WO2015162584A1 - Crystalline forms of the sulfate salt of n-[5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide - Google Patents

Crystalline forms of the sulfate salt of n-[5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide Download PDF

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WO2015162584A1
WO2015162584A1 PCT/IB2015/052973 IB2015052973W WO2015162584A1 WO 2015162584 A1 WO2015162584 A1 WO 2015162584A1 IB 2015052973 W IB2015052973 W IB 2015052973W WO 2015162584 A1 WO2015162584 A1 WO 2015162584A1
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imidazol
thiazol
methanesulfonyl
phenyl
methyl
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PCT/IB2015/052973
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French (fr)
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Stéphanie MONNIER
Frédéric NOBS
Thomas Rigassi
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Novartis Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • 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

Definitions

  • the present invention generally relates to polymorphic forms of the sulfate salt of N-[5-(3- imidazol-1 -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide.
  • the present invention also generally relates to a pharmaceutical composition comprising the polymorphic forms, as well of methods of using the polymorphic forms in the treatment of rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion; chronic autoimmune urticaria; asthma; allergic asthma; or asthma associated with allergic rhinitis, methods for obtaining such polymorphic forms and combinations comprising such polymorphic forms.
  • RA rheumatoid arthritis
  • AS ankylosing spondylitis
  • PsA psoriasis arthritis
  • SLE systemic lupus erythematosus
  • pSS primary Sjogren's syndrom
  • N-[5-(3-Imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide is described in WO2003/072557.
  • PI3K phosphoinositide-3 kinase
  • PI3Ks have been identified, divided into three main classes (I, II and III) on the basis of their genetic sequence, structure, adapter molecules,
  • class I family comprising isoforms PI3K ⁇ , ⁇ , ⁇ and ⁇
  • class IB consist of an 85 kDa regulatory/adapter protein and three 110 kDa catalytic subunits (pi 10a, pi 10 ⁇ and pi 105) which are activated in the tyrosine kinase system
  • class IB consists of a single pi 10 ⁇ isoform ( ⁇ 3 ⁇ ) which is activated by G protein-coupled receptors.
  • PI3K5 and ⁇ 3 ⁇ are both lipid kinases belonging to the class I PI3K family (PI3K ⁇ , ⁇ , ⁇ and ⁇ ).
  • PI3K5 generates second messenger signals downstream of tyrosine kinase-linked receptors while ⁇ 3 ⁇ is primarily activated by G protein-coupled
  • GPCR GPCR receptors
  • PI3K5 and ⁇ 3 ⁇ are heterodimers composed of an adaptor protein and a pi 105 or pi 10 ⁇ catalytic subunit, respectively, which converts phosphatidylinositol-4, 5 -bis- phosphate (PtdInsP2) to phosphatidylinositol-3,4,5-tri-phosphate (PtdInsP3). Effector proteins interact with PtdInsP3 and trigger specific signaling pathways involved in cell activation, differentiation, migration, and cell survival.
  • B cells play also a critical role in the pathogenesis of a number of autoimmune and allergic diseases as well as in the process of transplant rejection (Martin and Chan, Annu. Rev. Immunol. 24:467 (2006)).
  • a link between ⁇ 3 ⁇ and processes such as leukocyte chemotaxis and mast cell degranulation has been shown, thereby generating interest in this target for the treatment of autoimmune and inflammatory disorders (Ghigo et al, Bioessays, 2010, 32, 185-196; Reif et al, J. Immunol., 2004, 173, 2236-2240; Laffargue et al, Immunity, 2002, 16, 441-451).
  • Chemotaxis is involved in many autoimmune or inflammatory diseases, in angiogenesis, invasion/metastasis, neurodegeneration or wound healing (Gerard et al. Nat. Immunol. 2:108 (2001)). Temporarily distinct events in leukocyte migration in response to
  • chemokines are fully dependent on ⁇ and ⁇ (Liu et al. Blood 110: 1191 (2007)).
  • PI3K5 and/or ⁇ 3 ⁇ has been associated for example with asthma, arthritis, and lupus (Okkenhaug Chemistry & Biology 20:1309 (2013))
  • PI3Ka and ⁇ 3 ⁇ play an essential role in maintaining homeostasis
  • PI3Ka is involved in insulin signaling and cellular growth pathways.
  • PI3K5 and/or PI3K5 are involved in insulin signaling and cellular growth pathways.
  • ⁇ 3 ⁇ isoform-selective inhibition is expected to avoid potential side effects such as hyperglycemia, and metabolic or growth disregulation.
  • PI3K especially PI3K5 has been associated with malaria, leishmaniasis, trypanosomiasis, toxoplasmosis and/or neurocysticercosis, via functional inhibition of TLR9
  • the present invention provides crystalline forms of the sulfate salt of N-[5-(3-imidazol-l -yl- 4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide.
  • Embodiments of the crystalline forms include those characterized herein as forms A, H A , He and 3 ⁇ 4.
  • the names used herein to characterize a specific form, e.g. "A" etc., should not be considered limiting with respect to any other substance possessing similar or identical physical and chemical characteristics, but rather it should be understood that these designations are mere identifiers that should be interpreted according to the characterization information also presented herein.
  • Figure 1 x-ray powder diffraction (XRPD) patterns (in reflection) of the crystalline form A of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate.
  • XRPD x-ray powder diffraction
  • FIG. 2 Differential scanning calorimetry (DSC) thermogram of the crystalline form A of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate.
  • DSC Differential scanning calorimetry
  • FIG. 3 Thermogravimetric analysis (TGA) diagram of the crystalline form A of N-[5-(3- imidazol-1 -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate.
  • Figure 4 FT-IR spectrum in Nujol of the crystalline form A of N- [5 -(3 -imidazol-1 -yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate.
  • Figure 5 FT-Raman spectrum of the crystalline form A of N-[5-(3-imidazol-l-yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate.
  • Figure 6 Scanning electron microscope (SEM) picture of the crystalline form A of N-[5-(3- imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate.
  • Figure 7 x-ray powder diffraction (XRPD) patterns (in transmission) of the crystalline form HA of N-[5-(3 -imidazol-1 -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate dihydrate.
  • XRPD x-ray powder diffraction
  • FIG. 8 Differential scanning calorimetry (DSC) thermogram of the crystalline form HA of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate dihydrate.
  • FIG. 9 Thermogravimetric analysis (TGA) diagram of the crystalline form HA of N-[5-(3- imidazol-1 -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate dihydrate.
  • Figure 10 x-ray powder diffraction (XRPD) patterns (in transmission) of the crystalline form H B of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate hemihydrate.
  • XRPD x-ray powder diffraction
  • FIG 11 Differential scanning calorimetry (DSC) thermogram of the crystalline form H B of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate hemihydrate.
  • DSC Differential scanning calorimetry
  • FIG. 12 Thermogravimetric analysis (TGA) diagram of the crystalline form H B of N-[5-(3- imidazol-1 -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate hemihydrate.
  • Figure 13 x-ray powder diffraction (XRPD) patterns (in transmission) of the crystalline form He of N-[5-(3 -imidazol-1 -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate tetrahydrate or pentahydrate.
  • XRPD x-ray powder diffraction
  • FIG. 14 Differential scanning calorimetry (DSC) thermogram of the crystalline form He of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate tetrahydrate or pentahydrate.
  • DSC Differential scanning calorimetry
  • FIG. 15 Thermogravimetric analysis (TGA) diagram of the crystalline form He of N-[5-(3- imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate tetrahydrate or pentahydrate.
  • Figure 16 x-ray powder diffraction (XRPD) patterns (in transmission) of the crystalline form N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide free base.
  • TGA Thermogravimetric analysis
  • Figure 17 x-ray powder diffraction (XRPD) patterns (in transmission) of the crystalline form N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide malonate.
  • Figure 18 x-ray powder diffraction (XRPD) patterns (in transmission) of the crystalline form N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide phosphate monohydrate.
  • Figure 19 x-ray powder diffraction (XRPD) patterns (in transmission) of the crystalline form N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide di- mesylate.
  • XRPD x-ray powder diffraction
  • the invention relates to crystalline forms of the sulfate salt of N-[5-(3-imidazol-l-yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide, which are described and characterized herein. Definitions
  • polymorph refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms, and/or ions forming the crystal.
  • solvate refers to a crystalline form of a molecule, atom, and/or ions that further comprises molecules of a solvent or solvents incorporated into the crystalline lattice structure.
  • the solvent molecules in the solvate may be present in a regular arrangement and/or a non-ordered arrangement.
  • the solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules.
  • a solvate with a nonstoichiometric amount of solvent molecules may result from partial loss of solvent from the solvate.
  • Solvates may occur as dimers or oligomers comprising more than one molecule of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate within the crystalline lattice structure.
  • amorphous refers to a solid form of a molecule, atom, and/or ions that is not crystalline. An amorphous solid does not display a definitive X-ray diffraction pattern.
  • substantially pure when used in reference to a form, means a compound having a purity greater than 90 weight %, including greater than 90 , 91 , 92, 93, 94, 95, 96, 97, 98, and 99 weight %, and also including equal to about 100 weight % of N-[5-(3- imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate, based on the weight of the compound.
  • the remaining material comprises other form(s) of the compound, and/or reaction impurities and/or processing impurities arising from its preparation.
  • a crystalline form of N-[5-(3-imidazol-l-yl-4-methanesulfonyl- phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate may be deemed substantially pure in that it has a purity greater than 90 weight %, as measured by means that are at this time known and generally accepted in the art, where the remaining less than 10 weight % of material comprises other form(s) of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide sulfate and/or reaction impurities and/or processing impurities.
  • the term "consisting essentially of refers to the specified material(s) and allows the presence of other components in addition to the specified material
  • free form refers to the compound per se without salt formation or association with a solvent (e.g., solvate).
  • Methotrexate is also known as amethopterin, (2S)-2-[(4- ⁇ [(2,4-diaminopteridin-6- yl)methyl](methyl)amino ⁇ benzoyl)amino]pentanedioic acid or TrexallTM.
  • DMARD disease-modifying antirheumatic drug
  • sDMARDs synthetic disease-modifying antirheumatic drug
  • tsDMARDs biological disease- modifying antirheumatic drugs
  • Biological disease-modifying antirheumatic drugs comprise original and biological disease-modifying antirheumatic drugs (boDMARDs) and biobimilar disease-modifying antirheumatic drug (bsDMARDs).
  • boDMARDs biological disease-modifying antirheumatic drugs
  • bsDMARDs biobimilar disease-modifying antirheumatic drug
  • examples of conventional synthetic disease-modifying antirheumatic drugs are methotrexate, sulfasalazine, leflunomide, hydroxychloroquine and gold salts.
  • the term "pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing
  • a therapeutically effective amount of a form of the present invention refers to an amount of the form of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
  • a therapeutically effective amount refers to the amount of the form of the present invention that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent and/or ameliorate a condition, or a disorder or a disease (i) mediated by class I PI3 kinases or (ii) associated with class I PI3 kinase activity, or (iii) characterized by activity (normal or abnormal) of class I PI3 kinases or (2) reduce or inhibit the activity of class I PI3 kinases or (3) reduce or inhibit the expression of class I PI3 kinases.
  • a therapeutically effective amount refers to the amount of the form of the present invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of class I PI3 kinases ; or at least partially reducing or inhibiting the expression of class I PB kinases.
  • the meaning of the term "a therapeutically effective amount” as illustrated in the above embodiment for class I PI3 kinases also applies by the same means to any other relevant proteins/peptides/enzymes.
  • the term "subject” refers to an animal. Typically the animal is a mammal.
  • a subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like.
  • the subject is a primate.
  • the subject is a human.
  • the term “inhibit”, “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • the term “treat”, “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treat”, “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • treat refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • treat refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • a crystalline form of the sulfate salt of N-[5-(3- imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide is provided in substantially pure form.
  • This crystalline form of N-[5-(3-imidazol-l-yl-4-methanesulfonyl- phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate may be employed in pharmaceutical compositions which may optionally include one or more other components selected, for example, from the group consisting of pharmaceutically acceptable carriers.
  • the crystalline form has substantially pure phase homogeneity as indicated by less than 10%, preferably less than 5 %, and more preferably less than 2 % of the total peak area in the experimentally measured XRPD pattern arising from the extra peaks that are absent from the simulated XRPD pattern.
  • a composition consisting essentially of the crystalline form A of N- [5 -(3 -imidazol- 1 -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl] -acetamide sulfate.
  • composition of this embodiment may comprise at least 90 weight % of the crystalline form A of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2- yl]-acetamide sulfate, based on the weight of N-[5-(3-imidazol-l-yl-4-methanesulfonyl- phenyl)-4-methyl-thiazol-2-yl] -acetamide sulfate in the composition.
  • composition consisting essentially of the crystalline form H A of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2- yl]-acetamide sulfate dihydrate.
  • composition of this embodiment may comprise at least 90 weight % of the crystalline form H A of N- [5 -(3 -imidazol- 1-yl -4-methanesulfonyl-phenyl)- 4-methyl-thiazol-2-yl]-acetamide sulfate dihydrate, based on the weight of N-[5-(3-imidazol- l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate dihydrate in the composition.
  • a composition consisting essentially of the crystalline form 3 ⁇ 4 of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2- yl]-acetamide sulfate hemihydrate.
  • composition of this embodiment may comprise at least 90 weight % of the crystalline form 3 ⁇ 4 of N-[5-(3-imidazol-l-yl-4-methanesulfonyl- phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate hemihydrate, based on the weight of N-[5- (3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate dihydrate in the composition.
  • a composition consisting essentially of the crystalline form He of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2- yl]-acetamide sulfate tetra- to pentahydrate.
  • composition of this embodiment may comprise at least 90 weight % of the crystalline form 3 ⁇ 4 of N-[5-(3-imidazol-l -yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate tetra- to pentahydrate, based on the weight of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2- yl]-acetamide sulfate tetra- to pentahydrate in the composition.
  • Form A exists primarily as a crystalline, solvent-free form.
  • Form A is a white to yellowish-beige powder. It is very soluble in 0.1N HC1.
  • the water sorption-desorption isotherm of form A recorded on a dynamic vapor sorption (DVS) instrument, shows a slightly hygroscopic behavior. The maximum water uptake is 0.8% at 25°C up to 92% RH.
  • the XRPD is changed after exposure to 92% RH and corresponds to the hemihydrate form H B .
  • Form A shows a tendency to form hydrates. Several hydrate forms (H A , H B and He) could be identified.
  • form A is the thermodynamically stable form compared to the hydrate forms (H A , H B and He), the hydrate forms are found to be stable in water or an environment with a water activity only.
  • Form H A is a dihydrate obtained by evaporation of solutions or after water-sorption experiments. A dehydration of form H A occurs through intermediated H AI and H A2 upon heating at 100°C and 140°C respectively; at 210°C form A is obtained.
  • Form H B is a hemihydrate obtained by equilibration in water at 5°C. This form quickly changes back to form A at ambient temperature.
  • Form He is a tetra- or pentahydrate obtained by equilibration in water at 5°C. Upon heating, this form changes to free base at 80°C.
  • reaction impurities and/or processing impurities may be determined by analytical techniques known in the art, such as, for example, chromatography, nuclear magnetic resonance spectroscopy, mass spectrometry, or infrared spectroscopy.
  • the present invention provides a crystalline form of N-[5-(3-imidazol-l -yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in Figure 1.
  • the present invention provides a crystalline form of N-[5-(3-imidazol-l -yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate dihydrate having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in Figure 7.
