WO2024200410A1 - Formes microcristallines de (r)-2-(n-[4-amino-5-(4-méthoxybenzoyl)thiazol-2-yl]-4-fluoroanilino)propanamide et leurs procédés de préparation - Google Patents

Formes microcristallines de (r)-2-(n-[4-amino-5-(4-méthoxybenzoyl)thiazol-2-yl]-4-fluoroanilino)propanamide et leurs procédés de préparation Download PDF

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Publication number
WO2024200410A1
WO2024200410A1 PCT/EP2024/058061 EP2024058061W WO2024200410A1 WO 2024200410 A1 WO2024200410 A1 WO 2024200410A1 EP 2024058061 W EP2024058061 W EP 2024058061W WO 2024200410 A1 WO2024200410 A1 WO 2024200410A1
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WO
WIPO (PCT)
Prior art keywords
thiazol
amino
methoxybenzoyl
propanamide
anilino
Prior art date
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Ceased
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PCT/EP2024/058061
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English (en)
Inventor
Michal SOWA
Lucas SCHREYER
Adrian Dobrowolski
Christoph NÜBOLDT
Giovanni Maria Maggioni
Eva LESSMANN
Kersten Matthias Gericke
Maximilian Franz Ludwig KARL
Marko UKRAINCZYK
Eoghan DELANY
Jacek ZEGLINSKI
Gary Morris
Brendan Roche
Richard MALPASS-EVANS
Ulrike RÖHN
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Deutsches Krebsforschungszentrum DKFZ
Bayer AG
Original Assignee
Deutsches Krebsforschungszentrum DKFZ
Bayer AG
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Application filed by Deutsches Krebsforschungszentrum DKFZ, Bayer AG filed Critical Deutsches Krebsforschungszentrum DKFZ
Priority to JP2025556507A priority Critical patent/JP2026511647A/ja
Priority to EP24719093.7A priority patent/EP4688760A1/fr
Priority to CN202480021576.8A priority patent/CN120957975A/zh
Publication of WO2024200410A1 publication Critical patent/WO2024200410A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • BHC 223014 FC Microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide and processes for their preparation
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, processes for their preparation, and pharmaceutical compositions comprising them.
  • APIs Active Pharmaceutical Ingredients
  • the suitability of a given particle size distribution range for pharmaceutical development of a given API depends on a variety of parameters, including but not limited to the intended route of administration and the solubility properties of the respective API (see e.g. B. Y. Shekunov et al., Pharmaceutical Research 2007, 24 (2), 203.
  • (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2- BHC 223014 FC yl]-4-fluoro-anilino)propanamide requires comminution of particles to provide good bioavailability following e.g. oral administration through sufficient solubility and dissolution rate, which correlates with the particle surface and hence also particle size.
  • Particle Size Distribution of x10 / x50 / x90: >0.3 / 1-8 / ⁇ 20 ⁇ m was chosen as the target size distribution for micronised (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide of the present invention, processes for their preparation, and pharmaceutical compositions comprising them.
  • Prior art (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide is a chemical compound known to inhibit the zeta isoform of diacylglycerol kinase (DGKzeta) and is disclosed in the International patent application PCT/EP2021/060167, published as WO 2021/214019, as Example 62.2.
  • DGKzeta diacylglycerol kinase
  • microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide of the present invention are, within the accuracy of the analytical methods used, void of amorphous material, feature particle size distributions in the desired range and show substantially improved dissolution properties as compared to macrocrystalline material of the same compound.
  • the processes for their preparation are robust, highly efficient, and deliver material of excellent chemical and enantiomeric purity.
  • the present invention covers microcrystalline forms of (R)-2- (N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide in which the presence of amorphous forms is below 15 %, and their particle size distribution is as follows: x10 is ⁇ 5 ⁇ m, x50 is ⁇ 10 ⁇ m, and x90 is ⁇ 35 ⁇ m.
  • the term “leaving group” means an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons.
  • such a leaving group is selected from the group comprising: a halogen atom, in particular a fluorine atom, a chlorine atom, a bromine atom or an iodide atom, being displaced as halide, in particular fluoride, chloride, bromide or iodide; (methylsulfonyl)oxy, [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl
  • microcrystalline refers to fully crystalline solid forms featuring a particle size distribution in the ranges of x10 / x50 / x90: ⁇ 5 / ⁇ 10 / ⁇ 35 ⁇ m, or ⁇ 3 / 10-15 / ⁇ 35 ⁇ m, or smaller, such as x10 / x50 / x90: ⁇ 5 / ⁇ 10 / ⁇ 20 ⁇ m, particularly in the ranges x10 / x50 / x90: 0.3-4 / 4-10 / 10-20 ⁇ m, 0.5-2.5 / 3-7 / 8-20 ⁇ m, 1-4 / 4-8 / 12-18 ⁇ m, 1-2 / 4-5.5 / 10-18 ⁇ m, or >0.3 / 1-8 / ⁇ 20 ⁇ m.
  • crocrystalline refers to fully crystalline solid forms featuring a particle size distribution in the range of x10 / x50 / x90: 3 / 10-15 / 35 ⁇ m, or larger.
  • C 1 -C 3 -alkyl means a linear or branched, saturated, monovalent hydrocarbon group having 1, 2 or 3 carbon atoms, e.g. a methyl, ethyl, propyl or isopropyl group.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide in which the presence of amorphous forms is below 15 %, and their particle size distribution is as follows: x10 is in the range of 0.3 to 4 ⁇ m, x50 is in the range of 4 to 10 ⁇ m, and x90 is in the range of 10 to 20 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the presence of amorphous forms is below 15 %, and their particle size distribution is as follows: x10 is in the range of 1 to 4 ⁇ m, x50 is in the range of 4 to 8 ⁇ m, and x90 is in the range of 12 to 18 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the presence of amorphous forms is below 15 %, and their particle size distribution is as follows: x10 is in the range of 0.5 to 2.5 ⁇ m, x50 is in the range of 3 to 7 ⁇ m, and x90 is in the range of 8 to 20 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the presence of amorphous forms is below 10 %, and their particle size distribution is as follows: x10 is in the range of 0.5 to 2.5 ⁇ m, x50 is in the range of 3 to 7 ⁇ m, and x90 is in the range of 8 to 20 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the presence of amorphous forms is below 10 %, and their particle size distribution is as follows: x10 is in the range of 0.3 to 4 ⁇ m, x50 is in the range of 4 to 10 ⁇ m, and x90 is in the range of 10 to 20 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the presence of amorphous forms is below 10 %, and their particle size distribution is as follows: x10 is in the range of 1 to 4 ⁇ m, x50 is in the range of 4 to 8 ⁇ m, and x90 is in the range of 12 to 18 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the enantiomeric excess is at least 95 %, the presence of amorphous forms is below 10 %, and their particle size distribution is as follows: x10 is in the range of 0.5 to 2.5 ⁇ m, x50 is in the range of 3 to 7 ⁇ m, and x90 is in the range of 8 to 20 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the enantiomeric excess is at least 95 %, the presence of amorphous forms is below 10 %, and their particle size distribution is as follows: x10 is in the range of 0.3 to 4 ⁇ m, x50 is in the range of 4 to 10 ⁇ m, and x90 is in the range of 10 to 20 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the enantiomeric excess is at least 95 %, the presence of amorphous forms is below 10 %, and their particle size distribution is as follows: x10 is in the range of 1 to 4 ⁇ m, x50 is in the range of 4 to 8 ⁇ m, and x90 is in the range of 12 to 18 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the presence of amorphous forms is below 5 %, and their particle size distribution is as follows: x10 is in the range of 0.5 to 2.5 ⁇ m, x50 is in the range of 3 to 7 ⁇ m, and x90 is in the range of 8 to 20 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the presence of amorphous forms is below 5 %, and their particle size distribution is as follows: x10 is in the range of 0.3 to 4 ⁇ m, x50 is in the range of 4 to 10 ⁇ m, and x90 is in the range of 10 to 20 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the presence of amorphous forms is below 5 %, and their particle size distribution is as follows: x10 is in the range of 1 to 4 ⁇ m, x50 is in the range of 4 to 8 ⁇ m, and x90 is in the range of 12 to 18 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the enantiomeric excess is at least 98 %, the presence of amorphous forms is below 5 %, and their particle size distribution is as follows: x10 is in the range of 0.5 to 2.5 ⁇ m, x50 is in the range of 3 to 7 ⁇ m, and x90 is in the range of 8 to 20 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the enantiomeric excess is at least 98 %, the presence of amorphous forms is below 5 %, and their particle size distribution is as follows: x10 is in the range of 0.3 to 4 ⁇ m, x50 is in the range of 4 to 10 ⁇ m, and x90 is in the range of 10 to 20 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the enantiomeric excess is at least 98 %, the presence of amorphous forms is below 5 %, and their particle size distribution is as follows: x10 is in the range of 1 to 4 ⁇ m, x50 is in the range of 4 to 8 ⁇ m, and x90 is in the range of 12 to 18 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the enantiomeric excess is at least 99 %, the presence of amorphous forms is below 5 %, and their particle size distribution is as follows: x10 is in the range of 1 to 2 ⁇ m, x50 is in the range of 4 to 5.5 ⁇ m, and x90 is in the range of 10 to 18 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the enantiomeric excess is at least 99 %, the presence of amorphous forms is below 5 %, and their particle size distribution is as follows: x10 is in the range of 1 to 4 ⁇ m, x50 is in the range of 4 to 8 ⁇ m, and x90 is in the range of 12 to 18 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the presence of amorphous forms is below 2.5 %, and their particle size distribution is as follows: x10 is in the range of 0.5 to 2.5 ⁇ m, x50 is in the range of 3 to 7 ⁇ m, and x90 is in the range of 8 to 20 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the presence of amorphous forms is below 2.5 %, and their particle size distribution is as follows: x10 is in the range of 0.3 to 4 ⁇ m, x50 is in the range of 4 to 10 ⁇ m, and x90 is in the range of 10 to 20 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the presence of amorphous forms is below 2.5 %, and their particle size distribution is as follows: x10 is in the range of 1 to 4 ⁇ m, x50 is in the range of 4 to 8 ⁇ m, and x90 is in the range of 12 to 18 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the presence of amorphous forms is below the detection limits of differential scanning calorimetry, and their particle size distribution is as follows: x10 is in the range of 1 to 2 ⁇ m, x50 is in the range of 4 to 5.5 ⁇ m, and x90 is in the range of 10 to 18 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the presence of amorphous forms is below the detection limits of differential scanning calorimetry, and their particle size distribution is as follows: x10 is in the range of 1 to 4 ⁇ m, x50 is in the range of 4 to 8 ⁇ m, and x90 is in the range of 12 to 18 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which BHC 223014 FC the presence of amorphous forms is below the detection limits of XRPD, and their particle size distribution is as follows: x10 is in the range of 1 to 2 ⁇ m, x50 is in the range of 4 to 5.5 ⁇ m, and x90 is in the range of 10 to 18 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the presence of amorphous forms is below the detection limits of XRPD, and their particle size distribution is as follows: x10 is in the range of 1 to 4 ⁇ m, x50 is in the range of 4 to 8 ⁇ m, and x90 is in the range of 12 to 18 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the presence of amorphous forms is below the detection limits of differential scanning calorimetry according to method DSC1, and their particle size distribution as determined according to method PSD2a is as follows: x10 is in the range of 1 to 2 ⁇ m, x50 is in the range of 4 to 5.5 ⁇ m, and x90 is in the range of 10 to 18 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the presence of amorphous forms is below the detection limits of differential scanning calorimetry according to method DSC1, and their particle size distribution as determined according to method PSD4 is as follows: x10 is in the range of 1 to 4 ⁇ m, x50 is in the range of 4 to 8 ⁇ m, and x90 is in the range of 12 to 18 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which BHC 223014 FC the presence of amorphous forms is below the detection limits of XRPD according to method XRPD1, and their particle size distribution as determined according to method PSD2a is as follows: x10 is in the range of 1 to 2 ⁇ m, x50 is in the range of 4 to 5.5 ⁇ m, and x90 is in the range of 10 to 18 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the presence of amorphous forms is below the detection limits of XRPD according to method XRPD1, and their particle size distribution as determined according to method PSD4 is as follows: x10 is in the range of 1 to 4 ⁇ m, x50 is in the range of 4 to 8 ⁇ m, and x90 is in the range of 12 to 18 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the enantiomeric excess is at least 95 %, the presence of amorphous forms is below 10 %, and their particle size distribution as determined according to method PSD2a is as follows: x10 is in the range of 0.5 to 2.5 ⁇ m, x50 is in the range of 3 to 7 ⁇ m, and x90 is in the range of 8 to 20 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the enantiomeric excess is at least 95 %, the presence of amorphous forms is below 10 %, BHC 223014 FC and their particle size distribution as determined according to method PSD4 is as follows: x10 is in the range of 0.3 to 4 ⁇ m, x50 is in the range of 4 to 10 ⁇ m, and x90 is in the range of 10 to 20 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the enantiomeric excess is at least 95 %, the presence of amorphous forms is below 10 %, and their particle size distribution as determined according to method PSD4 is as follows: x10 is in the range of 1 to 4 ⁇ m, x50 is in the range of 4 to 8 ⁇ m, and x90 is in the range of 12 to 18 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the presence of amorphous forms is below 5 %, and their particle size distribution as determined according to method PSD2a is as follows: x10 is in the range of 0.5 to 2.5 ⁇ m, x50 is in the range of 3 to 7 ⁇ m, and x90 is in the range of 8 to 20 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the presence of amorphous forms is below 5 %, BHC 223014 FC and their particle size distribution as determined according to method PSD4 is as follows: x10 is in the range of 1 to 4 ⁇ m, x50 is in the range of 4 to 8 ⁇ m, and x90 is in the range of 12 to 18 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the enantiomeric excess is at least 98 %, the presence of amorphous forms is below 5 %, and their particle size distribution as determined according to method PSD2a is as follows: x10 is in the range of 0.5 to 2.5 ⁇ m, x50 is in the range of 3 to 7 ⁇ m, and x90 is in the range of 8 to 20 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the enantiomeric excess is at least 98 %, the presence of amorphous forms is below 5 %, and their particle size distribution as determined according to method PSD4 is as follows: x10 is in the range of 0.3 to 4 ⁇ m, x50 is in the range of 4 to 10 ⁇ m, and x90 is in the range of 10 to 20 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the enantiomeric excess is at least 98 %, the presence of amorphous forms is below 5 %, and their particle size distribution as determined according to method PSD4 is as follows: x10 is in the range of 1 to 4 ⁇ m, x50 is in the range of 4 to 8 ⁇ m, and x90 is in the range of 12 to 18 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the enantiomeric excess is at least 99 %, the presence of amorphous forms is below 5 %, and their particle size distribution as determined according to method PSD2a is as follows: x10 is in the range of 1 to 2 ⁇ m, x50 is in the range of 4 to 5.5 ⁇ m, and x90 is in the range of 10 to 18 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the enantiomeric excess is at least 99 %, the presence of amorphous forms is below 5 %, and their particle size distribution as determined according to method PSD4 is as follows: x10 is in the range of 1 to 4 ⁇ m, x50 is in the range of 4 to 8 ⁇ m, and x90 is in the range of 12 to 18 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the presence of amorphous forms is below 2.5 %, and their particle size distribution as determined according to method PSD2a is as follows: x10 is in the range of 0.5 to 2.5 ⁇ m, x50 is in the range of 3 to 7 ⁇ m, and x90 is in the range of 8 to 20 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the presence of amorphous forms is below 2.5 %, and their particle size distribution as determined according to method PSD4 is as follows: x10 is in the range of 0.3 to 4 ⁇ m, x50 is in the range of 4 to 10 ⁇ m, and x90 is in the range of 10 to 20 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the presence of amorphous forms is below 2.5 %, and their particle size distribution as determined according to method PSD4 is as follows: x10 is in the range of 1 to 4 ⁇ m, x50 is in the range of 4 to 8 ⁇ m, and x90 is in the range of 12 to 18 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which their particle size distribution as determined according to method PSD2a is as follows: x10 is in the range of 1 to 2 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which their particle size distribution as determined according to method PSD2a is as follows: x50 is in the range of 4 to 5.5 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which their particle size distribution as determined according to method PSD4 is as follows: x50 is in the range of 4 to 8 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which their particle size distribution as determined according to method PSD2a is as follows: x90 is in the range of 10 to 18 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which their particle size distribution as determined according to method PSD4 is as follows: x90 is in the range of 12 to 18 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which their particle size distribution as determined according to method PSD2a is as follows: x10 is in the range of 1 to 2 ⁇ m, x50 is in the range of 4 to 5.5 ⁇ m, and x90 is in the range of 10 to 18 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which their particle size distribution as determined according to method PSD4 is as follows: x10 is in the range of 1 to 4 ⁇ m, x50 is in the range of 4 to 8 ⁇ m, and x90 is in the range of 12 to 18 ⁇ m.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the presence of amorphous forms is below 15 %. In accordance with a further embodiment of the first aspect, the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the presence of amorphous forms is below 10 %.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the presence of amorphous forms is below 5 %.
