ABSTRACT
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.
Subject(s)
Amides/chemical synthesis , Fluorine Radioisotopes , Pyridines/chemical synthesis , Radiopharmaceuticals/chemical synthesis , Receptor, Cannabinoid, CB1/metabolism , Amides/chemistry , Amides/pharmacokinetics , Animals , Brain/diagnostic imaging , Brain/metabolism , CHO Cells , Cricetinae , Cricetulus , Humans , Macaca mulatta , Positron-Emission Tomography , Pyridines/chemistry , Pyridines/pharmacokinetics , Radioligand Assay , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/pharmacokinetics , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Recombinant Proteins/metabolism , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Carbon/chemistry , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Sulfur/chemistry , Amyloid Precursor Protein Secretases/metabolism , Crystallization , Fluorine/chemistry , Keto Acids/chemical synthesis , Keto Acids/chemistry , Magnesium/chemistry , Molecular Structure , Oxidation-Reduction , Protease Inhibitors/chemistry , Solubility , Stereoisomerism , Sulfides/chemistry , TemperatureABSTRACT
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.
Subject(s)
Angiogenesis Inhibitors/chemical synthesis , Indoles/chemical synthesis , Piperazines/chemical synthesis , Protein-Tyrosine Kinases/antagonists & inhibitors , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/pharmacology , Catalysis , Indicators and Reagents , Indoles/chemistry , Indoles/pharmacology , Molecular Structure , Piperazines/chemistry , Piperazines/pharmacologyABSTRACT
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.
Subject(s)
Morpholines/chemical synthesis , Neurokinin-1 Receptor Antagonists , Aprepitant , Crystallography, X-Ray , Lactams/chemical synthesis , Lactams/chemistry , Molecular Structure , Morpholines/chemistry , Oxazines/chemistry , StereoisomerismABSTRACT
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%).