  • the present invention provides a crystalline form of N-[5-(3-imidazol-l -yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate hemihydrate having a X- ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in Figure 10.
  • the present invention provides a crystalline form of N-[5-(3-imidazol-l -yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate tetrahydrate or pentahydrate having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in Figure 13.
  • N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate is the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2- yl] -acetamide (1 : 1).
  • N-[5-(3-imidazol-l -yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide are N- ⁇ 5-[3-(lH-Imidazol-l -yl)- 4-(methylsulfonyl)phenyl]-4-methyl-l,3-thiazol-2-yl ⁇ acetamide or acetamide, ⁇ -[5-[3-(1 ⁇ - imidazol-l-yl)-4-(methylsulfonyl)phenyl]-4-methyl-2-thiazolyl].
  • Crystalline forms may be prepared by a variety of methods, including for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state transformation from another phase, crystallization from a supercritical fluid, and jet spraying.
  • Techniques for crystallization or recrystallization of crystalline forms from a solvent mixture include, for example, evaporation of the solvent, decreasing the temperature of the solvent mixture, crystal seeding a supersaturated solvent mixture of the molecule and/or salt, freeze drying the solvent mixture, and addition of antisolvents (countersolvents) to the solvent mixture.
  • High throughput crystallization techniques may be employed to prepare crystalline forms including polymorphs.
  • Crystals of drugs including polymorphs, methods of preparation, and characterization of drug crystals are discussed in Solid-State Chemistry of Drugs, S R. Byrn, R.R. Pfeiffer, and J.G. Stowell, 2 nd Edition, SSCI, West Lafayette, Indiana (1999).
  • solvent for crystallization techniques that employ solvent, the choice of solvent or solvents is typically dependent upon one or more factors, such as solubility of the compound, crystallization technique, and vapor pressure of the solvent. Combinations of solvents may be employed, for example, the compound may be solubilized into a first solvent to afford a solution, followed by the addition of an antisolvent to decrease the solubility of the compound in the solution and to afford the formation of crystals.
  • An antisolvent is a solvent in which the compound has low solubility.
  • Methods to obtain hydrates typically employ mixtures of organic solvents with water to achieve a water activity at which a desired hydrate form is formed preferably.
  • a compound is suspended and/or stirred in a suitable solvent to afford a slurry, which may be heated to promote dissolution.
  • a suitable solvent to afford a slurry, which may be heated to promote dissolution.
  • slurry means a saturated solution of the compound, which may also contain an additional amount of the compound to afford a heterogeneous mixture of the compound and a solvent at a given temperature.
  • Seed crystals may be added to any crystallization mixture to promote crystallization.
  • Seeding may be employed to control growth of a particular polymorph or to control the particle size distribution of the crystalline product. Accordingly, calculation of the amount of seeds needed depends on the size of the seed available and the desired size of an average product particle as described, for example, in "Programmed Cooling of Batch Crystallizers," J.W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971,26, 369-377. In general, seeds of small size are needed to control effectively the growth of crystals in the batch. Seed of small size may be generated by sieving, milling, or micronizing of large crystals, or by micro-crystallization of solutions. Care should be taken that milling or micronizing of crystals does not result in any change in crystallinity form the desired crystal form (i.e., change to amorphous or to another polymorph).
  • a cooled crystallization mixture may be filtered under vacuum, and the isolated solids may be washed with a suitable solvent, such as cold recrystallization solvent, and dried under a nitrogen purge to afford the desired crystalline form.
  • the isolated solids may be analyzed by a suitable spectroscopic or analytical technique, such as solid state nuclear magnetic resonance, differential scanning calorimetry, x-ray powder diffraction, or the like, to assure formation of the preferred crystalline form of the product.
  • the resulting crystalline form is typically produced in an amount of greater than about 70 weight % isolated yield, preferably greater than 90 weight % isolated yield, based on the weight of the compound originally employed in the crystallization procedure.
  • the product may be co-milled or passed through a mesh screen to delump the product, if necessary.
  • Crystalline forms may be prepared directly from the reaction medium of the final process for preparing N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]- acetamide sulfate. This may be achieved, for example, by employing in the final process step a solvent or a mixture of solvents from which N-[5-(3-imidazol-l-yl-4-methanesulfonyl- phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate may be crystallized.
  • Suitable solvents for this purpose include, for example, polar protic solvents such as alcohols, for example methanol, ethanol, propanols or butanols; acids, for example formic acid, acetic acid or mixtures thereof, as well as mixtures of alcohols or acids with water.
  • polar protic solvents such as alcohols, for example methanol, ethanol, propanols or butanols
  • acids for example formic acid, acetic acid or mixtures thereof, as well as mixtures of alcohols or acids with water.
  • the crystalline Form A of N-[5-(3-imidazol-l-yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate is obtained by dissolving N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide in a polar protic solvent at a temperature between room temperature and 80°C, followed by addition of H 2 S0 4
  • solid state nuclear magnetic resonance spectroscopy for example, the presence of extra peaks in the comparison of an XRPD
  • experimentally measured XRPD pattern with a simulated XRPD pattern may indicate more than one polymorph in the sample.
  • the simulated XRPD may be calculated from single crystal x-ray data, see Smith, D.K., "A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns," Lawrence Radiation Laboratory, Livermore, California, UCRL-7196 (April 1963) or TOPAS program (Total Pattern Analysis Solution, available through Brucker AXS Inc.).
  • an X-ray diffraction pattern may be obtained with a measurement error that is dependent upon the measurement conditions employed.
  • intensities in a X-ray diffraction pattern may fluctuate depending upon measurement conditions employed.
  • relative intensities may also vary depending upon experimental conditions and, accordingly, the exact order of intensity should not be taken into account.
  • a measurement error of diffraction angle for a conventional X-ray diffraction pattern is typically about 5% or less, and such degree of measurement error should be taken into account as pertaining to the aforementioned diffraction angles.
  • crystal forms of the instant invention are not limited to the crystal forms that provide X-ray diffraction patterns completely identical to the X-ray diffraction patterns depicted in the accompanying Figures disclosed herein. Any crystal forms that provide X- ray diffraction patterns substantially identical to those disclosed in the accompanying Figures fall within the scope of the present invention.
  • the ability to ascertain substantial identities of X-ray diffraction patterns is within the purview of one of ordinary skill in the art.
  • XRPD x-ray powder diffraction pattern
  • XRPD x-ray powder diffraction pattern
  • the crystalline form A of N-[5-(3-imidazol- l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate may be
  • XRPD x-ray powder diffraction pattern
  • XRPD x-ray powder diffraction pattern
  • the DSC instrument used to test the crystalline forms was a Mettler Perkin Elmer DSC7.
  • the DSC cell/sample chamber was purged with 20 ml/min of ultra-high purity nitrogen gas.
  • the instrument was calibrated with high purity indium.
  • the sample was placed into an open aluminum DSC pan and measured against an empty reference pan.
  • About 2-6 mg of sample powder was placed into the bottom of the pan and lightly tapped down to make contact with the pan.
  • the weight of the sample was measured accurately and recorded to a hundredth of a milligram.
  • the instrument was programmed to heat at 10°C per minute in the temperature range between 30 and 300°C. The plot was made with the endothermic peaks pointing down.
  • the endothermic melt peak was evaluated for extrapolated onset temperature, peak temperature, and heat of fusion in this analysis.
  • the crystalline form A of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide sulfate may be characterized by a differential scanning calorimetry (DSC) thermogram according to Figure 2.
  • the melting point as determined by differential scanning calorimetry (DSC) is 267°C.
  • the crystalline form H A of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide sulfate dihydrate may be characterized by a differential scanning calorimetry (DSC) thermogram according to Figure 8.
  • the crystalline form H B of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide sulfate hemihydrate may be characterized by a differential scanning calorimetry (DSC) thermogram according to Figure 11.
  • DSC differential scanning calorimetry
  • the TGA instruments used to test the crystalline forms was a Mettler TGA851e. Samples of 15 to 20 milligrams were analyzed under a nitrogen flow of 50 ml per minute at a heating rate of 20°C per minute in the temperature range between 30°C and about 300°C.
  • the crystalline form A of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide sulfate may be characterized by a thermogravimetric analysis (TGA) diagram according to Figure 3.
  • the crystalline form H A of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide sulfate dihydrate may be characterized by a thermogravimetric analysis (TGA) diagram according to Figure 9.
  • the crystalline form H B of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide sulfate hemihydrate may be characterized by a thermogravimetric analysis (TGA) diagram according to Figure 12.
  • TGA thermogravimetric analysis
  • the IR instrument used to test the crystalline forms was a FT-IR Bruker Vertex 70 with a TGS detector. The sample was placed in Nujol mull between two KBr-plates. Data was collected in in transmission mode in the wavelength range of 4000 to 600 cm "1 .
  • the crystalline form A of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide sulfate may be characterized by an FT-IR spectrum in Nujol according to Figure 4. V. Raman Spectrum (IR)
  • the IR instrument used to test the crystalline forms was a FT-Raman Bruker RFSIOO-S with a Ge-Detector. Data was collected in in reflection mode in the wavelength range of 3500 to 50 cm "1 .
  • the crystalline form A of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide sulfate may be characterized by an FT-Raman spectrum according to Figure 5.
  • the Microscope used to test the crystalline forms was a Zeiss Supra 40.
  • the crystalline form A of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide sulfate may be characterized by a scanning electron microscope (SEM) picture according to Figure 6.
  • the IDR for the crystalline form of N-[5-(3- imidazol-1 -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide phosphate monohydrate shows two steps: the first step shows a good dissolution rate for pH 3 and 4 but the second step presents a very low dissolution rate.
  • the crystalline forms of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)- 4-methyl-thiazol-2-yl]-acetamide are useful for the treatment of diseases that may be treated by inhibition of the PI3K isoforms such as rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion; chronic autoimmune urticaria; asthma; allergic asthma; or asthma associated with allergic rhinitis.
  • RA rheumatoid arthritis
  • AS ankylosing spondylitis
  • PsA psorias
  • the crystalline forms of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]- acetamide are useful as intermediates for preparing crystalline or amorphous forms of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]- acetamide that are useful for the treatment of diseases that may be treated by inhibition of the PI3K isoforms such as rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiit
  • the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide in therapy.
  • the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide in therapy, wherein the therapy is selected from a disease which may be treated by inhibition of the PI3K isoforms.
  • the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide in the treatment of rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion; chronic autoimmune urticaria; asthma; allergic asthma; or asthma associated with allergic rhinitis.
  • RA rheumatoid arthritis
  • AS ankylosing spondylitis
  • PsA psoriasis arthritis
  • SLE systemic lupus ery
  • the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide in the treatment of rheumatoid arthritis (RA).
  • RA rheumatoid arthritis
  • the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide in the treatment of rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria in combination with a disease- modifying antirheumatic drug (DMARD).
  • RA rheumatoid arthritis
  • AS ankylosing spondylitis
  • PsA psoriasis arthritis
  • SLE systemic lupus
  • the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide in the treatment of rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria in combination with a conventional synthetic disease-modifying antirheumatic drug (csDMARD).
  • RA rheumatoid arthritis
  • AS ankylosing spondylitis
  • PsA psoriasis arthritis
  • SLE systemic
  • the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide in the treatment of rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria in combination with methotrexat (MTX).
  • RA rheumatoid arthritis
  • AS ankylosing spondylitis
  • PsA psoriasis arthritis
  • SLE systemic lupus erythematosus
  • the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide in the treatment of rheumatoid arthritis (RA) in combination with methotrexat (MTX).
  • the invention provides the crystalline form A of the sulfate salt of N-[5- (3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for use in therapy.
  • the invention provides the crystalline form A of the sulfate salt of N-[5- (3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for use in therapy, wherein the therapy is selected from a disease which may be treated by inhibition of the PI3K isoforms.
  • the invention provides the crystalline form A of the sulfate salt of N-[5- (3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for use in the treatment of rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion; chronic autoimmune urticaria; asthma; allergic asthma; or asthma associated with allergic rhinitis.
  • RA rheumatoid arthritis
  • AS ankylosing spondylitis
  • PsA psoriasis arthritis
  • SLE systemic lupus erythe
  • the invention provides the crystalline form A of the sulfate salt of N-[5- (3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for use in the treatment of rheumatoid arthritis (RA).
  • RA rheumatoid arthritis
  • the invention provides the crystalline form A of the sulfate salt of N-[5- (3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for use in the treatment of rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria in combination a disease-modifying antirheumatic drug (DMARD).
  • RA rheumatoid arthritis
  • AS ankylosing spondylitis
  • PsA psoriasis arthritis
  • SLE systemic lupus erythe
  • the invention provides the crystalline form A of the sulfate salt of N-[5- (3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for use in the treatment of rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria in combination a conventional synthetic disease-modifying antirheumatic drug (csDMARD).
  • RA rheumatoid arthritis
  • AS ankylosing spondylitis
  • PsA psoriasis arthritis
  • SLE systemic lup
  • the invention provides the crystalline form A of the sulfate salt of N-[5- (3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for use in the treatment of rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria in combination with methotrexat (MTX).
  • RA rheumatoid arthritis
  • AS ankylosing spondylitis
  • PsA psoriasis arthritis
  • SLE systemic lupus erythematosus
  • the invention provides the crystalline form A of the sulfate salt of N-[5- (3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for use in the treatment of rheumatoid arthritis (RA) in combination with methotrexat (MTX).
  • RA rheumatoid arthritis
  • MTX methotrexat
  • the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for the manufacture of a medicament.
  • the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for the manufacture of a medicament, wherein the medicament is for treatment of a disease which may be treated by inhibition of the PBK isoforms.
  • the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for the manufacture of a medicament for the treatment of rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion; chronic autoimmune urticaria; asthma; allergic asthma; or asthma associated with allergic rhinitis.
  • RA rheumatoid arthritis
  • AS ankylosing spondylitis
  • PsA psoriasis arthritis
  • SLE system
  • the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for the manufacture of a medicament for the treatment of rheumatoid arthritis (RA).
  • RA rheumatoid arthritis
  • the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for the manufacture of a medicament for the treatment of rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria in combination with a disease-modifying antirheumatic drug
  • RA rheumatoid arthritis
  • AS ankylosing spondylitis
  • PsA psoriasis arthritis
  • SLE systemic l
  • the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for the manufacture of a medicament for the treatment of rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria in combination with a conventional synthetic disease-modifying antirheumatic drug (csDMARD).
  • RA rheumatoid arthritis
  • AS ankylosing spondylitis
  • PsA psoriasis arthritis
  • the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for the manufacture of a medicament for the treatment of rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria in combination with methotrexat (MTX).
  • RA rheumatoid arthritis
  • AS ankylosing spondylitis
  • PsA psoriasis arthritis
  • SLE systemic lupus
  • the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for the manufacture of a medicament for the treatment of rheumatoid arthritis (RA) in combination with methotrexat (MTX).
  • RA rheumatoid arthritis
  • MTX methotrexat
  • the invention provides a method of treating a disease comprising administration of a therapeutically acceptable amount of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide.
  • the invention provides a method of treating a disease which may be treated by inhibition of the PI3K isoforms comprising administration of a therapeutically acceptable amount of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide.
  • the invention provides a method of treating a disease selected from rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated a disease selected from rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated
  • RA rheumatoid arthritis
  • AS ankylosing spondylitis
  • PsA psoriasis arthritis
  • SLE systemic lupus erythematosus
  • pSS primary Sjogren's syndrom
  • vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion; chronic autoimmune urticaria; asthma; allergic asthma; or asthma associated with allergic rhinitis comprising administration of a therapeutically acceptable amount of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide.