  • BHC 223014 FC in accordance with a further embodiment of the first aspect, covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the presence of amorphous forms is below 2.5 %.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the presence of amorphous forms is below the detection limits of differential scanning calorimetry.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the presence of amorphous forms is below the detection limits of XRPD.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the presence of amorphous forms is below the detection limits of differential scanning calorimetry according to method DSC1.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the presence of amorphous forms is below the detection limits of XRPD according to method XRPD1.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide has an enantiomeric excess of at least 99 %.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide has an enantiomeric excess of at least 98 %.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide has an enantiomeric excess of at least 95 %.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide has an enantiomeric excess of at least 90 %.
  • the present invention covers combinations of two or more of the above mentioned embodiments under the heading “further embodiments of the first aspect of the present invention”.
  • the present invention covers any sub-combination within any embodiment or aspect of the present invention of microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2- yl]-4-fluoro-anilino)propanamide, processes for their preparation, and pharmaceutical compositions comprising them.
  • the present invention covers microcrystalline forms of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide of the present invention, as described in the Experimental Section herein.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, said methods comprising the steps of i. allowing an intermediate compound of formula (II) to react with an intermediate compound of formula (III) in which LG is a leaving group as defined supra, thereby giving (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, ii. dissolving the crude product resulting from step i.
  • step iii. bringing the solution resulting from step ii. together with an antisolvent, and iv. isolation and drying of the resulting precipitate, to give microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, said methods comprising the steps of i. allowing an intermediate compound of formula (II) to react with an intermediate compound of formula (III) in which LG is a leaving group as defined supra, thereby giving (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, ii.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, said methods comprising the steps of i. allowing an intermediate compound of formula (II) to react with an intermediate compound of formula (III) in which LG is a leaving group as defined supra, thereby giving (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, ii.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, said methods comprising the steps of iii. adding an optionally filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide in a dipolar aprotic and/or protic solvent to an antisolvent, and iv.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, said methods comprising the steps of i.
  • step (i) dissolving the crude product resulting from step (i) in a mixture of acetone and water in a ratio in the range of 8:1 (v/v) to 12:1 (v/v) in favour of acetone with subsequent filtering, iii. addition of the filtrate to water over a time in the range of 20 minutes and 1.5 hours, at a temperature in the range of 0°C to 20°C, and iv. isolation and drying of the resulting precipitate, to give microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, said methods comprising the steps of i.
  • step (i) dissolving the crude product resulting from step (i) in a mixture of acetone and water in a ratio in the range of 8:1 (v/v) to 12:1 (v/v) in favour of acetone with subsequent filtering, iii. addition of the filtrate to water over a time range of 30 minutes and 1 hour, at a temperature in the range of 4°C to 10°C, and iv. isolation and drying of the resulting precipitate, to give microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, said methods comprising the steps of i.
  • step (i) dissolving the crude product resulting from step (i) in a mixture of acetone and water in a ratio in the range of 8:1(v/v) to 12:1 (v/v) in favour of acetone with subsequent filtering, iii. addition of the filtrate to water over a time range of 30 minutes and 1 hour, at a temperature in the range of 4°C to 10°C, and iv. isolation and drying of the resulting precipitate, to give microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, said methods comprising the steps of iii.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which their particle size distribution is as follows: x10 is in the range of 1 to 2 ⁇ m.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which their particle size distribution is as follows: x50 is in the range of 4 to 5.5 ⁇ m.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which their particle size distribution is as follows: x50 is in the range of 4 to 8 ⁇ m.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which their particle size distribution is as follows: x90 is in the range of 10 to 18 ⁇ m.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which their particle size distribution is as follows: x10 is in the range of 1 to 2 ⁇ m, x50 is in the range of 4 to 5.5 ⁇ m, and x90 is in the range of 10 to 18 ⁇ m.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which their particle size distribution is as follows: x10 is in the range of 1 to 4 ⁇ m, x50 is in the range of 4 to 8 ⁇ m, and x90 is in the range of 12 to 18 ⁇ m.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which their particle size distribution as determined according to method PSD2a is as follows: x50 is in the range of 4 to 5.5 ⁇ m.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which their particle size distribution as determined according to method PSD4 is as follows: x50 is in the range of 4 to 8 ⁇ m.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which their particle size distribution as determined according to method PSD2a is as follows: x90 is in the range of 10 to 18 ⁇ m.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which their particle size distribution as determined according to method PSD4 is as follows: x90 is in the range of 12 to 18 ⁇ m.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which their particle size distribution as determined according to method PSD2a is as follows: x10 is in the range of 1 to 2 ⁇ m, x50 is in the range of 4 to 5.5 ⁇ m, and x90 is in the range of 10 to 18 ⁇ m.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which their particle size distribution as determined according to method PSD4 is as follows: x10 is in the range of 0.3 to 4 ⁇ m, x50 is in the range of 4 to 10 ⁇ m, and x90 is in the range of 10 to 20 ⁇ m.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which their particle size distribution as determined according to method PSD4 is as follows: x10 is in the range of 1 to 4 ⁇ m, x50 is in the range of 4 to 8 ⁇ m, and x90 is in the range of 12 to 18 ⁇ m.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the presence of amorphous forms is below 15 %.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which BHC 223014 FC the presence of amorphous forms is below 10 %.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the presence of amorphous forms is below 5 %.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the presence of amorphous forms is below 2.5 %.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the presence of amorphous forms is below the detection limits of differential scanning calorimetry.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the presence of amorphous forms is below the detection limits of XRPD.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the presence of amorphous forms is below the detection limits of differential scanning calorimetry according to method DSC1.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which BHC 223014 FC the presence of amorphous forms is below the detection limits of XRPD according to method XRPD1.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide has an enantiomeric excess of at least 99 %.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide has an enantiomeric excess of at least 98 %.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide has an enantiomeric excess of at least 95 %.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide has an enantiomeric excess of at least 90 %.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which BHC 223014 FC the leaving group LG in step i.
  • ⁇ is a chlorine atom, a bromine atom or an iodine atom, or a group selected from (methylsulfonyl)oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy, and [(4-methoxyphenyl)sulfonyl]oxy.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the leaving group LG in step i. is a chlorine atom, a bromine atom or an iodine atom, or a group selected from (methylsulfonyl)oxy, (phenylsulfonyl)oxy and [(4-methylphenyl)sulfonyl]oxy.
  • the leaving group LG in step i. is a chlorine atom, a bromine atom or an iodine atom, or a group selected from (methylsulfonyl)oxy, (phenylsulfonyl)oxy and [(4-methylphenyl)sulfonyl]oxy.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the leaving group LG in step i. is a chlorine atom.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the leaving group LG in step i.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the leaving group LG in step i. is a bromine atom or a [(4-methylphenyl)sulfonyl]oxy group.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the leaving group LG in step i. is a bromine atom.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which BHC 223014 FC step i.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step i. is carried out in the presence of a base selected from an alkali carbonate, an alkali bicarbonate and an alkali phosphate.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step i. is carried out in the presence of at least 1 equivalent of a base selected from an alkali carbonate, an alkali bicarbonate, an alkali phosphate and N, N, N, N-tetra (C 1 -C 3 -alkyl)guanidine.
  • a base selected from an alkali carbonate, an alkali bicarbonate, an alkali phosphate and N, N, N, N-tetra (C 1 -C 3 -alkyl)guanidine.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step i. is carried out in the presence of 1.5 to 6 equivalents of a base selected from an alkali carbonate, an alkali bicarbonate, an alkali phosphate and N, N, N, N-tetra (C 1 -C 3 -alkyl)guanidine.
  • a base selected from an alkali carbonate, an alkali bicarbonate, an alkali phosphate and N, N, N, N-tetra (C 1 -C 3 -alkyl)guanidine.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step i. is carried out in the presence of 1.5 to 6 equivalents of a base selected from an alkali carbonate, an alkali bicarbonate and an alkali phosphate.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step i. is carried out in the presence of 1.5 to 6 equivalents of a base selected from an alkali carbonate selected from sodium carbonate, potassium carbonate and cesium carbonate, an alkali bicarbonate selected from sodium bicarbonate, potassium bicarbonate, and cesium BHC 223014 FC bicarbonate, and an alkali phosphate selected from sodium phosphate, potassium phosphate and cesium phosphate.
  • a base selected from an alkali carbonate selected from sodium carbonate, potassium carbonate and cesium carbonate
  • an alkali bicarbonate selected from sodium bicarbonate, potassium bicarbonate, and cesium BHC 223014 FC bicarbonate
  • an alkali phosphate selected from sodium phosphate, potassium phosphate and cesium phosphate.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step i. is carried out in the presence of a base selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate, and potassium phosphate.
  • a base selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate, and potassium phosphate.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step i. is carried out in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate, and potassium phosphate.
  • a base selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate, and potassium phosphate.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step i. is carried out in the presence of a base selected from potassium carbonate and potassium phosphate.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step i.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step i. is carried out in the presence of 1.5 to 3 equivalents of potassium phosphate.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step i. is carried out in the presence of 2 to 6 equivalents of potassium carbonate.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step i.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step i. is carried out at a temperature in the range of 20°C to 90°C.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step i. is carried out at a temperature in the range of 40°C to 80°C.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step i.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step i. is carried out at a temperature in the range of 40°C to 80°C, optionally followed by lowering the temperature to 20°C over a time in the range of up to one hour.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step i. is carried out at a temperature in the range of 50°C to 70°C, optionally followed by lowering the temperature to 20°C over a time in the range of up to one hour.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step i. is carried out at a temperature in the range of 40°C to 80°C, followed by lowering the temperature to 20°C over a time in the range of up to one hour.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step i. is carried out at a temperature in the range of 50°C to 70°C, followed by lowering the temperature to 20°C over a time in the range of up to one hour.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step i. is carried out in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methyl pyrrolidinone, acetone, and iso-propanol, or a mixture of acetone and iso-propanol.
