Effect of Particle Size and Morphology on the Dehydration Mechanism of a Non-Stoichiometric Hydrate

A hydrated form of 7-methoxy-1-methyl-5-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[4,3-a]quinolin-4-amine (designated Form B) exhibits moisture sorption behavior that is very strongly affected by particle size and morphology. When studied pre- and post-micronization, the simple rate of dehydration at ambient temperature is faster by >2 orders of magnitude after micronization. Complementary techniques were employed to understand this behavior including environmental X-ray powder diffractometry (XRPD), gravimetric vapor sorption (GVS), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot-stage microscopy (HSM), single-crystal X-ray diffractometry (SCXRD), and solid-state nuclear magnetic resonance (SSNMR). Solid-state kinetics analysis of thermal data revealed that dehydration of the nonmicronized material follows a two-step consecutive reaction with the first step being a diffusion limited reaction and the second step being a first order reaction, whereas the micronized material follows a simple one-step <i>n</i>th order reaction. The crystal structure of Form B was determined, and the difference in dehydration kinetics was linked to narrow and staggered water channels observed along the crystallographic <i>a</i>-axis. Micronization cleaves slip planes that are approximately perpendicular to the long-axis of the water channels, allowing for easier egress and causing drastic changes in moisture sorption properties. Morphology predictions suggest that Form B has a tendency to have high aspect ratios along the <i>a</i>-axis, the longest axis of the columnar-shaped crystals, so that the rate of dehydration is limited by long channel systems. The crystal structure shows two crystallographically distinct water molecules with slightly different hydrogen bonding networks. SSNMR experiments are used to directly observe the preferential dehydration of one water molecule, and density functional theory and Monte Carlo sorption calculations are used to probe energetic differences between the water environments

Effect of Particle Size and Morphology on the Dehydration Mechanism of a Non-Stoichiometric Hydrate

A hydrated form of 7-methoxy-1-methyl-5-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[4,3-a]quinolin-4-amine (designated Form B) exhibits moisture sorption behavior that is very strongly affected by particle size and morphology. When studied pre- and post-micronization, the simple rate of dehydration at ambient temperature is faster by >2 orders of magnitude after micronization. Complementary techniques were employed to understand this behavior including environmental X-ray powder diffractometry (XRPD), gravimetric vapor sorption (GVS), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot-stage microscopy (HSM), single-crystal X-ray diffractometry (SCXRD), and solid-state nuclear magnetic resonance (SSNMR). Solid-state kinetics analysis of thermal data revealed that dehydration of the nonmicronized material follows a two-step consecutive reaction with the first step being a diffusion limited reaction and the second step being a first order reaction, whereas the micronized material follows a simple one-step <i>n</i>th order reaction. The crystal structure of Form B was determined, and the difference in dehydration kinetics was linked to narrow and staggered water channels observed along the crystallographic <i>a</i>-axis. Micronization cleaves slip planes that are approximately perpendicular to the long-axis of the water channels, allowing for easier egress and causing drastic changes in moisture sorption properties. Morphology predictions suggest that Form B has a tendency to have high aspect ratios along the <i>a</i>-axis, the longest axis of the columnar-shaped crystals, so that the rate of dehydration is limited by long channel systems. The crystal structure shows two crystallographically distinct water molecules with slightly different hydrogen bonding networks. SSNMR experiments are used to directly observe the preferential dehydration of one water molecule, and density functional theory and Monte Carlo sorption calculations are used to probe energetic differences between the water environments

Conversion of a Benzofuran Ester to an Amide through an Enamine Lactone Pathway: Synthesis of HCV Polymerase Inhibitor GSK852A

HCV NS5B polymerase inhibitor GSK852A (<b>1</b>) was synthesized in only five steps from ethyl 4-fluorobenzoylacetate (<b>3</b>) in 46% overall yield. Key to the efficient route was the synthesis of the highly functionalized benzofuran core <b>15</b> from the β-keto ester in one pot and the efficient conversion of ester <b>6</b> to amide <b>19</b> via enamine lactone <b>22</b>. Serendipitous events led to identification of the isolable enamine lactone intermediate <b>22</b>. Single crystal X-ray diffraction and NMR studies supported the intramolecular hydrogen bond shown in enamine lactone <b>22</b>. The hydrogen bond was considered an enabler in the proposed pathway from ester <b>6</b> to enamine lactone <b>22</b> and its rearrangement to amide <b>19</b>. GSK852A (<b>1</b>) was obtained after reductive amination and mesylation with conditions amenable to the presence of the boronic acid moiety which was considered important for the desirable pharmacokinetics of <b>1</b>. The overall yield of 46% in five steps was a significant improvement to the previous synthesis from the same β-keto ester in 5% yield over 13 steps

Pro-Formal: políticas y opciones regulatorias para reconocer e integrar mejor el sector doméstico de la madera en los países tropicales

CXCR2 has emerged as a therapeutic target for not only peripheral inflammatory diseases but also neurological abnormalities in the central nervous system (CNS). Herein, we describe the discovery of a novel 1-cyclopentenyl-3-phenylurea series as potent and CNS penetrant CXCR2 antagonists. Extensive SAR studies, wherein molecules’ property forecast index (PFI) was carefully optimized for overall balanced developability profiles, led to the discovery of the advanced lead compound <b>68</b> with a desirable PFI. Compound <b>68</b> demonstrated good in vitro pharmacology with excellent selectivity over CXCR1 and other chemokine receptors. Rat and dog pharmacokinetics (PK) revealed good oral bioavailability, high oral exposure, and desirable elimination half-life of the compound in both species. In addition, the compound demonstrated dose-dependent efficacy in the in vivo pharmacology neutrophil infiltration “air pouch” model in rodents after oral administration. Further, compound <b>68</b> is a CNS penetrant molecule with high unbound fraction in brain tissue

Synthesis and Structure–Activity Relationships of Indazole Arylsulfonamides as Allosteric CC-Chemokine Receptor 4 (CCR4) Antagonists

A series of indazole arylsulfonamides were synthesized and examined as human CCR4 antagonists. Methoxy- or hydroxyl- containing groups were the more potent indazole C4 substituents. Only small groups were tolerated at C5, C6, or C7, with the C6 analogues being preferred. The most potent <i>N</i>3-substituent was 5-chlorothiophene-2-sulfonamide. <i>N</i>1 <i>meta</i>-substituted benzyl groups possessing an α-amino-3-[(methylamino)­acyl]– group were the most potent <i>N</i>1-substituents. Strongly basic amino groups had low oral absorption in vivo. Less basic analogues, such as morpholines, had good oral absorption; however, they also had high clearance. The most potent compound with high absorption in two species was analogue <b>6</b> (GSK2239633A), which was selected for further development. Aryl sulfonamide antagonists bind to CCR4 at an intracellular allosteric site denoted site II. X-ray diffraction studies on two indazole sulfonamide fragments suggested the presence of an important intramolecular interaction in the active conformation