  • the invention provides a method of treating a disease selected from rheumatoid arthritis (RA) comprising administration of a therapeutically acceptable amount of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl- phenyl)-4-methyl-thiazol-2-yl]-acetamide.
  • RA rheumatoid arthritis
  • the invention provides a method of treating a disease selected from rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria comprising administration of a therapeutically acceptable amount of the crystalline form A of the sulfate salt of N-[5-(3- imidazol-1 -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide in combination with a disease-modifying antirheumatic drug (DMARD).
  • RA rheumatoid arthritis
  • AS ankylosing spondylitis
  • PsA psoria
  • the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for the manufacture of a medicament for the treatment of rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria in combination with a conventional synthetic disease-modifying antirheumatic drug (csDMARD).
  • RA rheumatoid arthritis
  • AS ankylosing spondylitis
  • PsA psoriasis arthritis
  • the invention provides a method of treating a disease selected from rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated a disease selected from rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated
  • RA rheumatoid arthritis
  • AS ankylosing spondylitis
  • PsA psoriasis arthritis
  • SLE systemic lupus erythematosus
  • pSS primary Sjogren's syndrom
  • vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria comprising administration of a therapeutically acceptable amount of the crystalline form A of the sulfate salt of N-[5-(3- imidazol-1 -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide in combination with methotrexat (MTX).
  • MTX methotrexat
  • the invention provides a method of treating rheumatoid arthritis (RA) comprising administration of a therapeutically acceptable amount of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]- acetamide in combination with methotrexat (MTX).
  • RA rheumatoid arthritis
  • MTX methotrexat
  • the crystalline forms of the present invention may be administered either simultaneously with, or before or after, one or more other therapeutic agent(s).
  • the crystalline forms of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents.
  • a therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment or nucleic acid, which is therapeutically active or enhances the therapeutic activity when administered to a patient in combination with a form of the invention.
  • the invention provides a product comprising a crystalline form of the present invention and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy.
  • Products provided as a combined preparation include a composition comprising a crystalline form of the present invention and the other therapeutic agent(s) together in the same pharmaceutical composition, or a crystalline form of the present invention and the other therapeutic agent(s) in separate form, e.g. in the form of a kit.
  • the invention provides a pharmaceutical composition comprising a crystalline form of the present invention and another therapeutic agent.
  • the pharmaceutical composition may comprise a pharmaceutically acceptable carrier.
  • the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a crystalline form of the present invention.
  • the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.
  • the kit of the invention may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit of the invention typically comprises directions for administration.
  • the crystalline form of the present invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers.
  • the form of the invention and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the form of the invention and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the form of the invention and the other therapeutic agent.
  • the invention provides the use of a crystalline form of N-[5-(3-imidazol-l-yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate for the treatment of diseases that may be treated by inhibition of the PI3K isoforms, wherein the medicament is prepared for administration with another therapeutic agent.
  • the invention also provides the use of another therapeutic agent for the treatment of diseases that may be treated by inhibition of the PI3K isoforms, wherein the medicament is administered with a crystalline form of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate.
  • the invention also provides a crystalline form of N-[5-(3-imidazol-l-yl-4-methanesulfonyl- phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate for use in a method of treating a disease which may be treated by inhibition of the PBK isoforms, wherein the crystalline form of N- [5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate is prepared for administration with another therapeutic agent.
  • the invention also provides another therapeutic agent for use in a method of treating a disease which may be treated by inhibition of the PI3K isoforms, wherein the other therapeutic agent is prepared for administration with a crystalline form of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)- 4-methyl-thiazol-2-yl]-acetamide sulfate.
  • the invention also provides a crystalline form of N-[5-(3-imidazol-l-yl-4-methanesulfonyl- phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate for use in a method of treating a disease which may be treated by inhibition of the PI3K isoforms, wherein the crystalline form of N- [5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate is administered with another therapeutic agent.
  • the invention also provides another therapeutic agent for use in a method of treating a disease which may be treated by inhibition of the PI3K isoforms, wherein the other therapeutic agent is administered with a crystalline form of N-[5- (3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate.
  • the invention also provides the use of a crystalline form of N-[5-(3-imidazol-l -yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate for treating a disease or condition mediated by the PI3K isoforms, wherein the patient has previously (e.g. within 24 hours) been treated with another therapeutic agent.
  • the invention also provides the use of another therapeutic agent for treating a disease or condition mediated by the PI3K isoforms, wherein the patient has previously (e.g.
  • the invention provides the use of the crystalline Form A of N-[5-(3- imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate for the treatment of a disease selected from rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria, wherein the medicament is prepared for administration with a disease-modifying antirheumatic drug (DMARD).
  • RA rheumatoid arthritis
  • AS ankylosing spondylitis
  • PsA psoriasis arthritis
  • the invention provides the use of a disease-modifying antirheumatic drug (DMARD) for the treatment of a disease selected from rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticarial, wherein the medicament is administered with the crystalline Form A of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide sulfate.
  • RA rheumatoid arthritis
  • AS ankylosing spondylitis
  • PsA psoriasis arthritis
  • the invention provides the crystalline Form A of N-[5-(3-imidazol-l- yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate for use in a method of treating a disease selected from rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria, wherein the crystalline Form A of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2- yl]-acetamide sulf
  • the invention provides a disease-modifying antirheumatic drug (DMARD) for use in a method of treating a disease selected from rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria, wherein the disease-modifying antirheumatic drug (DMARD) is prepared for administration with the crystalline Form A of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate.
  • RA rheumatoid arthritis
  • AS ankylosing spondylitis
  • the invention provides the crystalline Form A of N-[5-(3-imidazol-l- yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate for use in a method of treating a disease selected from rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria, wherein the crystalline Form A of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2- yl]-acetamide
  • the invention provides a disease-modifying agent (DMARD).
  • DMARD disease-modifying agent
  • DMARD antirheumatic drug
  • RA rheumatoid arthritis
  • AS ankylosing spondylitis
  • PsA psoriasis arthritis
  • SLE systemic lupus erythematosus
  • pSS primary Sjogren's syndrom
  • ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria, wherein the disease-modifying antirheumatic drug (DMARD) is administered with the crystalline Form A of N-[5-(3- imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate.
  • the invention provides the use of the crystalline Form A of N-[5-(3- imidazol-1 -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate for treating a disease selected from rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria, wherein the patient has previously (e.g.
  • RA rheumatoid arthritis
  • AS ankylosing spondylitis
  • PsA psoriasis arthritis
  • SLE systemic lupus erythematosus
  • the invention provides the use of a disease-modifying antirheumatic drug (DMARD) agent for treating a disease selected from rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria, wherein the patient has previously (e.g.
  • RA rheumatoid arthritis
  • AS ankylosing spondylitis
  • PsA psoriasis arthritis
  • SLE systemic lupus erythematosus
  • pSS primary Sjogren's syndrom
  • ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg
  • a product comprising the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide and a disease-modifying antirheumatic drug (DMARD) as a combined preparation for simultaneous or sequential use in therapy.
  • DMARD disease-modifying antirheumatic drug
  • a pharmaceutical composition comprising the crystalline form A of the sulfate salt of N-[5-(3 -imidazol-1 -yl -4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide, a disease-modifying antirheumatic drug (DMARD) and a pharmaceutically acceptable carrier.
  • DMARD disease-modifying antirheumatic drug
  • a product comprising the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide and a conventional synthetic disease-modifying antirheumatic drug (csDMARD) as a combined preparation for simultaneous or sequential use in therapy.
  • csDMARD synthetic disease-modifying antirheumatic drug
  • a pharmaceutical composition comprising the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide, a conventional synthetic disease- modifying antirheumatic drug (csDMARD) and a pharmaceutically acceptable carrier.
  • csDMARD synthetic disease- modifying antirheumatic drug
  • a product comprising the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide and methotrexat (MTX) as a combined preparation for simultaneous or sequential use in therapy.
  • MTX methotrexat
  • a pharmaceutical composition comprising the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide, methotrexat (MTX) and a pharmaceutically acceptable carrier.
  • MTX methotrexat
  • the various crystalline forms of the invention may be used alone or in combination, or formulated with other pharmaceutically acceptable carriers to provide formulations suitable for the treatment of the indications identified above.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a crystalline form of the present invention, and a pharmaceutically acceptable carrier.
  • the present invention provides a pharmaceutical composition comprising a crystalline form of the present invention for oral administration.
  • the composition comprises at least two pharmaceutically acceptable carriers.
  • solvates and hydrates are generally considered compositions.
  • pharmaceutically acceptable carriers are sterile.
  • the pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal
  • compositions of the present invention can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions).
  • the pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.
  • compositions are gelatin capsules comprising the active ingredient together with one or more of:
  • diluents e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine
  • lubricants e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol
  • disintegrants e.g., starches, agar, alginic acid or its sodium salt.
  • the pharmaceutical composition or combination of the present invention can be in unit dosage of about 1 -500 mg of active ingredient(s) for a subject of about 50-70 kg, or about 1- 250 mg or about 10-100 mg or about 15-75 mg of active ingredients.
  • the pharmaceutical composition or combination of the present invention can be in unit dosage of about 10-100 mg or 15 -75 mg of active ingredient(s) dosed b.i.d. for a subject of about 50-70 kg.
  • the present invention provides a pharmaceutical composition comprising a crystalline form of the present invention, in a capsule.
  • a pharmaceutical composition comprising a crystalline form of the present invention, in a capsule.
  • N-[5-(3-Imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide was stirred with acetic acid and the solution was heated to approx. 60 °C to afford a clear solution. The solution was then cooled to approx. 5 °C and sulphuric acid 2.1 M was added at ca. 5 °C. The temperature was raised to 20-25 °C and to the persistently clear solution was added ethanol to initiate the slow precipitation.
  • Example 3 Manufacturing of 2 mg, 10 mg and 25 mg hard gelatin capsules comprising crystalline form A of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2- yl]-acetamide sulfate (Form A)
  • Table 2 Ingredients of hard gelatin capsules comprising crystalline form A of N-[5-(3- imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate (Form A)
  • Step 6 Add presieved magnesium stearate to the contents of Step 6 and mix.
  • Step 7 Fill the contents of Step 7 into capsule shells to produce hard gelatin capsules.
  • Step size 0.017deg (2theta)
  • Table 3 List of most significant peaks from x-ray powder diffraction (XRPD) patterns (in reflection) of the crystalline form A of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4- methyl-thiazol-2-yl]-acetamide sulfate
  • Table 4 List of most significant peaks from x-ray powder diffraction (XRPD) patterns (in transmission) of the crystalline form HA of N-[5-(3-imidazol-l -yl-4-methanesulfonyl- phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate dihydrate
  • Table 5 List of most significant peaks from x-ray powder diffraction (XRPD) patterns (in transmission) of the crystalline form HB of N-[5-(3-imidazol-l -yl-4-methanesulfonyl- phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate hemihydrate
  • Table 6 List of most significant peaks from x-ray powder diffraction (XRPD) patterns (in transmission) of the crystalline form 3 ⁇ 4 of N-[5-(3-imidazol-l -yl-4-methanesulfonyl- phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate tetrahydrate or pentahydrate
  • Scan rate 5°C/min, 10°C/min, 20°C/min
  • Scan rate 5°C/min, 10°C/min, 20°C/min
  • Table 7 The key absorbances for the crystalline form A of N-[5-(3-imidazol-l -yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate - Figure 4:
  • the kinase reaction is performed in a final volume of 50 ⁇ per well of a half area
  • the reaction is started by the addition of PI3 kinase, e.g. PI3 kinase a. pllOa.
  • the components of the assay are added per well as follows:
  • the background is determined by addition of 10 ⁇ control compound to the last 4 wells of column 1 and the first 4 wells of column 12.
  • the assay plate is sealed using TopSeal-S (heat seal for polystyrene microplates, PerkinElmer LAS [Deutschland] GmbH, Rodgau, Germany) and incubated at room temperature for at least 60 minutes.
  • TopSeal-S heat seal for polystyrene microplates, PerkinElmer LAS [Deutschland] GmbH, Rodgau, Germany
  • the assay plate is then centrifuged at 1500 rpm for 2 minutes using the Jouan bench top centrifuge (Jouan Inc., France).
  • the assay plate is counted using a Packard TopCount, each well being counted for 20 seconds.
  • the volume of enzyme is dependent on the enzymatic activity of the batch in use.
  • the kinase reaction is performed in a final volume of 10 ⁇ per well of a low volume non-binding CORNING, 384 well black plate (Cat. No. #3676).
  • the final concentrations of ATP and phosphatidyl inositol (PI) in the assay are 1 ⁇ and 10 ⁇ g/mL, respectively.
  • the reaction is started by the addition of ATP.
  • test compounds 50 nl test compounds in 90% DMSO per well, in columns 1-20, 8 concentrations (1/3 and 1/3.33 serial dilution step) in single.
  • the Z' value is a universal measurement of the robustness of an assay. A Z' between 0.5 and 1.0 is considered an excellent assay.
  • the TR-FRET AdaptaTM Universal Kinase Assay Kit was purchased from Invitrogen Corporation (Carlsbad/CA, USA) (Cat. No. PV5099).
  • the kit contains the following reagents: Adapta Eu-anti-ADP Antibody (Europium labeled anti-ADP antibody in HEPES buffered saline, Cat. No. PV5097), Alexa Fluor® 647-labeled ADP tracer (Alexa Fluor® 647-labeled ADP tracer in HEPES buffered saline, Cat. No. PV5098), proprietary TR-FRET dilution buffer pH 7.5 (Cat. No. PV3574).
  • Adapta Eu-anti-ADP Antibody Europium labeled anti-ADP antibody in HEPES buffered saline, Cat. No. PV5097
  • Alexa Fluor® 647-labeled ADP tracer Alexa Fluor® 647-labeled ADP tracer in HEPES buffered
  • PIK3CD substrate Phosphatidylinositol was obtained from Invitrogen (vesicules consisting of 2 mM PI in 50mM HEPES pH7.5; Cat. No. PV5371).
  • PIK3CG substrate Phosphatidylinositol was obtained from Invitrogen (vesicules consisting of 2 mM PI in 50mM HEPES pH7.5; Cat. No. PV5371).
  • Phosphatidylinositol-4,5-bisphosphate was obtained from Invitrogen (PIP2:PS large unilamellar vesicules consisting of ImM PIP2: 19mM PS in 50mM HEPES pH7.5, 3mM MgC12, ImM EGTA; Cat. No. PV5100).
  • TR-FRET Time-Resolved Fluorescence Resonance Energy Transfer
  • TR-FRET assays for protein kinases use a long-lifetime lanthanide Terbium or Europium chelates as the donor species which overcome interference from compound autofluorescence or light scatter from precipitated compounds, by introducing a delay after excitation by a flashlamp excitation source.
  • Results are often expressed as a ratio of the intensities of the acceptor and donor fluorophores.
  • the ratiometric nature of such a value corrects for differences in assay volumes between wells, as well as corrects for quenching effects due to colored compounds.
  • the AdaptaTM assay can be divided into two phases: a kinase reaction phase and an ADP detection phase. In the kinase reaction phase, all kinase reaction components are added to the well and the reaction is allowed to incubate for a set period of time specific for each kinase.
  • a detection solution of Eu-labeled anti-ADP antibody, Alexa Fluor® 647- labeled ADP tracer, and EDTA (to stop the kinase reaction) are added to the assay well.
