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WO2015166278A1 - Forme polymorphe de l'acide [5-fluoro-3-({2-[(4-fluorobenzène)sulfonyl]pyridin-3-yl}méthyl)-2-méthylindol-1-yl]-acétique - Google Patents

Forme polymorphe de l'acide [5-fluoro-3-({2-[(4-fluorobenzène)sulfonyl]pyridin-3-yl}méthyl)-2-méthylindol-1-yl]-acétique Download PDF

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WO2015166278A1
WO2015166278A1 PCT/GB2015/051293 GB2015051293W WO2015166278A1 WO 2015166278 A1 WO2015166278 A1 WO 2015166278A1 GB 2015051293 W GB2015051293 W GB 2015051293W WO 2015166278 A1 WO2015166278 A1 WO 2015166278A1
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compound
polymorphic form
treatment
disease
methyl
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Katja GROSSE-SENDER
Rolf Hilfiker
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Atopix Therapeutics Ltd
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Atopix Therapeutics Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Definitions

  • the present invention relates to a novel polymorphic form of a compound which is useful as a pharmaceutical, to methods for preparing this polymorph, compositions containing it and its use in the treatment and prevention of allergic diseases such as asthma, allergic rhinitis and atopic dermatitis and other inflammatory diseases mediated by prostaglandin D 2 (PGD 2 ) or other agonists acting at the CRTH2 receptor on cells including eosinophils, basophils and Th2 lymphocytes.
  • PPD 2 prostaglandin D 2
  • PGD 2 is an eicosanoid, a class of chemical mediator synthesised by cells in response to local tissue damage, normal stimuli or hormonal stimuli or via cellular activation pathways. Eicosanoids bind to specific cell surface receptors on a wide variety of tissues throughout the body and mediate various effects in these tissues. PGD 2 is known to be produced by mast cells, macrophages and Th2 lymphocytes and has been detected in high concentrations in the airways of asthmatic patients challenged with antigen (Murray et al, (1986), N. Engl J. Med. 315: 800-804). Instillation of PGD 2 into airways can provoke many features of the asthmatic response including bronchoconstriction (Hardy et al, (1984) N. Engl.
  • the first receptor specific for PGD 2 to be discovered was the DP receptor which is linked to elevation of the intracellular levels of cAMP.
  • PGD 2 is thought to mediate much of its proinflammatory activity through interaction with a G protein- coupled receptor termed CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) which is expressed by Th2 lymphocytes, eosinophils and basophils (Hirai et al, (2001) J. Exp. Med. 193: 255-261, and EP0851030 and EP-A- 1211513 and Bauer et al, EP-A-1170594).
  • CRTH2 chemoattractant receptor-homologous molecule expressed on Th2 cells
  • the selective DP agonist BW245C does not promote migration of Th2 lymphocytes or eosinophils (Hirai et al, 2001; Gervais et al, (2001) J. Allergy Clin. Immunol. 108: 982-988). Based on this evidence, antagonising PGD 2 at the CRTH2 receptor is an attractive approach to treat the inflammatory component of Th2-dependent allergic diseases such as asthma, allergic rhinitis and atopic dermatitis.
  • EP-A-1170594 suggests that the method to which it relates can be used to identify compounds which are of use in the treatment of allergic asthma, atopic dermatitis, allergic rhinitis, autoimmune, reperfusion injury and a number of inflammatory conditions, all of which are mediated by the action of PGD 2 or other agonists at the CRTH2 receptor.
  • the compounds described in WO2009/090414 are, as predicted, useful in the treatment of diseases and conditions mediated by the action of PGD 2 at the CRTH2 receptor.
  • One of these compounds [5-fluoro-3-( ⁇ 2-[(4- fluorobenzene)sulfonyl]pyridin-3 -yl ⁇ methyl)-2-methylindol- 1 -yl]-acetic acid (Compound 1) is particularly useful.
  • Crystalline forms are often more stable than amorphous forms and so an amorphous form may spontaneously convert to a crystalline form over time. This is clearly a disadvantage in the case of pharmaceutically active compounds as different forms of a compound may have different pharmacokinetic properties.
  • Non-solvated forms are often more suitable for the preparation of pharmaceutical compositions as many solvates are thermodynamically unstable at ambient temperature, although hydrates are generally preferred to other solvates.
  • the first polymorphic form (Form 1) is the easiest to obtain and, for example, can easily be prepared from either the amorphous form or the solvate obtained by the method described in WO2009/090414.
