RESUMO
A novel series of cyanoguanidine-piperazine P2X(7) antagonists were identified and structure-activity relationship (SAR) studies described. Compounds were assayed for activity at human and rat P2X(7) receptors in addition to their ability to inhibit IL-1 beta release from stimulated human whole blood cultures. Compound 27 possesses potent activity (0.12 microM) in this latter assay and demonstrates moderate clearance in-vivo.
Assuntos
Guanidinas/química , Piperazinas/química , Antagonistas do Receptor Purinérgico P2 , Animais , Química Farmacêutica/métodos , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Interleucina-1beta/antagonistas & inibidores , Modelos Químicos , Estrutura Molecular , Piperazina , Ratos , Receptores Purinérgicos P2/química , Receptores Purinérgicos P2X7 , Relação Estrutura-AtividadeRESUMO
[reaction: see text] A readily available iso-leucine-based phosphine ligand is used to promote Ag-catalyzed Mannich reactions between silylketene acetals and various alkynyl imines. Reactions can be effected in the presence of 5 mol % catalyst, without the need for rigorous exclusion of air, and with commercially available solvents (without purification) to afford the desired beta-alkynyl-beta-amino esters in 84-94% ee and 61-91% isolated yield.
Assuntos
Alcinos/química , Alcinos/síntese química , Aminoácidos/síntese química , Acetais/química , Catálise , Ésteres , Iminas/química , Indicadores e Reagentes , Estrutura Molecular , Silanos/química , Prata/química , EstereoisomerismoRESUMO
An efficient catalytic and enantioselective method (up to >98% ee) for Mannich reactions between trimethylsilyl enol ethers derived from acetone and acetophenone and aryl, alkenyl, alkynyl, and alkyl imines is disclosed. A large variety of beta-amino ketones can be synthesized in the presence of 1-5 mol % AgOAc and an inexpensive and readily available amino acid-derived phosphine. All Ag-catalyzed asymmetric Mannich reactions can be run in undistilled THF and air. The o-anisyl activating groups of product amines can be removed in >70% isolated yield through a single vessel operation. The synthetic utility of the catalytic asymmetric method is illustrated by a four-pot synthesis of optically pure alkaloid (-)-sedamine.
Assuntos
Iminas/química , Bases de Mannich/síntese química , Prata/química , Compostos de Trimetilsilil/química , Catálise , Ciclização , Éteres/química , Bases de Mannich/química , Estrutura MolecularRESUMO
An efficient Ag-catalyzed method for asymmetric addition of the Danishefsky diene to various aryl imines to afford cycloadducts in > or =89% ee and > or =85% isolated yield is reported. Reactions are effected with 0.1-1 mol % catalyst (4 degrees C), and the chiral ligand is readily prepared from commercially available materials, including the inexpensive i-Leu. These catalytic asymmetric cycloadditions can be carried out without the use of solvent or with undistilled THF in air. A first generation supported chiral catalyst that effectively promotes the cycloaddition reaction and can be recycled (five cycles) is described.