  • ADP formed by the kinase reaction will displace the Alexa Fluor® 647-labeled ADP tracer from the antibody, resulting in a decrease in TR-FRET signal.
  • the amount of ADP formed by the kinase reaction is reduced, and the resulting intact antibody- tracer interaction maintains a high TR-FRET signal.
  • the donor Europium-anti-ADP antibody
  • the acceptor Alexa Fluor® 647-labeled ADP tracer
  • the emission from the Alexa Fluor® 647 can be monitored with a filter centered at 665 nm because it is located between the emission peaks of the donor, which is measured at 615/620 nm.
  • PBKgamma and PBKdelta and lipid substrate PI or PIP2:PS
  • ATP final assay volume 10 ⁇
  • the standard reaction buffer for the AdaptaTM TR-FRET assay contained lOmM Tris-HCl pH 7.5, 3mM MgC12, 50mM NaCl, ImM DTT, 0.05% CHAPS.
  • Reactions were stopped with 5 ⁇ of a mixture of EDTA containing the Eu-labeled anti-ADP antibody and the Alexa Fluor® 647-labeled ADP tracer in TR-FRET dilution buffer (proprietary to IVG). Plates are read 15 to 60 mins later in a Synergy2 reader using an integration time of 0.4 seconds and a delay of 0.05 seconds. Control for the 100% inhibition of the kinase reaction was performed by replacing the PI3K by the standard reaction buffer. The control for the 0% inhibition was given by the solvent vehicle of the compounds (90% DMSO in H20).
  • FCA Freund's complete adjuvant
  • a 3-way valve (Edwards Lifesciences, V540A69B, lot U02C2104) was connected to the glass syringe and a second sterile glass syringe was connected to the valve.
  • the suspension was squeezed through the valve back and forth from one syringe to the other about 40 times for intensive emulsification, the whole process being performed on ice.
  • the emulsion was kept on 4 °C.
  • the mice were anaesthetized by s.c. injection of a sterile filtrated mixture of 0.2 ml anaesthetic (ketamine 1.03 mg/mouse + xylazine 0.21 mg/mouse in water).
  • N-[5-(3-Imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate was suspended in 10 ml/kg of vehicle (0.5% methylcellulose) and was administered orally by gavage at a dose of 2x 10 mg/kg/day, given to 12 mice, starting at day 7 after immunization and continuing until day 43.
  • Rat collagen-induced arthritis in vivo (therapeutic dose-response study: swelling of hind paws)
  • N-[5-(3-Imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate was investigated in the collagen-induced arthritis model (CIA) in the rat (WAGxBUF/Fl strain) in a therapeutic protocol.
  • the rats were immunized with bovine collagen type II and developed an arthritic-like disease (CIA), manifested in swelling of the hind paws and histological changes.
  • the compound was dosed p.o. twice daily by gavage at the peak of the hind paw swelling, at doses of 2 x 3, 2 x 10, 2 x 30 and 2 x 100 mg/kg per day for up to 14 days.
  • N-[5-(3-Imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate showed marked, dose-dependent and statistically significant inhibition of the swelling as of day 5 after start of therapeutic dosing until the end of the study on day 14 of dosing.
  • AUC0- 14d was reduced by 23, 48, 47 and 81 %, respectively, in the four dosing groups.
  • the body weight course was normal for almost all groups, except for the highest dosing group, 2x 100 mg/kg/day, where the experiment was terminated prematurely due to loss of weight of the rats.
  • mice were anaesthetized by s.c. injection of a sterile filtrated mixture of 0.2 ml anaesthetic (ketamine 1.03 mg/mouse + xylazine 0.21 mg/mouse). Subsequently, serum from K/BxN mice (pool, received from GNF, San Diego, CA, USA) was injected i.p. to these recipient mice (250 ⁇ per mouse).
  • N-[5-(3-Imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate delayed the onset of swelling in the KRN mice, when administered at the day of serum transfer. This effect significantly persisted for 3-4 days, thereafter the swelling was not statistically significantly different from the vehicle control animals
  • Table 11 Inhibition (-%vs vehicle control) of paw swelling (scores) in KRN mice treated with 2x10 or 2x50 mg/kg/day of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4- methyl-thiazol-2-yl]-acetamide sulfate prophy tactically

Abstract

Crystalline forms of N-[5-(3-Imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2- yl]-acetamide, useful in the treatment of diseases which may be treated by inhibition of the PI3K isoforms. Formula (I)

Description

Crystalline Forms of the Sulfate Salt of N-[5-(3-Imidazol-l-yl-4-methanesulfonyl- phenyl)-4-methyl-thiazol-2-yl]-acetamide FIELD OF INDUSTRIAL APPLICABILITY
The present invention generally relates to polymorphic forms of the sulfate salt of N-[5-(3- imidazol-1 -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide. The present invention also generally relates to a pharmaceutical composition comprising the polymorphic forms, as well of methods of using the polymorphic forms in the treatment of rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion; chronic autoimmune urticaria; asthma; allergic asthma; or asthma associated with allergic rhinitis, methods for obtaining such polymorphic forms and combinations comprising such polymorphic forms.
BACKGROUND OF THE INVENTION
N-[5-(3-Imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide is described in WO2003/072557.
Members of the phosphoinositide-3 kinase (PI3K) family are involved in cell growth, differentiation, survival, cytoskeletal remodeling and the trafficking of intracellular organelles in many different types of cells (Okkenhaug and Wymann, Nature Rev.
Immunol. 3:317 (2003).
To date, eight mammalian PI3Ks have been identified, divided into three main classes (I, II and III) on the basis of their genetic sequence, structure, adapter molecules,
expression, mode of activation, and preferred substrate. The most widely understood class I family (comprising isoforms PI3K α, β, γ and δ) is further subdivided into subclasses IA and IB. Class IA PI3 kinases (isoforms ΡΒΚα, ΡΒΚβ and PI3K5) consist of an 85 kDa regulatory/adapter protein and three 110 kDa catalytic subunits (pi 10a, pi 10β and pi 105) which are activated in the tyrosine kinase system whilst class IB consists of a single pi 10γ isoform (ΡΙ3Κγ) which is activated by G protein-coupled receptors.
PI3K5 and ΡΙ3Κγ are both lipid kinases belonging to the class I PI3K family (PI3K α, β, γ and δ). PI3K5 generates second messenger signals downstream of tyrosine kinase-linked receptors while ΡΙ3Κγ is primarily activated by G protein-coupled
receptors (GPCR).
PI3K5 and ΡΙ3Κγ are heterodimers composed of an adaptor protein and a pi 105 or pi 10γ catalytic subunit, respectively, which converts phosphatidylinositol-4, 5 -bis- phosphate (PtdInsP2) to phosphatidylinositol-3,4,5-tri-phosphate (PtdInsP3). Effector proteins interact with PtdInsP3 and trigger specific signaling pathways involved in cell activation, differentiation, migration, and cell survival.
Expression of the pi 105 and pi 10γ catalytic subunits is preferential to leukocytes.
Expression is also observed in smooth muscle cells, myocytes and endothelial cells. In contrast, pi 10a and pi 10β are expressed by all cell types. ΡΙ3Κδ is associated with B cell development and function.
B cells play also a critical role in the pathogenesis of a number of autoimmune and allergic diseases as well as in the process of transplant rejection (Martin and Chan, Annu. Rev. Immunol. 24:467 (2006)). A link between ΡΙ3Κγ and processes such as leukocyte chemotaxis and mast cell degranulation has been shown, thereby generating interest in this target for the treatment of autoimmune and inflammatory disorders (Ghigo et al, Bioessays, 2010, 32, 185-196; Reif et al, J. Immunol., 2004, 173, 2236-2240; Laffargue et al, Immunity, 2002, 16, 441-451). Chemotaxis is involved in many autoimmune or inflammatory diseases, in angiogenesis, invasion/metastasis, neurodegeneration or wound healing (Gerard et al. Nat. Immunol. 2:108 (2001)). Temporarily distinct events in leukocyte migration in response to
chemokines are fully dependent on ΡΒΚδ and ΡΒΚγ (Liu et al. Blood 110: 1191 (2007)).
PI3K5 and/or ΡΙ3Κγ has been associated for example with asthma, arthritis, and lupus (Okkenhaug Chemistry & Biology 20:1309 (2013))
PI3Ka and ΡΙ3Κβ play an essential role in maintaining homeostasis and
pharmacological inhibition of these molecular targets has been associated with cancer therapy.
PI3Ka is involved in insulin signaling and cellular growth pathways. PI3K5 and/or
ΡΙ3Κγ isoform-selective inhibition is expected to avoid potential side effects such as hyperglycemia, and metabolic or growth disregulation.
PI3K, especially PI3K5 has been associated with malaria, leishmaniasis, trypanosomiasis, toxoplasmosis and/or neurocysticercosis, via functional inhibition of TLR9
(WO2013/088404) and PI3K5 and/or ΡΙ3Κγ has been associated with leishmaniasis (Liu et al. J Immunol 2009; 183: 1921-1933; Cummings et al. PNAS 2012; 109: 1251-1256; Oghumu et al. Communicative & Integrative Biology 2013;6:2, e23360) SUMMARY OF THE INVENTION
The present invention provides crystalline forms of the sulfate salt of N-[5-(3-imidazol-l -yl- 4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide. Embodiments of the crystalline forms include those characterized herein as forms A, HA, He and ¾. The names used herein to characterize a specific form, e.g. "A" etc., should not be considered limiting with respect to any other substance possessing similar or identical physical and chemical characteristics, but rather it should be understood that these designations are mere identifiers that should be interpreted according to the characterization information also presented herein. BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 : x-ray powder diffraction (XRPD) patterns (in reflection) of the crystalline form A of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate.
Figure 2: Differential scanning calorimetry (DSC) thermogram of the crystalline form A of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate.
Figure 3: Thermogravimetric analysis (TGA) diagram of the crystalline form A of N-[5-(3- imidazol-1 -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate.
Figure 4: FT-IR spectrum in Nujol of the crystalline form A of N- [5 -(3 -imidazol-1 -yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate. Figure 5: FT-Raman spectrum of the crystalline form A of N-[5-(3-imidazol-l-yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate.
Figure 6: Scanning electron microscope (SEM) picture of the crystalline form A of N-[5-(3- imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate.
Figure 7: x-ray powder diffraction (XRPD) patterns (in transmission) of the crystalline form HA of N-[5-(3 -imidazol-1 -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate dihydrate.
Figure 8: Differential scanning calorimetry (DSC) thermogram of the crystalline form HA of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate dihydrate.
Figure 9: Thermogravimetric analysis (TGA) diagram of the crystalline form HA of N-[5-(3- imidazol-1 -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate dihydrate. Figure 10: x-ray powder diffraction (XRPD) patterns (in transmission) of the crystalline form HB of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate hemihydrate. Figure 11 : Differential scanning calorimetry (DSC) thermogram of the crystalline form HB of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate hemihydrate.
Figure 12: Thermogravimetric analysis (TGA) diagram of the crystalline form HB of N-[5-(3- imidazol-1 -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate hemihydrate.
Figure 13: x-ray powder diffraction (XRPD) patterns (in transmission) of the crystalline form He of N-[5-(3 -imidazol-1 -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate tetrahydrate or pentahydrate.
Figure 14: Differential scanning calorimetry (DSC) thermogram of the crystalline form He of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate tetrahydrate or pentahydrate.
Figure 15: Thermogravimetric analysis (TGA) diagram of the crystalline form He of N-[5-(3- imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate tetrahydrate or pentahydrate. Figure 16: x-ray powder diffraction (XRPD) patterns (in transmission) of the crystalline form N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide free base.
Figure 17: x-ray powder diffraction (XRPD) patterns (in transmission) of the crystalline form N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide malonate. Figure 18: x-ray powder diffraction (XRPD) patterns (in transmission) of the crystalline form N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide phosphate monohydrate.
Figure 19: x-ray powder diffraction (XRPD) patterns (in transmission) of the crystalline form N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide di- mesylate. DETAILED DESCRIPTION OF THE INVENTION
The invention relates to crystalline forms of the sulfate salt of N-[5-(3-imidazol-l-yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide, which are described and characterized herein. Definitions
As used herein "polymorph" refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms, and/or ions forming the crystal. As used herein "solvate" refers to a crystalline form of a molecule, atom, and/or ions that further comprises molecules of a solvent or solvents incorporated into the crystalline lattice structure. The solvent molecules in the solvate may be present in a regular arrangement and/or a non-ordered arrangement. The solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules. For example, a solvate with a nonstoichiometric amount of solvent molecules may result from partial loss of solvent from the solvate. Solvates may occur as dimers or oligomers comprising more than one molecule of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate within the crystalline lattice structure.
As used herein "amorphous" refers to a solid form of a molecule, atom, and/or ions that is not crystalline. An amorphous solid does not display a definitive X-ray diffraction pattern. As used herein, "substantially pure," when used in reference to a form, means a compound having a purity greater than 90 weight %, including greater than 90 , 91 , 92, 93, 94, 95, 96, 97, 98, and 99 weight %, and also including equal to about 100 weight % of N-[5-(3- imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate, based on the weight of the compound. The remaining material comprises other form(s) of the compound, and/or reaction impurities and/or processing impurities arising from its preparation. For example, a crystalline form of N-[5-(3-imidazol-l-yl-4-methanesulfonyl- phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate may be deemed substantially pure in that it has a purity greater than 90 weight %, as measured by means that are at this time known and generally accepted in the art, where the remaining less than 10 weight % of material comprises other form(s) of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide sulfate and/or reaction impurities and/or processing impurities. The term "consisting essentially of refers to the specified material(s) and allows the presence of other components in addition to the specified material(s), provided that the essential characteristics of the material(s) are not materially affected by their presence.
The term "free form" refers to the compound per se without salt formation or association with a solvent (e.g., solvate).
Methotrexate (MTX) is also known as amethopterin, (2S)-2-[(4-{[(2,4-diaminopteridin-6- yl)methyl](methyl)amino}benzoyl)amino]pentanedioic acid or Trexall™. As used herein, the term "disease-modifying antirheumatic drug (DMARD)" includes synthetic disease-modifying antirheumatic drug (sDMARDs) and biological disease- modifying antirheumatic drug. sDMARDs comprise conventional synthetic disease- modifying antirheumatic drugs (csDMARDs) and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs). Biological disease-modifying antirheumatic drugs comprise original and biological disease-modifying antirheumatic drugs (boDMARDs) and biobimilar disease-modifying antirheumatic drug (bsDMARDs). Examples of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) are methotrexate, sulfasalazine, leflunomide, hydroxychloroquine and gold salts.
As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing
Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
The term "a therapeutically effective amount" of a form of the present invention refers to an amount of the form of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. In one non-limiting embodiment, the term "a therapeutically effective amount" refers to the amount of the form of the present invention that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent and/or ameliorate a condition, or a disorder or a disease (i) mediated by class I PI3 kinases or (ii) associated with class I PI3 kinase activity, or (iii) characterized by activity (normal or abnormal) of class I PI3 kinases or (2) reduce or inhibit the activity of class I PI3 kinases or (3) reduce or inhibit the expression of class I PI3 kinases. In another non-limiting embodiment, the term "a therapeutically effective amount" refers to the amount of the form of the present invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of class I PI3 kinases ; or at least partially reducing or inhibiting the expression of class I PB kinases. The meaning of the term "a therapeutically effective amount" as illustrated in the above embodiment for class I PI3 kinases also applies by the same means to any other relevant proteins/peptides/enzymes. As used herein, the term "subject" refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
As used herein, the term "inhibit", "inhibition" or "inhibiting" refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process. As used herein, the term "treat", "treating" or "treatment" of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment "treat", "treating" or "treatment" refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, "treat", "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treat", "treating" or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder.