  • a polymorphic form of [5-fluoro-3-( ⁇ 2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl ⁇ methyl)-2- methylindol-l-yl]-acetic acid (Compound 1), characterised in that it gives an FT- Raman spectrum which is characterised by peaks at 3120 ⁇ 2 cm “1 , 3065 ⁇ 2 cm “1 , 2952 ⁇ 2 cm “1 , 2924 ⁇ 2 cm “1 , 2907 ⁇ 2 cm “1 , 1576 ⁇ 2 cm “1 , 1560 ⁇ 2 cm “1 , 1419 ⁇ 2 cm “1 , 1344 ⁇ 2 cm “1 , 1181 ⁇ 2 cm “1 , 1160 ⁇ 2 cm “1 , 1144 ⁇ 2 cm “1 , 1090 ⁇ 2 cm “1 , 1056 ⁇ 2 cm “1 , 886 ⁇ 2 cm “1 ,
  • the complete Raman spectrum for Polymorphic Form 1 of Compound 1 is characterised by peaks at 3120 ⁇ 2 cm “1 , 3083 ⁇ 2 cm “1 , 3065 ⁇ 2 cm “1 , 2952 ⁇ 2 cm “ 2924 ⁇ 2 cm “1 , 2907 ⁇ 2 cm “1 , 1628 ⁇ 2 cm “1 , 1576 ⁇ 2 cm “1 , 1560 ⁇ 2 cm “1 , 1462 ⁇ 2 cm “1 , 1419 ⁇ 2 cm “1 , 1385 ⁇ 2 cm “1 , 1344 ⁇ 2 cm “1 , 1311 ⁇ 2 cm “1 , 1300 ⁇ 2 cm “1 , 1267 ⁇ 2 cm “1 , 1235 ⁇ 2 cm “1 , 1211 ⁇ 2 cm “1 , 1181 ⁇ 2 cm “1 , 1160 ⁇ 2 cm “1 , 1152 ⁇ 2 cm “1 , 1144 ⁇ 2 cm “1 , 1129 ⁇ 2 cm “1 , 1090 ⁇ 2
  • the pattern of form 1 could successfully be indexed and the lattice was found to be triclinic (space group P-l).
  • This polymorphic form (known as Form 1) is particularly useful because it is readily formed from the amorphous form produced by the process described in WO2009/090414 or from the solvates obtained from recrystallisation of the amorphous product. It is the most easily obtained polymorph and can be prepared in a pure form without difficulty.
  • Polymorphic Form 1 has a melting signal at 203.7°C as measured by differential scanning calorimetry and this melting signal passes directly into decomposition.
  • This polymorphic form is stable at high temperatures, although as explained above, the transition temperature above which it becomes the most stable form is difficult to determine as the measurement is usually carried out using a suspension equilibration experiment with a mixture of the different forms of Compound 1 and, in this experiment, Compound 1 appears to decompose before the transition temperature is reached.
  • Form 1 is the thermodynamically stable form at high temperatures
  • Form 2 is the thermodynamically stable form at room temperature and at temperatures up to about 60 to 65°C.
  • Form 3 is the most thermodynamically stable form in a temperature range between that for Form 2 and Form 1.
  • Polymorphic Form 1 of Compound 1 will be pure or substantially pure. Thus, it will usually comprise not more than 10% of other forms of Compound 1, preferably not more than 5%, more preferably not more than 2% and most preferably not more than 1% of other forms of Compound 1.
  • the other forms of Compound 1 may be the amorphous form or Forms 2 or 3.
  • the Polymorphic Form 1 of Compound 1 is substantially free of other impurities, for example traces of solvent. Therefore, suitably, the Polymorphic Form 1 of compound 1 comprises not more than 1% by weight of solvent. More suitably it comprises not more than 0.5% by weight preferably not more than 0.2% and more preferably not more than 0.1% by weight.
  • a method for the preparation of Compound 1 is set out in WO2009/090414. However, as already discussed, the method described appears to lead to an amorphous form of the compound.
  • Polymorphic form 1 has the advantage of being readily obtainable: it can be obtained from recrystallisation of the amorphous form or the solvate obtained by the method set out in WO2009/090414.
  • Polymorphic form 1 may be prepared from the amorphous material obtained by the method described in WO2009/090414 by crystallisation in a suitable solvent to obtain a crystalline solvate, followed by drying of the solvate.
  • a cooling crystallisation method may be used to obtain the required polymorph in which the amorphous material is dissolved in the solvent at a raised temperature to obtain a saturated solution, following which the solution is cooled, for example to about 0 to 10°C, typically about 5°C.
