Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
  • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
  • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to new solid state forms of a drug, to pharmaceutical compositions containing them, to processes for obtaining them and to the use of the new solid state forms and compositions containing them in medical treatment.
• compositions which are formulated for inhaled administration must be in a form which enables appropriate processing techniques, such as micronisation, and which enables delivery using a suitable delivery device, for example a dry powder inhaler, a metered dose inhaler, a nebuliser or a nasal delivery device.
• the drug substance, and compositions containing it should be capable of being effectively stored over appreciable periods of time, without exhibiting a significant change in the active component's physico-chemical characteristics (e.g. its chemical composition, density, melting point, hygroscopicity and solubility).
• crystalline drug compounds have been shown to provide more reliable and reproducible plasma concentration profiles following administration to a patient.
• different crystalline forms of a compound may exhibit different physico- chemical properties, such as melting point, solubility and hygroscopicity.
• different crystalline forms of a compound may exhibit different pharmacokinetic characteristics, such as total lung exposure, total lung retention, total blood exposure, peak plasma exposure and oral bioavailability. Additionally, it is desirable for the drug substance to be in a thermodynamically stable form in order to prevent or minimize the risk of conversion to another alternative form during the manufacturing or formulation process, or during or following
• Amorphous, or semi-amorphous materials may present significant problems in this regard. For example, such materials are typically difficult to handle and to formulate, provide for an unreliable solubility, and are often found to be unstable and chemically impure.
• WO 2008/076048 also discloses, as Example 6, the specific compound 2,2,2- trifluoro-N- [( 1 R,2S)- 1 - [ 1 -(4-fluorophenyl)indazol-5 -yl]oxy- 1 -(3 -methoxyphenyl)propan- 2-yl]acetamide (referred to hereinafter as Compound (I)).
• the Compound (I) obtained by following the procedure described therein is non-crystalline.
• Compound (I) may be prepared in crystalline form, including a new, thermodynamically stable, crystalline form of Compound (I), or a pharmaceutically acceptable salt thereof.
• Form A of Compound (I) is substantially crystalline.
• Form A of Compound (I) is crystalline.
• Form B of Compound (I) is substantially crystalline.
• Form B of Compound (I) is crystalline.
• Solvates of Compound (I) include hydrates and alcoholates (such as propanol and iso-propanol solvates).
• Compound (I) is not in the form of a salt.
• Compound (I) is not in the form of a solvate, i.e. it is an "ansolvate”.
• the term “anhydrate” encompasses "ansolvate”.
• Compound (I) may be obtained in forms that are substantially crystalline in nature.
• the degree of crystallinity as determined by X-ray powder diffraction data is for example greater than about 60%, such as greater than about 80%, particularly greater than about 90%, more particularly greater than about 95%.
• the degree of crystallinity as determined by X-ray powder diffraction data is greater than about 98%, wherein the % crystallinity refers to the % by weight of the total sample mass which is crystalline.
• Compound (I) may be produced in a crystalline form that is an anhydrate.
• the crystalline form contains less than 10% of hydrate form(s) (e.g. a monohydrate) of Compound (I).
• Form A and Form B of Compound (I) are anhydrate crystalline forms.
• Form B of Compound (I) is characterised by an X-ray powder diffraction pattern, measured using a wavelength of X-rays 1.5418 A, with peaks at 2- Theta (in degrees) of 9.2, 17.4 and 21.5.
• Form B of Compound (I) is characterised by an X-ray powder diffraction pattern, measured using a wavelength of X-rays 1.5418 A, with peaks at 2- Theta (in degrees) of 9.2, 11.8, 15.7, 17.4 and 21.5.
• Form B of Compound (I) is characterised by an X-ray powder diffraction pattern, measured using a wavelength of X-rays 1.5418 A, with peaks at 2-Theta (in degrees) as shown in Table 1 hereafter.
• Form B of Compound (I) is characterised by and hence the form may be characterized by the X-ray powder diffraction pattern substantially as shown in Figure 1, when measured using a wavelength of X-rays 1.5418 A. .
• Form B of Compound (I) is characterized by a differential scanning calorimetry curve, at a heating rate of 5°C per minute in a closed aluminium cup under a nitrogen atmosphere, exhibiting an onset temperature of the melting endotherm of about 109°C.
• Form B of Compound (I) is characterized by the differential calorimetry curve substantially as shown in Figure 2.
• Form B of Compound (I) is characterized by a differential scanning calorimetry curve, at a heating rate of 5°C per minute in a closed aluminium cup under a nitrogen atmosphere, exhibiting an onset temperature of the melting endotherm of about 109°C and/or an X-ray powder diffraction pattern, measured using a wavelength of X-rays 1.5418 A, with peaks at 2-Theta (in degrees) of 9.2, 11.8, 15.7, 17.4 and 21.5.
• Form B of Compound (I) is characterized by the differential calorimetry curve substantially as shown in Figure 2 and/or an X-ray powder diffraction pattern substantially as shown in Figure 1.
• a crystalline modification of a compound according to the invention is substantially free from other crystalline modifications of the compound.
• Form B of Compound (I) is substantially free of Form A of Compound (I).
• a described crystalline modification of Compound (I) that is substantially free from other crystalline modifications of the compound includes less than, for example, 20%, 15%), 10%o, 5%), 3%) or particularly, less than 1%> by weight of other crystalline forms of that compound.
• Crystalline anhydrates of Compound (I) may be prepared as described herein by crystallizing Compound (I) from one or more suitable solvents or mixtures thereof.
• Anhydrate may be produced by crystallization from a solvent system which is substantially free of water (which may have been dried, and/or may be dried during the crystallization process). Solvent may be dried during the crystallization process, for example by decreasing the water content of a mixture of the compound to be crystallized in a suitable organic solvent / aqueous solvent system (e.g. by increasing the amount of organic solvent that is present and/or removal of water by formation of an azeoptrope, with successive distillations).
• crystalline anhydrates of Compound (I) may also be prepared from water and/or water/alcohol mixtures.
• Compounds of the invention that are anhydrates typically contain no more than 2%, particularly 1%, more particularly 0.5% and more particularly 0.2% (w/w) water, whether such water is bound (crystal water or otherwise) or not.
• crystallisations may be carried out by seeding with nuclei and/or seed crystals of the desired crystalline form in the absence of nuclei and/or seed crystals of other crystalline forms.
• concentration in solution of the compound that is to be crystallised, and the solvent system that is used may influence crystallisation temperatures and crystallisation times. Different crystalline forms may have different solubility in different organic solvents at any given temperature.
• solvents may be employed as "antisolvents" (i.e. a solvent in which compounds of the invention are poorly soluble, but which is miscible with another solvent, in which compounds of the invention are more soluble), and may thus aid the crystallisation process.
