RESUMO
The discovery of a structurally distinct cannabinoid-1 receptor (CB1R) positron emission tomography tracer is described. Starting from an acyclic amide CB1R inverse agonist (1) as the lead compound, an efficient route to introduce 18F to the molecule was developed. Further optimization focused on reducing the lipophilicity and increasing the CB1R affinity. These efforts led to the identification of [18F]-16 that exhibited good brain uptake and an excellent signal-to-noise ratio in rhesus monkeys.
Assuntos
Amidas/síntese química , Radioisótopos de Flúor , Piridinas/síntese química , Compostos Radiofarmacêuticos/síntese química , Receptor CB1 de Canabinoide/metabolismo , Amidas/química , Amidas/farmacocinética , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Células CHO , Cricetinae , Cricetulus , Humanos , Macaca mulatta , Tomografia por Emissão de Pósitrons , Piridinas/química , Piridinas/farmacocinética , Ensaio Radioligante , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Relação Estrutura-AtividadeRESUMO
This paper describes a remarkably efficient process for the preparation of gamma-secretase inhibitor 1. The target is synthesized in only five steps with an overall yield of 58%. The key operation is a highly selective and practical, crystallization-driven transformation for the conversion of a mixture of tertiary benzylic alcohols into the desired sulfide diastereomer with 94:6 dr. This unprecedented process is based upon a reversible carbon-sulfur bond formation under acidic conditions.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Carbono/química , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Enxofre/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Cristalização , Flúor/química , Cetoácidos/síntese química , Cetoácidos/química , Magnésio/química , Estrutura Molecular , Oxirredução , Inibidores de Proteases/química , Solubilidade , Estereoisomerismo , Sulfetos/química , TemperaturaRESUMO
An efficient synthesis of the potent KDR inhibitor 3-[5-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-1H-indole-2-yl]quinolin-2(1H)-one (1) is described. The process features a noncryogenic indole boronation and a dicyclohexylamine-mediated Suzuki coupling.
Assuntos
Inibidores da Angiogênese/síntese química , Indóis/síntese química , Piperazinas/síntese química , Proteínas Tirosina Quinases/antagonistas & inibidores , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Catálise , Indicadores e Reagentes , Indóis/química , Indóis/farmacologia , Estrutura Molecular , Piperazinas/química , Piperazinas/farmacologiaRESUMO
2-Indolyl borates are prepared via addition of LDA to a mixture of N-Boc-indole and triisopropyl borate at 0-5 degrees C. Following acidic hydrolysis, the boronic acids are isolated by crystallization in good to excellent yield (73-99%). The method is quite general, tolerating a wide range of functional groups, and also provides access to 2-silyl derivatives (80-91%).
Assuntos
Indóis/síntese química , Silanos/síntese química , Ácidos Bóricos/síntese química , Ácidos Bóricos/química , Indicadores e Reagentes , Indóis/química , Estrutura Molecular , Silanos/químicaRESUMO
An efficient stereoselective synthesis of the orally active NK(1) receptor antagonist Aprepitant is described. A direct condensation of N-benzyl ethanolamine with glyoxylic acid yielded a 2-hydroxy-1,4-oxazin-3-one which was activated as the corresponding trifluoroacetate. A Lewis acid mediated coupling with enantiopure (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol afforded a 1:1 mixture of acetal diastereomers which was converted into a single isomer via a novel crystallization-induced asymmetric transformation. The resulting 1,4-oxazin-3-one was converted via a unique and highly stereoselective one-pot process to the desired alpha-(fluorophenyl)morpholine derivative. Interesting and unexpected [1,2]-Wittig and [1,3]-sigmatropic rearrangements were identified during the optimization of these key steps. In the final step, a triazolinone side chain was appended to the morpholine core. The targeted clinical candidate was thus obtained in 55% overall yield over the longest linear sequence.