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Mini-tablets are advantageous over liquid formulations in overcoming challenges related to stability, taste, and dosage. This open-label, single-dose, cross-over study investigated the acceptability and safety of drug-free, film-coated mini-tablets in children aged 1 month–6 years (stratified: 4–6 years, 2–<4 years, 1–<2 years, 6–<12 months, and 1–<6 months), and their preference for swallowing either a high quantity of 2.0 mm or a low quantity of 2.5 mm diameter mini-tablets. The primary endpoint was acceptability derived from swallowability. The secondary endpoints were investigator-observed palatability, acceptability as a composite endpoint derived from both swallowability and palatability, and safety. Of 320 children randomized, 319 completed the study. Across all tablet sizes, quantities and age groups, acceptability rates based on swallowability were high (at least 87%). Palatability was rated as "pleasant/neutral" in 96.6% of children. The acceptability rates as per the composite endpoint were at least 77% and 86% for the 2.0 mm and 2.5 mm film-coated mini-tablets, respectively. No adverse events or deaths were reported. Recruitment in the 1–<6-months group was stopped early due to coughing—evaluated as "choked on" in three children. Both 2.0 mm and 2.5 mm film-coated mini-tablets are suitable formulations for young children. [ABSTRACT FROM AUTHOR]

A novel and concise synthesis of the DP2 receptor antagonist Fevipiprant (NVP‐QAW039) was developed. The initial research route was suffering from a long reaction sequence to the functionalized 7‐aza‐indole core followed by a poorly selective N(1)‐alkylation with the benzyl side chain. These limitations were overcome by introducing the side chain early by reductive amination between the functionalized aldehyde and 2‐amino‐3‐bromopyridine. The Sonogashira coupling with prop‐2‐yn‐1‐ol introduces the 3 missing carbon atoms to build the 7‐aza‐indole core and sets the stage for the innovative Johnson‐Claisen key step. The reaction of the advanced propargylic alcohol derivative with trimethyl orthoacetate led to a reactive allene intermediate which spontaneously and selectively cyclizes to the 7‐aza‐indole QAW039‐methyl ester. QAW039 was isolated after ester saponification. Selectivity, yield, and ecological footprint of the new synthesis were significantly improved, and scalability was demonstrated. [ABSTRACT FROM AUTHOR]

The preparation of various 2-(7-azaindolyl)carboxylic esters by Pd-catalyzed coupling of Reformatsky reagents with TBDMS-protected 3-bromo-7-azaindoles leading to a wide range of arylated ester derivatives is reported. After removal of the protecting group, the corresponding free 2-(7-azaindolyl)carboxylic esters are obtained in satisfactory yields. [ABSTRACT FROM AUTHOR]

A one-pot protocol is described which allows direct access to azaindoles from amino-halopyridines and ketones. [ABSTRACT FROM AUTHOR]

A rapid and convenient method for the synthesis of a wide range of 2-substituted 7-azaindole derivatives from methyl ketones and 2-amino-3-halopyridines is given. [ABSTRACT FROM AUTHOR]

Abstract: Compound 4p was identified from a series of 6-hydroxy-4H-benzo[1,4]oxazin-3-ones as potent agonist of the human β2-adrenoceptor with a high β1/β2-selectivity. A complete reversal of acetylcholine-induced bronchoconstriction which lasted over the whole study period of 5h was demonstrated for 4p in a guinea pig in vivo model without any signs of cardiovascular effects up to 10-fold above the first dose reaching 100% bronchoprotection. The enantiomerically pure (R)-form of 4p exerted a bronchodilatory efficacy over 24h in dogs and guinea pigs in the absence of systemic pharmacodynamic effects. Formoterol which was tested as comparator in the same in vivo models of acetylcholine-induced bronchoconstriction did not retain efficacy after 24h. In summary, the preclinical profile of compound (R)-4p (olodaterol, also known as BI 1744 CL) suggests a potential for once-daily dosing in man accompanied with an improved safety profile. [Copyright &y& Elsevier]

Abstract: β2-Adrenoceptor agonists with basic and acidic groups attached via an alkyl linker to the phenyl ethanolamine core were prepared and investigated in vitro and in vivo. The compounds exhibited a high potency in a functional cellular assay and a bronchoprotective effect in a guinea pig model which lasted over the complete study period of 5h. [Copyright &y& Elsevier]