• the crystalline form that is obtained depends upon both the kinetics and the thermodynamics of the crystallisation process. Under certain thermodynamic conditions (solvent system, temperature, pressure and concentration of the compound of the invention), one crystalline form may be more stable than another (or indeed any other). However, other crystalline forms that may have, in comparison, a relatively low thermodynamic stability, may be kinetically- favoured. Thus, in addition, kinetic factors, such as time, impurity profile, agitation, the presence of seeds, etc. may also influence which forms appear. Thus, the procedures discussed herein may be adapted by the skilled person as appropriate in order to obtain the particular crystalline form of Compound (I).
• a process for the production of a compound of the invention which comprises crystallizing Compound (I) from a solution, suspension or slurry of Compound (I) with a suitable solvent system.
• a process for the production of a compound of the invention which comprises crystallizing Compound (I) from a solution, suspension or slurry of Compound (I) with a suitable solvent system.
• the length of time depends on the level of saturation so that highly saturated solutions may crystallize within hours or a day or two, whereas less saturated solutions may require longer (for example a week or more).
• Suitable mixing for example by stirring, is believed to be important, possibly since it creates sites for primary, as well as secondary nucleation, thus speeding up the crystallisation process.
• seed crystals of the form to be crystallised
• the addition of seed crystals (of the form to be crystallised) to the solution, suspension or slurry will speed up the crystallisation process since the time for primary nucleation will then be shortened.
• a further process of the invention provides the production of a compound of the invention which comprises crystallising Compound (I) from a solution, suspension or slurry of the compound with a suitable solvent using seeds of the relevant compound to initiate and/or facilitate crystallisation.
• Suitable solvents include alcohols (such as ethanol, propanol and isopropanol), ethyl acetate, isopropyl acetate, aqueous systems and suitable mixtures thereof (for example, water/propanol, water/isopropanol).
• Other suitable solvents include ethereal solvents (such as methyl tert-butyl ether).
• Antisolvents such as heptanes may also be used as appropriate.
• a particular process of the invention comprises the use of a two solvent system that favours aggregation of crystals, i.e use of a good solvent and an antisolvent, such as the good solvent 1 -propanol and the antisolvent n-heptane or the good solvent methyl tert-butyl ether and the anti-solvent n-heptane.
• a good solvent and an antisolvent such as the good solvent 1 -propanol and the antisolvent n-heptane or the good solvent methyl tert-butyl ether and the anti-solvent n-heptane.
• Form B of Compound (I) may be prepared by crystallization of Compound (I) in amorphous form in a suitable solvent system.
• Compound (I) in amorphous form is suspended or slurried (or partially dissolved) in a suitable solvent system and thereafter the suspension or slurry is heated and then allowed to cool.
• the suspension or slurry is heated to a sufficient temperature to afford dissolution of compound (I) before being allowed to cool.
• the suspension or slurry is heated to at least 75°C (such as at least 80°C for example about 87°C).
• the solvent system includes any suitable solvent, or mixture of solvents, that do not result in the formation of a solvate of Compound (I) at room temperature.
• the solvent system may include those in which Compound (I) is only partially (or is at least partially) soluble.
• the solvent system comprises a two solvent system comprising a good solvent and an antisolvent.
• the solvent system comprises an organic solvent that is polar, e.g. alcohols (such as lower alkyl alcohols, e.g. a Ci_ 6 alcohol for example 1-propanol or isopropanol) or acetates (such as isopropyl acetate) and an alkyl antisolvent such as heptanes.
• the solvent system comprises isopropyl acetate and n-heptane.
• n-heptane constitutes at least 75% w/w (e.g. at least 85% such as about
• the solvent system may contain up to 25% w/w (e.g. up to 15%, or about 10%) of isopropyl acetate.
• the crystallization of Form B of Compound (I) may also be promoted by the addition of seed crystals of Form B (once available).
• a crystalline form obtainable by such a seeding process.
• Compound (I) in amorphous form may be suspended or slurried (or at least partially dissolved) in a suitable solvent system (solvent system V) and thereafter seeds of Form B (for example 0.2 to 1.5% w/w, e.g.
• solvent system V includes any suitable solvent, or mixture of solvents, that do not result in the formation of a solvate of Compound (I).
• solvent system V may include those in which Compound (I) is only partially (or is at least partially) soluble.
• solvent system V comprises a two solvent system comprising a good solvent and an antisolvent.
• solvent system V comprises an organic solvent that is polar, e.g. alcohols (such as lower alkyl alcohols, e.g. a Ci_ 6 alcohol) and an alkyl antisolvent such as heptanes.
• solvent system V comprises 1-propanol and n- heptane.
• n-heptane constitutes at least 50%> w/w (e.g. at least 60%> such as about 70%>) of the total solvent system employed in solvent system V. That is, solvent system V may contain up to 50%> w/w (e.g. up to 40%>, or about 30%>) of 1-propanol.
• antisolvent W is an alkyl antisolvent such as n-heptane.
• solvent system V is heated and then cooled before the seed crystals are added and the mixture is allowed to cool further before antisolvent W is added.
• solvent system V is heated to at least 55°C (such as at least 60°C for example about 65°C) then allowed to cool to 40°C to 50°C (such as 45°C to 50°C for example about 50°C) then the seed crystals of Form B are added (for example 0.2 to 1.5% w/w, e.g. 0.5 to 1.0%> w/w, such as 0.5%> w/w) and the mixture gradually cooled to at least room temperature (such as at least 25°C for example at least 15°C such as at least 8°C).
• solvent system V comprises an organic solvent that is ethereal and an alkyl antisolvent such as a heptane.
• solvent system V comprises methyl tert-butyl ether and n-heptane.
• n- heptane constitutes at least 20%> w/w (e.g. such as about 30%>) of the total solvent system employed in solvent system V. That is, solvent system V may contain up to 80%> w/w (e.g. up to about 70%) of methyl tert-butyl ether.
• antisolvent W is an alkyl antisolvent such as n-heptane.
• solvent system V is heated and then cooled before the seed crystals are added.
• solvent system V is heated to at least 30°C (such as about 35°C) then allowed to cool to 20°C to 25°C (such as about 21°C) then the seed crystals of Form B added.
• the amorphous form of Compound (I) referred to herein is synthesised via the route described in Example 1, steps (ii) to (vii).
• suspension and “slurried” (or “partially dissolved”) are well understood by the skilled person. For instance to form a suspension or slurry, an excess of the solid substance, relative to the solubility in the solvent, is added such that there is (undissolved) solid in the solvent system throughout the “suspension” or “slurrying" procedure.
• Crystalline Form B of Compound (I) may also be prepared by seeding a suspension of an alternative form of Compound (I) (hereinafter referred to as "Form A") in a solvent system with seeds of Form B of Compound (I).
• Form A an alternative form of Compound (I)
• the preparation of Form A of Compound (I) is described below at Example 4 and Example 5.
• the characteristic X-ray powder diffraction pattern peaks of Form A are tabulated in Table 2 below and the X-ray powder diffraction diffractogram shown in Figure 3 below.
• the characteristic differential calorimetry curve of Form A of Compound (I) is shown in Figure 4 below.
• a crystalline form of Compound (I) obtainable by such a (crystallisation) conversion process.
• a suspension process is essentially a "slurrying" process or a process that involves at least partial (but not complete) dissolution in a solvent system.
