The
crystal forms of the active pharmaceutical ingredient enzalutamide,
a drug used for the treatment of metastatic prostate cancer, have
been investigated by X-ray, thermogravimetric analysis, and differential
scanning calorimetry techniques. The single crystal structure of the
anhydrous form R1 (marketed by Astellas) has been determined and compared
with the powder diffraction data. Upon crystallization from MeOH and
formic acid, a new solvate form called R2 has been discovered and
characterized. The crystal structure of R2 contains voids that can
host other small molecules such as formic acid, methanol, or water.
Form R2 loses solvent at ca. 120–140 °C and recrystallizes
into the stable unsolvated form R1. In the case of isopropyl alcohol,
a solvate form R3 has also been obtained. R1 converts into R3 under
slurry conditions in isopropyl alcohol. The structure of R3 has been
determined from powder diffraction data. Importantly, while form R1
is easily contaminated with O-enzalutamide (the substitution
impurity of S-enzalutamide) by forming stable solid
solutions up to 50%, form R3 does not and can be used to easily purify
the raw S-enzalutamide.
Aliskiren is the first‐in‐class orally active direct renin inhibitor. It was approved in 2007 for the treatment of hypertension. We have designed a new strategy for the convergent synthesis of aliskiren that involves a catalytic stereoselective nitroaldol reaction as the key step. A new enantiopure nitroalkane (synthon A1), prepared in only three steps from a commercially available enantiopure 2‐(arylmethyl)‐3‐methyl butanol derivative, was successfully used in a copper‐catalysed Henry reaction to give a nitrolactone intermediate in which the correct configuration for the final product was established at all four stereocentres. Nitro‐group reduction, Boc‐protection of the resulting amine, aminolysis of the lactone with 3‐amino‐2,2‐dimethylpropionamide, and finally Boc‐deprotection led to the enantiopure renin inhibitor aliskiren.
The thermodynamics and kinetics of binding of model tripeptides epsilon-N-acetyl-alpha-N-dansyl-L-Lys-D-Ala-D-Ala (ADLAA) or alpha-N,epsilon-N-diacetyl-L-Lys-D-Ala-D-Ala (AALAA) to teicoplanin (1a) and a series of semisynthetic derivatives with (1b-f) or devoid of (2a-g) the glycidic side arms and modified at the terminal amino acids of the peptide backbone have been studied by fluorescence or UV spectroscopy. The binding process is suggested to occur via a two-step mechanism. The first, fast process is likely governed by an electrostatic interaction between the C- and N-termini of the peptide chain of the substrate and of the antibiotic, respectively, while the second slower one, accounts for the formation of the hydrogen bonds responsible of the major contribution to the overall binding energy. The binding constants with all modified derivatives are smaller than that with native teicoplanin. Larger modification of the overall binding constant are observed when the sugar residues are removed and, to a lower extent, when the N-terminus of the peptide chain is acylated. The kinetic process is very little affected by the modifications introduced.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.