RESUMEN
The design and optimization of a novel series of renin inhibitor is described herein. Strategically, by committing the necessary resources to the development of synthetic sequences and scaffolds that were most amenable for late stage structural diversification, even as the focus of the SAR campaign moved from one end of the molecule to another, highly potent renin inhibitors could be rapidly identified and profiled.
Asunto(s)
Alcoholes/síntesis química , Antihipertensivos/síntesis química , Antihipertensivos/uso terapéutico , Diseño de Fármacos , Hipertensión/tratamiento farmacológico , Piperidinas/síntesis química , Renina/antagonistas & inhibidores , Alcoholes/química , Alcoholes/uso terapéutico , Animales , Antihipertensivos/química , Estructura Molecular , Piperidinas/química , Piperidinas/uso terapéutico , Ratas , Renina/química , Relación Estructura-ActividadRESUMEN
A practical large-scale chromatography-free synthesis of EP4 antagonist MF-310, a potential new treatment for chronic inflammation, is presented. The synthetic route provided MF-310 as its sodium salt in 10 steps and 17% overall yield from commercially available pyridine dicarboxylate 7. The key features of this sequence include a unique regioselective reduction of succinimide 2 controlled by the electronic properties of a remote pyridine ring, preparation of cyclopropane carboxylic acid 3 via a Corey-Chaykovsky cyclopropanation, and a short synthesis of sulfonamide 5.
Asunto(s)
Química Orgánica/métodos , Química Farmacéutica/métodos , Ciclopropanos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Receptores de Prostaglandina E/antagonistas & inhibidores , Succinimidas/química , Ácidos Carboxílicos/química , Química Orgánica/instrumentación , Química Farmacéutica/instrumentación , Cristalización , Ciclopropanos/química , Diseño de Fármacos , Electrónica , Compuestos Heterocíclicos con 3 Anillos/química , Modelos Químicos , Estructura Molecular , Subtipo EP4 de Receptores de Prostaglandina E , Estereoisomerismo , Sulfonamidas/química , Tecnología FarmacéuticaRESUMEN
A novel two-step procedure for the synthesis of 3-amino-5-substituted-isoxazoles is described. In the presence of a base, readily available 3-bromoisoxazolines react with amines to afford 3-aminoisoxazolines. An oxidation protocol was developed for these heterocycles to provide 3-aminoisoxazoles in consistently high yield.
Asunto(s)
Aminas/química , Aminas/síntesis química , Hidrocarburos Bromados/química , Isoxazoles/síntesis química , Catálisis , Técnicas Químicas Combinatorias , Isoxazoles/química , Estructura Molecular , Oxidación-ReducciónRESUMEN
We describe a tandem Mitsunobu/3,3-sigmatropic rearrangement of allylic azides on a chiral auxiliary system that favors one regioisomer thanks to its exceptional steric bias. The sequence may be completed by the oxidative cleavage of the auxiliary or by a ring-closing metathesis reaction that produces a carbo- or heterocycle directly and a recyclable form of the chiral auxiliary. Applications of the methodology to the total synthesis of (+)-coniine, (+)-lentiginosin, and (+)-pumiliotoxin C are reported.
Asunto(s)
Alcaloides/síntesis química , Compuestos Alílicos/química , Azidas/química , Compuestos Alílicos/síntesis química , Aminoácidos/síntesis química , Animales , Azidas/síntesis química , Compuestos Heterocíclicos/síntesis química , Piperidinas/síntesis química , Quinolinas/síntesis química , EstereoisomerismoRESUMEN
[reaction: see text] Homochiral alpha-amino acids, heterocycles, and carbocycles are efficiently constructed via a short sequence of reactions starting from the chiral auxiliary p-menthane-3-carboxaldehyde. The key feature of the sequence is a highly selective tandem Mitsunobu/3,3-sigmatropic rearrangement of hydrazoic acid that procures enantiomerically enriched allylic azides. The sequence is either terminated by oxidative cleavage to provide amino acids or by ring-closing metathesis to provide heterocycles or carbocycles bearing nitrogen.