• Form A may be suspended or slurried (or at least partially dissolved) in a suitable solvent system and thereafter seeds of Form B (for example 1.0 to 2.5% w/w, e.g. 2 % w/w) added.
• solvent systems employed to obtain Form B of Compound (I) by suspension or slurrying include any suitable solvent, or mixture of solvents, that do not result in the formation of a solvate of Compound (I).
• solvent systems may include those in which Compound (I) is only partially (or is at least partially) soluble.
• the solvent system comprises a two solvent system comprising a good solvent and a moderate solvent.
• the solvent system comprises an organic solvent that is polar, e.g. alcohols (such as lower alkyl alcohols, e.g. a Ci_ 6 alcohol) and water.
• the solvent system comprises isopropanol and water.
• water constitutes at least 60% w/w (e.g. at least 75% such as about 80%>) of the total solvent system employed to obtain Form B. That is, the solvent system may contain up to 40%) w/w (e.g. up to 25%o, or about 20%>) of isopropanol.
• the phase conversion in the solvent system to obtain Form B of Compound (I) may take a number of hours or days (e.g. 4 days, see Example 3 hereinafter), but the length of time may be reduced depending on for example the temperature of the process (or it may take longer if performed at lower temperatures) or the concentration of the solution, etc.
• Form B of Compound (I) has improved physical properties when compared with other forms of Compound (I) which may have previously been prepared (for example compared with the amorphous free-base form or with Form A).
• Form B of Compound (I) has, for example, a different hygroscopicity profile compared to the amorphous free-base form which may be useful in formulations comprising the compounds of the invention. Furthermore, Form B of Compound (I) has a different solubility profile and/or dissolution rate compared to Form A (in various solvents, for example buffered aqueous systems or propanol/heptane systems) and a different melting point compared to Form A which may be useful in the manufacturing process and in formulations comprising the compounds of the invention. Furthermore, we have found that by employing the crystallisation or conversion processes described herein, it is possible to produce Form B of Compound (I) with a high chemical purity.
• Form A of Compound (I) is converted to Form B in the conversion processes described herein, showing that Form B is a thermodynamically more stable form of Compound (I), at least at the relevant temperature range, and may be particularly advantageous for use as a medicament.
• Form B of Compound (I) exhibits different pharmacokinetic properties compared with other forms of Compound (I) (such as Form A).
• Form B of Compound (I) exhibits an increased level of total lung exposure (expressed as "Area Under the Curve” or AUC) when compared with Form A.
• Form B of Compound (I) exhibits a reduced level of peak blood level (expressed as Cmax) when compared with Form A.
• Differences in pharmacokinetic properties may lead to differences in the pharmacological efficacy and may provide improved safety margins.
• chemical stability we include that the compound can be stored in an isolated solid form, or in the form of a solid formulation in which it may be provided in admixture with pharmaceutically acceptable carriers, diluents or adjuvants, under normal storage conditions, with an insignificant degree of chemical degradation or decomposition.
• solid state stability we include that the compound can be stored in an isolated solid form, or in the form of a solid formulation in which it may be provided in admixture with pharmaceutically acceptable carriers, diluents or adjuvants, under normal storage conditions, with an insignificant degree of solid state transformation (e.g. crystallisation, recrystallisation, loss of crystallinity, solid state phase transition, hydration, dehydration, solvatisation or desolvatisation).
• solid state transformation e.g. crystallisation, recrystallisation, loss of crystallinity, solid state phase transition, hydration, dehydration, solvatisation or desolvatisation.
• compounds of the invention may be found to be less than about 15%, more preferably less than about 10%>, and especially less than about 5%, chemically degraded/decomposed, or solid-state transformed, as appropriate.
• upper and lower limits for temperature and pressure represent extremes of normal storage conditions, and that certain combinations of these extremes will not be experienced during normal storage (e.g. a temperature of 50°C and a pressure of 0.1 bar).
• normal storage conditions may also include relative humidities of between 5 and 95% (preferably 10 to 60%).
• relative humidities of between 5 and 95% (preferably 10 to 60%).
• changes in conformation or crystal structure by hydration and/or dehydration may occur as a result of prolonged exposure to certain extremes of relative humidities, at normal temperatures/pressures.
• salts that may be mentioned include acid addition salts and base addition salts.
• XRPD X-ray powder diffraction
• the crystalline form that is obtained may be significantly influenced by the synthetic process undertaken to produce the compound to be crystallised.
• factors such as the nature of reactants, the nature of the reagents, the nature of the solvents and the nature of the purification techniques (if any) utilised in any previous steps (and in particular in the penultimate and/or immediately preceeding step) may all affect the crystalline form that is obtained.
• L 1 is an alkoxy or trifluoroacetoxy group.
• the acylating agent is ethyl trifluoracetate.
• compound (II) is in the hydrochloride salt- form.
• the compound of formula (III) is either commercially available or it may be prepared using well-known chemistry from commercially available starting materials.
• the methods which may be utilized to couple compounds of formula (II) and formula (III) are well known in the art.
• the coupling reaction may be carried out by mixing compounds of formula (II) and (III) in a suitable solvent (e.g. an ethereal solvent such as methyl tert-butyl ether) in the presence of a suitable base (e.g. an organic base such as triethylamine) at a suitable temperature (e.g. ambient temperature) for a suitable time (e.g. 24 hours).
• a suitable solvent e.g. an ethereal solvent such as methyl tert-butyl ether
• a suitable base e.g. an organic base such as triethylamine
• R 1 is alkyl (unsubstituted or substituted by silylalkyl), dialkylamino, aryl
• R 1 is aryl (unsubstituted or substituted by one or more of halogen, haloalkyl, alkyl or N0 2 ).
• the deprotection may be carried out by mixing a compound of formula (IV) in a suitable solvent (e.g. an organic solvent such as acetonitrile) in the presence of a suitable base (e.g. an inorganic base such as potassium carbonate) with a suitable deprotecting agent such as a thiol nucelophile (e.g. thioglycolic acid) at a suitable temperature (e.g. 60-100°C such as 75°C) for a suitable time (e.g. 18 hours).
• a suitable solvent e.g. an organic solvent such as acetonitrile
• a suitable base e.g. an inorganic base such as potassium carbonate
• a suitable deprotecting agent such as a thiol nucelophile (e.g. thioglycolic acid)
• a suitable temperature e.g. 60-100°C such as 75°C
• a suitable time e.g. 18 hours.
• the deprotection may be carried out using other well-known deprotecting agents, for example strong acids (such as hydrobromic acid or sulphuric acid), strong reducing agents (such as ground magnesium or sodium in liquid ammonia or sodium naphthalene or tributyl tin hydride) or samarium iodide.
• strong acids such as hydrobromic acid or sulphuric acid
• strong reducing agents such as ground magnesium or sodium in liquid ammonia or sodium naphthalene or tributyl tin hydride
• samarium iodide samarium iodide.
• Alternative methods for carrying out this deprotection are described in standard chemistry texts, for example Greene, T.W. & Wuts, P.G.M. (2006), Greene's Protective Groups in Organic Synthesis, Wiley-Interscience; or Kocienski, P. (2005), Protecting Groups, Thieme.