  • a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methyl pyrrolidinone, acetone, and iso-propanol, or a mixture of acetone and iso-propanol.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step i. is carried out in a solvent selected from N,N-dimethylformamide, acetonitrile, N-methyl pyrrolidinone, acetone, and iso-propanol, or a mixture of acetone and iso-propanol in a range of 5:1 (v/v) to 1:5 (v/v).
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step i. is carried out in a solvent selected from N,N-dimethylformamide and acetonitrile.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step i. is carried out in N,N-dimethylformamide as a solvent.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step i.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step i. is carried out over a time in the range of 30 minutes to 24 hours.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step i. is carried out over a time in the range of 30 minutes to 6 hours.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step i.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step i. is carried out over a time in the range of 1 to 2 hours.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step ii. is carried out in one or more dipolar aprotic and/or polar solvent, optionally mixed with water.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step ii.
  • solvents selected from dimethylsulfoxide, N-methyl-2- pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, 1,2-dimethoxyethane, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, acetonitrile, diethylketone, methylethylketone, acetone, 1,4-dioxane and 2-methyltetrahydrofuran, optionally mixed with water.
  • solvents selected from dimethylsulfoxide, N-methyl-2- pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, 1,2-dimethoxyethane, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, acetonitrile, diethylketone, methylethylketone, acetone, 1,4
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step ii. is carried out in one or more solvents selected from 1,2-dimethoxyethane, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, acetonitrile, diethylketone, methylethylketone, acetone, 1,4-dioxane and 2-methyltetrahydrofuran, optionally mixed with water.
  • solvents selected from 1,2-dimethoxyethane, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, acetonitrile, diethylketone, methylethylketone, acetone, 1,4-dio
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step ii. is carried out in one or more solvents selected from isopropanol, tetrahydrofuran, acetonitrile, diethylketone, methylethylketone, acetone, 1,4-dioxane and 2- methyltetrahydrofuran, optionally mixed with water.
  • solvents selected from isopropanol, tetrahydrofuran, acetonitrile, diethylketone, methylethylketone, acetone, 1,4-dioxane and 2- methyltetrahydrofuran, optionally mixed with water.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step ii. is carried out in one or more solvents selected from acetonitrile, diethylketone, methylethylketone, acetone and 1,4-dioxane, optionally mixed with water.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step ii. is carried out in one or more solvents selected from acetonitrile, acetone and 1,4-dioxane, optionally mixed with water.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step ii. is carried out in a mixture of acetone and water.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step ii.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step ii. is carried out in a mixture of acetone and water in a ratio in the range of 6:1 (v/v) to 15:1 (v/v) in favour of acetone.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which BHC 223014 FC step ii. is carried out in a mixture of acetone and water in a ratio in the range of 6:1 (v/v) to 12:1 (v/v) in favour of acetone.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step ii. is carried out in a mixture of acetone and water in a ratio in the range of 8:1 (v/v) to 12:1 (v/v) in favour of acetone.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step ii. is carried out in a mixture of acetone and water in a ratio in the range of 8:1 (v/v) to 10:1 (v/v) in favour of acetone.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of the solvent and (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide employed in step ii. is in the range of 6:1 to 20:1 (w/w; solvent : compound).
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of the solvent and (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide employed in step ii. is in the range of 8:1 to 15:1 (w/w; solvent : compound).
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which BHC 223014 FC the ratio of the solvent and (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide employed in step ii. is in the range of 10:1 (w/w) to 14:1 (w/w) in favour of the solvent.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of the solvent and (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide employed in step ii. is in the range of 11:1 (w/w) to 12:1 (w/w) in favour of the solvent.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of the mixture of acetone and water and (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide employed in step ii. is in the range of 8:1 (w/w) to 15:1 (w/w) in favour of the mixture of acetone and water.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of the mixture of acetone and water and (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide employed in step ii. is in the range of 10:1 (w/w) to 14:1 (w/w) in favour of the mixture of acetone and water.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of the mixture of acetone and water and (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide employed in step ii. is in the range of 11:1 (w/w) to 12:1 (w/w) in favour of the mixture of acetone and water.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the solvent in step iii. is one or more dipolar aprotic and/or polar solvent, optionally mixed with water.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the solvent in step iii.
  • solvents selected from dimethylsulfoxide, N-methyl-2- pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, 1,2-dimethoxyethane, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, acetonitrile, diethylketone, methylethylketone, acetone, 1,4-dioxane and 2-methyltetrahydrofuran, optionally mixed with water.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the solvent in step iii. is one or more solvents selected from 1,2-dimethoxyethane, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, acetonitrile, diethylketone, methylethylketone, acetone, 1,4-dioxane and 2-methyltetrahydrofuran, optionally mixed with water.
  • the solvent in step iii. is one or more solvents selected from 1,2-dimethoxyethane, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, acetonitrile, diethylketone, methylethy
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the solvent in step iii. is one or more solvents selected from isopropanol, tetrahydrofuran, acetonitrile, diethylketone, methylethylketone, acetone, 1,4-dioxane and 2- methyltetrahydrofuran, optionally mixed with water.
  • the solvent in step iii. is one or more solvents selected from isopropanol, tetrahydrofuran, acetonitrile, diethylketone, methylethylketone, acetone, 1,4-dioxane and 2- methyltetrahydrofuran, optionally mixed with water.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the solvent in step iii. is one or more solvents selected from acetonitrile, diethylketone, methylethylketone, acetone and 1,4-dioxane, optionally mixed with water.
  • the solvent in step iii. is one or more solvents selected from acetonitrile, diethylketone, methylethylketone, acetone and 1,4-dioxane, optionally mixed with water.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the solvent in step iii. is one or more solvents selected from acetonitrile, acetone and 1,4- dioxane, optionally mixed with water.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the solvent in step iii. is a mixture of acetone and water.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the solvent in step iii.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the solvent in step iii. is a mixture of acetone and water in a ratio in the range of 6:1 (v/v) to 15:1 (v/v) in favour of acetone.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the solvent in step iii. is a mixture of acetone and water in a ratio in the range of 6:1 (v/v) to 12:1 (v/v) in favour of acetone.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the solvent in step iii. is a mixture of acetone and water in a ratio in the range of 8:1 (v/v) to 10:1 (v/v) in favour of acetone.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of the solvent and (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in the solution employed in step iii. is in the range of 6:1 to 20:1 (w/w; solvent : compound).
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of the solvent and (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in the solution employed in step iii. is in the range of 8:1 to 15:1 (w/w; solvent : compound).
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of the solvent and (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in the solution employed in step iii. is in the range of 10:1 (w/w) to 14:1 (w/w) in favour of the solvent.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of the solvent and (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in the solution employed in step iii. is in the range of 11:1 (w/w) to 12:1 (w/w) in favour of the solvent.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the antisolvent in step iii. is water, or a mixture of water with one or more organic solvents selected from the group comprising methanol, ethanol and isopropanol.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the antisolvent in step iii. is water.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the antisolvent in step iii.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide and the antisolvent in step iii. is in the range of 1:2 to 1:50 (w/w) in favour of the antisolvent.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which BHC 223014 FC the ratio of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide and the antisolvent in step iii. is in the range of 1:6 to 1:40 (w/w) in favour of the antisolvent.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide and the antisolvent in step iii. is in the range of 1:10 to 1:30 (w/w) in favour of the antisolvent.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide and the water used as an antisolvent in step iii. is in the range of 1:4 to 1:40 (w/w) in favour of the water.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide and the water used as an antisolvent in step iii. is in the range of 1:6 to 1:40 (w/w) in favour of the water.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide and the water used as an antisolvent in step iii. is in the range of 1:10 to 1:30 (w/w) in favour of the water.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of solvent employed in step ii. and the antisolvent in step iii. is in the range of 1:10 to 10:1 (v/v; solvent : antisolvent).
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of solvent employed in step ii. and the antisolvent in step iii. is in the range of 1:6 to 6:1 (v/v; solvent : antisolvent).
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of solvent employed in step ii. and the antisolvent in step iii. is in the range of 1:4 to 4:1 (v/v; solvent : antisolvent).
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of solvent employed in step ii. and the antisolvent in step iii. is in the range of 1:3 to 2:1 (v/v; solvent : antisolvent).
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of solvent employed in step ii. and the antisolvent in step iii. is in the range of 1:2 to 1:1 (v/v; solvent : antisolvent).
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of solvent used in the solution and the antisolvent in step iii. is in the range of 1:10 to 10:1 (v/v; solvent : antisolvent).
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of solvent used in the solution and the antisolvent in step iii. is in the range of 1:6 to 6:1 (v/v; solvent : antisolvent).
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of solvent used in the solution and the antisolvent in step iii. is in the range of 1:4 to 4:1 (v/v; solvent : antisolvent).
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of solvent used in the solution and the antisolvent in step iii. is in the range of 1:3 to 2:1 (v/v; solvent : antisolvent).
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of solvent used in the solution and the antisolvent in step iii. is in the range of 1:2 to 1:1 (v/v; solvent : antisolvent).
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step iii. is carried out over a time in the range of 20 minutes to 2 hours at a temperature in the range of 0°C to 20 °C.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step iii. is carried out over a time in the range of 20 minutes to 1.5 hours at a temperature in the range of 0°C to 20 °C.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step iii. is carried out over a time in the range of 30 minutes to 1 hour at a temperature in the range of 2°C to 15 °C.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step iii. is carried out over a time in the range of 30 minutes to 1 hour at a temperature in the range of 4°C to 10 °C.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step iii. is carried out over a time in the range of 30 to 45 minutes at a temperature in the range of 2°C to 15 °C.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which BHC 223014 FC step iii. is carried out over a time in the range of 35 to 40 minutes at a temperature in the range of 4°C to 10 °C.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which adding an optionally filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide in step iii. is carried out over a time in the range of 20 minutes to 2 hours at a temperature in the range of 0°C to 20 °C.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which adding an optionally filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide in step iii. is carried out over a time in the range of 20 minutes to 1.5 hours at a temperature in the range of 0°C to 20 °C.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which adding an optionally filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide in step iii. is carried out over a time in the range of 30 minutes to 1 hour at a temperature in the range of 2°C to 15 °C.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which adding a filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in step iii. is carried out over a time in the range of 30 minutes to 1 hour at a temperature in the range of 2°C to 15 °C.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which BHC 223014 FC adding an optionally filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide in step iii. is carried out over a time in the range of 30 minutes to 1 hour at a temperature in the range of 4°C to 10 °C.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which adding a filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in step iii. is carried out over a time in the range of 30 minutes to 1 hour at a temperature in the range of 4°C to 10 °C.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which adding a filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in step iii. is carried out over a time in the range of 30 to 45 minutes at a temperature in the range of 2°C to 15 °C.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which adding a filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in step iii. is carried out over a time in the range of 35 to 40 minutes at a temperature in the range of 4°C to 10 °C.
  • the present invention covers combinations of two or more of the above mentioned embodiments under the heading “further embodiments of the second aspect of the present invention”.
  • the present invention covers any sub-combination within any embodiment or aspect of the present invention of microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2- yl]-4-fluoro-anilino)propanamide, processes for their preparation, and pharmaceutical compositions comprising them.