  • the product obtained is usually a solvate, which can then be dried to obtain crystalline Compound 1, polymorphic form 1.
  • polymorphic form 1 may be prepared from the amorphous product described in WO2009/090414 by phase equilibration for a prolonged period, typically 15 to 30 days at room temperature in a suitable solvent.
  • suitable solvents include ethyl acetate, acetone, dichloromethane, ethanol, formic acid and tetrahydrofuran.
  • crysalline product obtained is found to adopt polymorphic Form 1.
  • suitable solvents include ethyl acetate, acetone, dichloromethane, ethanol, formic acid and tetrahydrofuran, with ethyl acetate and ethanol being particularly suitable.
  • the value of the "elevated temperature” depends upon the chosen solvent.
  • the elevated temperature will be higher than room temperature (18-23°C) but it will, of course be lower than the boiling point of the solvent.
  • the elevated temperature will be chosen such that it is close to, the boiling point of the solvent in order that the maximum possible amount of Compound 1 is in solution.
  • phase equilibration is more typically carried out over about 15 to 20 days, for example 17 days.
  • Suitable bases for use in step Ilia include sodium and potassium hydroxide, with potassium hydroxide being especially suitable.
  • the ester of Compound 1 Before reaction with the aqueous base in step Ilia, the ester of Compound 1 may be taken up n a suitable organic solvent, for example tetrahydrofuran.
  • Particularly suitable esters of Compound 1 are the methyl and ethyl esters.
  • Suitable organic solvents in step Illb include diethyl ether, dichloromethane and ethyl acetate, with ethyl acetate being especially suitable.
  • Acidification in step IIIc may be carried out using aqueous hydrochloric acid.
  • Compound 1 has CRTH2 antagonist activity and is therefore useful in the treatment of conditions which are mediated by PGD 2 or other agonists binding to CRTH2.
  • asthma includes all types of asthma, for example allergic asthma, non allergic asthma, eosinophilic asthma, steroid resistant asthma, Th2 dependent asthma, non-Th2 dependent asthma and aspirin induced asthma.
  • the asthma is allergic asthma and in another embodiment the asthma is eosinophilic asthma.
  • Asthma exacerbations includes exacerbations induced by viral infections, especially infection with respiratory syncytial virus (RSV) or rhinovirus.
  • Allergic rhinitis includes both perennial allergic rhinitis and seasonal allergic rhinitis.
  • Constivitis includes, in particular, allergic conjunctivitis, vernal keratoconjunctivitis and atopic keratoconjunctivitis.
  • “Infection” includes bacterial, viral or fungal infection.
  • the infection may occur in patients who are atopic or are at risk of becoming atopic and may be, for example a rhinovirus, influenza or RSV infection, especially in asthmatic patients.
  • the infection may be a bacterial infection for example a Staphylococcus aureus infection, particularly in patients suffering from atopic dermatitis.
  • fibrotic diseases includes, in particular, fibrotic diseases caused/exacerbated by Th2 immune responses, for example idiopathic pulmonary fibrosis, scleroderma and hypertrophic scars.
  • Polymorph 1 of Compound 1 may also be of use in the treatment of other PGD2- mediated diseases.
  • Diseases which may be mediated by PGD2 include autoimmune diseases such as systemic lupus erythematus, psoriasis, acne, allograft rejection, rheumatoid arthritis, psoriatic arthritis and osteoarthritis.
  • the invention further provides a method for the treatment or prevention of a disease or condition selected from those listed above, the method comprising administering to a patient in need of such treatment an effective amount of Polymorphic Form 1 of Compound 1 as defined above.
  • the patient will be a mammal, for example a human.
  • Polymorphic Form 1 of [5-fluoro-3-( ⁇ 2-[(4-fluorobenzene)sulfonyl] pyridin-3- yl ⁇ methyl)-2-methylindol-l-yl]-acetic acid must be formulated in an appropriate manner depending upon the diseases or conditions it is required to treat.
  • a pharmaceutical or veterinary composition comprising Polymorphic Form 1 of [5-fluoro-3-( ⁇ 2-[(4- fluorobenzene)sulfonyl] pyridin-3-yl ⁇ methyl)-2-methylindol-l-yl]-acetic acid as defined above together with a pharmaceutically or veterinarily acceptable excipient.
  • a pharmaceutically or veterinarily acceptable excipient may also be present, as may be considered appropriate or advisable for the disease or condition being treated or prevented.
  • the excipient, or, if more than one be present, each of the excipients, must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient.
  • the formulations include those suitable for oral (including viscous oral formulations), rectal, nasal, bronchial (inhaled), topical (including 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.