• R 1 is alkyl (unsubstituted or substituted by silylalkyl), dialkylamino, aryl
• R 1 is aryl (unsubstituted or substituted by one or more of halogen, haloalkyl, alkyl or N0 2 ).
• the compound of formula (VII) is either commercially available or it may be prepared using well-known chemistry from commercially available starting materials. Processes to compound of formula (XI) are described in WO 2008/079073 (example 1) and in the Examples herein. The methods which may be utilized to form compounds of formula (IV) are well known in the art, for instance those described in the Examples herein.
• compound of formula (XIII) may be prepared by mixing compounds of formula (VI) and formula (XII) in a suitable solvent (for example an organic solvent such as 2-methyltetrahydrofuran) in the presence of a suitable base (for example an organic base such as N-methylmorpholine) at a suitable temperature (e.g. ambient temperature) for a suitable time (e.g. 1 hour).
• a suitable solvent for example an organic solvent such as 2-methyltetrahydrofuran
• a suitable base for example an organic base such as N-methylmorpholine
• suitable temperature e.g. ambient temperature
• suitable time e.g. 1 hour
• Compound of formula (XV) may be prepared by adding a suitable base (such as an inorganic base, e.g. sodium hydroxide) to a compound of formula (XIV) in a suitable solvent (such as an organic solvent e.g. 2-methyltetrahydrofuran) at a suitable temperature (e.g. ambient temperature).
• a suitable base such as an inorganic base, e.g. sodium hydroxide
• a suitable solvent such as an organic solvent e.g. 2-methyltetrahydrofuran
• a suitable temperature e.g. ambient temperature
• the suitable base such as an inorganic base, e.g. sodium hydroxide
• Compound of formula (V) may be prepared by adding compound of formula (XI) directly to the reaction mixture containing compound of formula (XV) and a suitable base (such as an inorganic base, e.g. sodium hydroxide) at a itable temperature (e.g. 40°C) for a suitable time (e.g. 17 hours).
• a suitable base such as an inorganic base, e.g. sodium hydroxide
• R is alkyl (unsubstituted or substituted by silylalkyl), dialkylamino, aryl (unsubstituted or substituted by one or more of halogen, haloalkyl, alkyl or N0 2 ) or heteroaryl (unsubstituted or substituted by one or more of halogen, haloalkyl, alkyl or N0 2 ).
• R 1 is aryl (unsubstituted or substituted by one or more of halogen, haloalkyl, alkyl or N0 2 ).
• Alkyl groups and moieties are straight or branched chain and comprise, for example, 1 to 6 (such as 1 to 4) carbon atoms.
• alkyl groups are methyl, ethyl, n-propyl, iso-propyl or tert-butyl.
• Aryl groups and moieties are monocyclic or multicyclic aromatic carbocycles comprising, for example, 6 to 14 (such as 6 to 10) carbon atoms.
• Examples of aryl groups are phenyl or napthyl.
• Dialkylamino means a -N(alkyl) 2 group in which alkyl is defined as above.
• dialkylamino groups are dimethylamino or diethylamino.
• Haloalkyl means an alkyl group as defined above which is substituted by one or more halo atoms. Examples of haloalkyl are trifluoromethyl and trifluoroethyl.
• Silylalkyl means a -Si(alkyl) 3 group in which alkyl is defined as above.
• Examples of silylalkyl groups are trimethylsilyl, triethylsilyl and tert-butyl dimethylsilyl.
• compounds of the invention are useful as anti-inflammatory agents, and can also display antiallergic, immunosuppressive and anti-proliferative actions.
• compounds of the invention, or a pharmaceutically acceptable salt thereof can be used as a medicament for the treatment or prophylaxis of one or more of the following pathologic conditions (disease states) in a mammal (such as a human):
• chronically obstructive lung diseases of any origin, mainly bronchial asthma, chronic obstructive pulmonary disease (COPD)
• COPD chronic obstructive pulmonary disease
• ARDS Adult respiratory distress syndrome
• ARDS acute respiratory distress syndrome
• Rheumatic diseases/auto-immune diseases/degenerative joint diseases which coincide with inflammatory, allergic and/or proliferative processes: all forms of rheumatic diseases, especially rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica, collagenoses, Beliefs disease
• collagen diseases of other origins for example systemic lupus erythematodes, discoid lupus erythematosus, sclerodermia, polymyositis, dermatomyositis, polyarteritis nodosa, temporal arteritis
• nephritides such as, for example, glomerulonephritis
• acute hepatitis of different origins for example virally-, toxically- or pharmaceutical agent- induced chronically aggressive and/or chronically intermittent hepatitis
• Gastrointestinal diseases which coincide with inflammatory, allergic and/or proliferative processes:
• otitis externa for example caused by contact dermatitis, infection, etc.
• cerebral edema mainly tumor-induced cerebral edema
• thrombocytopenia such as for example idiopathic thrombocytopenia
• Substitution therapy which coincides with inflammatory, allergic and/or proliferative processes, with: innate primary suprarenal insufficiency, for example congenital adrenogenital syndrome acquired primary suprarenal insufficiency, for example Addison's disease, autoimmune adrenalitis, meta-infective, tumors, metastases, etc.
• innate primary suprarenal insufficiency for example congenital adrenogenital syndrome acquired primary suprarenal insufficiency, for example Addison's disease, autoimmune adrenalitis, meta-infective, tumors, metastases, etc.
• the compounds of the invention can also be used to treat disorders such as: diabetes type I (insulin-dependent diabetes), Guillain-Barre syndrome, restenoses after percutaneous transluminal angioplasty, Alzheimer's disease, acute and chronic pain, arteriosclerosis, reperfusion injury, thermal injury, multiple organ injury secondary to trauma, acute purulent meningitis, necrotizing enterocolitis and syndromes associated with hemodialysis, leukopheresis, granulocyte transfusion, Conies Syndrome, primary and secondary hyperaldosteronism, increased sodium retention, increased magnesium and potassium excretion (diuresis), increased water retention, hypertension (isolated systolic and combined systolic/diastolic), arrhythmias, myocardial fibrosis, myocardial infarction, Bartter's Syndrome, disorders associated with excess catecholamine levels, diastolic and systolic congestive heart failure (CHF), peripheral vascular disease,
• disorders such as: diabetes
• CHF congestive heart failure
• 'congestive heart disease refers to a disease state of the cardiovascular system whereby the heart is unable to efficiently pump an adequate volume of blood to meet the requirements of the body's tissues and organ systems.
• CHF is characterized by left ventricular failure (systolic dysfunction) and fluid accumulation in the lungs, with the underlying cause being attributed to one or more heart or cardiovascular disease states including coronary artery disease, myocardial infarction, hypertension, diabetes, valvular heart disease, and cardiomyopathy.
• diastolic congestive heart failure refers to a state of CHF characterized by impairment in the ability of the heart to properly relax and fill with blood.