As used herein, the term "a," "an," "the" and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context. In one embodiment of the invention, a crystalline form of the sulfate salt of N-[5-(3- imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide is provided in substantially pure form. This crystalline form of N-[5-(3-imidazol-l-yl-4-methanesulfonyl- phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate may be employed in pharmaceutical compositions which may optionally include one or more other components selected, for example, from the group consisting of pharmaceutically acceptable carriers.
Preferably, the crystalline form has substantially pure phase homogeneity as indicated by less than 10%, preferably less than 5 %, and more preferably less than 2 % of the total peak area in the experimentally measured XRPD pattern arising from the extra peaks that are absent from the simulated XRPD pattern. Most preferred is a crystalline form having substantially pure phase homogeneity with less than 1% of the total peak area in the experimentally measured XRPD pattern arising from the extra peaks that are absent from the simulated XRPD pattern.
In one embodiment, a composition is provided consisting essentially of the crystalline form A of N- [5 -(3 -imidazol- 1 -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl] -acetamide sulfate. The composition of this embodiment may comprise at least 90 weight % of the crystalline form A of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2- yl]-acetamide sulfate, based on the weight of N-[5-(3-imidazol-l-yl-4-methanesulfonyl- phenyl)-4-methyl-thiazol-2-yl] -acetamide sulfate in the composition. In another one embodiment, a composition is provided consisting essentially of the crystalline form HA of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2- yl]-acetamide sulfate dihydrate. The composition of this embodiment may comprise at least 90 weight % of the crystalline form HA of N- [5 -(3 -imidazol- 1-yl -4-methanesulfonyl-phenyl)- 4-methyl-thiazol-2-yl]-acetamide sulfate dihydrate, based on the weight of N-[5-(3-imidazol- l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate dihydrate in the composition.
In another one embodiment, a composition is provided consisting essentially of the crystalline form ¾ of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2- yl]-acetamide sulfate hemihydrate. The composition of this embodiment may comprise at least 90 weight % of the crystalline form ¾ of N-[5-(3-imidazol-l-yl-4-methanesulfonyl- phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate hemihydrate, based on the weight of N-[5- (3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate dihydrate in the composition.
In another one embodiment, a composition is provided consisting essentially of the crystalline form He of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2- yl]-acetamide sulfate tetra- to pentahydrate. The composition of this embodiment may comprise at least 90 weight % of the crystalline form ¾ of N-[5-(3-imidazol-l -yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate tetra- to pentahydrate, based on the weight of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2- yl]-acetamide sulfate tetra- to pentahydrate in the composition.
Form A (needles) exists primarily as a crystalline, solvent-free form. Form A is a white to yellowish-beige powder. It is very soluble in 0.1N HC1. The water sorption-desorption isotherm of form A, recorded on a dynamic vapor sorption (DVS) instrument, shows a slightly hygroscopic behavior. The maximum water uptake is 0.8% at 25°C up to 92% RH. The XRPD is changed after exposure to 92% RH and corresponds to the hemihydrate form HB. Form A shows a tendency to form hydrates. Several hydrate forms (HA, HB and He) could be identified. No change of crystalline form A has been observed by XRPD after compression for 5 min at 10 tons, but the peaks of the XRPD pattern are broader and the substance is less crystalline. At lower water activities, form A is the thermodynamically stable form compared to the hydrate forms (HA, HB and He), the hydrate forms are found to be stable in water or an environment with a water activity only. Form HA is a dihydrate obtained by evaporation of solutions or after water-sorption experiments. A dehydration of form HA occurs through intermediated HAI and HA2 upon heating at 100°C and 140°C respectively; at 210°C form A is obtained.
Form HB is a hemihydrate obtained by equilibration in water at 5°C. This form quickly changes back to form A at ambient temperature.
Form He is a tetra- or pentahydrate obtained by equilibration in water at 5°C. Upon heating, this form changes to free base at 80°C.
The presence of reaction impurities and/or processing impurities may be determined by analytical techniques known in the art, such as, for example, chromatography, nuclear magnetic resonance spectroscopy, mass spectrometry, or infrared spectroscopy.
The present invention provides a crystalline form of N-[5-(3-imidazol-l -yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in Figure 1.
The present invention provides a crystalline form of N-[5-(3-imidazol-l -yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate dihydrate having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in Figure 7.
The present invention provides a crystalline form of N-[5-(3-imidazol-l -yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate hemihydrate having a X- ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in Figure 10.
The present invention provides a crystalline form of N-[5-(3-imidazol-l -yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate tetrahydrate or pentahydrate having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in Figure 13.
The term "essentially the same" with reference to X-ray diffraction peak positions means that typical peak position and intensity variability are taken into account. For example, one skilled in the art will appreciate that the peak positions (2Θ) will show some inter-apparatus variability, typically as much as 0.2°. Further, one skilled in the art will appreciate that relative peak intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be taken as qualitative measure only. 1) Definition ofN-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]- acetamide sulfate:
N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate is the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2- yl] -acetamide (1 : 1). Alternative chemical names for N-[5-(3-imidazol-l -yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide are N- {5-[3-(lH-Imidazol-l -yl)- 4-(methylsulfonyl)phenyl]-4-methyl-l,3-thiazol-2-yl}acetamide or acetamide, Ν-[5-[3-(1Η- imidazol-l-yl)-4-(methylsulfonyl)phenyl]-4-methyl-2-thiazolyl].
Structural formula of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2- yl ] -acetamide sulfate :
Figure imgf000014_0001
2) Synthesis and isolation ofN-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl] -acetamide sulfate:
Syntheses of N-[5-(3-Imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]- acetamide is described in WO2003/0725572 or by H. Hirt et al, Org Process R&D 2008, 12,111-115 which are wherewith incorporated by reference. The preparation of N-[5-(3- imidazol-1 -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate is described herein in Example 1. 3) Crystallization process:
Preparation of Crystalline Materials:
Crystalline forms may be prepared by a variety of methods, including for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state transformation from another phase, crystallization from a supercritical fluid, and jet spraying. Techniques for crystallization or recrystallization of crystalline forms from a solvent mixture include, for example, evaporation of the solvent, decreasing the temperature of the solvent mixture, crystal seeding a supersaturated solvent mixture of the molecule and/or salt, freeze drying the solvent mixture, and addition of antisolvents (countersolvents) to the solvent mixture. High throughput crystallization techniques may be employed to prepare crystalline forms including polymorphs.
Crystals of drugs, including polymorphs, methods of preparation, and characterization of drug crystals are discussed in Solid-State Chemistry of Drugs, S R. Byrn, R.R. Pfeiffer, and J.G. Stowell, 2nd Edition, SSCI, West Lafayette, Indiana (1999).
For crystallization techniques that employ solvent, the choice of solvent or solvents is typically dependent upon one or more factors, such as solubility of the compound, crystallization technique, and vapor pressure of the solvent. Combinations of solvents may be employed, for example, the compound may be solubilized into a first solvent to afford a solution, followed by the addition of an antisolvent to decrease the solubility of the compound in the solution and to afford the formation of crystals. An antisolvent is a solvent in which the compound has low solubility.
Methods to obtain hydrates typically employ mixtures of organic solvents with water to achieve a water activity at which a desired hydrate form is formed preferably.
In one method to prepare crystals, a compound is suspended and/or stirred in a suitable solvent to afford a slurry, which may be heated to promote dissolution. The term "slurry", as used herein, means a saturated solution of the compound, which may also contain an additional amount of the compound to afford a heterogeneous mixture of the compound and a solvent at a given temperature.
Seed crystals may be added to any crystallization mixture to promote crystallization.
Seeding may be employed to control growth of a particular polymorph or to control the particle size distribution of the crystalline product. Accordingly, calculation of the amount of seeds needed depends on the size of the seed available and the desired size of an average product particle as described, for example, in "Programmed Cooling of Batch Crystallizers," J.W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971,26, 369-377. In general, seeds of small size are needed to control effectively the growth of crystals in the batch. Seed of small size may be generated by sieving, milling, or micronizing of large crystals, or by micro-crystallization of solutions. Care should be taken that milling or micronizing of crystals does not result in any change in crystallinity form the desired crystal form (i.e., change to amorphous or to another polymorph).
A cooled crystallization mixture may be filtered under vacuum, and the isolated solids may be washed with a suitable solvent, such as cold recrystallization solvent, and dried under a nitrogen purge to afford the desired crystalline form. The isolated solids may be analyzed by a suitable spectroscopic or analytical technique, such as solid state nuclear magnetic resonance, differential scanning calorimetry, x-ray powder diffraction, or the like, to assure formation of the preferred crystalline form of the product. The resulting crystalline form is typically produced in an amount of greater than about 70 weight % isolated yield, preferably greater than 90 weight % isolated yield, based on the weight of the compound originally employed in the crystallization procedure. The product may be co-milled or passed through a mesh screen to delump the product, if necessary.
Crystalline forms may be prepared directly from the reaction medium of the final process for preparing N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]- acetamide sulfate. This may be achieved, for example, by employing in the final process step a solvent or a mixture of solvents from which N-[5-(3-imidazol-l-yl-4-methanesulfonyl- phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate may be crystallized. Suitable solvents for this purpose include, for example, polar protic solvents such as alcohols, for example methanol, ethanol, propanols or butanols; acids, for example formic acid, acetic acid or mixtures thereof, as well as mixtures of alcohols or acids with water.
In one embodiment of the invention, the crystalline Form A of N-[5-(3-imidazol-l-yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate is obtained by dissolving N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide in a polar protic solvent at a temperature between room temperature and 80°C, followed by addition of H2S04 The presence of more than one polymorph in a sample may be determined by techniques such as x-ray powder diffraction (XRPD) or solid state nuclear magnetic resonance spectroscopy. For example, the presence of extra peaks in the comparison of an
experimentally measured XRPD pattern with a simulated XRPD pattern may indicate more than one polymorph in the sample. The simulated XRPD may be calculated from single crystal x-ray data, see Smith, D.K., "A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns," Lawrence Radiation Laboratory, Livermore, California, UCRL-7196 (April 1963) or TOPAS program (Total Pattern Analysis Solution, available through Brucker AXS Inc.).
Various analytical methods may be used for characterization.
I. X-ray Powder Diffraction Measurements
One of ordinary skill in the art will appreciate that an X-ray diffraction pattern may be obtained with a measurement error that is dependent upon the measurement conditions employed. In particular, it is generally known that intensities in a X-ray diffraction pattern may fluctuate depending upon measurement conditions employed. It should be further understood that relative intensities may also vary depending upon experimental conditions and, accordingly, the exact order of intensity should not be taken into account. Additionally, a measurement error of diffraction angle for a conventional X-ray diffraction pattern is typically about 5% or less, and such degree of measurement error should be taken into account as pertaining to the aforementioned diffraction angles. Consequently, it is to be understood that the crystal forms of the instant invention are not limited to the crystal forms that provide X-ray diffraction patterns completely identical to the X-ray diffraction patterns depicted in the accompanying Figures disclosed herein. Any crystal forms that provide X- ray diffraction patterns substantially identical to those disclosed in the accompanying Figures fall within the scope of the present invention. The ability to ascertain substantial identities of X-ray diffraction patterns is within the purview of one of ordinary skill in the art.
The instrument used to obtain the X-ray powder diffraction (XRPD) data of the crystalline forms was Bruker D8 Advance. Data is given in reflection mode. A scan rate of 0.3 sec/step and a step size of 0.017deg (2theta) in the measurement range from 2° to 40° was used. Powder samples were placed on a zero background sample holder. The radiation was Cu Ka (λ = 1.5418 A).
X-ray powder diffraction (XRPD) data of the crystalline forms were also obtained using a Stoe STADI P in transmission mode. Powder samples were placed in thin walled glass capillaries of 1mm or less in diameter; the capillary was rotated during data collection. A scan rate of 0.5deg/min in the measurement range from 2° to 40° was used. The radiation was Οι Κα (λ = 1.5418 A)).
The crystalline form A of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide sulfate may be characterized by a x-ray powder diffraction pattern (XRPD) comprising four or more 2theta values (CuKa λ=1.5418 A) selected from the group consisting of 10.5, 14.2, 15.4, 17.4, 20.2, 21.0, 22.1 and 25.7, measured at a temperature of about 22°C and an x-ray wavelength, λ, of 1.5418 A. Preferably, the crystalline form A of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate may be characterized by a x-ray powder diffraction pattern comprising five or more 2theta values (CuKa λ=1.5418 A) selected from the group consisting of 10.5, 14.2, 15.4, 17.4, 20.2, 21.0, 22.1 and 25.7, measured at a temperature of about 22°C.
The crystalline form HA of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide sulfate may be characterized by a x-ray powder diffraction pattern (XRPD) comprising four or more 2theta values (CuKa λ=1.5418 A) selected from the group consisting of 7.9, 9.5, 10.7, 13.8, 21.4 and 30.2, measured at a temperature of about 22°C and an x-ray wavelength, λ, of 1.5418 A. Preferably, the crystalline form A of N-[5-(3-imidazol- l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate may be
characterized by a x-ray powder diffraction pattern comprising five or more 2th eta values
(CuKa λ=1.5418 A) selected from the group consisting of 7.9, 9.5, 10.7, 13.8, 21.4 and 30.2, measured at a temperature of about 22°C.
The crystalline form ¾ of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide sulfate may be characterized by a x-ray powder diffraction pattern (XRPD) comprising four or more 2theta values (CuKa λ=1.5418 A) selected from the group consisting of 10.5, 15.7, 20.9, 22.0 and 26.3, measured at a temperature of about 22°C and an x-ray wavelength, λ, of 1.5418 A. Preferably, the crystalline form A of N-[5-(3-imidazol-l- yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate may be characterized by a x-ray powder diffraction pattern comprising five 2theta values (CuKa λ=1.5418 A) selected from the group consisting of 10.5, 15.7, 20.9, 22.0 and 26.3, measured at a temperature of about 22°C.
The crystalline form ¾ of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide sulfate may be characterized by a x-ray powder diffraction pattern (XRPD) comprising four or more 2theta values (CuKa λ=1.5418 A) selected from the group consisting of 5.6, 7.0, 11.4, 19.1, 21.1 , 21.3 and 30.5, measured at a temperature of about 22°C and an x-ray wavelength, λ, of 1.5418 A. Preferably, the crystalline form A of N-[5-(3- imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate may be characterized by a x-ray powder diffraction pattern comprising five or more 2theta values (CuKa λ=1.5418 A) selected from the group consisting of 5.6, 7.0, 11.4, 19.1, 21.1, 21.3 and 30.5, measured at a temperature of about 22°C.
Π. Differential Scanning Calorimetry (DSC)
The DSC instrument used to test the crystalline forms was a Mettler Perkin Elmer DSC7. The DSC cell/sample chamber was purged with 20 ml/min of ultra-high purity nitrogen gas. The instrument was calibrated with high purity indium. The sample was placed into an open aluminum DSC pan and measured against an empty reference pan. About 2-6 mg of sample powder was placed into the bottom of the pan and lightly tapped down to make contact with the pan. The weight of the sample was measured accurately and recorded to a hundredth of a milligram. The instrument was programmed to heat at 10°C per minute in the temperature range between 30 and 300°C. The plot was made with the endothermic peaks pointing down. The endothermic melt peak was evaluated for extrapolated onset temperature, peak temperature, and heat of fusion in this analysis. The crystalline form A of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide sulfate may be characterized by a differential scanning calorimetry (DSC) thermogram according to Figure 2. The melting point as determined by differential scanning calorimetry (DSC) is 267°C.