  • the route of administration will depend upon the condition to be treated but preferred compositions are formulated for oral, nasal, bronchial or topical administration.
  • the composition may be prepared by bringing into association Polymorphic Form 1 of [5-fluoro-3-( ⁇ 2-[(4-fluorobenzene)sulfonyl] pyridin-3-yl ⁇ methyl)-2-methylindol- l-yl]-acetic acid 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 Polymorphic Form 1 of [5-fluoro-3-( ⁇ 2-[(4- fluorobenzene)sulfonyl] pyridin-3-yl ⁇ methyl)-2-methylindol-l-yl]-acetic acid in conjunction or association with a pharmaceutically or veterinarily acceptable excipient.
  • Formulations for oral administration in the present invention may be presented as: discrete units such as capsules, sachets, tablets, troches or lozenges each containing a predetermined amount of Polymorph 1 of Compound 1; 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 syrup or elixir; 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; wetting agents/surfactants such as poloxamers, polysorbates, sodium docusate and sodium lauryl sulfate; disintegrants such as starch or sodium starch glycolate; and lubricants such as magnesium stearate, sodium stearate and other metallic stearates, glycerol stearate, stearic acid, silicone fluid, talc waxes, oils and colloidal silica.
  • Sweetening agents and flavouring agents such as peppermint, oil of winter
  • 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 Polymorphic Form 1 of Compound 1 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 may comprise a mucoadherent, for example a mucopolysaccharide such as sodium hyaluronate.
  • a mucoadherent for example a mucopolysaccharide such as sodium hyaluronate.
  • Such compositions may be formulated as, for example, liquids, liquid syrups, soft gels, liquid gels, flowable gels or aqueous suspensions and may, in addition to the active agent and the mucoadherent, also contain one or more additional excipients as set out above.
  • Liquid formulations will usually also contain a liquid carrier, which may be a solvent or suspending agent, for example water or saline solution and may also contain a substance to increase their viscosity, for example sodium carboxymethylcellulose, sorbitol or dextran.
  • compositions suitable for oral administration include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising Polymorphic Form 1 of Compound 1 in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier.
  • the composition may be made up into a cream, ointment, jelly, solution or suspension etc.
  • Cream or ointment formulations that may be used for Polymorphic Form 1 of Compound 1 are conventional formulations well known in the art, for example, as described in standard text books of pharmaceutics such as the British Pharmacopoeia.
  • the composition defined above may be used for the treatment of the respiratory tract by nasal, bronchial or buccal administration of, for example, aerosols or sprays which can disperse the pharmacological active ingredient in the form of a powder or in the form of drops of a solution or suspension.
  • Pharmaceutical compositions with powder-dispersing properties include dry powder inhalers and metered dose inhalers.
  • Dry powder inhalers usually contain, in addition to Polymorphic Form 1 of Compound 1, a suitable carrier such lactose and, if desired, adjuncts, such as surfactants and/or diluents and/or flow aids and/or lubricants.
  • Metered dose inhalers for dispersing powders usually contain, in addition to the Polymorphic Form 1 of Compound 1, a liquid propellant with a boiling point below room temperature and, if desired, adjuncts, such as liquid or solid non-ionic or anionic surfactants and/or diluents.
  • compositions for treatment of the respiratory tract in which the pharmacologically active ingredient is in solution contain, in addition to this, a suitable propellant, and furthermore, if necessary, an additional solvent and/or a stabiliser.
  • a suitable propellant e.g., either solution for nebulisation or metered dose inhalers
  • compressed air can also be used, it being possible for this to be produced as required by means of a suitable compression and expansion device.
  • Parenteral formulations will generally be sterile.
  • the dose of Compound 1 will be about 0.01 to 100 mg/kg; so as to maintain the concentration of drug in the plasma at a concentration effective to inhibit PGD 2 at the CRTH2 receptor.
  • the precise amount of Compound 1 which is therapeutically effective, and the route by which such compound is best administered, is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect.
  • the pharmaceutical composition is most suitably formulated as a once-a-day administration, although more frequent dosing may be used in some cases, for example twice, three times or four times daily dosing. On the other hand, it may sometimes be possible to dose less frequently than once daily, for example once every two days.
  • a dosage regimen may be used in which the composition is administered for a first period and then, during a second period, administration ceases or, alternatively, the composition administered at a lower dose.
  • a dosage regimen is described in WO 2009/063202.
  • Polymorphic Form 1 as defined above may be used in combination with one or more active agents which are useful in the treatment of the diseases and conditions listed above, although these active agents are not necessarily inhibitors of PGD 2 at the CRTH2 receptor.
