Classifications

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  • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • A—HUMAN NECESSITIES
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
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• • A—HUMAN NECESSITIES
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  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
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  • A61P17/04—Antipruritics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61P31/10—Antimycotics
• • A—HUMAN NECESSITIES
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  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs

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. Therefore, the inventors set out to develop a crystalline form of Compound 1.
• 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 third polymorphic form although not the most thermodynamically stable form at room temperature and has the advantage. of having a higher solubility than Forml and Form 2 It is therefore an highly advantageous form of Compound 1.
• 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 3068 ⁇ 2 cm “1 , 3054 ⁇ 2 cm “1 , 2976 ⁇ 2 cm “1 . 1582 ⁇ 2 cm “1 . 1427 ⁇ 2 cm “1 . 1298 ⁇ 2 cm “1 . 1213 ⁇ 2 cm “1 . 1190 ⁇ 2 cm “ 1164 ⁇ 2 cm “1 . 1060 ⁇ 2 cm “1 .
• Form 3 This polymorphic form (known as Form 3) is thermodynamically stable at temperatures above about 60-65°C Furthermore, Form 3 is the most soluble crystalline form of Compound 1 in both fasted state and fed state simulated intestinal fluid and this may prove advantageous both for formulation purposes and for its bioavailability in vivo.
• Polymorphic Form 3 of Compound 1, optionally in admixture with Polymorphic Form 2, is a useful starting material for the preparation of pure Polymorphic Form 2.
• Polymorphic Form 3 has a melting signal at 200°C as measured by differential scanning calorimetry and is stable at temperatures above about 60-65°C. Below this temperature, Form 2 is the thermodynamically more stable form, with Form 1 being the thermodynamically stable form at very high temperatures, although it is difficult to determine a transition temperature between Forms 2 and 3 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.
• Polymorphic Form 3 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 1 or 3.
• the Polymorphic Form 3 of Compound 1 is substantially free of other impurities, for example traces of solvent. Therefore, suitably, the Polymorphic Form 2 of compound 1 comprises not more thanl% by weight of solvent (e.g. methyl ethylketone). 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.
• solvent e.g. methyl ethylketone
• Polymorphic Form 3 may be prepared from the product described in WO2009/090414 by phase equilibration for a prolonged period, typically 15 to 30 days at room temperature in methylethylketone. In some cases, Polymorphic form 2 is obtained in admixture with polymorphic form, Form 3.
• Polymorphic Form 3 may be obtained from a mixture of Forms 2 and 3 by further phase equilibration in methylethylketone at elevated temperature, typically 60 to 80°C, but more usually at 65 to 80°C and typically 70- 75°C, for a period of about 20-36 hours, but suitably 24-26 hours.
• the process may comprise seeding a saturated solution of Compound 1 in methylethyletone at an elevated temperature of about 65 to 80°C, more usually 70-75°C, with crystals of Polymorphic Form 3 obtained from the step above and allowing crystallisation to take place, followed by isolating the crystals of polymorphic Form 3. Therefore, in a further aspect of the invention there is provided a process for the preparation of Polymorphic form 2 of [5-fluoro-3-( ⁇ 2-[(4-fluorobenzene)sulfonyl] pyridin-3-yl ⁇ methyl)-2-methylindol-l-yl]-acetic acid as defined above, the process comprising: a.
• the product will generally be a mixture of Polymorphic Forms 2 and 3. Therefore, the process may further comprise the steps of:
• step (c) dissolving the product of step (c) in methyl ethyl ketone at an elevated temperature of from about 65 to 80°C to obtain a saturated solution;
• the process may comprise the additional steps of:
• step (g) i. seeding the solution with the crystalline product of step (g);
• steps (h) to (k) may be repeated using the product of step (k) as the seed crystals for the next crystallisation step.
• the starting Compound 1 used in the process may be amorphous material, polymorphic Form 1 or polymorphic Form 2 mixtures of any of these. However, this process is particularly useful when starting from amorphous material, for example material obtained from the process described in WO2009/090414.
• the phase equilibration is more typically carried out over about 15 to 20 days, for example 17 days.
• Polymorphic Form 3 is, of course, useful as a pharmaceutical but, in addition, it has been found to be the most suitable starting material in the preparation of Polymorphic Form 2, which is the most thermodynamically stable form at temperatures up to about 65°C.