  • BHC 223014 FC The present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino- 5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide of the present invention, said methods comprising the steps as described in the Experimental Section herein.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, said methods comprising the steps of allowing an intermediate compound of formula (II) to react with an intermediate compound of formula (III) in which LG is a leaving group as defined supra, thereby giving (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, dissolving the resulting crude product in a solvent or solvent mixture, followed by bringing the resulting solution together with an antisolvent, followed by isolation and drying of the resulting precipitate, BHC 223014 FC to give microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, said methods comprising the steps of allowing an intermediate compound of formula (II) to react with an intermediate compound of formula (III) in which LG is a leaving group as defined supra, thereby giving (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, dissolving the resulting crude product in acetone containing water in a range from 0 % to 30 % (v/v), followed by bringing the resulting solution together with water, followed by isolation and drying of the resulting precipitate, BHC 223014 FC to give microcrystalline forms of (R)-2-(N-[4-amino-5-(
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide, said methods comprising the steps of dissolving (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in a solvent or solvent mixture, followed by bringing the resulting solution together with an antisolvent, followed by isolation and drying of the resulting precipitate, to give microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, said methods comprising the steps of dissolving (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in acetone containing water in a range from 0 % to 30 % (v/v), followed by bringing the resulting solution together with water, followed by isolation and drying of the resulting precipitate, to give microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide, said methods comprising the steps of 1) allowing an intermediate compound of formula (II) BHC 223014 FC (II) to react with an intermediate compound of formula (III) in which LG is a leaving group as defined supra, thereby giving (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, 2) dissolving the crude product resulting from step 1) in a solvent, 3) creating a supersaturation, 4) adding a nanosuspension comprising further (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide, said methods comprising the steps of BHC 223014 FC 2) dissolving (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in a solvent, 3) creating a supersaturation, 4) adding a nanosuspension comprising further (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, antisolvent, at least one surfactant and at least one polymer, 5) followed by one or more of the sub-steps selected from a.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, said methods comprising the steps of 1) allowing an intermediate compound of formula (II) to react with an intermediate compound of formula (III) in which LG is a leaving group as defined supra, thereby giving BHC 223014 FC (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, 2) dissolving the crude product resulting from step 1) in a dipolar aprotic and/or protic solvent with optional filtering, 3) creating a supersaturation via one or more of the sub-steps selected from a.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, said methods comprising the steps of 2) dissolving (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in a dipolar aprotic and/or protic solvent with optional filtering, 3) creating a supersaturation via one or more of the sub-steps selected from a. cooling b.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide, said methods comprising the steps of 1) allowing an intermediate compound of formula (II) to react with an intermediate compound of formula (III) in which LG is a leaving group as defined supra, thereby giving BHC 223014 FC (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, 2) dissolving the crude product resulting from step 1) in a dipolar aprotic and/or protic solvent with optional filtering, 3) creating a supersaturation via cooling, 4) adding a nanosuspension comprising further (R)-2-(N-[4-amino-5-(4- methoxy
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide, said methods comprising the steps of 2) dissolving (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in a dipolar aprotic and/or protic solvent with optional filtering, 3) creating a supersaturation via cooling, 4) adding a nanosuspension comprising further (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, antisolvent, at least one surfactant and at least one polymer, 5) followed by a
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, said methods comprising the steps of 1) allowing an intermediate compound of formula (II) to react with an intermediate compound of formula (III) in which LG is a leaving group as defined supra, in the presence of at least 1 equivalent of a base selected from an alkali carbonate, an alkali bicarbonate and an alkali phosphate, at a temperature in the range of 20 to 80 °C, in a solvent selected from N,N-dimethylformamide, N,N- dimethylacetamide, acetonitrile, propionitrile, N-methyl pyrrolidinone, acetone, and iso-propanol, for a time in the range of 30 minutes to 24 hours, thereby giving (R)-2-(N-(N-
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, said methods comprising the steps of 2) dissolving (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in acetone containing water in the range from 10 to 30 % v/v, with optional filtering, 3) creating a supersaturation via cooling, the reduction of the temperature being in the range from 5°C to 30°C, 4) adding a nanosuspension comprising further (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, said methods comprising the steps of 1) allowing an intermediate compound of formula (II) to react with an intermediate compound of formula (III) in which LG is a bromine atom, in the presence of 1.5 to 5 equivalents of potassium phosphate, at a temperature in the range of 50 to 70 °C in acetonitrile for a time in the range of 1 to 2 hours, thereby giving (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, 2) dissolving the crude product resulting from step 1) in acetone containing water in the range from 10 to 30 % v
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, said methods comprising the steps of 2) dissolving (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in acetone containing water in the range from 10 to 30 % v/v, at a temperature in the range from 40°C to 70°C, with optional filtering, 3) creating a supersaturation via cooling, the reduction of the temperature being in the range from 15°C to 25°C, 4) adding a nanosuspension comprising further (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, said methods comprising the steps of 1) allowing an intermediate compound of formula (II) to react with an intermediate compound of formula (III) in which LG is a bromine atom, in the presence of 1.5 to 5 equivalents of potassium phosphate, at a temperature in the range of 50 to 70 °C in acetonitrile for a time in the range of 1 to 2 hours, optionally followed by lowering the temperature to 20°C over a time in the range of up to one hour, thereby giving (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, 2) dissolving the crude
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, said methods comprising the steps of 2) dissolving (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in acetone containing water in the range from 10 to 30 % v/v, at a temperature in the range from 40°C to 70°C, with optional filtering, 3) creating a supersaturation via cooling, the reduction of the temperature being in the range from 15°C to 25°C, 4) adding a nanosuspension comprising further (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which their particle size distribution is as follows: x10 is in the range of 1 to 2 ⁇ m.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which their particle size distribution is as follows: x50 is in the range of 4 to 5.5 ⁇ m.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which their particle size distribution is as follows: x50 is in the range of 4 to 8 ⁇ m.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which their particle size distribution is as follows: x90 is in the range of 10 to 18 ⁇ m.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which their particle size distribution is as follows: x10 is in the range of 1 to 2 ⁇ m, x50 is in the range of 4 to 5.5 ⁇ m, and x90 is in the range of 10 to 18 ⁇ m.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which their particle size distribution is as follows: x10 is in the range of 1 to 4 ⁇ m, x50 is in the range of 4 to 8 ⁇ m, and x90 is in the range of 12 to 18 ⁇ m.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which their particle size distribution as determined according to method PSD2a is as follows: x10 is in the range of 1 to 2 ⁇ m.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which their particle size distribution as determined according to method PSD2a is as follows: x50 is in the range of 4 to 5.5 ⁇ m.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which their particle size distribution as determined according to method PSD4 is as follows: x50 is in the range of 4 to 8 ⁇ m.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which their particle size distribution as determined according to method PSD2a is as follows: x90 is in the range of 10 to 18 ⁇ m.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which their particle size distribution as determined according to method PSD4 is as follows: x90 is in the range of 12 to 18 ⁇ m.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which their particle size distribution as determined according to method PSD2a is as follows: x10 is in the range of 1 to 2 ⁇ m, x50 is in the range of 4 to 5.5 ⁇ m, and x90 is in the range of 10 to 18 ⁇ m.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which their particle size distribution as determined according to method PSD4 is as follows: x10 is in the range of 0.3 to 4 ⁇ m, x50 is in the range of 4 to 10 ⁇ m, and x90 is in the range of 10 to 20 ⁇ m.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which their particle size distribution as determined according to method PSD4 is as follows: x10 is in the range of 1 to 4 ⁇ m, x50 is in the range of 4 to 8 ⁇ m, and x90 is in the range of 12 to 18 ⁇ m.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the presence of amorphous forms is below 15 %.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the presence of amorphous forms is below 10 %.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the presence of amorphous forms is below 5 %.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the presence of amorphous forms is below 2.5 %.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the presence of amorphous forms is below the detection limits of differential scanning calorimetry.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the presence of amorphous forms is below the detection limits of XRPD.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the presence of amorphous forms is below the detection limits of differential scanning calorimetry according to method DSC1.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the presence of amorphous forms is below the detection limits of XRPD according to method XRPD1.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide has an enantiomeric excess of at least 99 %.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide has an enantiomeric excess of at least 98 %.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide has an enantiomeric excess of at least 95 %.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide has an enantiomeric excess of at least 90 %.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the leaving group LG in step 1) is a chlorine atom, a bromine atom or an iodine atom, or a group selected from (methylsulfonyl)oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy, and [(4-methoxyphenyl)sulfonyl]oxy.
  • the leaving group LG in step 1) is a chlorine atom, a bromine atom or an iodine atom, or a group selected from (methylsulfonyl)oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the leaving group LG in step 1) is a chlorine atom, a bromine atom or an iodine atom, or a group selected from (methylsulfonyl)oxy, (phenylsulfonyl)oxy and [(4-methylphenyl)sulfonyl]oxy.
  • the leaving group LG in step 1) is a chlorine atom, a bromine atom or an iodine atom, or a group selected from (methylsulfonyl)oxy, (phenylsulfonyl)oxy and [(4-methylphenyl)sulfonyl]oxy.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the leaving group LG in step 1) is a chlorine atom.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the leaving group LG in step 1) is a [(4-methylphenyl)sulfonyl]oxy group.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which BHC 223014 FC the leaving group LG in step 1) is a bromine atom or a [(4-methylphenyl)sulfonyl]oxy group.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the leaving group LG in step 1) is a bromine atom.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 1) is carried out in the presence of a base selected from an alkali carbonate, an alkali bicarbonate, an alkali phosphate and N, N, N, N-tetra (C 1 -C 3 -alkyl)guanidine.
  • a base selected from an alkali carbonate, an alkali bicarbonate, an alkali phosphate and N, N, N, N-tetra (C 1 -C 3 -alkyl)guanidine.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 1) is carried out in the presence of a base selected from an alkali carbonate, an alkali bicarbonate and an alkali phosphate.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 1) is carried out in the presence of at least 1 equivalent of a base selected from an alkali carbonate, an alkali bicarbonate, an alkali phosphate and N, N, N, N-tetra (C 1 -C 3 -alkyl)guanidine.
  • a base selected from an alkali carbonate, an alkali bicarbonate, an alkali phosphate and N, N, N, N-tetra (C 1 -C 3 -alkyl)guanidine.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 1) is carried out in the presence of 1.5 to 6 equivalents of a base selected from an alkali carbonate, an alkali bicarbonate, an alkali phosphate and N, N, N, N-tetra (C 1 -C 3 -alkyl)guanidine.
  • a base selected from an alkali carbonate, an alkali bicarbonate, an alkali phosphate and N, N, N, N-tetra (C 1 -C 3 -alkyl)guanidine.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 1) is carried out in the presence of 1.5 to 6 equivalents of a base selected from an alkali carbonate, an alkali bicarbonate and an alkali phosphate.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 1) is carried out in the presence of 1.5 to 6 equivalents of a base selected from an alkali carbonate selected from sodium carbonate, potassium carbonate and cesium carbonate, an alkali bicarbonate selected from sodium bicarbonate, potassium bicarbonate, and cesium bicarbonate, and an alkali phosphate selected from sodium phosphate, potassium phosphate and cesium phosphate.
  • a base selected from an alkali carbonate selected from sodium carbonate, potassium carbonate and cesium carbonate
  • an alkali bicarbonate selected from sodium bicarbonate, potassium bicarbonate, and cesium bicarbonate
  • an alkali phosphate selected from sodium phosphate, potassium phosphate and cesium phosphate.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 1) is carried out in the presence of a base selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate, and potassium phosphate.
  • a base selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate, and potassium phosphate.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 1) is carried out in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate, and potassium phosphate.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 1) is carried out in the presence of a base selected from potassium carbonate and potassium phosphate.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 1) is carried out in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate and potassium phosphate.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 1) is carried out in the presence of 1.5 to 3 equivalents of potassium phosphate.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 1) is carried out in the presence of 2 to 6 equivalents of potassium carbonate.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 1) is carried out at a temperature in the range of 0°C to 100°C.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 1) is carried out at a temperature in the range of 20°C to 90°C.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 1) is carried out at a temperature in the range of 40°C to 80°C.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 1) is carried out at a temperature in the range of 50°C to 70°C.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 1) is carried out at a temperature in the range of 40°C to 80°C, optionally followed by lowering the temperature to 20°C over a time in the range of up to one hour.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 1) is carried out at a temperature in the range of 50°C to 70°C, optionally followed by lowering the temperature to 20°C over a time in the range of up to one hour.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 1) is carried out at a temperature in the range of 40°C to 80°C, followed by lowering the temperature to 20°C over a time in the range of up to one hour.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 1) is carried out at a temperature in the range of 50°C to 70°C, followed by lowering the temperature to 20°C over a time in the range of up to one hour.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which BHC 223014 FC step 1) is carried out in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methyl pyrrolidinone, acetone, and iso-propanol, or a mixture of acetone and iso-propanol.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 1) is carried out in a solvent selected from N,N-dimethylformamide, acetonitrile, N-methyl pyrrolidinone, acetone, and iso-propanol, or a mixture of acetone and iso-propanol in a range of 5:1 (v/v) to 1:5 (v/v).
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 1) is carried out in a solvent selected from N,N-dimethylformamide and acetonitrile.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 1) is carried out in N,N-dimethylformamide as a solvent.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 1) is carried out in acetonitrile as a solvent.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 1) is carried out over a time in the range of 30 minutes to 24 hours.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 1) is carried out over a time in the range of 30 minutes to 6 hours.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 1) is carried out over a time in the range of 30 minutes to 2 hours.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 1) is carried out over a time in the range of 1 to 2 hours.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 2) is carried out in one or more dipolar aprotic and/or polar solvent, optionally mixed with water.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 2) is carried out in one or more solvents selected from dimethylsulfoxide, N-methyl-2- pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, 1,2-dimethoxyethane, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, acetonitrile, diethylketone, methylethylketone, acetone, 1,4-dioxane and 2-methyltetrahydrofuran, optionally mixed with water.
  • solvents selected from dimethylsulfoxide, N-methyl-2- pyrrolidone, N,N-dimethylacetamide, N,N-dimethyl
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which BHC 223014 FC step 2) is carried out in one or more solvents selected from 1,2-dimethoxyethane, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, acetonitrile, diethylketone, methylethylketone, acetone, 1,4-dioxane and 2-methyltetrahydrofuran, optionally mixed with water.
  • solvents selected from 1,2-dimethoxyethane, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, acetonitrile, diethylketone, methylethylketone, acetone, 1,4-
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 2) is carried out in one or more solvents selected from isopropanol, tetrahydrofuran, acetonitrile, diethylketone, methylethylketone, acetone, 1,4-dioxane and 2- methyltetrahydrofuran, optionally mixed with water.
  • solvents selected from isopropanol, tetrahydrofuran, acetonitrile, diethylketone, methylethylketone, acetone, 1,4-dioxane and 2- methyltetrahydrofuran, optionally mixed with water.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 2) is carried out in one or more solvents selected from acetonitrile, diethylketone, methylethylketone, acetone and 1,4-dioxane, optionally mixed with water.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 2) is carried out in one or more solvents selected from acetonitrile, acetone and 1,4-dioxane, optionally mixed with water.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 2) is carried out in a mixture of acetone and water.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 2) is carried out in a mixture of acetone and water, the acetone containing water in the range from 0 to 50 % v/v.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 2) is carried out in a mixture of acetone and water, the acetone containing water in the range from 10 to 30 % v/v.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 2) is carried out in a mixture of acetone and water, the acetone containing water in the range from 10 to 30 % v/v, at a temperature in the range from 40°C to 70°C.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of the solvent and (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide employed in step 2) is in the range of 4:1 to 10:1 (w/w; solvent : compound).