  • the pharmaceutical composition described above may additionally contain one or more of these active agents.
  • Polymorphic Form 1 of Compound 1 as defined above in the preparation of an agent for the treatment of diseases and conditions mediated by CRTH2 receptor agonists, especially PGD 2 , wherein the agent also comprises an additional active agent useful for the treatment of the same diseases and conditions.
  • additional active agents may be other CRTH2 receptor antagonists or may have a completely different mode of action. They include existing therapies for allergic and other inflammatory diseases including:
  • ⁇ 2 adrenoreceptor agonists such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, indacaterol, terbutaline, orciprenaline, bitolterol mesylate and pirbuterol or methylxanthines such as theophylline and aminophylline, mast cell stabilisers such as sodium cromoglycate or muscarinic receptor antagonists such as tiotr opium;
  • antihistamines for example histamine Hi receptor antagonists such as loratadine, cetirizine, desloratadine, levocetirizine, fexofenadine, astemizole, azelastine and chlorpheniramine or H 4 receptor antagonists;
  • a 2 adrenoreceptor agonists such as propylhexedrine phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride and ethylnorepinephrine hydrochloride;
  • modulators of chemokine receptor function for example CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family) or CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C- X-C family) and CX 3 CR1 for the C-X3-C family;
  • Leukotriene antagonists such as montelukast, pranlukast and zafirlukast
  • leukotriene biosynthesis inhibitors such as 5 -lipoxygenase inhibitors or 5- lipoxygenase activating protein (FLAP) inhibitors such as zileuton, ABT-761, fenleuton, tepoxalin, Abbott-79175, N-(5-substituted)-thiophene-2- alkylsolfonamides, 2,6-di-tert-butylphenol hydrazones, methoxytetrahydropyrans such as ZD2138, SB-210661, pyridinyl-substituted-2-cyanonaphthalene compounds such as L-739010, 2-cyanoquinoline compounds such as L-746,530, indole and quinoline compounds such as MK-591, MK-886 and BAY x 1005;
  • FLAP 5- lipoxygenase activating protein
  • Phosphdiesterase inhibitors including PDE4 inhibitors such as roflumilast;
  • anti-IgE antibody therapies such as omalizumab
  • anti-infectives such as fusidic acid (particularly for the treatment of atopic dermatitis);
  • anti-fungals such as clotrimazole (particularly for the treatment of atopic dermatitis); immunosuppressants such as tacrolimus and particularly pimecrolimus in the case of inflammatory skin disease or alternatively FK-506, rapamycin, cyclosporine, azathioprine or methotrexate;
  • Immunotherapy agents including allergen immunotherapy such as Grazax;
  • corticosteroids such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate mometasone furoate and fluticasone furoate drugs which promote Thl cytokine response such as interferons, TNF or GM-CSF.
  • CRTH2 antagonists may also be combined with therapies that are in development for inflammatory indications including:
  • drugs that modulate cytokine production such as inhibitors of TNFa converting enzyme (TACE) anti-TNF monoclonal antibodies, TNF receptor immunoglobulin molecules, inhibitors of other TNF isoforms, non-selective COX-l/COX-2 inhibitors such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefanamic acid, indomethacin, sulindac and apazone, pyrazolones such as phenylbutazone, salicylates such as aspirin; COX-2 inhibitors such as meloxicam, celecoxib, rofecoxib, valdecoxib and etoricoxib, low dose methotrexate, lefunomide, ciclesonide, hydroxychloroquine, d-penicillamine, auranofin or parent
  • Th2 cytokines IL-4 and IL-5 drugs that modulate the activity of Th2 cytokines IL-4 and IL-5 such as blocking monoclonal antibodies and soluble receptors;
  • PPAR- ⁇ agonists such as rosiglitazone
  • anti-RSV antibodies such as Synagis (palivizumab) and agents that may be used to treat rhinovirus infection in the future e.g. intereferon-alpha, interferon-beta or other interferons.
  • Combinations of Polymorphic Form 1 of Compound 1 as defined above with leukotriene antagonists such as montelukast, pranlukast and zafirlukast are particularly suitable, especially combinations with montelukast.
  • leukotriene antagonists such as montelukast, pranlukast and zafirlukast
  • a product comprising Polymorphic Form 1 of Compound 1 as defined above and one or more of the agents listed above as a combined preparation for simultaneous, separate or sequential use in the treatment of a disease or condition mediated by the action of PGD 2 at the CRTH2 receptor.
