Based on SAR from bicyclic GnRH antagonists such as 6-aminomethyl-7-arylpyrrolo[1,2-a]pyrimid-4-ones (1) and 2-aryl-3-aminomethylimidazolo[1,2-a]pyrimid-5-ones (2a,b), a series of novel uracil compounds (4) were derived as the GnRH antagonists. Their syntheses and initial SAR are discussed herein. This is the first time that monocycle-based GnRH receptor antagonists are reported.

Based on the SAR from bicyclic gonadotropin-releasing hormone (GnRH) antagonists such as 6-aminomethyl-7-aryl-pyrrolo[1,2-a]pyrimid-4-ones (5) and 2-aryl-3-aminomethyl-imidazolo[1,2-a]pyrimid-5-ones (6a,b), a series of novel uracil compounds (8) were derived as GnRH antagonists. The synthesis and SAR studies of 6-methyluracils as human GnRH receptor antagonists are discussed herein. Introduction of a small methyl substituent at the beta-position of the N3 side-chain improved the GnRH binding potency by 5-10-fold. Introduction of a methyl group of (R)-configuration at the alpha-carbon of the N-3 side-chain gave a modest improvement in binding affinity over the unsubstituted ethylene analogues. This modification enabled us to make uracil compounds without the labile 2-pyridylethyl motif on the basic nitrogen while still maintained excellent potency against the hGnRH receptor.

Ring closure reactions of homoallylic alcohols 1 can be effected by various electrophiles (E+), which commonly include protons, Hg+2,1 various sources of I+,2 and PhSeX (X = Cl, phthalimide).3 Stereoselectivities of cyclizations vary widely depending upon substrate structure (Figure 1) as well as choices of E*, temperature, and especially solvent.33 ® We now describe a new reagent for purposes of providing a general solution to tetrahydrofuranforming processes of the 5-endo-trig-like type.4 Moreover, in many cases, remarkably enhanced diastereoselectivities are to be expected relative to previously reported results.The reagent (2,4,6-triisopropylphenyl)selenium bromide, 4, derives from diselenide 3. This precursor is a known, stable, orange-yellow solid (mp 101-103 °C),5 prepared from commercially available 2,4,6-triisopropylbromobenzene (2)6 via lithiation and subsequent treatment with selenium (Scheme 1). Dissolution of 3 in CH2CI2 followed by cooling to -78°and dropwise addition of Br2 (1 equiv) generates 4 which is immediately ready for use.

No abstract

A strategy for the salt selection of NBI-75043 is presented and summarized in a decision-tree format. This is followed by the first scale-up of the process, confirmation of a new polymorph, and description of a method for its conversion to the initial form.