RESUMEN
Osteoarthritis (OA) and the associated joint pain are highly prevalent and a leading cause of disability. We have previously reported the identification of a series of purines as selective CB2 agonists and the identification of compound 1 as a clinical candidate for the treatment of joint pain. In this article we describe the further SAR development of the purine scaffold leading to the discovery of compound 6 as a potent, CNS penetrating CB2 agonist with high selectivity for CB2 over CB1 and oral efficacy in animal models of chronic OA pain.
Asunto(s)
Agonistas de Receptores de Cannabinoides/uso terapéutico , Dolor Crónico/tratamiento farmacológico , Piperazinas/química , Purinas/química , Receptor Cannabinoide CB2/agonistas , Animales , Agonistas de Receptores de Cannabinoides/química , Agonistas de Receptores de Cannabinoides/farmacocinética , Modelos Animales de Enfermedad , Perros , Semivida , Humanos , Microsomas Hepáticos/metabolismo , Osteoartritis/tratamiento farmacológico , Piperazinas/farmacocinética , Piperazinas/uso terapéutico , Purinas/farmacocinética , Purinas/uso terapéutico , Ratas , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Relación Estructura-ActividadRESUMEN
Microflow technology is established as a modern and fashionable tool in synthetic organic chemistry, bringing great improvement and potential, on account of a series of advantages over flask methods. The study presented here focuses on the application of flow chemistry process in performing an efficient multiple step syntheses of (±)-fluoxetine as an alternative to conventional synthetic methods, and one of the few examples of total synthesis accomplished by flow technique.
Asunto(s)
Química Orgánica/métodos , Fluoxetina/síntesis química , Química Orgánica/instrumentación , Fluoxetina/química , Halógenos/química , Estereoisomerismo , Especificidad por SustratoRESUMEN
The selective reduction of one of the three carboxyl groups of two chiral citric acid derivatives to the corresponding aldehydes, under Rosenmund conditions, are reported together with the application of these aldehydes to the syntheses of the ester side chains of some potently antileukemic Cephalotaxus alkaloids e.g. anhydroharringtonine.
Asunto(s)
Alcaloides/química , Antineoplásicos/química , Cephalotaxus/química , Citratos/química , Ésteres/síntesis química , Antineoplásicos/síntesis química , Ésteres/química , Estructura Molecular , Oxidación-Reducción , EstereoisomerismoRESUMEN
[reaction: see text] (+/-)-Cytisine has been synthesized in 19% overall yield via a six-step approach from commercially available materials. Key features of this new strategy are as follows: (i) initial construction of the bispidine core, (ii) lithiation-transmetalation-allylation of an N-Boc-bispidine, and (iii) a Pd/C-mediated dihydropyridone oxidation-N-debenzylation process.