• Polymorphic Form 2 of Compound 1 can be prepared by preparing a saturated solution of Polymorphic Form 3 of Compound 1 in acetonitrile or in a mixture of acetonitrile and water, seeding the solution with crystals of Polymorphic Form 2 and allowing crystallisation to take place.
• 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.
• the compound is also of use in the treatment of infection.
• 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.
• RSV respiratory syncytial virus
• Allergic rhinitis includes both perennial allergic rhinitis and seasonal allergic rhinitis.
• Constivitis includes, in particular, allergic conjunctivitis, vernal keratoconj uncti viti s and atopi c keratoconj uncti viti s .
• “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 3 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 3 of Compound 1 as defined above.
• the patient will be a mammal, for example a human.
• Polymorphic Form 3 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 3 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.
• Other active materials may also be present, as may be considered appropriate or advisable for the disease or condition being treated or prevented.
• 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.
• compositions for oral, nasal, bronchial or topical administration.
• the composition may be prepared by bringing into association Polymorphic Form 3 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 3 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 2 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, g
• binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, poly
• Sweetening agents and flavouring agents such as peppermint, oil of wintergreen, cherry flavouring and the like can also be used. It may be desirable to add a colouring agent to make the dosage form readily identifiable. Tablets may also be coated by methods well known in the art.
• 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 3 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 3 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 3 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 3 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 3 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. Such a dosage regimen is described in WO 2009/063202.
• Polymorphic Form 3 of Compound 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 3 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-X 3 -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 3 of Compound 1 as defined above with leukotriene antagonists such as montelukast, pranlukast and zafirlukast are particularly suitable, especially combinations with montelukast.
• a product comprising Polymorphic Form 3 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 3 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 P15 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.
• Figure 18 shows the PRXD pattern of Polymorphic Form 3 (the product of Example 6).
• Figure 19 shows the FT Raman spectrum of Polymorphic Form 3 (the product of Example 6).
• 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 spectroscopy: FT-Raman spectra were recorded on a Bruker RFS 100 FTRaman 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 FTRaman 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.
• Compound 1 was prepared by the method set out in WO2009/090414 which is as follows. i. 2-( -FluorobenzenesulfonvD-pyridine-3-carboxaldehyde
• 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.
• 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 labeled in the figure.
• 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.
• 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).
• the FT-Raman Spectrum of the product of Experiment P9 of Example 4 (Form 2) is shown in Figure 12 and its PXRD pattern is shown in Figure 13. It could successfully be indexed and this confirms that Form 2 corresponds to a true polymorphic form and not to a mixture of forms.
• a 1H MR was recorded of the product of Experiment P9 of Example 4 (Form 2) in DMSO-d6 (see Figure 14). The spectrum confirms chemical integrity. iii. Polymorphic 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 labelled in the figure.
• Example 7 Thermodynamic Stability of Polymorphic Forms
• 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 for
• FaSSIF fasted state simulated intestinal fluid
• FeSSIF fed state simulated intestinal fluid
• FaSSIF and FeSSIF were prepared from SIF powder, available at PHARES, Switzerland. Suspensions of both forms were prepared and equilibrated for 24 hours at 25°C. The suspensions were filtered. The pH values of the resulting saturated solutions were measured. The filtrates were diluted and analyzed by HPLC using a general, unoptimized method. The values listed below are averages over multiple repetitions. Additionally Raman spectra of the recovered solids were recorded.
• Form 1 FaSSIF 0.72 Agrees with Form 1 5.7
• Form 3 FaSSIF 1.31 Agrees with Form 3 5.4

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