The crystalline form HA of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide sulfate dihydrate may be characterized by a differential scanning calorimetry (DSC) thermogram according to Figure 8.
The crystalline form HB of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide sulfate hemihydrate may be characterized by a differential scanning calorimetry (DSC) thermogram according to Figure 11.
The crystalline form ¾ of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide sulfate tetrahydrate or may be characterized by a differential scanning calorimetry (DSC) thermogram according to Figure 14.
III. Thermogravimetric Analysis (TGA)
The TGA instruments used to test the crystalline forms was a Mettler TGA851e. Samples of 15 to 20 milligrams were analyzed under a nitrogen flow of 50 ml per minute at a heating rate of 20°C per minute in the temperature range between 30°C and about 300°C.
The crystalline form A of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide sulfate may be characterized by a thermogravimetric analysis (TGA) diagram according to Figure 3. The crystalline form HA of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide sulfate dihydrate may be characterized by a thermogravimetric analysis (TGA) diagram according to Figure 9.
The crystalline form HB of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide sulfate hemihydrate may be characterized by a thermogravimetric analysis (TGA) diagram according to Figure 12. The crystalline form ¾ of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide sulfate tetrahydrate or may be characterized by thermogravimetric analysis (TGA) diagram according to Figure 15.
IV. Infrared Spectrum (IR)
The IR instrument used to test the crystalline forms was a FT-IR Bruker Vertex 70 with a TGS detector. The sample was placed in Nujol mull between two KBr-plates. Data was collected in in transmission mode in the wavelength range of 4000 to 600 cm"1.
The crystalline form A of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide sulfate may be characterized by an FT-IR spectrum in Nujol according to Figure 4. V. Raman Spectrum (IR)
The IR instrument used to test the crystalline forms was a FT-Raman Bruker RFSIOO-S with a Ge-Detector. Data was collected in in reflection mode in the wavelength range of 3500 to 50 cm"1. The crystalline form A of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide sulfate may be characterized by an FT-Raman spectrum according to Figure 5.
VI. Scanning electron microscope (SEM) picture
The Microscope used to test the crystalline forms was a Zeiss Supra 40.
The crystalline form A of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide sulfate may be characterized by a scanning electron microscope (SEM) picture according to Figure 6.
When compared to the crystalline form of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)- 4-methyl-thiazol-2-yl]-acetamide free base Figure 16, the crystalline form A of N-[5-(3- imidazol-1 -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate shows much improved intrinsic dissolution rates (IDR) at pH=3, pH=4 and pH=5 in citrate buffer. Other crystalline forms, e.g. from N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4- methyl-thiazol-2-yl]-acetamide free base (Figure 16), from N-[5-(3-imidazol-l-yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide malonate (Figure 17), from N-[5- (3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide phosphate monohydrate (Figure 18) and from N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4- methyl-thiazol-2-yl]-acetamide di-mesylate (Figure 19) were obtained.
Table 1 : Data from water sorption and desorption experiments and intrinsic dissolution rates
Figure imgf000022_0001
When compared to the crystalline form of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)- 4-methyl-thiazol-2-yl]-acetamide free base, the crystalline form A of N-[5-(3-imidazol-l -yl- 4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate shows much improved intrinsic dissolution rates (IDR) at pH=3, pH=4 and pH=5 in citrate buffer. When compared to the crystalline form of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)- 4-methyl-thiazol-2-yl]-acetamide malonate, the crystalline form A of N-[5-(3-imidazol-l -yl- 4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate shows improved intrinsic dissolution rates (IDR) at pH=3 and much improved IDR's at pH=4 and pH=5 in citrate buffer. In addition, the crystalline form of N-[5-(3-imidazol-l-yl-4-methanesulfonyl- phenyl)-4-methyl-thiazol-2-yl]-acetamide malonate could not be manufactured reproducibly and often the crystalline form of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide free base was obtained.
When compared to the crystalline form of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)- 4-methyl-thiazol-2-yl]-acetamide phosphate monohydrate, the crystalline form A of N-[5-(3- imidazol-1 -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate shows improved intrinsic dissolution rates (IDR). The IDR for the crystalline form of N-[5-(3- imidazol-1 -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide phosphate monohydrate shows two steps: the first step shows a good dissolution rate for pH 3 and 4 but the second step presents a very low dissolution rate.
When compared to the crystalline form of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)- 4-methyl-thiazol-2-yl]-acetamide di-mesylate, the crystalline form A of N-[5-(3-imidazol-l- yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate shows much less hygroscopic behavior The crystalline form of N-[5-(3-imidazol-l-yl-4-methanesulfonyl- phenyl)-4-methyl-thiazol-2-yl]-acetamide di-mesylate shows a very hygroscopic behavior (liquid if RH above 70 % RH).
The crystalline forms of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)- 4-methyl-thiazol-2-yl]-acetamide are useful for the treatment of diseases that may be treated by inhibition of the PI3K isoforms such as rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion; chronic autoimmune urticaria; asthma; allergic asthma; or asthma associated with allergic rhinitis. The crystalline forms of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]- acetamide are useful as intermediates for preparing crystalline or amorphous forms of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]- acetamide that are useful for the treatment of diseases that may be treated by inhibition of the PI3K isoforms such as rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion; chronic autoimmune urticaria; asthma; allergic asthma; or asthma associated with allergic rhinitis.
In one embodiment, the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide in therapy.
In one embodiment, the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide in therapy, wherein the therapy is selected from a disease which may be treated by inhibition of the PI3K isoforms.
In one embodiment, the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide in the treatment of rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion; chronic autoimmune urticaria; asthma; allergic asthma; or asthma associated with allergic rhinitis.
In one embodiment, the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide in the treatment of rheumatoid arthritis (RA). In one embodiment, the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide in the treatment of rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria in combination with a disease- modifying antirheumatic drug (DMARD). In one embodiment, the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide in the treatment of rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria in combination with a conventional synthetic disease-modifying antirheumatic drug (csDMARD).
In one embodiment, the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide in the treatment of rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria in combination with methotrexat (MTX).
In one embodiment, the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide in the treatment of rheumatoid arthritis (RA) in combination with methotrexat (MTX). In one embodiment, the invention provides the crystalline form A of the sulfate salt of N-[5- (3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for use in therapy.
In one embodiment, the invention provides the crystalline form A of the sulfate salt of N-[5- (3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for use in therapy, wherein the therapy is selected from a disease which may be treated by inhibition of the PI3K isoforms.
In one embodiment, the invention provides the crystalline form A of the sulfate salt of N-[5- (3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for use in the treatment of rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion; chronic autoimmune urticaria; asthma; allergic asthma; or asthma associated with allergic rhinitis.
In one embodiment, the invention provides the crystalline form A of the sulfate salt of N-[5- (3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for use in the treatment of rheumatoid arthritis (RA). In one embodiment, the invention provides the crystalline form A of the sulfate salt of N-[5- (3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for use in the treatment of rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria in combination a disease-modifying antirheumatic drug (DMARD).
In one embodiment, the invention provides the crystalline form A of the sulfate salt of N-[5- (3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for use in the treatment of rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria in combination a conventional synthetic disease-modifying antirheumatic drug (csDMARD). In one embodiment, the invention provides the crystalline form A of the sulfate salt of N-[5- (3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for use in the treatment of rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria in combination with methotrexat (MTX).
In one embodiment, the invention provides the crystalline form A of the sulfate salt of N-[5- (3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for use in the treatment of rheumatoid arthritis (RA) in combination with methotrexat (MTX).
In one embodiment, the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for the manufacture of a medicament.
In one embodiment, the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for the manufacture of a medicament, wherein the medicament is for treatment of a disease which may be treated by inhibition of the PBK isoforms.
In one embodiment, the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for the manufacture of a medicament for the treatment of rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion; chronic autoimmune urticaria; asthma; allergic asthma; or asthma associated with allergic rhinitis.
In one embodiment, the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for the manufacture of a medicament for the treatment of rheumatoid arthritis (RA).
In one embodiment, the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for the manufacture of a medicament for the treatment of rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria in combination with a disease-modifying antirheumatic drug
(DMARD).
In one embodiment, the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for the manufacture of a medicament for the treatment of rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria in combination with a conventional synthetic disease-modifying antirheumatic drug (csDMARD). In one embodiment, the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for the manufacture of a medicament for the treatment of rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria in combination with methotrexat (MTX). In one embodiment, the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for the manufacture of a medicament for the treatment of rheumatoid arthritis (RA) in combination with methotrexat (MTX).
In one embodiment, the invention provides a method of treating a disease comprising administration of a therapeutically acceptable amount of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide.
In one embodiment, the invention provides a method of treating a disease which may be treated by inhibition of the PI3K isoforms comprising administration of a therapeutically acceptable amount of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide.
In one embodiment, the invention provides a method of treating a disease selected from rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated
vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion; chronic autoimmune urticaria; asthma; allergic asthma; or asthma associated with allergic rhinitis comprising administration of a therapeutically acceptable amount of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide. In one embodiment, the invention provides a method of treating a disease selected from rheumatoid arthritis (RA) comprising administration of a therapeutically acceptable amount of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl- phenyl)-4-methyl-thiazol-2-yl]-acetamide. In one embodiment, the invention provides a method of treating a disease selected from rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria comprising administration of a therapeutically acceptable amount of the crystalline form A of the sulfate salt of N-[5-(3- imidazol-1 -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide in combination with a disease-modifying antirheumatic drug (DMARD).
In one embodiment, the invention provides the use of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide for the manufacture of a medicament for the treatment of rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria in combination with a conventional synthetic disease-modifying antirheumatic drug (csDMARD).
In one embodiment, the invention provides a method of treating a disease selected from rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated
vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria comprising administration of a therapeutically acceptable amount of the crystalline form A of the sulfate salt of N-[5-(3- imidazol-1 -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide in combination with methotrexat (MTX). In one embodiment, the invention provides a method of treating rheumatoid arthritis (RA) comprising administration of a therapeutically acceptable amount of the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]- acetamide in combination with methotrexat (MTX). The crystalline forms of the present invention may be administered either simultaneously with, or before or after, one or more other therapeutic agent(s). The crystalline forms of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents. A therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment or nucleic acid, which is therapeutically active or enhances the therapeutic activity when administered to a patient in combination with a form of the invention.
In one embodiment, the invention provides a product comprising a crystalline form of the present invention and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. Products provided as a combined preparation include a composition comprising a crystalline form of the present invention and the other therapeutic agent(s) together in the same pharmaceutical composition, or a crystalline form of the present invention and the other therapeutic agent(s) in separate form, e.g. in the form of a kit. In one embodiment, the invention provides a pharmaceutical composition comprising a crystalline form of the present invention and another therapeutic agent. Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable carrier.
In one embodiment, the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a crystalline form of the present invention. In one embodiment, the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like. The kit of the invention may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit of the invention typically comprises directions for administration.
In the combination therapies of the invention, the crystalline form of the present invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the form of the invention and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the form of the invention and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the form of the invention and the other therapeutic agent.
Accordingly, the invention provides the use of a crystalline form of N-[5-(3-imidazol-l-yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate for the treatment of diseases that may be treated by inhibition of the PI3K isoforms, wherein the medicament is prepared for administration with another therapeutic agent. The invention also provides the use of another therapeutic agent for the treatment of diseases that may be treated by inhibition of the PI3K isoforms, wherein the medicament is administered with a crystalline form of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate.
The invention also provides a crystalline form of N-[5-(3-imidazol-l-yl-4-methanesulfonyl- phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate for use in a method of treating a disease which may be treated by inhibition of the PBK isoforms, wherein the crystalline form of N- [5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate is prepared for administration with another therapeutic agent. The invention also provides another therapeutic agent for use in a method of treating a disease which may be treated by inhibition of the PI3K isoforms, wherein the other therapeutic agent is prepared for administration with a crystalline form of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)- 4-methyl-thiazol-2-yl]-acetamide sulfate.
The invention also provides a crystalline form of N-[5-(3-imidazol-l-yl-4-methanesulfonyl- phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate for use in a method of treating a disease which may be treated by inhibition of the PI3K isoforms, wherein the crystalline form of N- [5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate is administered with another therapeutic agent. The invention also provides another therapeutic agent for use in a method of treating a disease which may be treated by inhibition of the PI3K isoforms, wherein the other therapeutic agent is administered with a crystalline form of N-[5- (3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate.
The invention also provides the use of a crystalline form of N-[5-(3-imidazol-l -yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate for treating a disease or condition mediated by the PI3K isoforms, wherein the patient has previously (e.g. within 24 hours) been treated with another therapeutic agent. The invention also provides the use of another therapeutic agent for treating a disease or condition mediated by the PI3K isoforms, wherein the patient has previously (e.g. within 24 hours) been treated with a crystalline form of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate.
In one embodiment, the invention provides the use of the crystalline Form A of N-[5-(3- imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate for the treatment of a disease selected from rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria, wherein the medicament is prepared for administration with a disease-modifying antirheumatic drug (DMARD). In another embodiment, the invention provides the use of a disease-modifying antirheumatic drug (DMARD) for the treatment of a disease selected from rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticarial, wherein the medicament is administered with the crystalline Form A of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide sulfate.
In another embodiment, the invention provides the crystalline Form A of N-[5-(3-imidazol-l- yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate for use in a method of treating a disease selected from rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria, wherein the crystalline Form A of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2- yl]-acetamide sulfate is prepared for administration with a disease-modifying antirheumatic drug (DMARD). In another embodiment, the invention provides a disease-modifying antirheumatic drug (DMARD) for use in a method of treating a disease selected from rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria, wherein the disease-modifying antirheumatic drug (DMARD) is prepared for administration with the crystalline Form A of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate. In another embodiment, the invention provides the crystalline Form A of N-[5-(3-imidazol-l- yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate for use in a method of treating a disease selected from rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria, wherein the crystalline Form A of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2- yl]-acetamide sulfate is administered with a disease-modifying antirheumatic drug
(DMARD). In another embodiment, the invention provides a disease-modifying
antirheumatic drug (DMARD) for use in a method of treating a disease selected from rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria, wherein the disease-modifying antirheumatic drug (DMARD) is administered with the crystalline Form A of N-[5-(3- imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate.
In another embodiment, the invention provides the use of the crystalline Form A of N-[5-(3- imidazol-1 -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate for treating a disease selected from rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria, wherein the patient has previously (e.g. within 24 hours) been treated a disease-modifying antirheumatic drug (DMARD). In another embodiment, the invention provides the use of a disease- modifying antirheumatic drug (DMARD) agent for treating a disease selected from rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion or chronic autoimmune urticaria, wherein the patient has previously (e.g. within 24 hours) been treated with the crystalline Form A of N-[5-(3 -imidazol-1 -yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate.
In one embodiment of the invention, there is provided a product comprising the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide and a disease-modifying antirheumatic drug (DMARD) as a combined preparation for simultaneous or sequential use in therapy.
In one embodiment of the invention, there is provided a pharmaceutical composition comprising the crystalline form A of the sulfate salt of N-[5-(3 -imidazol-1 -yl -4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide, a disease-modifying antirheumatic drug (DMARD) and a pharmaceutically acceptable carrier.
In one embodiment of the invention, there is provided a product comprising the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide and a conventional synthetic disease-modifying antirheumatic drug (csDMARD) as a combined preparation for simultaneous or sequential use in therapy.
