Chiral cis-imidazolines

This application is a continuation of U.S. application Ser. No. 11/129,621, filed May 13, 2005, now pending, which claims the benefit of provisional Application(s) Ser. No. 60/572,275, filed May 18, 2004; Ser. No. 60/615,534 filed Oct. 1, 2004 and Ser. No. 60/668,772, filed Apr. 5, 2005. The entire contents of the above identified applications are hereby incorporated by reference.

This invention is related to at least one compound selected from a compound of formula I

or the pharmaceutically acceptable salts thereof, wherein X₁, X₂, X₃, R, Y₁ and Y₂ are described in this application. These compounds are believed to inhibit the interaction of MDM2 protein with a p-53-like peptide and have antiproliferative activity.

p53 is a tumor suppresser protein that plays a central role in protection against development of cancer. It guards cellular integrity and prevents the propagation of permanently damaged clones of 1 cells by the induction of growth arrest or apoptosis. At the molecular level, p53 is a transcription factor that can activate a panel of genes implicated in the regulation of cell cycle and apoptosis. p53 is a potent cell cycle inhibitor which is tightly regulated by MDM2 at the cellular level. MDM2 and p53 form a feedback control loop. MDM2 can bind p53 and inhibit its ability to transactivate p53-regulated genes. In addition, MDM2 mediates the ubiquitin-dependent degradation of p53. p53 can activate the expression of the MDM2 gene, thus raising the cellular level of MDM2 protein. This feedback control loop insures that both MDM2 and p53 are kept at a low level in normal proliferating cells. MDM2 is also a cofactor for E2F, which plays a central role in cell cycle regulation.

The ratio of MDM2 to p53 (E2F) is dysregulated in many cancers. Frequently occurring molecular defects in the p161NK4/p19ARF locus, for instance, have been shown to affect MDM2 protein degradation. Inhibition of MDM2-p53 interaction in tumor cells with wild-type p53 should lead to accumulation of p53, cell cycle arrest and/or apoptosis. MDM2 antagonists, therefore, can offer a novel approach to cancer therapy as single agents or in combination with a broad spectrum of other antitumor therapies. The feasibility of this strategy has been shown by the use of different macromolecular tools for inhibition of MDM2-p53 interaction (e.g. antibodies, antisense oligonucleotides, peptides). MDM2 also binds E2F through a conserved binding region as p53 and activates E2F-dependent transcription of cyclin A, suggesting that MDM2 antagonists might have effects in p53 mutant cells.

Wells et al. J. Org. Chem., 1972, 37, 2158-2161, report synthesis of imidazolines. Hunter et al., Can. J. Chem., 1972, Vol. 50, pgs. 669-77, report the preparation of amarine and isoamarine compounds which had previously been studied for chemiluminescence (McCapra et al. Photochem. and Photobiol. 1965, 4, 1111-1121). Zupane et al. Bull. Soc. Chem. & Tech. (Yugoslavia) 1980-81, 27/28, 71-80, report the use of triaryl imidazolines as starting materials in the preparation of EDTA derivatives.

EP 363 061 to Matsumoto reports imidazoline derivatives useful as immunomodulators. The compounds were indicated to have low toxicity. Treatment and/or prevention of rheumatoid arthritis, multiple sclerosis, systemic lupus, erythemathodes, and rheumatic fever were implicated. WO 00/78725 to Choueiry et al. report a method for making substituted amidine compounds, and indicate that imidazoline-type compounds may be useful in the treatment of diabetes or related diseases involving impaired glucose disposal.

U.S. Pat. No. 6,617,346 B1 issued Sep. 9, 2003 and U.S. Pat. No. 6,734,302 B2 issued May 11, 2004 disclose related racemic cis-imidazolines.

The present invention provides at least one compound of formula I