  • kits for the treatment of a disease or condition mediated by the action of PGD 2 at the CRTH2 receptor comprising a first container comprising Polymorphic Form 1 of Compound 1 as defined above and a second container comprising one or more of the active agents listed above.
  • Figure 1 shows the PXRD pattern of Compound 1, Batch 1.
  • Figure 2 shows the PXRD pattern of Compound 1, Batch 3.
  • Figure 3 shows the FT-Raman spectrum of Compound 1, Batch 3. The spectrum was used as a reference for the preliminary polymorphism study. The most pronounced Raman peaks are labeled in the figure.
  • Figure 4 shows a plot of TG-FTIR of Compound 1, Batch 3 in a temperature range of 25°C to 250°C and a heating rate of 10°C/min.
  • Figure 5 is a differential scanning calorimetry trace for Compound 1, Batch 1.
  • Figure 6 is a dynamic vapour sorption curve for Compound 1, Batch 1 showing relative humidity over the sample and sample weight percent versus time.
  • Figure 7 is a further dynamic vapour sorption curve for Compound 1, Batch 1 showing sample weight percent against relative humidity.
  • Figure 8 shows the PXRD pattern of Compound 1, Batch 2.
  • Figure 9 shows the PXRD pattern of the product obtained by recrystallising Compound 1, Batch 1 from ethyl acetate and then drying the crystalline solid obtained (Example 3).
  • Figure 10 is a detail of the PXRD pattern of the recrystallised and dried product from Example 3 (Polymorphic Form 1) showing the fit between the experimental pattern of the product of Example 3 (Form 1; red, file: H906) and the data calculated based upon a LeBail-fit (blue). Below is the difference plot shown in red.
  • Figure 11 is a 1H MR plot of the product of Experiment PI 5 of Example 4 (Polymorphic Form 1) in DMSO-d6.
  • Figure 12 shows FT-Raman spectrum of the product of Experiment P9 of Example 4 (Polymorphic Form 2).
  • Figure 13 shows the PXRD pattern of the product of Experiment P9 of Example 4 (Polymorphic Form 2).
  • the material is crystalline.
  • Figure 14 is a 1H MR was recorded of the product of Experiment P9 of Example 4 (Form 2) in DMSO-d6.
  • Figure 15 shows the FT-Raman spectrum of Product P6 of Example 4 (Form 3 in a mixture with Form 2).
  • Figure 16 is a detail of the PXRD pattern of Product P6 of Example 4 in comparison with that of Product P9 of Example 4 (Form 2)
  • Figure 17 is a detail of the PXRD pattern of Product P24 of Example 6 (Polymorphic Form 2) showing the fit between the experimental pattern of Product P24 (red, file: J893) and the data calculated based upon a LeBail-fit (blue). Below is the difference plot shown in red.
  • 1H-NMR 1H- MR spectra were recorded using a Bruker DPX300 spectrometer with a proton frequency of 300.13 MHz, a 30° excitation pulse, and a recycle delay of 1 s. 16 scans were accumulated. d6-DMSO was used as the solvent.
  • DSC Differential scanning calorimetry was carried out with a Perkin Elmer DSC-7 instrument (closed gold sample pan under N 2 atmosphere).
  • DVS Sorption Measurement System SPSl l-lOOn.
  • the sample was placed in an Al crucible, and the sample was allowed to equilibrate at a given r.h. before starting a predefined humidity program.
  • the used measurement program can be recognized in the corresponding figures (blue line).
  • FT-Raman spectroscopy FT-Raman spectra were recorded on a Bruker RFS 100 FT-Raman system with a near infrared Nd:YAG laser operating at 1064 nm and a liquid nitrogen-cooled germanium detector. For each sample, a minimum of 64 scans with a resolution of 2 cm “1 were accumulated. 300 mW laser power was used. The FT-Raman data are shown in the region between 3500 to 100 cm "1 . Below 100 cm "1 the data are meaningless due to the filter cut-off.
  • Powder X-ray diffraction Bruker D8; Copper Ka radiation, 40 kV/40 mA; LynxEye detector, 0.02° 2 Theta step size, 37 s step time.
  • Sample preparation The samples were generally measured without any special treatment other than the application of slight pressure to get a flat surface. Silicon single crystal sample holders were used (0.1 mm deep). The samples were rotated during the measurement.
  • TG-FTIR Thermogravimetric measurements were carried out with a Netzsch Thermo-Microbalance TG 209 coupled to a Bruker FTIR Spectrometer Vector 22 or IFS 28 (sample pans with a pinhole, N2 atmosphere, heating rate 10°C/min, range 25°C up to 250°C).
