WO2015162584A1 - Formes cristallines du sel de sulfate de n-[5-(3-imidazol-1-yl-4-méthanesulfonyl-phényl)-4-méthyl-thiazol-2-yl]-acétamide - Google Patents

Formes cristallines du sel de sulfate de n-[5-(3-imidazol-1-yl-4-méthanesulfonyl-phényl)-4-méthyl-thiazol-2-yl]-acétamide 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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English (en)
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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

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Abstract

L'invention concerne des formes cristallines du N-[5-(3-imidazol-1-yl-4-méthanesulfonyl-phényl)-4-méthyl-thiazol-2-yl]-acétamide, se révélant utiles dans le traitement de maladies pouvant être traitées par inhibition des isoformes de la PI3K. Formule (I)
PCT/IB2015/052973 2014-04-24 2015-04-23 Formes cristallines du sel de sulfate de n-[5-(3-imidazol-1-yl-4-méthanesulfonyl-phényl)-4-méthyl-thiazol-2-yl]-acétamide WO2015162584A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2017118965A1 (fr) * 2016-02-10 2017-07-13 Novartis Ag Utilisation d'inhibiteurs de l'activité ou du rôle de pi3k pour le traitement du syndrome de sjögren primaire
EP3695840A1 (fr) * 2016-02-10 2020-08-19 Novartis AG Utilisation de leniolisib pour le traitement du syndrome de sjögren primaire
RU2749731C2 (ru) * 2016-02-10 2021-06-16 Новартис Аг Применение ингибиторов активности или функции pi3k для лечения первичного синдрома шегрена

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