• systolic congestive heart failure refers to a state of CHF
• chronic a condition of slow progress and long continuance. As such, a chronic condition is treated when it is diagnosed and treatment continued throughout the course of the disease.
• acute means an exacerbated event or attack, of short course, followed by a period of remission.
• treatment of physiological disorders contemplates both acute events and chronic conditions.
• compound is administered at the onset of symptoms and discontinued when the symptoms disappear.
• the present invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in therapy (such as a therapy described above).
• the present invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a
• glucocorticoid receptor mediated disease state such as a disease state described above.
• the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of an inflammatory condition (such as an arthritic).
• an inflammatory condition such as an arthritic
• the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a respiratory condition (for example a lung disease as described above).
• the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of asthma.
• the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of COPD.
• the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of allergic rhinitis.
• the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of irritable bowel syndrome.
• the present invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in treating an inflammatory condition, asthma, COPD, allergic rhinitis or irritable bowel syndrome.
• the present invention provides a method of treating a glucocorticoid receptor mediated disease state (such as a disease state described above) in a mammal (such as man), which comprises administering to a mammal in need of such treatment an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
• a glucocorticoid receptor mediated disease state such as a disease state described above
• a mammal such as man
• the present invention provides a method of treating an
• a inflammatory condition such as an arthritic
• a mammal such as man
• administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
• the present invention provides a method of treating a respiratory condition (such as a lung disease described above) in a mammal (such as man), which comprises administering to a mammal in need of such treatment an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
• a respiratory condition such as a lung disease described above
• a mammal such as man
• the invention provides a method of treating asthma in a mammal (such as man), which comprises administering to a mammal in need of such treatment an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
• the invention provides a method of treating COPD in a mammal (such as man), which comprises administering to a mammal in need of such treatment an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
• the invention provides a method of treating allergic rhinitis in a mammal (such as man), which comprises administering to a mammal in need of such treatment an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
• the invention provides a method of treating irritable bowel syndrome in a mammal (such as man), which comprises administering to a mammal in need of such treatment an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
• the present invention further provides a method of treating a glucocorticoid receptor mediated disease state (such as a disease state described above), an inflammatory condition, asthma, COPD, allergic rhinitis and/or irritable bowel syndrome, in a mammal (such as man), which comprises administering to a mammal in need of such treatment an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
• a glucocorticoid receptor mediated disease state such as a disease state described above
• an inflammatory condition such as asthma, COPD, allergic rhinitis and/or irritable bowel syndrome
• the term “therapy” and “treatment” also includes prophylaxis and prevention unless there are specific indications to the contrary.
• the terms “therapeutic” and “therapeutically” should be construed accordingly.
• inhibitor and “antagonist” mean a compound that by any means, partly or completely, blocks the transduction pathway leading to the production of a response by the agonist.
• An agonist may be a full or partial agonist.
• disorder means any condition and disease associated with glucocorticoid receptor activity.
• said active ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, (active ingredient) and a pharmaceutically acceptable adjuvant, diluent or carrier.
• a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, for treating a glucocorticoid receptor mediated disease state (such as a disease state described above), an inflammatory condition, asthma and/or COPD.
• a further aspect the present invention provides a process for the preparation of said composition comprising mixing the active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier.
• the pharmaceutical composition can comprise from 0.05 to 99 %w (per cent by weight), for example from 0.05 to 80 %w, such as from 0.10 to 70 %w (for example from 0.10 to 50 %w), of active ingredient, all percentages by weight being based on total composition.
• a pharmaceutical composition of the present invention can be administered in a standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration.
• a compound of the invention or a pharmaceutically acceptable salt thereof may be formulated into the form of, for example, an aerosol, a powder (for example dry or dispersible), a tablet, a capsule, a syrup, a granule, an aqueous or oily solution or suspension, an (lipid) emulsion, a suppository, an ointment, a cream, drops, or a sterile injectable aqueous or oily solution or suspension.
• a suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule containing between 0.1 mg and 10 g of active ingredient.
• composition of the invention is one suitable for intravenous, subcutaneous, intraarticular or intramuscular injection.
• the compounds of the invention or a pharmaceutically acceptable salt thereof are administered orally.
• the compounds of the invention, or a pharmaceutically acceptable salt thereof are administered by inhalation. In another embodiment the compounds of the invention, or a pharmaceutically acceptable salt thereof, are administered nasally.
• Inhalation is a particularly useful method for administering a compound of the invention (or a pharmaceutically acceptable salt thereof) when treating respiratory diseases such as chronic obstructive pulmonary disease (COPD) or asthma.
• a compound of the invention or a pharmaceutically acceptable salt thereof
• COPD chronic obstructive pulmonary disease
• a compound of the invention or a pharmaceutically acceptable salt thereof
• a pharmaceutical composition of the invention may be administered by oral inhalation in any suitable form and using any suitable inhaler device.
• suitable inhaler devices are known to persons skilled in the art and may be manual or breath actuated.
• the pharmaceutical composition may be formulated as a dry powder, as a suspension (in a liquid or gas) or as a solution (in a liquid) for administration by oral inhalation by means of a suitable inhaler device.
• Inhaler devices suitable for pulmonary administration include metered dose inhalers (MDIs), dry powder inhalers (DPIs), nebulisers and soft mist inhalers.
• MDIs metered dose inhalers
• DPIs dry powder inhalers
• nebulisers nebulisers
• soft mist inhalers nebulisers
• Multi- chamber devices may be used to allow for delivery of a compound of the invention (or a pharmaceutically acceptable salt thereof) and one or more further active ingredients (when present).
• a preferred metered dose inhaler device is a pressurised metered dose inhaler (pMDI).
• a pharmaceutical composition for use in a pMDI may be provided in the form of a solution or suspension comprising the active ingredient and one or more excipients, the excipients including a suitable propellant in which the active ingredient is dissolved or dispersed.
• suitable propellants are known to persons skilled in the art and include hydrocarbon, chlorofluorocarbon and hydrofluoroalkane propellants, or mixtures of any such propellants. Examples of propellants are 1,1,1,2,-tetrafluoroethane (HFA or HFC 134a) and 1,1, 1,2,3, 3,3-heptafluoropropane (HFA or HFC 227), each of which may be used alone or in combination with other propellants and/or other excipients.
• HFA or HFC 134a 1,1,1,2,3, 3,3-heptafluoropropane
• a pMDI device contains the pharmaceutical composition in a pressurised container.
• the active ingredient is delivered by actuating a valve of the container of the pMDI device.
• Actuation may be manual or breath actuated.
• the device is actuated by a user as they inhale, for example by pressing a suitable release mechanism on the pMDI device.
• a breath actuated pMDI device is actuated automatically when the user inhales through a mouthpiece of the pMDI.
• Examples of pMDI devices include for example Rapihaler®, Vannair®, Ventolin® HFA, Evohaler®, Maxair®, Autohaler® and Easi-Breathe®.
• a metered dose inhaler device (such as a pMDI) may be used in combination with a spacer device.
• Suitable spacer devices are well known to persons skilled in the art and include Nebuchamber® or Volumatic®.