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of the solvent and (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide employed in step 2) is in the range of 4:1 to 8:1 (w/w; solvent : compound).
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of the solvent and (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide employed in step 2) is in the range of 5:1 (w/w) to 7:1 (w/w) in favour of the solvent.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of the solvent and (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide employed in step 2) is in the range of 5.5:1 (w/w) to 6:1 (w/w) in favour of the solvent.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of the mixture of acetone and water and (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide employed in step 2) is in the range of 4:1 (w/w) to 8:1 (w/w) in favour of the mixture of acetone and water.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of the mixture of acetone and water and (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide employed in step 2) is in the range of 5:1 (w/w) to 7:1 (w/w) in favour of the mixture of acetone and water.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the ratio of the mixture of acetone and water and (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide employed in step 2) is in the range of 5.5:1 (w/w) to 6:1 (w/w) in favour of the mixture of acetone and water.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which creating of a supersaturation in step 3) is accomplished by cooling.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which creating of a supersaturation in step 3) is accomplished by adding an antisolvent.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which creating of a supersaturation in step 3) is accomplished by evaporating solvent.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which creating of a supersaturation in step 3) is accomplished by cooling, the reduction of the temperature being in the range from 5°C to 30°C.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which creating of a supersaturation in step 3) is accomplished by cooling, the reduction of the temperature being in the range from 15°C to 25°C.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which creating of a supersaturation in step 3) is accomplished by cooling, the reduction of the temperature being in the range from 5°C to 30°C, and in which the solvent is acetone containing water in the range from 10 to 30 % v/v.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which creating of a supersaturation in step 3) is accomplished by cooling, the reduction of the temperature being in the range from 15°C to 25°C, and in which the solvent is acetone containing water in the range from 10 to 30 % v/v.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- BHC 223014 FC 2-yl]-4-fluoro-anilino)propanamide, in which creating of a supersaturation in step 3) is accomplished by cooling, the reduction of the temperature being in the range from 15°C to 25°C, and in which the solvent is acetone containing water in the range from 10 to 30 % v/v.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the nanosuspension employed in step 4) comprises (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide in a range from 5 to 20 % w/w.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the antisolvent in the nanosuspension employed in step 4) is water.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the nanosuspension employed in step 4) comprises water in a range from 60 to 90 % w/w.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the nanosuspension employed in step 4) comprises at least one surfactant in a range from 0.05 to 1 % w/w.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the nanosuspension employed in step 4) contains one surfactant in a range from 0.05 to 1 % w/w.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the nanosuspension employed in step 4) contains BHC 223014 FC one surfactant in a range from 0.05 to 1 % w/w, and in which said surfactant is an alkali salt of a C8-C20–alkylsulfuric acid.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the nanosuspension employed in step 4) contains one surfactant in a range from 0.05 to 1 % w/w, and in which said surfactant is a sodium or potassium salt of a C 10 -C 16 –alkylsulfuric acid.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the nanosuspension employed in step 4) contains one surfactant in a range from 0.05 to 1 % w/w, and in which said surfactant is sodium dodecyl sulfate.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the nanosuspension employed in step 4) comprises at least two polymers, independently from each other in a range from 0.5 to 15 % w/w.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the nanosuspension employed in step 4) comprises at least two polymers, independently from each other in a range from 0.5 to 15 % w/w, in which one polymer is hydroxypropyl cellulose and one polymer is polyvinylpyrrolidone.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the nanosuspension employed in step 4) contains two polymers, independently from each other in a range from 0.5 to 15 % w/w, in which one polymer is hydroxypropyl cellulose and one polymer is polyvinylpyrrolidone.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- BHC 223014 FC 2-yl]-4-fluoro-anilino)propanamide, in which the quantity of the nanosuspension employed in step 4) is in the range of 0.1 to 20 % w/w of the supersaturated solution resulting from step 3).
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the quantity of the nanosuspension employed in step 4) is in the range of 0.25 to 10 % w/w of the supersaturated solution resulting from step 3).
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the quantity of the nanosuspension employed in step 4) is in the range of 1 to 6 % w/w of the supersaturated solution resulting from step 3).
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the quantity of the nanosuspension employed in step 4) is in the range of 2 to 4 % w/w of the supersaturated solution resulting from step 3).
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the quantity of the nanosuspension employed in step 4) is in the range of 2.5 to 3.0 % w/w of the supersaturated solution resulting from step 3).
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 5) is accomplished by cooling, followed by the addition of an antisolvent.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 5) is accomplished by cooling, followed by the addition of water.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which step 5) is accomplished by cooling, the reduction of the temperature being in the range from 5°C to 25°C, followed by the addition of water.
  • the present invention covers any sub-combination within any embodiment or aspect of the present invention of microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2- yl]-4-fluoro-anilino)propanamide, processes for their preparation, and pharmaceutical compositions comprising them.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino- 5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide of the present invention, said methods comprising the steps as described in the Experimental Section herein.
  • the present invention covers methods of preparing (R)-2-(N- [4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide said methods comprising the step of allowing an intermediate compound of formula (II) to react with an intermediate compound of formula (III) in which LG is a leaving group as defined supra, thereby giving BHC 223014 FC (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in an enantiomeric excess of at least 80 %, said methods comprising the step of allowing an intermediate compound of formula (II) to react with an intermediate compound of formula (III) in which LG is a leaving group as defined supra, thereby giving BHC 223014 FC (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide in an enantiomeric excess of at least 80 %.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in an enantiomeric excess of at least 90 %, said methods comprising the step of allowing an intermediate compound of formula (II) to react with an intermediate compound of formula (III) in which LG is a leaving group as defined supra, thereby giving (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide in an enantiomeric excess of at least 90 %.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- BHC 223014 FC anilino)propanamide in an enantiomeric excess of at least 90 %, said methods comprising the step of allowing an intermediate compound of formula (II) to react with an intermediate compound of formula (III) in which LG is a leaving group as defined supra, in the presence of at least 1 equivalent of a base selected from an alkali carbonate, an alkali bicarbonate and an alkali phosphate, at a temperature in the range of 20 to 80 °C, in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N- methyl pyrrolidinone, acetone, and iso-propanol, for a time in the range of
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide in an enantiomeric excess of at least 90 %, said methods comprising the step of BHC 223014 FC allowing an intermediate compound of formula (II) to react with an intermediate compound of formula (III) in which LG is a bromine atom, in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate and potassium phosphate, at a temperature in the range of 40 to 80 °C, in a solvent selected from N,N-dimethylformamide and acetonitrile, for a time in the range of 30 minutes to 6 hours, thereby giving (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in an enantiomeric excess of at least 90 %, said methods comprising the step of allowing an intermediate compound of formula (II) BHC 223014 FC to react with an intermediate compound of formula (III) in which LG is a bromine atom, in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate and potassium phosphate, at a temperature in the range of 40 to 80 °C, in a solvent selected from N,N-dimethylformamide and acetonitrile, for a time in the range of 30 minutes to 6 hours, optionally followed by lowering the temperature to 20°C over a time in the range of up to one hour, thereby giving (R)-2-(N-[4-amino-5-(4-me
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in an enantiomeric excess of at least 95 %, said methods comprising the step of allowing an intermediate compound of formula (II) BHC 223014 FC to react with an intermediate compound of formula (III) in which LG is a bromine atom, in the presence of 1.5 to 5 equivalents of potassium phosphate, at a temperature in the range of 50 to 70 °C in acetonitrile for a time in the range of 1 to 2 hours, thereby giving (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide in an enantiomeric excess of at least 95 %.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in an enantiomeric excess of at least 95 %, said methods comprising the step of allowing an intermediate compound of formula (II) BHC 223014 FC to react with an intermediate compound of formula (III) in which LG is a bromine atom, in the presence of 1.5 to 5 equivalents of potassium phosphate, at a temperature in the range of 50 to 70 °C in acetonitrile for a time in the range of 1 to 2 hours, optionally followed by lowering the temperature to 20°C over a time in the range of up to one hour, thereby giving (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which BHC 223014 FC the leaving group LG in the step comprised therein is a chlorine atom, a bromine atom or an iodine atom, or a group selected from (methylsulfonyl)oxy, (phenylsulfonyl)oxy and [(4-methylphenyl)sulfonyl]oxy.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the leaving group LG in the step comprised therein is a chlorine atom.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the leaving group LG in the step comprised therein is a bromine atom or a [(4-methylphenyl)sulfonyl]oxy group.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the leaving group LG in the step comprised therein is a bromine atom.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the step comprised therein is carried out in the presence of a base selected from an alkali carbonate, an alkali bicarbonate, an alkali phosphate and N, N, N, N-tetra (C 1 -C 3 -alkyl)guanidine.
  • a base selected from an alkali carbonate, an alkali bicarbonate, an alkali phosphate and N, N, N, N-tetra (C 1 -C 3 -alkyl)guanidine.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the step comprised therein is carried out in the presence of a base selected from an alkali carbonate, an alkali bicarbonate and an alkali phosphate.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the step comprised therein is carried out in the presence of at least 1 equivalent of a base selected from an alkali carbonate, an alkali bicarbonate, an alkali phosphate and N, N, N, N- tetra (C 1 -C 3 -alkyl)guanidine.
  • a base selected from an alkali carbonate, an alkali bicarbonate, an alkali phosphate and N, N, N, N- tetra (C 1 -C 3 -alkyl)guanidine.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the step comprised therein is carried out in the presence of 1.5 to 6 equivalents of a base selected from an alkali carbonate, an alkali bicarbonate, an alkali phosphate and N, N, N, N- tetra (C 1 -C 3 -alkyl)guanidine.
  • a base selected from an alkali carbonate, an alkali bicarbonate, an alkali phosphate and N, N, N, N- tetra (C 1 -C 3 -alkyl)guanidine.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the step comprised therein is carried out in the presence of 1.5 to 6 equivalents of a base selected from an alkali carbonate, an alkali bicarbonate and an alkali phosphate.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the step comprised therein is carried out in the presence of 1.5 to 6 equivalents of a base selected from an alkali carbonate selected from sodium carbonate, potassium carbonate and cesium carbonate, an alkali bicarbonate selected from sodium bicarbonate, potassium bicarbonate, and cesium bicarbonate, and an alkali phosphate selected from sodium phosphate, potassium phosphate and cesium phosphate.
  • a base selected from an alkali carbonate selected from sodium carbonate, potassium carbonate and cesium carbonate
  • an alkali bicarbonate selected from sodium bicarbonate, potassium bicarbonate, and cesium bicarbonate
  • an alkali phosphate selected from sodium phosphate, potassium phosphate and cesium phosphate.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the step comprised therein is carried out in the presence of a base selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate, and potassium phosphate.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the step comprised therein is carried out in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate, and potassium phosphate.
  • a base selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate, and potassium phosphate.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the step comprised therein is carried out in the presence of a base selected from potassium carbonate and potassium phosphate.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the step comprised therein is carried out in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate and potassium phosphate.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the step comprised therein is carried out in the presence of 1.5 to 3 equivalents of potassium phosphate.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the step comprised therein is carried out in the presence of 2 to 6 equivalents of potassium carbonate.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the step comprised therein is carried out at a temperature in the range of 0°C to 100°C.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the step comprised therein is carried out at a temperature in the range of 20°C to 90°C.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the step comprised therein is carried out at a temperature in the range of 40°C to 80°C.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the step comprised therein is carried out at a temperature in the range of 50°C to 70°C.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the step comprised therein is carried out at a temperature in the range of 40°C to 80°C, optionally followed by lowering the temperature to 20°C over a time in the range of up to one hour.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the step comprised therein is carried out at a temperature in the range of 50°C to 70°C, optionally followed by lowering the temperature to 20°C over a time in the range of up to one hour.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the step comprised therein is carried out at a temperature in the range of 40°C to 80°C, followed by lowering the temperature to 20°C over a time in the range of up to one hour.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the step comprised therein is carried out at a temperature in the range of 50°C to 70°C, followed by lowering the temperature to 20°C over a time in the range of up to one hour.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the step comprised therein is carried out in a solvent selected from N,N-dimethylformamide, N,N- dimethylacetamide, acetonitrile, propionitrile, N-methyl pyrrolidinone, acetone, and iso-propanol, or a mixture of acetone and iso-propanol.
  • a solvent selected from N,N-dimethylformamide, N,N- dimethylacetamide, acetonitrile, propionitrile, N-methyl pyrrolidinone, acetone, and iso-propanol, or a mixture of acetone and iso-propanol.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the step comprised therein is carried out in a solvent selected from N,N-dimethylformamide, acetonitrile, N-methyl pyrrolidinone, acetone, and iso-propanol, or a mixture of acetone and iso- propanol in a range of 5:1 to 1:5.
