Complex sentence: Isaac, despite his protests, never actively threatened Manuel's rule, however, and despite Manuel's repeated disgrace and imprisonment of the "sebastokratorissa" Irene, he showed great favour to the couple's sons, particularly Alexios' older brother John.
Split into simpler sentences: Isaac, despite his protests, never actively threatened Manuel's rule, however. Although Alexios' mother, the "sebastokratorissa" Irene, suffered repeated disgrace and imprisonment at the hands of Manuel, the emperor showed great favour to her sons, particularly Alexios' older brother John.