Synthesis and pharmacological activity of a series of dihydro-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-diones, a novel class of potent cognition enhancers

Abstract

A series of dihydro-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-diones were synthesized. These bicylic derivatives contain both the 2-pyrrolidinone and 4-imidazolidinone nuclei, already recognized as important for cognition enhancing activity. In addition, these structures maintain the backbone of piracetam and oxiracetam with the acetamide side chain restricted in a folded conformation. Their ability to reverse scopolamine-induced amnesia was assessed in a one trial, step-through, passive avoidance paradigm. The main features observed are a potent antiamnestic activity after ip administration (minimal effective dose being between 0.3 and 1 mg/kg ip for most compounds), the presence of a bell-shaped dose-response curve and, generally, a reduction of biological activity after po administration. However, the unsubstituted compound (15, dimiracetam) shows no evidence of a bell-shaped dose-response curve and completely retains activity when given orally, being 10-30 times more potent than the reference drug oxiracetam.

Synthesis and Nootropic Activity of Some 2,3‐Dihydro‐1H‐isoindol‐1‐one Derivatives Structurally Related with Piracetam

“…1). Compound (RS)-2 from 0.3 to 10 mg/kg reverted scopolamine-induced amnesia [2] [17]. At doses higher than 10 mg/kg, (RS)-2 showed toxicity signs in mice, such as ataxia and tremors; therefore, we did not continue tests with doses higher than 10 mg/kg for nootropic activity.…”

“…Cognition enhancers, often referred as nootropics, are frequently used to treat such cognitive alterations. In some European countries, piracetam has been used for patients with a moderate degree of Alzheimers disease to increase the cognitive functions [1] with excellent tolerance and security [2]. Although the mode of action of piracetam in the nervous system is not well-defined, its efficacy has been documented in a wide range of clinical indications like cognitive disorders and dementia, vertigo, and dyslexia, as well as cortical myoclonus [3] [4].…”

“…At doses higher than 10 mg/kg, (RS)-2 showed toxicity signs in mice, such as ataxia and tremors; therefore, we did not continue tests with doses higher than 10 mg/kg for nootropic activity. Apparently, the absolute configuration of the stereogenic center is important for the activity, since (R,R)-3 was more active as nootropic than (R,S)-3 to inhibit the scopolamine-induced amnesia in the avoidance test in mice [2] Fig. 1), however, it was sufficient to revert the scopolamine-induced amnesia.…”

Novel Reductive Amination of Nitriles: An Efficient Route to 5‐Hydroxypiperidone‐Derived N,N‐Acetals

“…The most related exam- An Efficient Route to 5-Hydroxypiperidone-Derived N,N-Acetals COMMUNICATIONS ples of N,N-acetal formation are those where amino amides or diamines react with w-oxo-esters. [14] An advantage of our approach though, is that in combination with the HNL-mediated enantiopure cyanohydrin synthesis, we have facile access to the corresponding enantiomerically pure N,N-acetals. Beside the novel reductive amination of nitriles, by adjusting the reaction conditions and working with equimolar amounts of simple amines, we have also single step access to enantiomerically pure N-alkylated lactams from the same precursors.…”

Functional rearrangement of polychlorinated pyrrolidin-2-ones to 5-imino-lactams promoted by n-propylamine

“…This includes herbicides and plant growth regulators, 1-10 nootropic agents, 11 cognition enhancing pharmaceuticals, 12 antidepressants 13,14 and azamitosane systems. 15,16 Moreover, some g-lactams have found application in the assembly of polymers with semiconducting properties.…”