  • a solvent selected from N,N-dimethylformamide, acetonitrile, N-methyl pyrrolidinone, acetone, and iso-propanol, or a mixture of acetone and iso- propanol in a range of 5:1 to 1:5.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the step comprised therein is carried out in a solvent selected from N,N-dimethylformamide and acetonitrile.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the step comprised therein is carried out in N,N-dimethylformamide as a solvent.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the step comprised therein is carried out in acetonitrile as a solvent.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the step comprised therein is carried out over a time in the range of 30 minutes to 24 hours.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the step comprised therein is carried out over a time in the range of 30 minutes to 6 hours.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the step comprised therein is carried out over a time in the range of 30 minutes to 2 hours.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the step comprised therein is carried out over a time in the range of 1 to 2 hours.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide said methods comprising the step of allowing an intermediate compound of formula (II) to react with an intermediate compound of formula (III) in which LG is a leaving group as defined supra, thereby giving microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide in an enantiomeric excess of at least 80 %, said methods comprising the step of allowing an intermediate compound of formula (II) to react with an intermediate compound of formula (III) in which LG is a leaving group as defined supra, thereby giving microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in an enantiomeric excess of at least 80 %.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide in an enantiomeric excess of at least 90 %, said methods comprising the step of allowing an intermediate compound of formula (II) BHC 223014 FC to react with an intermediate compound of formula (III) in which LG is a leaving group as defined supra, thereby giving microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in an enantiomeric excess of at least 90 %.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide in an enantiomeric excess of at least 90 %, said methods comprising the step of allowing an intermediate compound of formula (II) BHC 223014 FC to react with an intermediate compound of formula (III) in which LG is a leaving group as defined supra, in the presence of at least 1 equivalent of a base selected from an alkali carbonate, an alkali bicarbonate and an alkali phosphate, at a temperature in the range of 20 to 80 °C, in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N- methyl pyrrolidinone, acetone, and iso-propanol, for a time
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide in an enantiomeric excess of at least 90 %, said methods comprising the step of allowing an intermediate compound of formula (II) to react with an intermediate compound of formula (III) BHC 223014 FC in which LG is a bromine atom, in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate and potassium phosphate, at a temperature in the range of 40 to 80 °C, in a solvent selected from N,N-dimethylformamide and acetonitrile, for a time in the range of 30 minutes to 6 hours, thereby giving microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide in an enantiomeric excess of at least 90 %, said methods comprising the step of allowing an intermediate compound of formula (II) to react with an intermediate compound of formula (III) BHC 223014 FC in which LG is a bromine atom, in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate and potassium phosphate, at a temperature in the range of 40 to 80 °C, in a solvent selected from N,N-dimethylformamide and acetonitrile, for a time in the range of 30 minutes to 6 hours, optionally followed by lowering the temperature to 20°C over a time in the range of up to one hour, thereby giving microcrystalline forms of (R)-2-(N-[4-a
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide in an enantiomeric excess of at least 95 %, said methods comprising the step of allowing an intermediate compound of formula (II) to react with an intermediate compound of formula (III) BHC 223014 FC in which LG is a bromine atom, in the presence of 1.5 to 5 equivalents of potassium phosphate, at a temperature in the range of 50 to 70 °C in acetonitrile for a time in the range of 1 to 2 hours, thereby giving microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in an enantiomeric excess of at least 95 %.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide in an enantiomeric excess of at least 95 %, said methods comprising the step of allowing an intermediate compound of formula (II) to react with an intermediate compound of formula (III) BHC 223014 FC (III) in which LG is a bromine atom, in the presence of 1.5 to 5 equivalents of potassium phosphate, at a temperature in the range of 50 to 70 °C in acetonitrile for a time in the range of 1 to 2 hours, optionally followed by lowering the temperature to 20°C over a time in the range of up to one hour, thereby giving microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide in an enantiomeric excess of at least 98 %, said methods comprising the step of allowing an intermediate compound of formula (II) to react with an intermediate compound of formula (III) in which LG is a bromine atom, BHC 223014 FC in the presence of 1.5 to 5 equivalents of potassium phosphate, at a temperature in the range of 50 to 70 °C in acetonitrile for a time in the range of 1 to 2 hours, thereby giving microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in an enantiomeric excess of at least 98 %, said methods comprising the step of allowing an
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide in an enantiomeric excess of at least 98 %, said methods comprising the step of allowing an intermediate compound of formula (II) to react with an intermediate compound of formula (III) in which LG is a bromine atom, in the presence of 1.5 to 5 equivalents of potassium phosphate, at a temperature in the range of 50 to 70 °C in acetonitrile for a time in the range of 1 to 2 hours, thereby giving BHC 223014 FC microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in an enantiomeric excess of at least 98 %, said methods comprising the step of allowing an
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide in an enantiomeric excess of at least 98 %, said methods comprising the step of allowing an intermediate compound of formula (II) to react with an intermediate compound of formula (III) in which LG is a bromine atom, in the presence of 1.5 to 5 equivalents of potassium phosphate, at a temperature in the range of 50 to 70 °C in acetonitrile for a time in the range of 1 to 2 hours, thereby giving BHC 223014 FC microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in an enantiomeric excess of at least 98 %, said methods comprising the step of allowing an
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide in an enantiomeric excess of at least 99 %, said methods comprising the step of allowing an intermediate compound of formula (II) to react with an intermediate compound of formula (III) in which LG is a bromine atom, in the presence of 1.5 to 5 equivalents of potassium phosphate, at a temperature in the range of 50 to 70 °C in acetonitrile for a time in the range of 1 to 2 hours, thereby giving BHC 223014 FC microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in an enantiomeric excess of at least
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide in an enantiomeric excess of at least 99 %, said methods comprising the step of allowing an intermediate compound of formula (II) to react with an intermediate compound of formula (III) in which LG is a bromine atom, in the presence of 1.5 to 5 equivalents of potassium phosphate, at a temperature in the range of 50 to 70 °C in acetonitrile for a time in the range of 1 to 2 hours, thereby giving BHC 223014 FC microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in an enantiomeric excess of at least 99 %
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide in an enantiomeric excess of at least 99 %, said methods comprising the step of allowing an intermediate compound of formula (II) to react with an intermediate compound of formula (III) in which LG is a bromine atom, in the presence of 1.5 to 5 equivalents of potassium phosphate, at a temperature in the range of 50 to 70 °C in acetonitrile for a time in the range of 1 to 2 hours, thereby giving BHC 223014 FC microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in an enantiomeric excess of at least 99 %
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide in an enantiomeric excess of at least 99 %, said methods comprising the step of allowing an intermediate compound of formula (II) to react with an intermediate compound of formula (III) in which LG is a bromine atom, in the presence of 1.5 to 5 equivalents of potassium phosphate, at a temperature in the range of 50 to 70 °C in acetonitrile for a time in the range of 1 to 2 hours, thereby giving BHC 223014 FC microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide in an enantiomeric excess of at least 99 %
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the leaving group LG in the step comprised therein is a chlorine atom, a bromine atom or an iodide atom, or a group selected from (methylsulfonyl)oxy, (phenylsulfonyl)oxy and [(4-methylphenyl)sulfonyl]oxy.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the leaving group LG in the step comprised therein is a chlorine atom.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the leaving group LG in the step comprised therein is a [(4-methylphenyl)sulfonyl]oxy group.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the leaving group LG in the step comprised therein is a bromine atom or a [(4-methylphenyl)sulfonyl]oxy group.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the leaving group LG in the step comprised therein is a bromine atom.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the step comprised therein is carried out in the presence of a base selected from an alkali carbonate, an alkali bicarbonate, an alkali phosphate and N, N, N, N-tetra (C 1 -C 3 -alkyl)guanidine.
  • a base selected from an alkali carbonate, an alkali bicarbonate, an alkali phosphate and N, N, N, N-tetra (C 1 -C 3 -alkyl)guanidine.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the step comprised therein is carried out in the presence of a base selected from an alkali carbonate, an alkali bicarbonate and an alkali phosphate.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the step comprised therein is carried out in the presence of at least 1 equivalent of a base selected from an alkali carbonate, an alkali bicarbonate, an alkali phosphate and N, N, N, N- tetra (C1-C3-alkyl)guanidine.
  • a base selected from an alkali carbonate, an alkali bicarbonate, an alkali phosphate and N, N, N, N- tetra (C1-C3-alkyl)guanidine.
  • the present invention covers methods of preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide, in which the step comprised therein is carried out in the presence of 1.5 to 6 equivalents of a base selected from an alkali carbonate, an alkali bicarbonate, an alkali phosphate and N, N, N, N- tetra (C 1 -C 3 -alkyl)guanidine.
  • a base selected from an alkali carbonate, an alkali bicarbonate, an alkali phosphate and N, N, N, N- tetra (C 1 -C 3 -alkyl)guanidine.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the step comprised therein is carried out in the presence of 1.5 to 6 equivalents of a base selected from an alkali carbonate, an alkali bicarbonate and an alkali phosphate.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the step comprised therein is carried out in the presence of 1.5 to 6 equivalents of a base selected from an alkali carbonate selected from sodium carbonate, potassium carbonate and cesium carbonate, an alkali bicarbonate selected from sodium bicarbonate, potassium bicarbonate, and cesium bicarbonate, and an alkali phosphate selected from sodium phosphate, potassium phosphate and cesium phosphate.
  • a base selected from an alkali carbonate selected from sodium carbonate, potassium carbonate and cesium carbonate
  • an alkali bicarbonate selected from sodium bicarbonate, potassium bicarbonate, and cesium bicarbonate
  • an alkali phosphate selected from sodium phosphate, potassium phosphate and cesium phosphate.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the step comprised therein is carried out in the presence of a base selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate, and potassium phosphate.
  • a base selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate, and potassium phosphate.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which BHC 223014 FC the step comprised therein is carried out in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate, and potassium phosphate.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the step comprised therein is carried out in the presence of a base selected from potassium carbonate and potassium phosphate.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the step comprised therein is carried out in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate and potassium phosphate.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the step comprised therein is carried out in the presence of 1.5 to 3 equivalents of potassium phosphate.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the step comprised therein is carried out in the presence of 2 to 6 equivalents of potassium carbonate.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the step comprised therein is carried out at a temperature in the range of 0°C to 100°C.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the step comprised therein is carried out at a temperature in the range of 20°C to 90°C.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the step comprised therein is carried out at a temperature in the range of 40°C to 80°C.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the step comprised therein is carried out at a temperature in the range of 50°C to 70°C.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the step comprised therein is carried out at a temperature in the range of 40°C to 80°C, optionally followed by lowering the temperature to 20°C over a time in the range of up to one hour.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the step comprised therein is carried out at a temperature in the range of 50°C to 70°C, optionally followed by lowering the temperature to 20°C over a time in the range of up to one hour.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the step comprised therein is carried out at a temperature in the range of 40°C to 80°C, followed by lowering the temperature to 20°C over a time in the range of up to one hour.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the step comprised therein is carried out at a temperature in the range of 50°C to 70°C, followed by lowering the temperature to 20°C over a time in the range of up to one hour.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the step comprised therein is carried out in a solvent selected from N,N-dimethylformamide, N,N- dimethylacetamide, acetonitrile, propionitrile, N-methyl pyrrolidinone, acetone, and iso-propanol, or a mixture of acetone and iso-propanol.
  • a solvent selected from N,N-dimethylformamide, N,N- dimethylacetamide, acetonitrile, propionitrile, N-methyl pyrrolidinone, acetone, and iso-propanol, or a mixture of acetone and iso-propanol.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the step comprised therein is carried out in a solvent selected from N,N-dimethylformamide, acetonitrile, N-methyl pyrrolidinone, acetone, and iso-propanol, or a mixture of acetone and iso- propanol in a range of 5:1 (v/v) to 1:5 (v/v).
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the step comprised therein is carried out in a solvent selected from N,N-dimethylformamide and acetonitrile.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the step comprised therein is carried out in N,N-dimethylformamide as a solvent.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the step comprised therein is carried out in acetonitrile as a solvent.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the step comprised therein is carried out over a time in the range of 30 minutes to 24 hours.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the step comprised therein is carried out over a time in the range of 30 minutes to 6 hours.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the step comprised therein is carried out over a time in the range of 30 minutes to 2 hours.
  • the present invention covers methods of preparing microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol- 2-yl]-4-fluoro-anilino)propanamide, in which the step comprised therein is carried out over a time in the range of 1 to 2 hours.
  • the present invention covers pharmaceutical compositions comprising microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide and one or more pharmaceutically acceptable excipients.
  • the present invention covers pharmaceutical compositions comprising microcrystalline forms of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide in which the presence of amorphous forms is below 15 %, and their particle size distribution is as follows: x10 is ⁇ 5 ⁇ m, x50 is ⁇ 10 ⁇ m, and x90 is ⁇ 35 ⁇ m. and one or more pharmaceutically acceptable excipients.
  • the present invention covers pharmaceutical compositions comprising microcrystalline forms of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide in which the presence of amorphous forms is below 15 %, and their particle size distribution is as follows: x10 is in the range of 0.5 to 2.5 ⁇ m, x50 is in the range of 3 to 7 ⁇ m, and x90 is in the range of 8 to 20 ⁇ m, and one or more pharmaceutically acceptable excipients.
  • the present invention covers pharmaceutical compositions comprising microcrystalline forms of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide in which the presence of amorphous forms is below 15 %, and their particle size distribution is as follows: x10 is in the range of 0.3 to 4 ⁇ m, x50 is in the range of 4 to 10 ⁇ m, and x90 is in the range of 10 to 20 ⁇ m, and one or more pharmaceutically acceptable excipients.
  • the present invention covers pharmaceutical compositions comprising microcrystalline forms of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide in which the presence of amorphous forms is below 15 %, and their particle size distribution is as follows: x10 is in the range of 1 to 4 ⁇ m, x50 is in the range of 4 to 8 ⁇ m, and x90 is in the range of 12 to 18 ⁇ m, and one or more pharmaceutically acceptable excipients.
