BETA-SUBSTITUTED GAMMA-AMINO ACIDS AND ANALOGS AS CHEMOTHERAPEUTIC AGENTS

摘要

β-Substituted γ-amino acids, β-substituted γ-amino acid derivatives, and β-substituted γ-amino acid analogs and (bio)isosteres and their use as chemotherapeutic agents are disclosed. The β-substituted γ-amino acid derivatives and β-substituted γ-amino acid analogs and (bio)isosteres are selective LAT1/4F2hc substrates, capable of passing through the blood-brain barrier, and exhibit rapid uptake and retention in tumors expressing the LAT1/4F2hc transporter. Methods of synthesizing the β-substituted γ-amino acid derivatives and β-substituted γ-amino acid analogs and (bio)isosteres and methods of using the compounds for treating tumors are also disclosed. The β-substituted γ-amino acid derivatives and β-substituted γ-amino acid analogs and (bio)isosteres exhibit an improved selectivity toward tumor cells expressing the LAT1/4F2hc transporter and accumulate in cancerous cells when administered to a subject in vivo. The β-substituted γ-amino acid derivatives and β-substituted γ-amino acid analogs and (bio)isosteres exhibit an increased efficacy on a variety of tumor types.

主权项

1. A compound of Formula (1): or a pharmaceutically acceptable salt thereof, wherein: R1 is C1-6 alkyl; one of R3 and R4 comprises a nitrogen mustard; each of the other of R2, R3, R4, and R5 is independently selected from hydrogen, deuterio, and C1-6 alkyl; R6 is —COOH; each R7 is independently selected from hydrogen and deuterio; R8 is selected from hydrogen, deuterio, and C1-6 alkyl; L is a bond.