An alternative to the use of δ-lactam urethanes in the “ring switch” approach to higher homologues of AMPA-type glutamate antagonists

Abstract

In an alternative strategy to the use of delta-lactam urethanes for the preparation of homologues of AMPA-type glutamate antagonists, we have used 5-exomethylene derivatives of pyroglutamate esters. The homochiral pyrazole amino acid derivatives 18 and 19 have been prepared in this way. Although this synthesis yields products with a glycine residue separated from a heterocyclic ring by two carbon atoms, the substitution of the heterocyclic ring is different from that in compounds prepared from delta-lactam urethanes. The branched chain compounds 32 and 33 have also been prepared in this way but the second chiral centre is epimerised during the synthesis. An interesting reaction, giving the pyridone 27 from the imino ether 24 and tert-butyl acetoacetate, is also reported.

Ethyl (2E)-3-oxo-2-(pyrrolidin-2-ylidene)butanoate

“…Cyclic enaminones in which a ring N atom is conjugated through an exocyclic double bond to two different carbonyl groups have found application in the synthesis of alkaloids (Wick et al, 1971), antitubercular indolizinones (Dannhardt et al, 1987) and potential glutamate antagonists (Hitchcock et al, 2003), among others. We required the title compound, (I), a simple example of this type of enaminone, as a precursor in our ongoing programme aimed at the total synthesis of indolizidine alkaloids (Michael et al, 1999).…”

Expedited Route to Fully Substituted Amino-Pyrazole Building Blocks and Their Further Transformations

“…These combined findings suggested that these 1,3-dielectrophilic compounds can be expected to react with hydrazine derivatives in a very regioselective fashion. − …”

Synthesis and Biological Evaluation of tert-Butyl Ester and Ethyl Ester Prodrugs of L-γ-Methyleneglutamic Acid Amides for Cancer

“…Treatment of 33 with 3M HCl removed only the Boc protecting group, 23 affording the desired 32 in 85% yield. Treatment of 35 with 3M HCl 23 produced the desired 34 in 66% yield. Scheme 3.…”

“…The capacity for the tert-butyl ester and ethyl ester prodrugs of the L-γ-methyleneglutamic acid amides (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) and the cyclic metabolite and its tert-butyl ester and ethyl ester prodrugs (31 -35) to inhibit the growth of the three breast cancer cell lines MCF-7, SK-BR-3, and MDA-MB-231 and the non-malignant MCF-10A breast cell line was assessed after 72 h of treatment (Figure 8). The potencies of all compounds on MCF-7 or SK-BR-3 cell lines were markedly reduced compared to those of previously identified leads (5, 6, or 9; Figure 2), and none exhibited a significant increase in potency compared to positive controls or were equipotent to compounds 5, 6, or 9.…”

“…Cell death for the tert-butyl ester and ethyl ester prodrugs of the L-γ-methyleneglutamic acid amides (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) and the cyclic metabolite and its tert-butyl ester and ethyl ester prodrugs (31 -35) on the three breast cancer cell lines MCF-7, SK-BR-3, and MDA-MB-231 and the non-malignant MCF-10A breast cell line was also assessed after 72 h of treatment (Figure 9). No compound exhibited significantly greater or equipotent effects to promote cancer cell death compared to 5, 6, or 9 on any breast cancer cell line.…”