Synthesis of a New Family of N‐Aryl Lactams Active on Chemesthesis and Taste

Abstract

A new class of synthetic compounds with chemesthetic activity has been identified. They have been designed ex‐novo by structural similarity with known cooling compounds such as menthol, icilin and cyclic ketoenamines. 19 new derivatives have been obtained easily and in high yields by Goldberg arylation or lactam ring closure on the appropriate phenol or benzoic acid derivative. The synthetic procedures are suitable for gram‐scale preparation, and the products are stable and easy to purify. 17 new compounds were submitted to preliminary sensory evaluation, and 3 of them showed cooling activity and, in some cases, tingling sensation in the oral cavity. These N‐aryl lactams seem to be an interesting class of compounds to be enlarged in order to derive structure‐activity relationships. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Tryptamine-Based Derivatives as Transient Receptor Potential Melastatin Type 8 (TRPM8) Channel Modulators

“…Introduction of substituents at position 2 of naphthalene ring, such as OMe (16) and OH (17) induced a shift from agonist to antagonistic activity for these derivatives at high concentration (Fig. 1 B).…”

“…The non-substituted N-1 indole derivatives (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21) were quite productive. A direct linkage of the amine moiety with different bulky aromatic groups, such as naphthalene and quinolines, gives compounds 8-11 unable to act as TRPM8 modulators ( Figures 1A and 1B).…”

Synthesis of Two Coumarins Isolated from Aster praealtus

“…However, under the CuI/Cs 2 CO 3 /1,10-phenanthroline/toluene/110 ℃ conditions [16] the coupling of 12 [18] with 3 proceeded smoothly (Scheme 2), affording the corresponding coupling product 11 in 71% isolated yield. Debenzylation of 13 could also be achieved satisfactorily under Liu's [19] Li/naphthalene conditions.…”

Transient Receptor Potential Melastatin 8 Channel (TRPM8) Modulation: Cool Entryway for Treating Pain and Cancer

“…The activation/sensitization to cold of mammalian TRPM8 seems to be responsible for the enhancement of innocuous cold and noxious cold sensations induced by camphor, which also potentiate heat sensations through activation of TRPV1 and TRPV3 channels. 150 5-Methyl-2-(1-pyrrolidinyl)-2-cyclopenten-1-one (11), isolated from roasted malt, 151 and some hybrid derivatives, 152 were identified as intense cooling compounds. Although authors mentioned TRPM8 channels as cold-sensitive receptors, no data is provided regarding the direct action of these compounds on the mentioned thermoreceptor.…”