  • the present invention covers pharmaceutical compositions comprising microcrystalline forms of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide in which the enantiomeric excess is at least 95 %, the presence of amorphous forms is below 10 %, and their particle size distribution is as follows: x10 is in the range of 0.5 to 2.5 ⁇ m, x50 is in the range of 3 to 7 ⁇ m, and x90 is in the range of 8 to 20 ⁇ m, and one or more pharmaceutically acceptable excipients.
  • the present invention covers pharmaceutical compositions comprising microcrystalline forms of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide in which the enantiomeric excess is at least 95 %, the presence of amorphous forms is below 10 %, and their particle size distribution is as follows: x10 is in the range of 0.3 to 4 ⁇ m, x50 is in the range of 4 to 10 ⁇ m, and x90 is in the range of 10 to 20 ⁇ m, and one or more pharmaceutically acceptable excipients.
  • the present invention covers pharmaceutical compositions comprising microcrystalline forms of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide in which the enantiomeric excess is at least 95 %, the presence of amorphous forms is below 10 %, and their particle size distribution is as follows: x10 is in the range of 1 to 4 ⁇ m, x50 is in the range of 4 to 8 ⁇ m, and x90 is in the range of 12 to 18 ⁇ m, and one or more pharmaceutically acceptable excipients.
  • the present invention covers pharmaceutical compositions comprising microcrystalline forms of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide in which the presence of amorphous forms is below 5 %, BHC 223014 FC and their particle size distribution is as follows: x10 is in the range of 0.5 to 2.5 ⁇ m, x50 is in the range of 3 to 7 ⁇ m, and x90 is in the range of 8 to 20 ⁇ m, and one or more pharmaceutically acceptable excipients.
  • the present invention covers pharmaceutical compositions comprising microcrystalline forms of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide in which the presence of amorphous forms is below 5 %, and their particle size distribution is as follows: x10 is in the range of 0.3 to 4 ⁇ m, x50 is in the range of 4 to 10 ⁇ m, and x90 is in the range of 10 to 20 ⁇ m, and one or more pharmaceutically acceptable excipients.
  • the present invention covers pharmaceutical compositions comprising microcrystalline forms of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide in which the presence of amorphous forms is below 5 %, and their particle size distribution is as follows: x10 is in the range of 1 to 4 ⁇ m, x50 is in the range of 4 to 8 ⁇ m, and x90 is in the range of 12 to 18 ⁇ m, and one or more pharmaceutically acceptable excipients.
  • the present invention covers pharmaceutical compositions comprising microcrystalline forms of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide in which the enantiomeric excess is at least 98 %, the presence of amorphous forms is below 5 %, and their particle size distribution is as follows: x10 is in the range of 0.5 to 2.5 ⁇ m, x50 is in the range of 3 to 7 ⁇ m, and x90 is in the range of 8 to 20 ⁇ m, and one or more pharmaceutically acceptable excipients.
  • the present invention covers pharmaceutical compositions comprising microcrystalline forms of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide in which BHC 223014 FC the enantiomeric excess is at least 98 %, the presence of amorphous forms is below 5 %, and their particle size distribution is as follows: x10 is in the range of 0.3 to 4 ⁇ m, x50 is in the range of 4 to 10 ⁇ m, and x90 is in the range of 10 to 20 ⁇ m, and one or more pharmaceutically acceptable excipients.
  • the present invention covers pharmaceutical compositions comprising microcrystalline forms of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide in which the enantiomeric excess is at least 98 %, the presence of amorphous forms is below 5 %, and their particle size distribution is as follows: x10 is in the range of 1 to 4 ⁇ m, x50 is in the range of 4 to 8 ⁇ m, and x90 is in the range of 12 to 18 ⁇ m, and one or more pharmaceutically acceptable excipients.
  • the present invention covers pharmaceutical compositions comprising microcrystalline forms of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide in which the enantiomeric excess is at least 99 %, the presence of amorphous forms is below 5 %, and their particle size distribution is as follows: x10 is in the range of 1 to 2 ⁇ m, x50 is in the range of 4 to 5.5 ⁇ m, and x90 is in the range of 10 to 18 ⁇ m, and one or more pharmaceutically acceptable excipients.
  • the present invention covers pharmaceutical compositions comprising microcrystalline forms of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide in which the enantiomeric excess is at least 99 %, the presence of amorphous forms is below 5 %, and their particle size distribution is as follows: x10 is in the range of 1 to 4 ⁇ m, x50 is in the range of 4 to 8 ⁇ m, and x90 is in the range of 12 to 18 ⁇ m, BHC 223014 FC and one or more pharmaceutically acceptable excipients.
  • the present invention covers pharmaceutical compositions comprising microcrystalline forms of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide in which the enantiomeric excess is at least 95 %, the presence of amorphous forms is below 10 %, and their particle size distribution as determined according to method PSD2a is as follows: x10 is in the range of 0.5 to 2.5 ⁇ m, x50 is in the range of 3 to 7 ⁇ m, and x90 is in the range of 8 to 20 ⁇ m, and one or more pharmaceutically acceptable excipients.
  • the present invention covers pharmaceutical compositions comprising microcrystalline forms of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide in which the enantiomeric excess is at least 95 %, the presence of amorphous forms is below 10 %, and their particle size distribution as determined according to method PSD4 is as follows: x10 is in the range of 0.3 to 4 ⁇ m, x50 is in the range of 4 to 10 ⁇ m, and x90 is in the range of 10 to 20 ⁇ m, and one or more pharmaceutically acceptable excipients.
  • the present invention covers pharmaceutical compositions comprising microcrystalline forms of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide in which the enantiomeric excess is at least 95 %, the presence of amorphous forms is below 10 %, and their particle size distribution as determined according to method PSD4 is as follows: x10 is in the range of 1 to 4 ⁇ m, x50 is in the range of 4 to 8 ⁇ m, and x90 is in the range of 12 to 18 ⁇ m, BHC 223014 FC and one or more pharmaceutically acceptable excipients.
  • the present invention covers pharmaceutical compositions comprising microcrystalline forms of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide in which the enantiomeric excess is at least 98 %, the presence of amorphous forms is below 5 %, and their particle size distribution as determined according to method PSD2a is as follows: x10 is in the range of 0.5 to 2.5 ⁇ m, x50 is in the range of 3 to 7 ⁇ m, and x90 is in the range of 8 to 20 ⁇ m, and one or more pharmaceutically acceptable excipients.
  • the present invention covers pharmaceutical compositions comprising microcrystalline forms of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide in which the enantiomeric excess is at least 98 %, the presence of amorphous forms is below 5 %, and their particle size distribution as determined according to method PSD4 is as follows: x10 is in the range of 0.3 to 4 ⁇ m, x50 is in the range of 4 to 10 ⁇ m, and x90 is in the range of 10 to 20 ⁇ m, and one or more pharmaceutically acceptable excipients.
  • the present invention covers pharmaceutical compositions comprising microcrystalline forms of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide in which the enantiomeric excess is at least 98 %, the presence of amorphous forms is below 5 %, and their particle size distribution as determined according to method PSD4 is as follows: x10 is in the range of 1 to 4 ⁇ m, x50 is in the range of 4 to 8 ⁇ m, and x90 is in the range of 12 to 18 ⁇ m, and one or more pharmaceutically acceptable excipients.
  • the present invention covers pharmaceutical compositions comprising microcrystalline forms of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide in which the enantiomeric excess is at least 99 %, the presence of amorphous forms is below 5 %, and their particle size distribution as determined according to method PSD2a is as follows: x10 is in the range of 1 to 2 ⁇ m, x50 is in the range of 4 to 5.5 ⁇ m, and x90 is in the range of 10 to 18 ⁇ m, and one or more pharmaceutically acceptable excipients.
  • the present invention covers pharmaceutical compositions comprising microcrystalline forms of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide in which the enantiomeric excess is at least 99 %, the presence of amorphous forms is below 5 %, and their particle size distribution as determined according to method PSD4 is as follows: x10 is in the range of 1 to 4 ⁇ m, x50 is in the range of 4 to 8 ⁇ m, and x90 is in the range of 12 to 18 ⁇ m, and one or more pharmaceutically acceptable excipients.
  • microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide of the present invention can be utilized to inhibit, block, reduce or decrease DGK] activity resulting in the modulation of dysregulated immune responses e.g. to block immunosuppression and increase immune cell activation and infiltration in the context of cancer and cancer immunotherapy that will eventually lead to reduction of tumour growth.
  • This method comprises administering to a mammal in need thereof, including a human, an amount of a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide; which is effective to treat the disorder.
  • the present invention also provides methods of treating a variety of other disorders wherein DGK] is involved such as, but not limited to, disorders with dysregulated immune responses, inflammation, vaccination for infection & cancer, virus infections, lymphoproliferative disorders, asthma, eye diseases, and type 2 diabetes/ insulin resistance.
  • BHC 223014 FC These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention.
  • the present invention covers microcrystalline forms of (R)- 2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, as described supra, for use in the treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant DGK] signaling.
  • the present invention covers the use of microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, as described supra, for the treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant DGK] signaling, particularly liquid and solid tumours.
  • the present invention covers the microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, as described supra, for the use in the treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant DGK] signaling, particularly liquid and solid tumours.
  • the present invention covers the use of microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, as described supra, in a method of treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant DGK] signaling, particularly liquid and solid tumours.
  • the present invention covers the use of a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, as described supra, in a method of treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant DGK] signaling, particularly liquid and solid tumours.
  • the present invention covers use of a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, as described supra, for the preparation of a pharmaceutical composition, preferably a medicament, for the prophylaxis or treatment of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant DGK] signaling, particularly liquid and solid tumours.
  • the present invention covers a method of treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant DGK] signaling, particularly liquid and solid tumours, using an effective amount of a microcrystalline form of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, as described supra.
  • the present invention covers pharmaceutical compositions, in particular a medicament, comprising a microcrystalline form of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, as described supra, and one or more excipients, in particular one or more pharmaceutically acceptable excipient(s).
  • a medicament comprising a microcrystalline form of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, as described supra, and one or more excipients, in particular one or more pharmaceutically acceptable excipient(s).
  • excipients in particular one or more pharmaceutically acceptable excipient(s).
  • Conventional procedures for preparing such pharmaceutical compositions in appropriate dosage forms can be utilized.
  • the present invention furthermore covers pharmaceutical compositions, in particular medicaments, which comprise at least one microcrystalline form of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide according to the invention, conventionally together with one or more pharmaceutically suitable excipients, and to their use for the above mentioned purposes. It is possible for the microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2- yl]-4-fluoro-anilino)propanamide according to the invention to have systemic and/or local activity.
  • Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal).
  • absorption step for example intravenous, intraarterial, intracardial, intraspinal or intralumbal
  • absorption for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal.
  • Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of suspensions, emulsions, lyophylisates or sterile powders.
  • Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.
  • inhalation inter alia powder inhalers, nebulizers
  • nasal drops nasal sprays
  • tablets/films/wafers/capsules for lingual, sublingual or buccal administration
  • microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide according to the invention can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients.
  • x fillers and carriers for example cellulose, microcrystalline cellulose (such as, for example, Avicel ® ), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos ® )
  • x ointment bases for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols), x bases for suppositories (for example polyethylene glycols, cacao butter, hard fat), x solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain-length triglycerides fatty oils, liquid polyethylene glycols, paraffins), x surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyl sulfate), lecithin
  • the present invention furthermore relates to a pharmaceutical composition which comprises at least one microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention.
  • the amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular microcrystalline form of (R)- 2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
  • the total amount of the microcrystalline forms of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day.
  • Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing.
  • drug holidays in which a patient is not dosed with a drug for a certain period of time, to be beneficial to the overall balance between pharmacological effect and tolerability.
  • a unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day.
  • the average daily dosage for administration by injection including intravenous, intramuscular, subcutaneous and BHC 223014 FC parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
  • the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
  • the Y axis relates to the dissolved amount (%), the X-axis relates to the time in minutes.
  • HPLC1 Preparative HPLC : Instrument: pump: Labomatic HD-5000 or HD-3000, head HDK 280, low pressure gradient module ND-B1000; manual injection valve: Rheodyne 3725i038; detector: Knauer Azura UVD BHC 223014 FC 2.15; collector: Labomatic Labocol Vario-4000; column: Chromatorex RP C-1810 ⁇ m, 125x30mm; eluent: solvent A: water + 0.2 vol-% ammonia (32%), solvent B: acetonitrile; gradient: 0.00-0.50 min 15% B (150 ml/min), 0.50–6.00 min 15-55% B (150 ml/min), 6.00-6.10 min 55-100% B (150 ml/min), 6.10-8.00 min 100% B (150 ml/min); UV: 361 nm Method HPLC2: Analytical
  • Method HPLC6 Preparative chiral HPLC: Instrument: Labomatic HD3000, Knauer Pump 100, Labcol Vario 4000 Plus, Knauer DAD 2600; Column: amylose SB 5 ⁇ 250x50mm Nr.34; eluent A: hexane + 0.1 Vol-% diethylamine (99%); eluent B: 2-propanol; isocratic: 60%A + 40%B; flow 150.0 ml/min, from 16 min 180ml/min; UV @ 254 nm BHC 223014 FC Particle Size Distribution (PSD) Method PSD1 : The Particle Size Distribution (PSD) was measured by laser diffraction using the Malvern Panalytical Mastersizer 3000.0.1 % Span 85 in Heptane was used as dispersant medium.
