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2004
Pyrrole derivatives
R 0120
Evaluation of Pyrrolidin-2-imines and 1,3-Thiazolidin-2-imines as Inhibitors of
Oxide Synthase. — The mono- and disubstituted pyrrolidinimines are prepared
52- 095 Nitric
essentially in three steps. Michael addition of nitroalkanes (II) to acrylates (I) followed
by hydrogenation of the intermediate nitroesters yield lactams (III). Lactams (III) are
transformed into amidines (VI) following two routes. The first method involves the
conversion of (III) to iminoether (V) followed by treatment of (V) with ammonium
chloride to give (VI) as mixture of stereoisomers. The second method which requires
the initial conversion of (III) into thioamides (VII) is preferred in these cases in which
the iminoethers (V) are too volatile. Quaternization of (VII) and reaction with methanolic ammonia afford (VI) as salts. Alternatively, (VII) can be directly converted into
(VI) by using gaseous ammonia. Small alkyl substituents at C-4 or C-5 lead to potent
amidines (VI) in addition to maintaining good selectivity (eNOS/iNOS). The class of
thiazolidinimines is far less significant both in potency and selectivity. —
(SHANKARAN*, K.; DONNELLY, K. L.; SHAH, S. K.; GUTHIKONDA, R. N.;
MACCOSS, M.; HUMES, J. L.; PACHOLOK, S. G.; GRANT, S. K.; KELLY, T. M.;
WONG, K. K.; Bioorg. Med. Chem. Lett. 14 (2004) 17, 4539-4544; Dep. Med.
Chem., Merck Res. Lab., Rahway, NJ 07065, USA; Eng.) — H. Hoennerscheid
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