of solvent. The samples were stirred at 50 °C, 400 rpm, for approximately 10 minutes between addition of aliquots of solvent. Solvent was added until a clear solution was formed or a maximum of 60 volumes (1.8 ml) of solvent was reached.
  • Results show that the sample was soluble in ethanol and THF. A lower solubility was observed in IPA, acetone and acetonitrile/water 80/20 v/v and partial dissolution occurred in acetonitrile. N-heptane, ethyl acetate, water, TBME and DCM were suitable anti-solvents, displaying no observable dissolution of the Compound 1.
  • the solvents selected for the stock solutions were based on the results of the solubility assessment of Example 3. Ethanol and THF were the solvents in which Compound 1 was most soluble. Compound 1 had a similar solubility in both acetone and I PA so either of these could have been used as the third solvent. As ethanol was already being used, acetone was selected to use three different types of solvent molecule (an ester, an alcohol and a ketone) rather than using two alcohols.
  • Anti-solvents were selected to be reasonably miscible with the solvent used in the stock solution and to have low solubility for Compound 1.
  • n-heptane, water and TBME were used as the anti-solvents. The results are shown in Table 5.
  • the sample prepared from (from acetone/n-heptane) had subtle differences from Form 2 in the initial XRPD diffractogram. This sample was re-analysed on a different XRPD instrument (in reflectance rather than transmission mode to reduce preferred orientation effects). Results showed that this sample was consistent with Form 2, so the subtle differences seen in the initial analysis are likely to be caused by preferred orientation.

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Abstract

L'invention concerne une nouvelle forme cristalline de 4- [[2-(5-chloro-2-hydroxy-phényl))acétyl]amino]-N-cyclohexyl-pyridine-2-carboxamide (composé 1), en particulier le polymorphe cristallin de forme 1 ayant le diffractogramme XRPD sensiblement tel que défini dans la description.
PCT/GB2020/051781 2019-07-25 2020-07-24 Forme cristalline de 4-[[2-(5-chloro-2-hydroxy-phényl)acétyl]amino]-n-cyclohexyl-pyridine-2-carboxamide WO2021014169A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005042524A1 (fr) * 2003-10-30 2005-05-12 Virochem Pharma Inc. Carboxamide de pyridine et methodes permettant d'inhiber l'integrase du vih
WO2019145726A1 (fr) * 2018-01-26 2019-08-01 Enterprise Therapeutics Limited Composés

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005042524A1 (fr) * 2003-10-30 2005-05-12 Virochem Pharma Inc. Carboxamide de pyridine et methodes permettant d'inhiber l'integrase du vih
WO2019145726A1 (fr) * 2018-01-26 2019-08-01 Enterprise Therapeutics Limited Composés

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WAN NAMKUNG ET AL: "TMEM16A Inhibitors Reveal TMEM16A as a Minor Component of Calcium-activated Chloride Channel Conductance in Airway and Intestinal Epithelial Cells*", THE JOURNAL OF BIOLOGICAL CHEMISTRY,, vol. 286, no. 3, 21 January 2011 (2011-01-21), pages 2365 - 2374, XP002790464, DOI: 10.1074/JBC.M110.175109 *

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