  • Compound 1 was prepared by the method set out in WO2009/090414 which is as follows.
  • reaction was quenched by the drop wise addition of saturated NaHC0 3 solution (10 ml) and the biphasic mixture extracted with DCM (2x 50 ml). The combined organics were washed with brine (50 ml) then dried (MgS0 4 ) and evaporated to dryness. The reaction was repeated on an identical scale and the two crude materials were purified separately.
  • the aqueous solution was washed with ethyl acetate to obtain a suspension.
  • the precipitated solid was removed by filtration and the pH of the aqueous phase adjusted to 1.5 using 0.1M HC1 solution and stirring vigorously for 15 minutes, before being isolated by suction filtration.
  • the collected solid was washed with water and then MTBE, pulled dry in air and then dried in vacuo at 50°C to afford 900 mg (64%) of the product as a tan solid.
  • Example 2 Characterisation of the Product of Example 1
  • Example 2 Three batches of product prepared by the method of Example 1 were characterised by FT-Raman spectroscopy, X-ray powder diffraction (PXRD), Thermogravimetry coupled to Fourier Transform Infrared Spectroscopy (TG-FTIR), differential scanning calorimetry (DSC) and DVS
  • Figure 1 shows the PXRD pattern of Batch 1.
  • the sample was measured as received.
  • the material is amorphous.
  • the signals at 28.4 °2 Theta and 40.5 °2 Theta could most likely be assigned to KC1.
  • Figure 2 shows the PXRD pattern of Batch 3, measured as received.
  • the sample is amorphous.
  • the signal at 28.3 °2 Theta could most likely be assigned to KC1.
  • Figure 3 shows the FT-Raman spectrum of Batch 3. The spectrum was used as a reference for the preliminary polymorphism study. The most pronounced Raman peaks are labelled in the figure.
  • Batch 3 was analyzed by TG-FTIR in a temperature range of 25°C to 250°C and a heating rate of 10°C/min.
  • TG-FTIR shows a loss of 1.2 wt.-% mass (residual FLO) from r.t. to 160°C. Decomposition occurs above ⁇ 160°C. Therefore the material is likely a non-solvated form.
  • Figure 4 Batch 1 was also analyzed by differential scanning calorimetry and Figure 5 shows the DSC trace. In the first scan (red trace) a glass transition point at about 79°C (ACp: 0.4 J/g*°C) and a recrystallization signal at about 155°C is observed. After cooling the sample is still partially amorphous.
  • the sample shows in the second step (0% r.h up to 95% r.h.) a continuous water uptake. At relative humidities above 84% r.h. an increased water uptake is observed. At 95% r.h. no equilibrium is reached. This is typical for amorphous material. At the end of the measurement (end humidity 50% r.h.) the sample has a 0.6% higher mass as the starting material.
  • the sample was checked by FT-Raman (pre- and post DVS measurements). The sample recovered from DVS shows no phase transition.
  • the KC1 impurity was removed by crystallization of 5 g of Batch 1 of Compound 1 in ethyl acetate.
  • the product was characterized by FT- Raman and TG-FTIR.
  • the TG-FTIR measurement showed a mass loss of 8.2% ethyl acetate at 140°C, which is above the boiling point. This shows that the solvent is strongly bound and is typical for a solvate formation.
  • the sample was dried under vacuum at r.t. and the product was characterized by FT-Raman, TG-FTIR and PXRD.
  • the material changed after drying to a non-solvated form because ethyl acetate was not longer detectable by TG-FTIR.
  • Figure 9 shows the PXRD pattern of the recrystallised product. The material is crystalline.
  • Table 1 summarizes the results of the suspension equilibration and cooling crystallization experiments.
  • Table 1 Results of the suspension equilibration and cooling crystallization experiments.
  • This polymorphic form was designated Form 1 and it was further characterised by PXRD. Indexing of PXRD can be used to determine if a given pattern corresponds to a pure solid phase.
  • the PXRD pattern of the recrystallised material (file: H906) could be successfully indexed, and the lattice was found to be triclinic.
  • the resulting lattice parameters can be seen in Table 2.
  • the final fit between the observed and calculated diffraction patterns is shown in Figure 10 and the low R-values (see Table 2) confirm the good fit. This confirms that Form 1 corresponds to a true polymorphic form and not to a mixture of forms.
  • Table 2 Lattice parameters and LeBail-Fit details for the laboratory PXRD data for Form 1 obtained at room temperature.