In one embodiment of the invention, there is provided a pharmaceutical composition comprising the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide, a conventional synthetic disease- modifying antirheumatic drug (csDMARD) and a pharmaceutically acceptable carrier. In one embodiment of the invention, there is provided a product comprising the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl- thiazol-2-yl]-acetamide and methotrexat (MTX) as a combined preparation for simultaneous or sequential use in therapy. In one embodiment of the invention, there is provided a pharmaceutical composition comprising the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l-yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide, methotrexat (MTX) and a pharmaceutically acceptable carrier. The various crystalline forms of the invention may be used alone or in combination, or formulated with other pharmaceutically acceptable carriers to provide formulations suitable for the treatment of the indications identified above.
In another aspect, the present invention provides a pharmaceutical composition comprising a crystalline form of the present invention, and a pharmaceutically acceptable carrier.
In another aspect, the present invention provides a pharmaceutical composition comprising a crystalline form of the present invention for oral administration. In a further embodiment, the composition comprises at least two pharmaceutically acceptable carriers. For purposes of the present invention, unless designated otherwise, solvates and hydrates are generally considered compositions. Preferably, pharmaceutically acceptable carriers are sterile. The pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal
administration, etc. In addition, the pharmaceutical compositions of the present invention can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.
Typically, the pharmaceutical compositions are gelatin capsules comprising the active ingredient together with one or more of:
a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; if desired
c) disintegrants, e.g., starches, agar, alginic acid or its sodium salt.
The pharmaceutical composition or combination of the present invention can be in unit dosage of about 1 -500 mg of active ingredient(s) for a subject of about 50-70 kg, or about 1- 250 mg or about 10-100 mg or about 15-75 mg of active ingredients. The therapeutically effective dosage of a compound or form, the pharmaceutical composition, or the
combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. In one embodiment of the invention, the pharmaceutical composition or combination of the present invention can be in unit dosage of about 10-100 mg or 15 -75 mg of active ingredient(s) dosed b.i.d. for a subject of about 50-70 kg.
In another aspect, the present invention provides a pharmaceutical composition comprising a crystalline form of the present invention, in a capsule. The following non-limiting examples are illustrative of the invention.
EXAMPLES
Example 1 : N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]- acetamide sulfate Form A
21.7 g (57.7 mMol) of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2- yl]-acetamide were suspended in 96 mL ethanol /water 8/2. At 50°C (inner temperature), 70 mL 1M H2SO4 in ethanol /water 8/2 (corresponds to 70 mMol resp. 1.2 equivalent) were added. A solution is formed where the sulfate salt crystallizes out. 130 mL Ethanol were added at 50°C (inner temperature) and the mixture was stirred for another 15 minutes at this temperature. Within 45 minutes, the mixture was cooled down to 30°C and stirred 2 hours at 0°C (outer temperature). The suspension was filtered and the obtained material was washed twice with 40 mL ethanol each. The sulfate salt was dried for 15h at 50°C. Yield: 26.28 g (95.8% of theoretical yield).
Example 2: N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]- acetamide sulfate Form A
N-[5-(3-Imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide was stirred with acetic acid and the solution was heated to approx. 60 °C to afford a clear solution. The solution was then cooled to approx. 5 °C and sulphuric acid 2.1 M was added at ca. 5 °C. The temperature was raised to 20-25 °C and to the persistently clear solution was added ethanol to initiate the slow precipitation.
Example 3 : Manufacturing of 2 mg, 10 mg and 25 mg hard gelatin capsules comprising crystalline form A of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2- yl]-acetamide sulfate (Form A) Table 2: Ingredients of hard gelatin capsules comprising crystalline form A of N-[5-(3- imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate (Form A)
Figure imgf000039_0001
* The weight Form A is taken with reference to the dried substance (100 percent) on the basis of the assay value (factorization). The difference in weight is adjusted by the amount of lactose monohydrate used.
Manufacturing process:
1. Add Form A and lactose monohydrate (in process) in a suitable container and mix.
2. Sieve the contents of Step 1.
3. Mix the contents of Step 2.
4. Repeat steps 1 , 2 and 3 by adding the remaining portions of lactose monohydrate and mixture of previous cycle and mix (2-4 cycles).
5. Add pregelatinized starch and silica, colloidal anhydrous to the final contents of Step 3.
6. Sieve the contents of Step 4.
7. Mix the contents of Step 5.
8. Add presieved magnesium stearate to the contents of Step 6 and mix.
9. Fill the contents of Step 7 into capsule shells to produce hard gelatin capsules. Instumentation,Methods and Data
XRPD-methods
Instrument: Bruker D8 Advance; (in reflexion mode) Irradiation: CuKa (30 kV, 40 mA)
Scan type: Continuous scan
Scan rate: 0. 3 sec/step
Step size: 0.017deg (2theta)
Scan range: 2° - 40° (2theta)
Instrument: Stoe STADI P; (in transmission mode) Irradiation: CuKa (45 kV, 40 mA)
Divergence:slice 2 mm (Stoe)
Measuring slice: 0.2 mm (Stoe)
Scan type: Continuous scan
Scan rate: 0.5°/min (2theta)
Scan range: 2° - 40° (2theta)
Form A
Bruker D8 Advance - Figure 1 Table 3: List of most significant peaks from x-ray powder diffraction (XRPD) patterns (in reflection) of the crystalline form A of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4- methyl-thiazol-2-yl]-acetamide sulfate
Angle d value Intensity %
2Theta ° Angstrom %
5.8 15.293 23
7.6 11 .606 19
10.5 8.435 56
1 1.6 7.627 16
14.2 6.231 100
15.4 5.752 82
17.4 5.085 78
18.7 4.731 27
19.6 4.522 10
20.2 4.390 30
21.0 4.219 34
21.7 4.092 25
22.1 4.023 47
23.2 3.831 30
24.2 3.678 15
24.9 3.574 25
25.7 3.470 39
26.0 3.421 17
26.5 3.359 21
27.0 3.294 25
27.4 3.249 26
28.3 3.153 30
29.4 3.040 1 1
30.5 2.930 13
31.1 2.876 10 STOE STADI P - Figure 7
Table 4: List of most significant peaks from x-ray powder diffraction (XRPD) patterns (in transmission) of the crystalline form HA of N-[5-(3-imidazol-l -yl-4-methanesulfonyl- phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate dihydrate
Angle d value Intensity %
2Theta ° Angstrom %
7.9 11 .201 66
9.5 9.293 53
10.7 8.225 52
13.8 6.395 100
15.4 5.763 39
18.8 4.717 39
20.7 4.290 40
21.4 4.151 50
24.9 3.568 32
25.9 3.435 44
30.2 2.957 80
STOE STADI P - Figure 10
Table 5: List of most significant peaks from x-ray powder diffraction (XRPD) patterns (in transmission) of the crystalline form HB of N-[5-(3-imidazol-l -yl-4-methanesulfonyl- phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate hemihydrate
Angle d value Intensity %
2Theta ° Angstrom %
10.5 8.452 61
10.9 8.141 18
14.8 5.973 19
15.0 5.883 18
15.7 5.628 52
18.3 4.835 28
19.1 4.649 17
20.9 4.241 65
21.4 4.154 14
21.6 4.104 36
22.0 4.036 71
23.6 3.767 34
25.7 3.461 17
26.3 3.382 100
29.7 3.002 19
30.3 2.947 25
31.1 2.876 18
31.7 2.820 15 Form Hr
STOE STADI P - Figure 13
Table 6: List of most significant peaks from x-ray powder diffraction (XRPD) patterns (in transmission) of the crystalline form ¾ of N-[5-(3-imidazol-l -yl-4-methanesulfonyl- phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate tetrahydrate or pentahydrate
Angle d value Intensity %
2Theta ° Angstrom %
5.6 15.776 62
7.0 12.628 63
8.8 10.036 53
1 1 .4 7.769 67
13.8 6.428 49
19.1 4.637 64
21 .1 4.215 70
21 .3 4.162 77
24.4 3.644 59
25.0 3.557 44
25.4 3.508 39
27.1 3.293 32
29.1 3.065 38
30.5 2.933 100
DSC-methods
Instrument: Perkin Elmer DSC7
Temperature rang 30-300°C
Scan rate: 5°C/min, 10°C/min, 20°C/min
Nitrogen flow: 20 ml/min Form A - Figure 2
Melting onset temperature: 261.4°C
Peak temperature: 270.0°C
Melting enthalpy: 187.8J/g TG-method
Instrument: Mettler TGA851e
Temperature range: 30-300°C
Scan rate: 5°C/min, 10°C/min, 20°C/min
Nitrogen flow: 50 ml/min
IR-method
Instrument: FT-IR Bruker Vertex 70
Detector: TGS
Mode: Transmission
Scan range: 4000 cm-1 - 400 cm-1
Technique: Nujol
Table 7: The key absorbances for the crystalline form A of N-[5-(3-imidazol-l -yl-4- methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate - Figure 4:
Wavenumber (cm 1) Assignment
3146, 31 19 v N-H amide incl. v C-H of imidazole ring
3080-3030 v C-H aromatic
2925, 2584 v C-H aliphatic incl. Nujol
About 2500 v N-H+
1691 v C=0 of secondary amide
1599, 1575, 1547 v C=C/v C=N of aromatic and imidazole ring incl. δ NH
1456/1376 δ CH aliphatic incl. Nujol
1319, 1 166, 1 150 v R-S02-R
1235, 1043 HO-SO3 " (sulfate)
852, 789 Out of plane δ-CH substituted aromatic heterocyclic ring v = stretching vibration
δ = deformation vibration
Raman-method
Instrument: FT-Raman Bruker RFS100-S
Detector: Ge-Detector
Mode: Reflection
Scan range: 3500 cm-1 - 50 cm-1
Laser intensity: 150 mW Biological assays
1 Determination of enzymatic PI3K alpha, PI3Kbeta, PI3Kgamma and PI3K delta isoform inhibition
1.1 Generation of gene constructs, protein expression and purification
For the enzymatic assays, the preparation of PI3K gene constructs, protein expression and purification for HTS are described in WO2012/004299. 1.2 Biochemical assays for PI3Kalpha, PI3Kbeta (Kinase-Glo format)
The efficacy of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2- yl]-acetamide sulfate as PI3 kinase inhibitor can be demonstrated as follows:
The kinase reaction is performed in a final volume of 50 μΐ per well of a half area
COSTAR, 96 well plate. The final concentrations of ATP and phosphatidyl inositol in the assay are 5 μΜ and 6 μg/mL, respectively. The reaction is started by the addition of PI3 kinase, e.g. PI3 kinase a. pllOa. The components of the assay are added per well as follows:
• 10 μΐ test compound in 5% DMSO per well in columns 2-1.
• Total activity is determined by addition 10 μΐ of 5% vol/vol DMSO in the first 4
wells of column 1 and the last 4 wells of column 12.
• The background is determined by addition of 10 μΜ control compound to the last 4 wells of column 1 and the first 4 wells of column 12.
• 2 mL 'Assay mix' are prepared per plate:
1.912 mL of HEPES assay buffer 8.33 μΐ of 3 mM stock of ATP giving a final concentration of 5 μΜ per well
1 μΐ of [33P]ATP on the activity date giving 0.05 μθί per well
30 μΐ of 1 mg/mL PI stock giving a final concentration of 6 μg/mL per well 5 μΐ of 1 M stock MgC^ giving a final concentration of 1 mM per well
• 20 μΐ of the assay mix are added per well.
• 2 mL 'Enzyme mix' are prepared per plate (x μΐ PI3 kinase pi 10a in 2 mL of kinase buffer). The 'Enzyme mix' is kept on ice during addition to the assay plates. · 20 μΐ 'Enzyme mix' are added/well to start the reaction.
• The plate is then incubated at room temperature for 90 minutes.
• The reaction is terminated by the addition of 50 μΐ WGA-SPA bead (wheat germ agglutinin-coated Scintillation Proximity Assay beads) suspension per well.
• The assay plate is sealed using TopSeal-S (heat seal for polystyrene microplates, PerkinElmer LAS [Deutschland] GmbH, Rodgau, Germany) and incubated at room temperature for at least 60 minutes.
• The assay plate is then centrifuged at 1500 rpm for 2 minutes using the Jouan bench top centrifuge (Jouan Inc., Nantes, France).
• The assay plate is counted using a Packard TopCount, each well being counted for 20 seconds.
* The volume of enzyme is dependent on the enzymatic activity of the batch in use.
In a more preferred assay, the kinase reaction is performed in a final volume of 10 μΐ per well of a low volume non-binding CORNING, 384 well black plate (Cat. No. #3676). The final concentrations of ATP and phosphatidyl inositol (PI) in the assay are 1 μΜ and 10 μg/mL, respectively. The reaction is started by the addition of ATP.
The components of the assay are added per well as follows:
50 nl test compounds in 90% DMSO per well, in columns 1-20, 8 concentrations (1/3 and 1/3.33 serial dilution step) in single.
• Low control: 50 nl of 90% DMSO in half the wells of columns 23-24 (0.45% in final).
• High control: 50 nl of reference compound (e.g. compound of Example 7 in WO 2006/122806) in the other half of columns 23-24 (2.5 μΜ in final). • Standard: 50 nl of reference compound as just mentioned diluted as the test compounds in columns 21 -22.
• 20 mL 'buffer' are prepared per assay :
200 μΐ of 1M TRIS HC1 pH7.5 (10 mM in final)
60 μΐ of 1M MgCl2 (3 mM in final)
500 μΐ of 2M NaCl (50 mM in final)
100 μΐ of 10% CHAPS (0.05% in final)
200 μΐ of lOOmM DTT (ImM in final)
18.94 mL of nanopure water
· 10 mL 'ΡΓ are prepared per assay :
200 μΐ of 1 mg/mL 1-alpha-Phosphatidylinositol (Liver Bovine, Avanti Polar Lipids Cat. No. 840042C MW=909.12) prepared in 3% OctylGlucoside (10 μg/mL in final)
9.8 mL of 'buffer'
· 10 mL 'ATP' are prepared per assay :
6.7 μΐ of 3 mM stock of ATP giving a final concentration of 1 μΜ per well
10 mL of 'buffer'
• 2.5 mL of each PI3K construct are prepared per assay in 'ΡΓ with the following final concentration :
10 nM PI3K alfa EMV B 1075
25 nM beta EMV BV949
• 5 μΐ of 'PI/PI3K' are added per well.
· 5 μΐ 'ATP' are added per well to start the reaction.
• The plates are then incubated at room temperature for 60 minutes.
• The reaction is terminated by the addition of 10 μΐ Kinase-Glo (Promega Cat. No.
#6714).
• The assay plates are read after 10 minutes in Synergy 2 reader (BioTek, Vermont USA) with an integration time of 100 milliseconds and sensitivity set to 191. • Output : The High control is around 60Ό00 counts and the Low control is 30Ό00 or lower
• This luminescence assay gives a useful Z' ratio between 0.4 and 0.7
The Z' value is a universal measurement of the robustness of an assay. A Z' between 0.5 and 1.0 is considered an excellent assay.
1.3 Biochemical assays for PI3Kdelta, PI3Kgamma (Adapta format)
The TR-FRET Adapta™ Universal Kinase Assay Kit was purchased from Invitrogen Corporation (Carlsbad/CA, USA) (Cat. No. PV5099). The kit contains the following reagents: Adapta Eu-anti-ADP Antibody (Europium labeled anti-ADP antibody in HEPES buffered saline, Cat. No. PV5097), Alexa Fluor® 647-labeled ADP tracer (Alexa Fluor® 647-labeled ADP tracer in HEPES buffered saline, Cat. No. PV5098), proprietary TR-FRET dilution buffer pH 7.5 (Cat. No. PV3574).
