Nitroimidazoles with a halogen-containing side-chain

Abstract

Syntheses are reported for: nine 2-nitroimidazoles, the abbreviated names all beginning with E, based on derivation from Etanidazole); five 2-methyl-5-nitroimidazoles (M compounds, derived from Metronidazole); and five 2-methyl-4-nitroimidazoles (labelled 2M4N compounds). The nitroimidazoles all have an amide side-chain at the N1 atom of the imidazole, with 17 of them containing one to five halogen atoms. The aim is to study compounds for comparison with EF5 (the number showing the presence of five F-atoms), a previously reported, pentafluoropropylacetamide derivative of 2-nitroimidazole that is currently used as a hypoxia marker drug to detect cancerous tumours. The new compounds are characterized by standard methods, including X-ray structural data for the fluorinated MF5, 2M4NF5, and 2M4NF1(−1) species, with the “–1” indicating two C-atoms in an alkylamide chain rather than the three C-atoms in the propylacetamide of EF5. Intra- and inter-molecular H-bonding is seen in the solid state structures, likely an important property in biological use; another key property of the nitroimidazoles is their reduction potentials, and the measured CV data confirm that 2NO2Im compounds with longer side-chains and more F-atoms (like EF5) are worth investigating for possible activity as hypoxia-selective, bioreductive agents.

Oxazolidine Formation, or Loss of Acid, from Attempted Fluorination of Amide Side‐Chain in 2‐Nitroimidazoles

“…The bond lengths and angles for the nitroimidazole component are very similar to those of EF5 with the ring being completely planar, no atoms deviating by more than 0.006 Å from the mean plane. The C(4)–C(5) bond length of 1.317 Å is consistent with the exocyclic methylene functionality.…”

“…Attempts to synthesize the tosylate derivative of Etanidazole using p ‐toluenesulfonyl chloride (TsCl) produced, presumably via a tosylate intermediate (Scheme ), the known ECl1(−1) , previously made from 1 and H 2 N(CH 2 ) 2 Cl . [The (−1) in ECl1(−1) implies one C‐atom less than in the E ‐compounds of Chart 1].…”

“…We have synthesized EF1(−1) by reaction of 1 with an amine side‐chain ( cf . synthesis of EF2Br —see below) . Johnstrom and Stone‐Elander have reported the synthesis of 2,2,2‐trifluoroethyl triflate , which in theory could be coupled to a nitroimidazolacetamide (e.g.…”

“…We published recently the syntheses of derivatives of 2‐nitroimidazole (2NO 2 Im), 2‐methyl‐5‐nitroimidazole, and 2‐methyl‐4‐nitroimidazole . The derivatives all have an amide side‐chain at the N1‐atom of the imidazole, and most of them contain halogen atoms in this side‐chain; the 2‐nitroimidazoles are of the type shown as the products in Chart 1 and are analogous to the currently used hypoxia marker [ 18 F] EF5 (Chart 1) used to detect cancerous tumors . The E ‐labelling derives from the related, so‐called Etanidazole (Chart 1), followed by the numbers of halogen atoms.…”

“…The E ‐labelling derives from the related, so‐called Etanidazole (Chart 1), followed by the numbers of halogen atoms. The syntheses of EF5 (and EF3 ) derivatives involve reaction of a fluorine‐containing amino side‐chain with a carboxylic acid derivative of 2NO 2 Im ( 1 ) (Chart 1). An alternative route to incorporate fluorine is use of simple halogen (or hydrogen) exchange via a fluoride salt, and such a process to incorporate 18 F in compounds for use in nuclear imaging techniques such as PET is attractive in terms of overall time needed to make the 18 F compound, the half‐life of 18 F being only 110 min .…”