922525-11-9

In order to develop novel κ agonists restricted to the periphery, a diastereo- and enantioselective synthesis of (4aR,5S,8aS)-configured decahydroquinoxalines 5-8 was developed. Physicochemical and pharmacological properties were fine-tuned by structural modifications in the arylacetamide and amine part of the pharmacophore as well as in the amine part outside the pharmacophore. The decahydroquinoxalines 5-8 show single-digit nanomolar to subnanomolar κ-opioid receptor affinity, full κ agonistic activity in the [35S]GTPγS assay, and high selectivity over μ, δ, σ1, and σ2 receptors as well as the PCP binding site of the NMDA receptor. Several analogues were selective for the periphery. The anti-inflammatory activity of 5-8 after topical application was investigated in two mouse models of dermatitis. The methanesulfonamide 8a containing the (S)-configured hydroxypyrrolidine ring was identified as a potent (Ki = 0.63 nM) and highly selective κ agonist (EC50 = 1.8 nM) selective for the periphery with dose-dependent anti-inflammatory activity in acute and chronic skin inflammation.

Neuroinflammatory disorders, such as multiple sclerosis or experimental autoimmune encephalomyelitis (EAE), an established mouse model mimicking part of the human pathology, are characterized by inflammatory infiltrates containing T helper 1 (TH1) and TH17 cells, which cause demyelination and neurodegeneration. Disease onset and perpetuation are mediated by peripherally generated autoreactive T cells infiltrating into the central nervous system, where they are restimulated by antigen-presenting cells. Here, we show that newly designed peripherally active, potent, and selective κ-opioid receptor (KOR) agonists comprising the ethylenediamine KOR pharmacophore in a perhydroquinoxaline scaffold exhibit potent anti-inflammatory capacities in primary antigen presenting cells as well as T cells. In the EAE model, the secondary amine 12 and the triazole 14 were able to ameliorate disease severity and to delay disease onset by blocking effector T cell activation. Importantly, the beneficial effects were mediated via signaling through KOR because off-target effects were excluded by using KOR-deficient mouse mutants.

Upon fusing the pyrazinyl pyrazole entity in giving pyrazolo[3,4-f]quinoxaline chelate, the corresponding Os(II) based NIR emitter exhibited “invisible” and efficient electroluminescence with a peak maximum at 811 nm. A maximum external quantum efficiency

Aromatic N-oxides (ArN?OX) are desirable biologically active compounds with a potential for application in pharmacy and agriculture industries. As biocatalysis is making a great impact in organic synthesis, there is still a lack of efficient and convenient enzyme-based techniques for the production of aromatic N-oxides. In this study, a recombinant soluble di-iron monooxygenase (SDIMO) PmlABCDEF overexpressed in Escherichia coli was showed to produce various aromatic N-oxides. Out of 98 tested N-heterocycles, seventy were converted to the corresponding N-oxides without any side oxidation products. This whole-cell biocatalyst showed a high activity towards pyridines, pyrazines, and pyrimidines. It was also capable of oxidizing bulky N-heterocycles with two or even three aromatic rings. Being entirely biocatalytic, our approach provides an environmentally friendly and mild method for the production of aromatic N-oxides avoiding the use of strong oxidants, organometallic catalysts, undesirable solvents, or other environment unfriendly reagents. (Figure presented.).

Substituted hydrazone compounds, methods of making such compounds and metal complexes thereof, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds and metal complexes to treat, prevent or ameliorate cancer are provided.

The present invention relates to perhydroquinoxaline compounds according to the general formula (1), their use as a medicament, in particular as analgesic, antipruritic and antiinflammatory agents, and their preparation.

The present invention relates to perhydroquinoxaline compounds according to the general formula (1), their use as a medicament, in particular as analgesic, antipruritic antiinflammatory agents, and their preparation.

Metal-catalyzed coupling process comprising reacting a compound of general formula 1 with a compound A-X, to obtain a compound of general formula 2, which may further be converted to a compound of general formula 3

New aspects of N-oxides: Pyrazine, pyridazine, and pyrimidine N-oxides are regioselectively arylated with aryl iodides, bromides, and chlorides in the presence of a palladium catalyst (see scheme). The resulting products can be deoxygenated in high yield