Synthesis of aza and carbocyclic β-carbolines for the treatment of alcohol abuse. Regiospecific solution to the problem of 3,6-disubstituted β- and aza-β-carboline specificity

Org Biomol Chem. 2015 Nov 21;13(43):10705-15. doi: 10.1039/c5ob01572c.

Abstract

A novel two step protocol was developed to gain regiospecific access to 3-substituted β- and aza-β-carbolines, 3-PBC (1), 3-ISOPBC (2), βCCt (3), 6-aza-3-PBC (4) and 6-aza-3-ISOPBC (5). These β-carbolines (1-3) are potential clinical agents to reduce alcohol self-administration, especially 3-ISOPBC·HCl (2·HCl) which appears to be a potent anti-alcohol agent active against binge drinking in a rat model of maternally deprived (MD) rats. The method consists of two consecutive palladium-catalyzed reactions: a Buchwald-Hartwig amination followed by an intramolecular Heck-type cyclization in high yield.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alcoholism / drug therapy*
  • Animals
  • Aza Compounds / chemical synthesis*
  • Aza Compounds / chemistry
  • Aza Compounds / therapeutic use
  • Binge Drinking / drug therapy
  • Carbolines / chemical synthesis*
  • Carbolines / chemistry
  • Carbolines / therapeutic use
  • Catalysis
  • Models, Molecular
  • Palladium / chemistry*
  • Rats
  • Stereoisomerism

Substances

  • Aza Compounds
  • Carbolines
  • Palladium