PIK3CD substrate Phosphatidylinositol was obtained from Invitrogen (vesicules consisting of 2 mM PI in 50mM HEPES pH7.5; Cat. No. PV5371). PIK3CG substrate
Phosphatidylinositol-4,5-bisphosphate (PIP(4,5)2 was obtained from Invitrogen (PIP2:PS large unilamellar vesicules consisting of ImM PIP2: 19mM PS in 50mM HEPES pH7.5, 3mM MgC12, ImM EGTA; Cat. No. PV5100).
Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) is a technology based on energy transfer between two adjacent dyes, from an excited electron in one dye (the donor) to an electron of an adjacent dye (the acceptor) through resonance, then released as a photon. This energy transfer is detected by an increase in the fluorescence emission of the acceptor, and a decrease in the fluorescence emission of the donor. TR-FRET assays for protein kinases use a long-lifetime lanthanide Terbium or Europium chelates as the donor species which overcome interference from compound autofluorescence or light scatter from precipitated compounds, by introducing a delay after excitation by a flashlamp excitation source. Results are often expressed as a ratio of the intensities of the acceptor and donor fluorophores. The ratiometric nature of such a value corrects for differences in assay volumes between wells, as well as corrects for quenching effects due to colored compounds. The Adapta™ assay can be divided into two phases: a kinase reaction phase and an ADP detection phase. In the kinase reaction phase, all kinase reaction components are added to the well and the reaction is allowed to incubate for a set period of time specific for each kinase. After the reaction, a detection solution of Eu-labeled anti-ADP antibody, Alexa Fluor® 647- labeled ADP tracer, and EDTA (to stop the kinase reaction) are added to the assay well. ADP formed by the kinase reaction will displace the Alexa Fluor® 647-labeled ADP tracer from the antibody, resulting in a decrease in TR-FRET signal. In the presence of an inhibitor, the amount of ADP formed by the kinase reaction is reduced, and the resulting intact antibody- tracer interaction maintains a high TR-FRET signal. In the Adapta™ assay, the donor (Europium-anti-ADP antibody) is excited at 340nm and will transfer its energy to the acceptor (Alexa Fluor® 647-labeled ADP tracer). The emission from the Alexa Fluor® 647 can be monitored with a filter centered at 665 nm because it is located between the emission peaks of the donor, which is measured at 615/620 nm.
50 nL of compound dilutions were dispensed onto white 384-well small volume polystyrene plate as described in section 2.2. Then 5 μΕ of PBKgamma and PBKdelta and lipid substrate (PI or PIP2:PS) followed by 5 μΕ of ATP (final assay volume 10 μΕ) are incubated at RT. The standard reaction buffer for the Adapta™ TR-FRET assay contained lOmM Tris-HCl pH 7.5, 3mM MgC12, 50mM NaCl, ImM DTT, 0.05% CHAPS. Reactions were stopped with 5 μΕ of a mixture of EDTA containing the Eu-labeled anti-ADP antibody and the Alexa Fluor® 647-labeled ADP tracer in TR-FRET dilution buffer (proprietary to IVG). Plates are read 15 to 60 mins later in a Synergy2 reader using an integration time of 0.4 seconds and a delay of 0.05 seconds. Control for the 100% inhibition of the kinase reaction was performed by replacing the PI3K by the standard reaction buffer. The control for the 0% inhibition was given by the solvent vehicle of the compounds (90% DMSO in H20).
Data are analyzed using Excel fit software or Graphpad Prism. EC50 values were derived by fitting a sigmoidal dose-response curve to a plot of assay readout over inhibitor
concentration. All fits were performed with the program XLfit4 (ID Business Solutions, Guildford, UK). Determination of EC50 values of the percentage inhibition of each compound at 8 concentrations (usually 10, 3.0, 1.0, 0.3, 0.1, 0.030, 0.010 and 0.003 μΜ) n=2 were derived by fitting a sigmoidal dose-response curve to a plot of assay readout over inhibitor concentration. All fits were performed with the program XLfit4 (ID Business Solutions, Guildford, UK). 1.4 Biological in vitro data
Table 8: Data from enzymatic assay
Figure imgf000050_0001
1.5. Collagen-induced arthritis (CIA) in mice
Naive male DBA/1 mice (Janvier, initially 10-12 weeks of age, catalogue no. MA515) were assigned into several groups, thereof one vehicle group (N = 8 -10), three N-[5-(3-imidazol- l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate treatment groups (N = 8-9) and one dexamethasone positive control group (N=6).
50 mg of mycobacterium tuberculosis (Mt; H37RA, 231141 , lot 3262349, Difco, Detroit,
USA) were mixed on ice with 9.8 ml of Freund's complete adjuvant (FCA; H37RA, 231131, lot 3136596, Difco, Detroit, USA) and thoroughly shaken (= solution A). Three ml of bovine collagen solution aliquots (5 mg/ml; Dr. L. Joosten, University of Nijmegen, the
Netherlands) were well mixed on ice with 4.5 ml of sterile PBS (Sigma P-4417, 1 tab in 200 ml of distilled water; sterilized via Acrodisc, 0.2 μιτι, Pall) (= solution B). Some 6.5 ml of solution A was filled in a sterile 20 ml glass syringe, thereafter 6.5 ml of solution B were injected with an Omnifix syringe (10 ml, Braun & Micro lance, 27G, ¾, 0.4x19 N'20) into solution A. Subsequently, a 3-way valve (Edwards Lifesciences, V540A69B, lot U02C2104) was connected to the glass syringe and a second sterile glass syringe was connected to the valve. The suspension was squeezed through the valve back and forth from one syringe to the other about 40 times for intensive emulsification, the whole process being performed on ice. During the complete immunization process (see below), the emulsion was kept on 4 °C. The mice were anaesthetized by s.c. injection of a sterile filtrated mixture of 0.2 ml anaesthetic (ketamine 1.03 mg/mouse + xylazine 0.21 mg/mouse in water). Upon narcosis, the root of the tail of each mouse was shaved and subsequently, 0.1 ml of the collagen- emulsion per mouse (containing 100 μg of collagen) was injected i.d. into the base of the tail. A second injection of collagen-emulsion was given i.p. on day 21 after the first immunization (= booster).
Prophylactic treatment in mouse CIA
N-[5-(3-Imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate was suspended in 10 ml/kg of vehicle (0.5% methylcellulose) and was administered orally by gavage at a dose of 2x 10 mg/kg/day, given to 12 mice, starting at day 7 after immunization and continuing until day 43. A mouse control group, receiving the vehicle alone, was included in the study.
N-[5-(3-Imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate inhibited paw swelling at a dose of 2x 10 mg/kg/day when administered prophy tactically in the CIA experiment. This inhibition was statistically significant starting at day 30 after immunization (= day 23 of treatment) and continued until termination on day 43 after immunization
Table 9: Inhibition (-% vs vehicle control)of paw swelling (scores) in CIA mice treated with 2x10 mg/kg/day of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4-m
acetamide sulfate prophylactically
Days after treatment start 14 16 18 21 23 25 29 32 36
Days after immunization 21 23 25 28 30 32 36 39 43
2x10 mg kg/day:
Inhibition of swelling in % -43 -54 -45 -71 -69 -61 -62 -52 -47
Significance (Punnet 2-sided test) ns ns Ns ns * * ** * *
1.6. Rat collagen-induced arthritis in vivo (therapeutic dose-response study: swelling of hind paws)
N-[5-(3-Imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate was investigated in the collagen-induced arthritis model (CIA) in the rat (WAGxBUF/Fl strain) in a therapeutic protocol. The rats were immunized with bovine collagen type II and developed an arthritic-like disease (CIA), manifested in swelling of the hind paws and histological changes. The compound was dosed p.o. twice daily by gavage at the peak of the hind paw swelling, at doses of 2 x 3, 2 x 10, 2 x 30 and 2 x 100 mg/kg per day for up to 14 days. Vehicle control animals, receiving only the solvent methylcellulose 0.5% (2 x 5 ml/kg per day), were included in the study. Swelling of the hind paws and body weight (both during the experimental course) served as parameters for the assessment of effects.
N-[5-(3-Imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate showed marked, dose-dependent and statistically significant inhibition of the swelling as of day 5 after start of therapeutic dosing until the end of the study on day 14 of dosing. AUC0- 14d was reduced by 23, 48, 47 and 81 %, respectively, in the four dosing groups. The body weight course was normal for almost all groups, except for the highest dosing group, 2x 100 mg/kg/day, where the experiment was terminated prematurely due to loss of weight of the rats.
Table 10 Inhibition (-%vs vehicle control) of paw swelling (scores) in CIA rats treated with 2x3, 2x10, 2x30 or 2x100 mg/kg/day of N-[5-(3-Imidazol-l-yl-4-methanesulfonyl- phenyl)-4-methyl-thiazol-2-yl] -acetamide sulfate
Days after treatment start 3 5 7 10 12 14 0-14 (AUC)
Days after immunization 20 22 24 27 29 31 17-31
2x3 mg/kg/day:
Inhibition of swelling in % -16.9 -15.8 -26.8 -39 -39.4 -59.4 -23
Significance (Dunnet 2-sided test) ns ns ns ns ns ns ± 11 .4
2x10 mg/kg/day:
Inhibition of swelling in % -59.8 -50.4 -59.5 -55.3 -46.4 -90.1 -48
Significance (Dunnet 2-sided test) ns ns ns ns ns ns ± 10.7
2x30 mg/kg/day:
Inhibition of swelling in % -67.3 -83.2 -66.9 -31.8 -37.1 -21 .1 -47
Significance (Dunnet 2-sided test) ns ** ns ns ns ns ± 14.9
2x100 mg/kg/d:
Inhibition of swelling in % -81.6 -89.3 -96.8 -127 n/a n/a -81 (0-1 Od) Significance (Dunnet 2-sided test) ** *** *** *** ± 6.7 1.7. Serum-transfer induced arthritis (KRN) in mice
Naive male BALB/c mice (Charier River WIGA, initially 13-15 weeks of age, catalogue no. MA312, order no. 61011, animal ID 63457) were assigned into three groups, thereof one vehicle group and two treatment groups (N = 7 each).
The mice were anaesthetized by s.c. injection of a sterile filtrated mixture of 0.2 ml anaesthetic (ketamine 1.03 mg/mouse + xylazine 0.21 mg/mouse). Subsequently, serum from K/BxN mice (pool, received from GNF, San Diego, CA, USA) was injected i.p. to these recipient mice (250 μΐ per mouse).
Prophylactic treatment in mouse KRN
Daily dosing of 2x 10 and 2x 50 mg/kg of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)- 4-methyl-thiazol-2-yl]-acetamide sulfate was done p.o. by gavage starting at the day of serum transfer (= day 0, prophylactic protocol) with each 10 ml/kg of the formulation of N-[5-(3- imidazol-1 -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate in methylcellulose (0.5%). Dosing was continued up to day 9 after serum transfer.
N-[5-(3-Imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide sulfate delayed the onset of swelling in the KRN mice, when administered at the day of serum transfer. This effect significantly persisted for 3-4 days, thereafter the swelling was not statistically significantly different from the vehicle control animals
Table 11 : Inhibition (-%vs vehicle control) of paw swelling (scores) in KRN mice treated with 2x10 or 2x50 mg/kg/day of N-[5-(3-imidazol-l-yl-4-methanesulfonyl-phenyl)-4- methyl-thiazol-2-yl]-acetamide sulfate prophy tactically
Days after treatment start 0 3 4 7 8 9
Days after KRN induction 0 3 4 7 8 9
2x10 mg kg/day:
Inhibition of swelling in % 0 -8 -21 -11 -8 3
Significance (Dunnet 2-sided test) - ns Ns ns ns ns
2x50 mg/kg/day:
Inhibition of swelling in % 0 -100 -61 -25 -17 -17
Significance (Dunnet 2-sided test) - ** * ns ns ns

Claims

1. A crystalline form of N-[5-(3-Imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol- 2-yl]-acetamide sulfate.
2. The crystalline form according to claim 1 comprising Form A.
3. The crystalline form according to claims 1 or 2 consisting essentially of Form A.
4. The crystalline form according to any one of claims 1 to 3, wherein said Form A is in substantially pure form.
5. The crystalline form according any one of claims 2 to 4 characterized by an x-ray powder diffraction pattern comprising four or more 2theta values selected from the group consisting of 10.5 ± 0.2, 14.2 ± 0.2, 15.4 ± 0.2, 17.4 ± 0.2, 20.2 ± 0.2, 21.0 ± 0.2, 22.1 ± 0.2, and 25.7 ± 0.2° at a temperature of about 22°C.
6. The crystalline form according to claim 5 further characterized by an x-ray powder diffraction pattern comprising five or more 2theta values selected from the group consisting of 10.5 ± 0.2, 14.2 ± 0.2, 15.4 ± 0.2, 17.4 ± 0.2, 20.2 ± 0.2, 21.0 ± 0.2, 22.1 ± 0.2, and 25.7 ± 0.2° .
7. A crystalline form of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol- 2-yl]-acetamide sulfate having a X-ray diffraction spectrum substantially the same as the X- ray powder diffraction spectrum shown in Figure 1.
8. A crystalline form of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol- 2-yl]-acetamide sulfate having a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in shown in Figure 2.
9. A crystalline form of N-[5-(3-imidazol-l -yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol- 2-yl]-acetamide sulfate having a thermo gravimetric analysis (TGA) diagram substantially the same as that shown in shown in Figure 3.
10. A pharmaceutical composition comprising the crystalline form according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier.
11. A pharmaceutical composition according to claim 10 comprising at least 90 weight % of the crystalline form A, based the weight of the composition.
12. A pharmaceutical composition according to claims 10-11 in form of a capsule.
13. A pharmaceutical composition comprising the crystalline form according to any one of claims 1 to 9 in combination with methotrexat (MTX).
14. A method of treating a disease selected from rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion; chronic autoimmune urticaria; asthma; allergic asthma; or asthma associated with allergic rhinitis comprising administration of a therapeutically acceptable amount of a crystalline form according to any one of claims 1 to 9.
15. The method according to claim 14, wherein the disease is rheumatoid arthritis (RA).
16. A crystalline form according to any one of claims 1 to 9 for use in the treatment of a disease selected from rheumatoid arthritis (RA); ankylosing spondylitis (AS); psoriasis arthritis (PsA); systemic lupus erythematosus (SLE); primary Sjogren's syndrom (pSS); ANCA-associated vasculitides such as Wegener disease, microscopic polyangiitis or Churg Strauss syndrome; ischemia reperfusion; chronic autoimmune urticaria; asthma; allergic asthma; or asthma associated with allergic rhinitis.
17. The crystalline form for use according to claim 16, wherein the disease is rheumatoid arthritis (RA).
18. A product comprising the crystalline form A of the sulfate salt of N-[5-(3-imidazol-l -yl- 4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide and methotrexat (MTX) as a combined preparation for simultaneous or sequential use in therapy.
19. A process of making Form A of N-[5-(3-Imidazol-l-yl-4-methanesulfonyl-phenyl)-4- methyl-thiazol-2-yl]-acetamide sulfate comprising the steps of dissolving N-[5-(3-imidazol- l-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide in a polar protic solvent, followed by addition of H2SO4.
PCT/IB2015/052973 2014-04-24 2015-04-23 Crystalline forms of the sulfate salt of n-[5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide WO2015162584A1 (en)

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