5-Arylidene-3-aryl-pyrrolidine-2,4-diones with Affinity to theN-Methyl-D-aspartate (Glycine Site) Receptor, Part I

Abstract

A series of new 5‐arylidene 3‐aryl‐pyrrolidine‐2,4‐diones has been prepared. Their binding affinity toward the N‐methyl‐D‐aspartate (glycine site) receptor has been measured as a basis for more detailed structure‐activity relationship studies.

Metal-Catalyzed and Metal-Mediated Approaches to the Synthesis and Functionalization of Tetramic Acids

“…After deprotection, the corresponding 3-hydroxy tetramic acid 63 is formed, thus leading to the monoether 64 at C-4 of the ring or to the dietheric tetramic acid 65. Later, the same group applied this method for the incorporation of an aryl group at C-3 of the ring using anisole or benzene instead of alcohol in a sealed tube (Scheme 20; Part B) [141]. This protocol was first presented for the synthesis of similar maleimide derivatives [142].…”

Grevellin Analogs with Affinity to theN-Methyl-D-aspartate (Glycine Site) Receptor, a Novel Lead Structure

“…In contrast to the highly active 3-aryl-4-hydroxyquinoline-2H(1H)-ones [4] and 3-aryltetramic acids [5,21] in this case the lipophilic aryl moiety is placed in 4-position and the acidic group in 3-position. Furthermore the requirement of a 1-NH group is to be questioned in the light of our findings.…”

“…Starting with the known 5-arylidene tetramic acids 6b-e [5] and 6f [9] , acid catalyzed condensation with acetone afforded the alkylidene pyrrolidinediones 7b-f. Oxidation with alkaline hydrogen peroxide led to oxides 8b-f and their cleavage by boron trifluoride or mineral acids to the reductones 9b-f. Oxidation of these compounds to the triones 10b-f was accomplished by elemental iodine.…”

“…A solution of the appropriate tetramic acids 6b-e [5] or 6f [9] in acetone (100 ml) was refluxed in the presence of aqueous hydrochloric acid (35%, 5 ml). Yellow crystals separated after a short period of time.…”

“…Therefore the glycine site on NMDA receptors represents an interesting target in the development of potential neuroprotective and other drugs. A number of compounds from different classes have been recognized as functional antagonists at the glycine site, inter alia 4-hydroxyquinoline-2(1H)ones 1 [4] , aryl-substituted 5-arylidene tetramic acids 2 [5] , and 5-arylidene pyrrolidine-2,3,4-triones or PTOs 3 [6] (Scheme 1). An account of aspects of structure-activity relationships of several compounds active at the glycine site of the NMDA receptor and possible therapeutic applications has been given by Dannhardt and Kohl [7] .…”