Patrick Pasau

First dual NK1 antagonists–serotonin reuptake inhibitors: synthesis and SAR of a new class of potential antidepressants

Compounds combining NK(1) antagonism and serotonin reuptake inhibition are described, and potentially represent a new generation of antidepressants. Compound 24 displays good affinities for both the NK(1) receptor and the serotonin reuptake site (32 and 25 nM, respectively).

Dual NK1 antagonists: Serotonin reuptake inhibitors as potential antidepressants. Part 2: Sar and activity of benzyloxyphenethyl piperazine derivatives

The synthesis, structure-affinity relationship and activity of benzyloxyphenethyl piperazine derivatives combining NK(1) antagonism and serotonin reuptake inhibition is described. Compound 7u was shown to be active in animal models of 5-HT reuptake inhibition and central NK(1) receptor blockade, and was demonstrated to be orally active in an integrated model sensitive to both mechanisms. This class of compounds potentially represents a new generation of antidepressants.

Multistep Flow Synthesis of 5-Amino-2-aryl-2H-[1,2,3]-triazole-4-carbonitriles

1,2,3-Triazole has become one of the most important heterocycles in contemporary medicinal chemistry. The development of the copper-catalyzed Huisgen cycloaddition has allowed the efficient synthesis of 1-substituted 1,2,3-triazoles. However, only a few methods are available for the selective preparation of 2-substituted 1,2,3-triazole isomers. In this context, we decided to develop an efficient flow synthesis for the preparation of various 2-aryl-1,2,3-triazoles. Our strategy involves a three-step synthesis under continuous-flow conditions that starts from the diazotization of anilines and subsequent reaction with malononitrile, followed by nucleophilic addition of amines, and finally employs a catalytic copper(II) cyclization. Potential safety hazards associated with the formation of reactive diazonium species have been addressed by inline quenching. The use of flow equipment allows reliable scale up processes with precise control of the reaction conditions. Synthesis of 2-substituted 1,2,3-triazoles has been achieved in good yields with excellent selectivities, thus providing a wide range of 1,2,3-triazoles.

Discovery of orally bioavailable NK1 receptor antagonists

Benzyloxyphenethylpiperazines are a new class of high affinity NK1 receptor antagonists. Oral bioavailability and selectivity can be fine tuned by the nature of the substituents on the basic nitrogen atom. Addition of substituents with a carboxylic acid group led to very selective and orally active NK1 antagonists free of interaction with L-type calcium channels.

C−H Cyanation of 6-Ring N-Containing Heteroaromatics

Abstract Heteroaromatic nitriles are important compounds in drug discovery, both for their prevalence in the clinic and due to the diverse range of transformations they can undergo. As such, efficient and reliable methods to access them have the potential for far‐reaching impact across synthetic chemistry and the biomedical sciences. Herein, we report an approach to heteroaromatic C−H cyanation through triflic anhydride activation, nucleophilic addition of cyanide, followed by elimination of trifluoromethanesulfinate to regenerate the cyanated heteroaromatic ring. This one‐pot protocol is simple to perform, is applicable to a broad range of decorated 6‐ring N‐containing heterocycles, and has been shown to be suitable for late‐stage functionalization of complex drug‐like architectures.

Development of a Flow Photochemical Aerobic Oxidation of Benzylic C–H Bonds

A continuous mesofluidic process has been developed for benzylic C-H oxidation with moderate to good yields using a photocatalyst (riboflavin tetraacetate, RFT) activated by a UV lamp and an iron additive [Fe(ClO4)2] via incorporation of singlet oxygen (1O2) for the direct formation of oxidized C═O or CH-OH compounds.