RESUMEN
An array of six pyridyl-substituted fused bicyclic piperidines was prepared as novel cores for medicinal chemistry. For maximum diversity, the size of the fused ring varied from three to six atoms and contained up to two oxygen atoms. The pyridine ring was incorporated to improve physicochemical properties and to challenge the robustness of the chemistry. The presence of the pyridine did interfere with our initial approaches to these molecules, and in several instances, a blocking strategy had to be employed. These new scaffolds possess high sp3 character and may prove useful in multiple medicinal chemistry applications.
Asunto(s)
Compuestos Bicíclicos con Puentes/síntesis química , Piperidinas/síntesis química , Compuestos Bicíclicos con Puentes/química , Química Farmacéutica , Conformación Molecular , Piperidinas/química , EstereoisomerismoRESUMEN
Lowering of intra-ocular pressure is the primary pharmacologic approach for the treatment of glaucoma and a number of distinct mechanisms of action have been clinically validated. Targeting of multiple mechanisms in combination therapies has proven effective both clinically and commercially although potential improvements with regards to efficacy, tolerability and dosing frequency remain. Application of Theravance's multivalent approach to drug discovery towards linked dual-pharmacology prostaglandin F receptor (FP) agonist/carbonic anhydrase (CA)-II inhibitor compounds is described. Compound 29 exhibits weak potency (pEC(50)=5.7, IA>1.0) as an FP agonist with high binding affinity (pK(i)=8.1) to the CA-II enzyme, and has comparable corneal permeability to the CA-II inhibitor dorzolamide.
Asunto(s)
Inhibidores de Anhidrasa Carbónica/farmacología , Glaucoma/tratamiento farmacológico , Prostaglandinas F Sintéticas/farmacología , Receptores de Prostaglandina/agonistas , Inhibidores de Anhidrasa Carbónica/química , Descubrimiento de Drogas , Humanos , Modelos Moleculares , Prostaglandinas F Sintéticas/química , Receptores de Prostaglandina/químicaAsunto(s)
Grafito/química , Mesilatos/química , Níquel/química , Compuestos de Tosilo/química , Catálisis , Mesilatos/síntesis química , Mesilatos/efectos de la radiación , Microondas , Estructura Molecular , Oxidación-Reducción , Tamaño de la Partícula , Compuestos de Tosilo/síntesis química , Compuestos de Tosilo/efectos de la radiaciónRESUMEN
A study involving the relatively rare combination of heterogeneous catalysis conducted under microwave conditions is presented. Carbon-carbon bond formation, including Negishi and Suzuki couplings, can be quickly effected with aryl chloride partners by using a base metal (nickel) adsorbed in the pores of activated charcoal. Aminations were also studied, along with cross-couplings of vinyl alanes with benzylic chlorides as a means to stereodefined allylated aromatics. Reaction times for all these processes are typically reduced from several hours to minutes in a microwave reactor.
Asunto(s)
Carbón Orgánico/química , Química Farmacéutica/métodos , Microondas , Níquel/química , Tecnología Farmacéutica/métodos , Carbono/química , Catálisis , Química Farmacéutica/instrumentación , Cloruros/química , Espectroscopía de Resonancia Magnética , Metales/química , Modelos Químicos , Espectroscopía Infrarroja por Transformada de Fourier , Tecnología Farmacéutica/instrumentación , Temperatura , UltrasonidoRESUMEN
[reaction: see text] Exposure of any of several mono- or bidentate phosphines to CuCl leads to quick removal of unwanted ligands from solution. Most phosphines, if desired, can be easily recovered.