A new method for the synthesis of 2,4- and 2,3,4-substituted pyrroles in two or three steps from commercially available ketones and allyl hydroxylamine is described. An iridium-catalyzed isomerization reaction has been developed to convert O-allyl oximes to O-vinyl oximes, which undergo a facile [3,3] rearrangement to form 1,4-imino aldehyde Paal-Knorr intermediates that cyclize to afford the corresponding pyrroles. Optimization and examples of the isomerization and pyrrole formation are discussed.
The regioselective synthesis of 2,3,4- or 2,3,5-trisubstituted pyrroles has been achieved via [3,3] and [1,3] sigmatropic rearrangements of O-vinyl oximes, respectively. Iridium-catalyzed isomerization of easily prepared O-allyl oximes enables rapid access to O-vinyl oximes. The regioselectivity of pyrrole formation can be controlled by either the identity of the α-substituent or through the addition of an amine base. When enolization is favored, a [3,3] rearrangement followed by a Paal-Knorr cyclization provides a 2,3,4-trisubstituted pyrrole; when enolization is disfavored, a [1,3] rearrangement occurs prior to enolization to produce a 2,3,5-trisubstituted pyrrole after cyclization. Optimization and scope of the O-allyl oxime isomerization and subsequent pyrrole formation are discussed and mechanistic pathways are proposed. Conditions are provided for selecting either the [3,3] rearrangement or the [1,3] rearrangement product with β-ester O-allyl oxime substrates.
Two in two: Dioxygenation of alkenyl boronic acids has been achieved with N-hydroxyphthalimide. The two-step process involves etherification of an alkenyl boronic acid with N-hydroxyphthalimide followed by a [3,3] rearrangement. The dioxygenated product can then be hydrolyzed to form either the corresponding α-hydroxy ketone or the α-benzoyloxy ketone.
Background
Letibotulinumtoxin A (Croma Pharma GmbH, Leobendorf, Austria) is a newly manufactured neurotoxin derived from the C. botulinum strain CBFC26.
Objectives
To assess efficacy and safety of letibotulinumtoxin A in reducing glabellar line severity (GLS) and to evaluate long term safety and efficacy following repeated injections.
Methods
In this prospective, randomized, parallel-group, double blind, multicentre, placebo – controlled phase III clinical trial, 355 subjects with moderate to severe glabella frown lines received injections with 20 U of letibotulinumtoxin A or placebo. Glabellar line severity (GLS), onset and duration of effect, time to re-treatment and adverse events were evaluated. Response to treatment was defined as a GLS score of 0 or 1 (assessed by the subject and investigator) and an improvement ≥2 points in GLS score relative to baseline, at week 4 from baseline.
Results
At 4 weeks, 78.6% of the active treatment subjects where responders (reduction of ≥2 – points on the GLS and GLS of 0 or 1) based on the investigator assessment and 68.8% based on the subject assessment, resulting in a composite responder rate 64.7% for the active treatment group, while it was 0.0% in the placebo group (p < 0.001). The median time to onset of effect was 3.0 days. Time until first re-treatment for the letibotulinumtoxin A group was 127.26 ± 65.6 days. Letibotulinumtoxin A was well tolerated.
Conclusions
Letibotulinumtoxin A demonstrates high efficacy and a convincing safety profile in the treatment of glabellar lines.
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