  • Method PSD2a The Particle Size Distribution (PSD) was measured by laser diffraction using the Sympatec Helos device. Water with a small amount of surfactant was used as dispersant medium. Samples were sonicated for 240 seconds.
  • Method PSD2b The Particle Size Distribution (PSD) was measured by laser diffraction using the Sympatec Helos device. Paraffin was used as dispersant medium. Samples were sonicated for 240 seconds.
  • Method PSD 3 Particle size analysis was performed by laser diffraction using Sympatec (HELOS) with Baysilone (Element 14 PDMS 10-A) as dispersion medium.
  • Method DSC2 Differential Scanning Calorimetry (DSC) was performed with a Mettler Toledo TGA/DSC 3+. The instrument was purged with nitrogen gas at a flow rate of 30 ml min -1 . Approximately 1 – 15 mg of each sample was placed into an aluminum crucible and heated at a heating rate of 10 or 20 °C min -1 starting from 25°C. No sample preparation.
  • BHC 223014 FC Method DSC 3 Differential scanning calorimetry (DSC) was performed with a Mettler Toledo DSC3.
  • the calorimeter was purged with nitrogen gas at a flow rate of 50 ml.min-1. Approximately 3 – 5 mg of sample was placed into an aluminum crucible without sample preparation. The temperature range was -10 – 230°C at a heating rate of 20°C.min -1 .
  • XRPD X-Ray Powder Diffraction
  • Method XRPD1 The X-Ray Powder Diffraction (XRPD) data was recorded on a Bruker D2 PHASER diffractometer with a LYNXEYE-2 detector using Cu K ⁇ 1 radiation (1.54060 ⁇ ). All samples were prepared and measured at ambient temperature, on Si-single-crystal low background sample holders, either open or with a PMMA dome.
  • the data were collected in the Bragg- Brentano ( ⁇ /2 ⁇ ) horizontal geometry between either 3 and 40° (2 ⁇ ) or 4 and 40° (2 ⁇ ), in 0.02° steps at 0.3 s step -1 .
  • the X-ray tube was operated at 30 kV and 10 mA.
  • Method XRPD2 X-ray powder diffraction (XRPD) data were recorded on a PANalytical X'Pert PRO diffractometer using monochromatized Cu-K alpha 1 radiation, at generator settings of 40 kV and 40 mA.
  • the samples were collected in transmission mode, being prepared as a thin layer between two foils.
  • the scanning rage was between 2° and 40° 2 theta with a 0.013° step at 25 seconds/step.
  • Method XRPD3 X-ray powder diffraction (XRPD) data were recorded on a STOE STADI P diffractometer using monochromatized Cu-K alpha 1 radiation, a position sensitive detector, at generator settings of 40 kV and 40 mA. The samples were collected in transmission mode, being prepared as a thin layer between two foils. The scanning rage was between 2° and 40° 2 theta with a 0.5° step at 15 seconds/step.
  • the 100% level was set at 201.5 ⁇ g/ml. Based on previous solubility data of (R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, the thermodynamic solubility of the compound from a crystalline batch should results in roughly 20% release. The higher weigh in was used to be able to detect a possible supersaturation of the investigated batches. Calibration Calibration and measurement were performed with the ⁇ Dissolver from PION, a small-scale dissolution apparatus with in-situ UV probes, which allow high time resolution.
  • Example 1b [4-amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl](4-methoxyphenyl)methanone (50 mg, 0.145 mmol) were dissolved in iso-propanol/acetone 3/1 (1.2 mL), followed by the addition of N,N,N,N- tetramethylguanidine (25 mg, 0.22 mmol) and (2S)-2-bromopropanamide (26.6 mg, 0.17 mmol).
  • Example 1c BHC 223014 FC [4-amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl](4-methoxyphenyl)methanone (50 mg, 0.145 mmol) were dissolved in 1-methyl-2-pyrrolidone (1.3 mL), followed by the addition of potassium carbonate (100 mg, 0.73 mmol) and (2S)-2-bromopropanamide (26.6 mg, 0.17 mmol).
  • Example 1d [4-amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl](4-methoxyphenyl)methanone (50 mg, 0.145 mmol) were dissolved in N,N-dimethylformamide (1.2 mL), followed by the addition of potassium bicarbonate (KHCO 3 , 73 mg, 0.73 mmol) and (2S)-2-bromopropanamide (26.6 mg, 0.17 mmol).
  • KHCO 3 potassium bicarbonate
  • 2S -2-bromopropanamide
  • Example 1e [4-amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl](4-methoxyphenyl)methanone (100 mg, 0.29 mmol) were dissolved in N,N-dimethylformamide (2.1 mL), followed by the addition of potassium carbonate (201 mg, 1.46 mmol) and (2S)-2-bromopropanamide (53.1 mg, 0.35 mmol).
  • Example 1f [4-amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl](4-methoxyphenyl)methanone (50 mg, 0.145 mmol) were dissolved in N,N-dimethylformamide (1.2 mL), followed by the addition of N,N,N,N- tetramethylguanidine (25 mg, 0.22 mmol) and (2S)-2-bromopropanamide (26.6 mg, 0.17 mmol).
  • Example 1g [4-amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl](4-methoxyphenyl)methanone (65 mg, 0.19 mmol) were dissolved in N,N-dimethylformamide (1.4 mL), followed by the addition of potassium carbonate (133 mg, 0.96 mmol) and (S)-1-amino-1-oxopropan-2-yl 4-methylbenzenesulfonate (56 mg, 0.23 mmol).
  • Example 1h BHC 223014 FC [4-amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl](4-methoxyphenyl)methanone (71.5 mg, 0.21 mmol) were dissolved in N,N-dimethylformamide (1.4 mL), followed by the addition of potassium carbonate (144 mg, 1.04 mmol) and (S)-1-amino-1-oxopropan-2-yl 4-methylbenzenesulfonate (61 mg, 0.25 mmol).
  • Example 1i [4-amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl](4-methoxyphenyl)methanone (71.5 mg, 0.21 mmol) were dissolved in N,N-dimethylformamide (1.4 mL), followed by the addition of N,N,N,N- tetramethylguanidine (36 mg, 0.31 mmol) and (S)-1-amino-1-oxopropan-2-yl 4- methylbenzenesulfonate (61 mg, 0.25 mmol).
  • Example 2 Crystallisation of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4- fluoro-anilino)propanamide to give a microcrystalline form of the present invention
  • 2.5 g of solid (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide was weighed into a 100 mL crystallisation vessel.26.74 g of acetone and 2.98 g of water were added. The suspension was stirred at 20 °C for 10 minutes, resulting in an API solution.
  • Example 3 Preparation of microcrystalline (2R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide
  • (2S)-2-bromopropanamide (63.7 g, 419 mmol, 1.2 equiv, 95% enantiomeric excess) and potassium phosphate (K 3 PO 4 , 148 g, 699 mmol, 2.0 equiv) in acetonitrile (1200 mL) was heated to 60 °C and stirred at that temperature for 1 h.
  • the wet filter cake was dissolved in a mixture of acetone (1350 mL) and water (130 mL) at ambient temperature, resulting in a solution with a small amount of residual solid. The mixture was filtered, and the filtrate was added to water (2000 mL) at 4 ⁇ 10 °C within 38 min.
  • Example 4 Preparation of microcrystalline (2R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide powder (essentially anhydrous, prepared according to the protocol described in Example 3) (180 g) was added to a mixture of acetone (877 g) and water (175.5 g) and heated up to 55 °C, resulting in a solution with a small amount of residual solid.
  • PSD as determined with Method PSD4 was found to be (x10 / x50 / x90): 3.22 / 6.87 / 13.2 ⁇ m ( Figure 13).
  • XRPD analysis (Method XRPD1) of the thus obtained (2R)-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide did not show any evidence of the presence of amorphous material or a difference in crystalline form as compared to the disclosure of WO 2021/214019 ( Figure 15); likewise, DSC analysis (Method DSC1) did not show any evidence of the presence of amorphous material ( Figure 14).
  • dissolution of the material was minimally faster or equal as compared to the dissolution of the material obtained from Example 3.
  • dissolution of tablets containing equal amounts of microcrystalline (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro- anilino)propanamide obtained as described in Example 3 (- ⁇ -) and Example 4 (- -) was determined according to PH. Eur.2.9.3., using acetate buffer pH 4.5 containing 2% SDS (sodium dodecyl sulfate) as dissolution medium (Figure 16).
  • a paddle apparatus as specified in the U.S.
  • the compound prepared as shown below (4.00 g) was sieved through a 1 mm manual sieve and added in small fractions to the air jet mill. Micronisation was carried out at room temperature (23°C, 40% relative humidity) with an injector pressure of 8 bar, a grinding pressure of 6 bar and nitrogen as air jet medium for a duration of about 1 h. Particle size analysis (Method PSD3), DSC (Method DSC2) and XRPD analysis (Method XRPD2) of the compound were performed after the micronisation process and the yield was determined (3.78 g, 94.5%).
  • PSD of the material thus obtained was found to be (x10 / x50 / x90): 2.55 / 11.08 / 25.95 ⁇ m.
  • (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide as obtained by chemical synthesis described below and as employed for jet milling is a crystalline solid, characterised by a diffractogram shown in Figure 7 (obtained with method XRPD2) and a thermal behaviour as characterised with method DSC2 ( Figure 8), where a single endothermic event (melting) occurs at 195 °C (onset).
  • reaction mixture was stirred for 45 minutes, then additional DBU (24.4 mL, 163.7 mmol), followed by 2-bromo-1-(4-methoxyphenyl) ethan-1-one (75 g, 327.4 mmol, CAS 2632- 13-5, Fluka and Aldrich) as a solution in acetonitrile (570 mL), were added at room temperature.
  • the reaction mixture was stirred for 48 h at rt upon formation of a suspension.
  • Plenty of water was added, the precipitate was filtered off, washed with water, suspended in water, and dried by lyophilization to yield 122.57 g (quant. yield, 91% pure) of a solid that was employed in the next step without further purification.
  • Step 2 rac-2-(N-[4-Amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide
  • [4-amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl](4-methoxyphenyl)methanone (87.36 g, 254.4 mmol) were dissolved in N,N-dimethylformamide (1863 mL, Aldrich), followed by the addition of potassium carbonate (175.8 g, 1272 mmol, Riedel-de-Haen) and rac-2-bromopropanamide (46.4 g, 305.3 mmol, CAS 5875-25-2, Aldrich).
  • R-2-(N-[4-amino-5-(4- methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide was suspended in methyl tert.- butylether (500 mL, Aldrich) and stirred for 16 days. The suspension was filtered and the solid was washed with methyl tert.-butylether. Water was added and the precipitate was filtered off, washed with water, suspended in water, and dried by lyophilization to give 35.7 g (84.44 mmol, 42.4% yield) of the title compound as crystalline material which was characterised as shown below, and as discussed above in context of Figures 7 and 8.

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Abstract

La présente invention concerne des formes microcristallines de (R)-2-(N-[4-amino-5-(4-méthoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino) propanamide, (I), (R)-2-(N-[4-amino-5-(4-méthoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino) propanamide, et des procédés pour leur préparation, et des compositions pharmaceutiques les comprenant.
PCT/EP2024/058061 2023-03-31 2024-03-26 Formes microcristallines de (r)-2-(n-[4-amino-5-(4-méthoxybenzoyl)thiazol-2-yl]-4-fluoroanilino)propanamide et leurs procédés de préparation Ceased WO2024200410A1 (fr)

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JP2025556507A JP2026511647A (ja) 2023-03-31 2024-03-26 （ｒ）－２－（ｎ－［４－アミノ－５－（４－メトキシベンゾイル）チアゾール－２－イル］－４－フルオロ－アニリノ）プロパンアミドの微結晶及びその調製
EP24719093.7A EP4688760A1 (fr) 2023-03-31 2024-03-26 Formes microcristallines de (r)-2-(n-[4-amino-5-(4-méthoxybenzoyl)thiazol-2-yl]-4-fluoroanilino)propanamide et leurs procédés de préparation
CN202480021576.8A CN120957975A (zh) 2023-03-31 2024-03-26 (r)-2-(n-[4-氨基-5-(4-甲氧基苯甲酰基)噻唑-2-基]-4-氟-苯胺基)丙酰胺的微晶形式及其制备方法

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WO2021214019A1 (fr) 2020-04-24 2021-10-28 Bayer Aktiengesellschaft Aminothiazoles substitués utilisés comme inhibiteurs de la dgk zêta pour l'activation immunitaire
EP4154872A1 (fr) 2021-09-24 2023-03-29 Bayer Aktiengesellschaft Procédé pour la fabrication de microparticules

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WO2021214019A1 (fr) 2020-04-24 2021-10-28 Bayer Aktiengesellschaft Aminothiazoles substitués utilisés comme inhibiteurs de la dgk zêta pour l'activation immunitaire
EP4154872A1 (fr) 2021-09-24 2023-03-29 Bayer Aktiengesellschaft Procédé pour la fabrication de microparticules

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WO2025167814A1 (fr) * 2024-02-06 2025-08-14 微境生物医药科技(上海)有限公司 COMPOSÉ UTILISÉ EN TANT QU'INHIBITEUR DE DGKζ

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