• a pharmaceutical composition for use in a dry powder inhaler device is provided in the form of a dry powder comprising the active ingredient and one or more excipients, the excipients typically including a suitable carrier and/or diluent and/or coating agent.
• the active ingredient is provided in an inhalable form and preferably the particles of the active ingredient have a mass median aerodynamic diameter of less than about ⁇ , more preferably of less than about 5 ⁇ , for example from 1 to 5 ⁇ . Persons skilled in the art may measure the mass median aerodynamic diameter using standard techniques known to them.
• Inhalable forms of the active ingredient may be may be prepared by a variety of techniques, including spray-drying, freeze-drying and micronisation.
• the dry powder composition may take the form of a powder agglomerate or an ordered mixture.
• the mixture may comprise inhalable particles of the active ingredient formulated with carrier particles that aid flow from the dry powder inhaler device into the lung.
• the particles of the active ingredient adhere to the carrier particles to form an ordered (interactive) powder mixture.
• Suitable carrier particles for inclusion in such dry powder compositions are known, and include sugars, for example, lactose, glucose, raffmose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol and starch.
• Suitable carriers are lactose particles and they may have a mass median aerodynamic diameter of greater than 90 ⁇ .
• the agglomerate may comprise the active ingredient in the form of microparticles formulated with one or more diluents.
• Suitable diluents include sugars, for example lactose, mannitol and sucrose.
• the active ingredient and/or excipients used in powder compositions for inhalation may be conditioned before, during or after formulation. Conditioning may be useful in, for example, restoring crystallinity and maintaining aerodynamic properties of the particles. Conditioning processes are well known and include exposure of particles to controlled temperature and humidity/solvent vapour. Examples of conditioning processes include those described in WO92/018110 and WO95/05805.
• Dry powder inhaler devices may be single dose, multiple unit dose or multi-dose (reservoir) inhalers, and may utilise a dry powder or a powder-containing capsule.
• single-dose dry powder inhaler devices individual doses are provided, usually in capsules (such as gelatine capsules), and are loaded into the device before use.
• capsules such as gelatine capsules
• these devices include Spinhaler ® , Rotahaler ® , AeroliserTM, Inhalator ® and Eclipse devices.
• Multiple unit dose dry powder inhaler devices contain a number of individually packaged doses, either as multiple capsules (such as gelatine capsules) or in blister packs. Examples of these devices include Diskhaler ® , Diskus ® and Aerohaler ® devices and breath-actuated, dry-powder inhaler devices having multiple cavities for powder arranged in a disc or ring, such as is disclosed in WO2005/002654, WO2012/010877, or
• WO2012/010878 In multi-dose (reservoir) dry powder inhaler devices, the active ingredient is stored in a bulk powder reservoir from which individual doses are metered. Examples of these devices include Turbuhaler ® , Easyhaler ® , Novolizer ® , Clickhaler ® , Spiromax ® , Airmax ® and Pulvinal ® devices.
• Nebuliser devices may for example be used to administer the active ingredient as an aqueous suspension or, preferably, solution, with or without a suitable pH and/or tonicity adjustment, either as a unit-dose or multi-dose formulation.
• Suitable nebulisers are well known to persons skilled in the art and include the eFlow®.
• Nasal administration of a compound of the invention may be provided by means of a spray from a suitable nasal delivery device, such as a spray pump or an MDI nasal delivery device, for example Rhinocort Aqua®.
• a suitable nasal delivery device such as a spray pump or an MDI nasal delivery device, for example Rhinocort Aqua®.
• the compound of the invention or a pharmaceutically acceptable salt thereof
• a pharmaceutical composition for use in a spray pump or MDI nasal delivery device may comprise a compound of the invention (or a pharmaceutically acceptable salt thereof) dispersed or preferably dissolved in a suitable aqueous medium. Where it is desirable to limit the penetration of the active ingredient into the lung and to retain the active ingredient in the nasal cavity, it may be necessary to use particles of the active ingredient having a mean mass aerodynamic diameter greater than about ⁇ , for example from 10 ⁇ to 50 ⁇ .
• Buffers such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexing agents such as hydroxy-propyl ⁇ - cyclodextrin may be used to aid formulation.
• Tablets may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.
• the invention further relates to combination therapies or compositions wherein the compounds of the invention, or a pharmaceutically acceptable salt thereof, or a
• composition comprising the compounds of the invention, or a
• pharmaceutically acceptable salt thereof is administered concurrently (possibly in the same composition) or sequentially with one or more agents for the treatment of any of the above disease states.
• a compound of the invention for the treatment of rheumatoid arthritis, osteoarthritis, COPD, asthma, irritable bowel syndrome or allergic rhinitis
• one or more agents for the treatment of such a condition.
• the one or more agents is selected from the list comprising:
• a PDE4 inhibitor including an inhibitor of the isoform PDE4D
• a selective ⁇ 2 adrenoceptor agonist such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline,
• bitolterol mesylate bitolterol mesylate
• pirbuterol indacaterol
• olodaterol milveterol or vilanterol
• a muscarinic receptor antagonist for example a Ml, M2 or M3 antagonist, such as a selective M3 antagonist
• a muscarinic receptor antagonist such as ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine, telenzepine, aclidinium bromide or
• a steroid such as budesonide
• chemokine receptor function such as a CCR1 receptor antagonist
• an inhibitor of p38 kinase function • a modulator of chemokine receptor function (such as a CCR1 receptor antagonist); • an inhibitor of p38 kinase function;
• neutrophil serine proteases • an inhibitor of neutrophil serine proteases, most preferably neutrophil elastase or proteinase 3.
• the compounds of the invention, or a pharmaceutically acceptable salt thereof can be administered by inhalation or by the oral route and the other agent, e.g. xanthine (such as aminophylline or theophylline) can be administered by inhalation or by the oral route.
• the other agent e.g. xanthine (such as aminophylline or theophylline)
• the compounds of the invention, or a pharmaceutically acceptable salt thereof, and the other agent, e.g xanthine may be administered together. They may be administered sequentially. Or they may be
• X-Ray powder diffraction analysis were performed on samples prepared according to standard methods, for example those described in Giacovazzo, C. et al (1995), Fundamentals of Crystallography, Oxford University Press; Jenkins, R. and Snyder, R. L. (1996), Introduction to X-Ray Powder Diffractometry, John Wiley & Sons, New York; Bunn, C. W. (1948), Chemical Crystallography, Clarendon Press, London; or Klug, H. P. & Alexander, L. E. (1974), X-ray Diffraction Procedures, John Wiley and Sons, New York.
• X-ray analyses were performed using a Panalytical X'Pert PRO MPD instrument with the following parameters:
• an X-ray powder diffraction pattern may be obtained which has one or more measurement errors depending on measurement conditions (such as equipment, sample preparation or machine used).
• intensities in an X-ray powder diffraction pattern may fluctuate depending on measurement conditions and sample preparation.
• persons skilled in the art of X-ray powder diffraction will realise that the relative intensities of the peaks may vary according to the orientation of the sample under test and on the type and setting of the instrument used.
