RESUMEN
Multisubstituted piperidines containing a phenyl group at C-2 can be opened regio- and stereoselectively with cyanogen bromide. The ring-opened products contain useful cyanamide and benzylic bromide functional groups. This methodology is useful for the stereoselective synthesis of uniquely substituted alkylamine derivatives containing multiple chiral centers and various functionality.
Asunto(s)
Amino Alcoholes/síntesis química , Piperidinas/química , Compuestos de Bencilo/química , Cianamida/química , Bromuro de Cianógeno/química , Ciclización , EstereoisomerismoRESUMEN
Various multisubstituted piperidines containing a phenyl group at C-2 can be opened regio- and stereoselectively with cyanogen bromide. The ring-opened products contain useful cyanamide and benzylic bromide functional groups. The benzyl bromide can be cleanly reduced, or substituted with various nucleophiles via an S(N)2 process to add additional heteroatoms stereoselectively. This methodology is useful for the stereoselective synthesis of uniquely substituted alkylamine derivatives containing multiple chiral centers and various functionality. Diastereomerically pure amino alcohols containing three to five contiguous stereocenters were prepared using this strategy.
Asunto(s)
Amino Alcoholes/química , Amino Alcoholes/síntesis química , Catálisis , Bromuro de Cianógeno/química , Hidrogenación , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Modelos Moleculares , Conformación Molecular , Piperidinas/química , Espectrofotometría Infrarroja , EstereoisomerismoRESUMEN
Multisubstituted piperidines containing a trimethylsilylmethyl group at C-2 can be opened regioselectively with TBAF and cyanogen bromide. The ring-opened products contain synthetically useful cyanamide and terminal alkene functional groups. This method is useful for the stereoselective synthesis of alkylamine derivatives containing multiple chiral centers.
Asunto(s)
Amino Alcoholes/síntesis química , Piperidinas/química , Compuestos de Trimetilsililo/química , Amino Alcoholes/química , Bromuro de Cianógeno/química , Estructura Molecular , EstereoisomerismoRESUMEN
A novel class of heat shock protein 90 (Hsp90) inhibitors was developed from an unbiased screen to identify protein targets for a diverse compound library. These indol-4-one and indazol-4-one derived 2-aminobenzamides showed strong binding affinity to Hsp90, and optimized analogues exhibited nanomolar antiproliferative activity across multiple cancer cell lines. Heat shock protein 70 (Hsp70) induction and specific client protein degradation in cells on treatment with the inhibitors supported Hsp90 inhibition as the mechanism of action. Computational chemistry and X-ray crystallographic analysis of selected member compounds clearly defined the protein-inhibitor interaction and assisted the design of analogues. 4-[6,6-Dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-[(trans-4-hydroxycyclohexyl)amino]benzamide (SNX-2112, 9) was identified as highly selective and potent (IC(50) Her2 = 11 nM, HT-29 = 3 nM); its prodrug amino-acetic acid 4-[2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-phenylamino]-cyclohexyl ester methanesulfonate (SNX-5422, 10) was orally bioavailable and efficacious in a broad range of xenograft tumor models (e.g. 67% growth delay in a HT-29 model) and is now in multiple phase I clinical trials.