  • Form 2 was obtained by phase equilibration experiments at room temperature, in water/acetonitrile (1 : 1) (Experiment P9) and acetonitrile (Experiment P12).
  • the phase equilibration experiment at r.t. in ethyl methyl ketone (Experiment P6) also gave rise to Form 2 in a mixture with another new form (Form 3).
  • Form 3 was obtained as a mixture with form 2 by a phase equilibration experiment at r.t. in ethyl methyl ketone (Example 4, Experiment P6).
  • Figure 15 shows the FT- Raman spectrum of Product P6 (Form 3 in a mixture with Form 2). The most pronounced Raman peaks are labeled in the figure.
  • Example 4 A mixture with similar ratios of the products of Example 4, Experiment 15 (Form 1), Example 4, Experiment 9 (form 2 + x) and Example 4, Experiment 6 (Form 2 + Form 3) were suspended in acetonitrile and shaken for 13 days at 22°C to give a product designated Product P24).
  • the solid was recovered by filter centrifugation and characterized by PXRD.
  • Figure 16 shows the PXRD pattern of Product P24 compared with that of the product of Experiment P9 of Example 4.
  • the two PXRD patterns are essentially the same although that of Product P9 shows a few additional signals. These signals could be assigned to (i) another crystalline form or (ii) the signals could not be detected for Product P24 because the diffractogram has a lower intensity.
  • Indexing of PXRD can be used to determine if a given pattern corresponds to a pure solid phase.
  • the PXRD pattern of Product P24 (file: J893) could be successfully indexed, and the lattice was found to be triclinic.
  • the resulting lattice parameters can be seen in Table 3.
  • the final fit between the observed and calculated diffraction patterns is shown in Figure 17 and the low R-values (see Table 3) confirm the good fit. This confirms that Form 2 corresponds to a true polymorphic form and not to a mixture of forms.
  • Product P9 of Example 4 could also be indexed within the same space group and similar lattice parameters. However, some few signals of product P9 could not be indexed. These signals could be assigned to another crystalline form (maybe e.g. polymorph, impurity or degradation).
  • Table 3 Lattice parameters and LeBail-Fit details for the laboratory PXRD data obtained at room temperature.

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Abstract

L'invention concerne une forme polymorphe de l'acide [5-fluoro-3-({2-[(4-fluorobenzène)sulfonyl]pyridin-3-yl} méthyl)-2-méthylindol-1-yl]-acétique qui peut être utilisé pour la préparation de formulations pharmaceutiques stables.
PCT/GB2015/051293 2014-05-02 2015-05-01 Forme polymorphe de l'acide [5-fluoro-3-({2-[(4-fluorobenzène)sulfonyl]pyridin-3-yl}méthyl)-2-méthylindol-1-yl]-acétique Ceased WO2015166278A1 (fr)

Applications Claiming Priority (2)

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GB1407813.3 2014-05-02
GBGB1407813.3A GB201407813D0 (en) 2014-05-02 2014-05-02 Polymorphic form

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WO2015166278A1 true WO2015166278A1 (fr) 2015-11-05

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GB (1) GB201407813D0 (fr)
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9951042B2 (en) 2014-05-02 2018-04-24 Atopix Therapeutics Limited Polymorphic form of [5-fluoro-3-({2-[(4-fluorobenzene) sulfonyl] pyridin-3-yl}methyl)-2-methylindol-1-yl]-acetic acid
US10011584B2 (en) 2014-05-02 2018-07-03 Atopix Therapeutics Limited Polymorphic form of [5-fluoro-3-({2-[(4-fluorobenzene) sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-acetic acid

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090186923A1 (en) * 2008-01-18 2009-07-23 Richard Edward Armer Compounds Having CRTH2 Antagonist Activity

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090186923A1 (en) * 2008-01-18 2009-07-23 Richard Edward Armer Compounds Having CRTH2 Antagonist Activity

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CAIRA: "Crystalline Polymorphism of Organic Compounds", TOPICS IN CURRENT CHEMISTRY, SPRINGER, BERLIN, DE, vol. 198, 1998, pages 163 - 208, XP008166276, ISSN: 0340-1022 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9951042B2 (en) 2014-05-02 2018-04-24 Atopix Therapeutics Limited Polymorphic form of [5-fluoro-3-({2-[(4-fluorobenzene) sulfonyl] pyridin-3-yl}methyl)-2-methylindol-1-yl]-acetic acid
US10011584B2 (en) 2014-05-02 2018-07-03 Atopix Therapeutics Limited Polymorphic form of [5-fluoro-3-({2-[(4-fluorobenzene) sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-acetic acid

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