• the position of reflections can be affected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer.
• the surface planarity of the sample may also have a small effect.
• a measurement error of a diffraction angle in an X-ray powder diffraction pattern is about 5% or less, typically plus or minus 0.2° 2-theta.
• Modulated Temperature Differential Scanning Calorimeter using a modulation of ⁇ 0.50°C in intervals of 40 seconds and a ramp rate of 5°C per minute. Approximately 1 mg of test sample was placed in aluminium cups with lids (no crimping) under a nitrogen atmosphere. Where a melting point is quoted, this refers to the onset temperature of the melting endotherm.
• melting point measured by DSC may occur as a result of variations in sample purity, sample preparation and the measurement conditions (e.g. heating rate). It will be appreciated that alternative readings of melting point may be given by other types of equipment or by using conditions different to those described hereinafter. Hence the melting point and endotherm figures quoted herein are not to be taken as absolute values and such measurement errors are to be taken into account when interpreting DSC data. Typically, measurement errors using DSC may vary by ⁇ 0.5°C or less. However, as a skilled person will realise, melting point can vary with sample purity and degree of crystallinity of the sample. Even low levels of impurities can affect the measured melting point.
• the melting points disclosed herein may vary by ⁇ 5°C from the values quoted herein and reference to a substance having a melting point of "about” are to be interpreted as having a value of ⁇ 5°C from the values quoted. It is to be understood that references to melting points disclosed herein refer to the onset temperature of the melting endotherm. A person skilled in the art can use routine optimization/calibration to set up instrumental parameters for a differential scanning calorimeter so that data comparable to the data presented herein can be collected.
• Proton (1H) nuclear magnetic resonance (NMR) spectra were acquired using Varian (Inova 400 MHz) or Bruker (Avance 500 or DPX 300) spectrometers, at 25 °C or 300 K.
• Samples were prepared as solutions in a suitable deuterated solvent ( ⁇ 3 ⁇ 4-DMSO - de- dimethyl sulfoxide, CDCI 3 - -chloroform, or ⁇ 3 ⁇ 4-acetone), optionally containing trimethylsilane (TMS).
• Sample solutions may also contain an internal standard (either maleic acid or 2,3,5,6-tetrachloronitrobenzene) for assay determination and/or added trifluoroacetic acid, to move exchangeable proton signals (e.g.
• Loss-on-drying analysis was performed using a Mettler Toledo HR83 Moisture Analyser or Perkin-Elmer TGA7 Thermogravimetric Analyzer.
• LC Liquid chromatography
• Gas chromatography (GC) was performed using helium as carrier gas on a DB-624 capillary column.
• Agilent 6890 GC instruments equipped with fiame-ionisation detectors were used.
• Table 1 shows the most significant peaks in the XRPD-diffractogram of crystalline Form B of Compound (I).
• Table 2 shows the most significant peaks in the XRPD-diffractogram of crystalline Form A of Compound.
• Figure 1 shows the XRPD-diffractogram of crystalline Form B of Compound (I).
• Figure 2 shows the differential scanning calorimetry profile of crystalline Form B of Compound (I).
• Figure 3 shows the XRPD-diffractogram of crystalline Form A of Compound (I).
• Figure 4 shows the differential scanning calorimetry profile of crystalline Form A of Compound (I).
• step (ii) was further diluted with 1-propanol (17.0 kg) and adjusted to 60 °C.
• n-Heptane (50.4 kg) was charged gradually whilst maintaining the temperature at 60 °C.
• the solution was cooled to 50 °C, charged with seeds of Form B of Compound (I) (50 g) to initiate crystallisation, and gradually cooled to 8 °C.
• Additional n-heptane (25.5 kg) was charged over 20 minutes before analysing a sample of the filtered crystals by XRPD, confirming crystallisation of Form B.
• the batch was filtered in two roughly equal parts, diluting the second part with further additional n- heptane (3.5 kg) before filtering.
• step (i) 2,2,2-Trifluoro- V-[(lR,25)-l-[l-(4-fluorophenyl)indazol-5-yl]oxy-l-(3- methoxyphenyl)propan-2-yl]acetamide
• Aqueous sodium hydroxide 53 kg, 45 mol was charged, the mixture stirred for 30 minutes (excess ethyl trifluoroacetate is hydrolysed to trifluoroacetic acid during this time) and then allowed to separate into layers before discarding the lower (aqueous) phase.
• the upper (organic) phase was washed successively with aqueous hydrochloric acid (50 kg, 50 mol) and then water (54 kg), and then screened through a 0.6 ⁇ filter into a clean vessel.
• the solution was concentrated by distilling off solvent (31 kg) at ⁇ 70 °C
• the organic solution was concentrated in vacuo to an oil and ethyl acetate (110 kg) was charged.
• the organic solution was concentrated in vacuo to an oil and ethyl acetate (110 kg) was charged.
• Hydrogen chloride gas (9.7 kg, 266 mol) was charged over 4 hours, maintaining the temperature between 0-5 °C. The reaction contents were heated to 15 °C and stirred for 12 hours.
• Dimethylhydroxylamine hydrochloride (31.5 kg, 323 mol) was added over 1 hour 30 minutes and the resultant solution maintained at 0-5 °C for 30 minutes.
• reaction mixture was washed sequentially with two portions of 1M hydrochloric acid (164.5 kg, 163 mol and 166 kg, 164 mol), 10%> aqueous sodium hydrogen carbonate (164.5 kg) and then 20%> aqueous sodium chloride solution (199 kg) to give an organic phase solution of tert-butyl N-[(15)-2-(methoxy (methyl)amino)-l-methyl-2-oxo-ethyl] carbamate (606 kg). Half of the solution (303 kg) was solvent swapped by distillation into tetrahydrofuran (220 kg).
• a Form B seed of Compound (I) (28.4 g) was charged to a stirring slurry of Form A of Compound (I) (1.45 kg) in water (101 L) and 2-propanol (22.5 L). The slurry was stirred for 4 days at 20-25 °C, by which time XRPD analysis showed conversion to Form B was complete. The Form B product was filtered off and dried at 40 °C in a vacuum oven to constant weight. Yield 1.41 kg (97%). 98.8% Assay (NMR).
• Trifluoroacetic anhydride (1.14 L, 8.14 mol) was charged to a stirring 20 °C suspension of (IR,2S)- 1 -[ 1 -(4-fluorophenyl)indazol-5-yl]oxy- 1 -(3-methoxyphenyl)propan- 2-amine hydrochloride (2.58 kg, 5.42 mol; 90% assay by mass) in methyl tert-butyl ether (9.30 L) and triethylamine (2.80 L, 20.1 mol) over 45 minutes, keeping the temperature below 40 °C. After 5 minutes, LC analysis showed ⁇ 0.05% amine starting material remaining by area.
• the main crystallisation vessel was heated to about 60 °C to re-dissolve some small deposits of amorphous solids before cooling back to 25 °C.
• the seed slurry was warmed to about 35 °C for better mobility and then charged to the main crystallisation vessel.
