Preparation of heterocyclic heme-oxygenase inhibitors and use in the treatment of cancer and CNS diseases.

Abstract

Disclosed are compds. of the general formula T-(C)n-D (wherein T is a hydrophobic moiety; n is 1-6: C is optionally substituted; D is a moiety that binds Fe), compns. comprising an effective amt. of said compds. either alone or in combination with other chemotherapeutic agents, and methods useful for treating or preventing cancer and for inhibiting tumor tissue growth. These compds. attenuate the oxidative damage assocd. with increased heme-oxygenase activity and can reduce cell proliferation in transformed cells. In addn., the described compds. and compns. are useful as neuroprotectants and for treating or preventing neurodegenerative disorders and other diseases of the central nervous system. Synthetic procedures for prepg. compds. of the invention are exemplified and claimed. Example compd. I was prepd. by reacting 4-(4-bromophenyl)-1-(1H-imidazol-1-yl)-2-butanone (prepn. given) with ethylene glycol. At 6.5 μM I significantly attenuated heme oxygenase activity in transiently transfected cells without affecting the expression levels. At this same concn. II significantly attenuated 3H-thymidine incorporation in human pancreatic tumor cells. [on SciFinder(R)]