• the slurry was warmed to 30 °C during a 3 hour stir to reduce viscosity.
• Water (5.70 L) was then charged over 15 minutes and stirring continued for 16 hours whilst the temperature was slowly varied in the range 30-38 °C.
• the 30 °C slurry was filtered and washed with a mixture of 2-propanol (2.30 L) and water (3.50 L).
• the solids were dried to constant mass at 40 °C and reduced pressure. Yield 2.45 kg (93%). 99.4% Assay (NMR), 0.04% water, 0.1% 2-propanol (all by mass).
• Example 4 (Form A of Compound (I)) is shown in Figure 3 below.
• the compound exhibited an onset temperature of the melting endotherm of 83 °C.
• ethylenediaminetetraacetate (disodium EDTA) (21.6 L) and aqueous sodium chloride (3.6 L; 20%) assay by mass) and then diluted with ethyl acetate (1.0 L).
• the solution was washed twice with a mixture of 0.1N aqueous disodium EDTA (21.6 L for each portion) and sodium chloride (3.6 L for each portion; 20%> assay by mass), then with aqueous sodium bicarbonate (21.6 L; 7.0% assay by mass) and then with aqueous sodium chloride (21.6 L; 10%o assay by mass).
• the solution was chromatographed in portions (0.2 L per cycle, 59 cycles) on Kromasil 6 ⁇ 10 ⁇ silica (2.0 kg), eluting with 15:85 v:v ethanokisohexane (20 L per cycle) containing 1% diethylamine.
• the column was washed with 1 :1 ethanokethyl acetate (3 L) and then equilibrated with 15:85 v:v ethanokisohexane (4 L); both solutions contained 1% diethylamine.
• step (vii) but without the exchange of solvent in step (ii) (ie. without distilling off methyl tert- butyl ether and thereafter replacing with 1-propanol).
• step (ii) the concentration of the methyl tert-butyl ether solution was adjusted to a 5.5 ml solution/g of 2,2,2-trifluoro-N-[(li?,2S 1 -[1 -(4-fluorophenyl)indazol-5-yl]oxy- 1 -(3- methoxyphenyl)propan-2-yl]acetamide through addition of further methyl tert-butyl ether.
• the solution was then cooled to 21°C.
• the solution was seeded with Form B crystals.
• the formed crystal slurry was stirred overnight. 5 ml n-heptane/g was added and the crystals were filtered off after 5 hours stirring.
• the crystals were washed with a mixture of 0.4 ml methyl tert-butyl ether/g and 0.6 ml n-heptane/g.
• the crystals were dried at 40°C vacuum.
• Each suspension is centrifuged twice (Sigma 2-16KCH, 8000 rpm, 25°C) and the supernatant transferred to a new vial after each centrifuge.
• the solubility of the supernatant is determined at room temperature using HPLC (Agilent Technologies 1100).
• Exposure by the inhalation route was performed using a nose-only "flow-past" exposure chamber (Minister AG, Switzerland).
• Forms A and B of Compound (I) were administered as a dry powder inhalation (DPI) to the rat (10 min exposure) and compound concentration was measured in plasma up to 24 hours after administration.
• DPI dry powder inhalation
• MIVIS small animal inhalation system
• a light scattering instrument was used (Casella 950 AMS, London, UK).
• the filters were positioned in the inhalation system in the same way as the animals were connected.
• the amount of Compound (I) Forms A and B on filters were analysed by HPLC.
• the correlation factor was used in the dose measurement program where particle concentration and tidal volume was used to estimate the inhaled dose.
• Target concentration on the Casella was 1,5 mg/m 3 (Casella no: 034022, range: 0-2000).
• the calibration was validated by filter sampling (2+2) at a flow of 0.25 L/min.
• the deposition probability of the inhaled particles was considered similar to that previously reported for the rat (Raabe OG, Yeh HC, Newton GJ, Phalen RF, Velasques DJ.
• the speed on the WDF (1200 - 1400 rpm) was controlled by a Motomatic II and the flow through WDF was 8.0 L/min.
• the air supply to each animal port was 0.3 L/min which is approximately two times the respiratory minute volume for a 210 g rat and considered sufficient to cover the oxygen requirement of the animal (Crosfill ML, Widdicombe JG. Physical characteristics of the chest and lungs and the work of breathing in different mammalian species. J Physiol 1961;158(1): 1-14). Breathing volume and particle concentration were monitored during inhalation.
• Target lung dose was 50 ⁇ g/kg (10 min inhalation). The administration was performed in the morning. The rats were observed continuously during the experiment and up to at least 2 hours after administration.
• Inhaled dose ((chamber concentration * exposure time * respiratory minute volume) / body weight in kg)
• Body Dose Inhaled dose * fraction deposited in body
• the blood samples were protein precipitated by cold, acidified acetonitrile containing a volume marker. After centrifugation the supernatant was diluted to match the mobile phase and the extracts were quantified using LC-MS/MS.
• the lung samples were prepared for analysis by first pulverizing in liquid nitrogen and then homogenizing in Ringer solution by adaptive focused acoustic energy (Covaris). The homogenates were protein precipitated by cold, acidified acetonitrile containing a volume marker and after centrifugation the supernatants were diluted to match the mobile phase for analysis by LC-MS/MS (Agilent 6460 triple quadropole with Agilent 1200 binary pump and a CTC autosampler). 4. Calculations

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• Immunology (AREA)
• Dermatology (AREA)
• Epidemiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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• 2012
  • 2012-06-27 RU RU2013153466/04A patent/RU2013153466A/ru not_active Application Discontinuation
  • 2012-06-27 JP JP2014517935A patent/JP2014527955A/ja active Pending
  • 2012-06-27 CA CA2839398A patent/CA2839398A1/en not_active Abandoned
  • 2012-06-27 WO PCT/GB2012/051503 patent/WO2013001294A1/en active Application Filing
  • 2012-06-27 BR BR112013031759A patent/BR112013031759A2/pt not_active IP Right Cessation
  • 2012-06-27 MX MX2013014566A patent/MX2013014566A/es not_active Application Discontinuation
  • 2012-06-27 SG SG2013089966A patent/SG195309A1/en unknown
  • 2012-06-27 EP EP12731150.4A patent/EP2726464A1/en not_active Withdrawn
  • 2012-06-27 KR KR1020137033086A patent/KR20140036230A/ko not_active Application Discontinuation
  • 2012-06-27 CN CN201280039142.8A patent/CN103814015A/zh active Pending
  • 2012-06-27 AU AU2012277514A patent/AU2012277514A1/en not_active Abandoned
  • 2012-06-27 IN IN23MUN2014 patent/IN2014MN00023A/en unknown
  • 2012-06-28 UY UY0001034170A patent/UY34170A/es not_active Application Discontinuation
  • 2012-06-28 TW TW101123228A patent/TW201305115A/zh unknown
  • 2012-06-29 AR ARP120102359A patent/AR086818A1/es unknown
• 2013
  • 2013-12-13 ZA ZA2013/09480A patent/ZA201309480B/en unknown

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