Synthesis and Anticonvulsant Activity of Substituted‐1,3‐diazaspiro[4.5]decan‐4‐ones

Abstract

A series of novel spiroimidazolidinone derivatives 6a-d and 8a-x were synthesized and biologically evaluated for their anticonvulsant activity in the maximal electroshock seizure (MES) assay and the subcutaneous pentylenetetrazole (scPTZ) screening test. Compound 8w was the most active derivative in the scPTZ screening test with an ED50 value by about 5- and 83.6-fold lower than those of phenobarbital and ethosuximide as reference drugs, respectively. Most of the tested compounds exhibited moderate to weak activity in the MES screen test, except for 8a which displayed 100% protection at 0.09 mmol/kg. Moreover, all the test compounds did not show any minimal motor impairment in the neurotoxicity test.

CyClick Chemistry for the Synthesis of Cyclic Peptides

“…In addition, this macrocyclization would lead to the generation of a new chiral center with high stereoselectivity and introduce a nonpeptidic moiety, 4‐imidazolidinone, into the macrocycle. This is a feature that is known to generally improve the intrinsic pharmacokinetic profile while maintaining biological activity …”

“…This approach represents ar are example of conformationally induced amide bond activation that might offer ageneral strategy for the efficient synthesis of 4-imidazolidinone-fused cyclic peptides ( Figure 1). 4-Imidazolidinone is an important structural motif found in many pharmaceuticals and biologically active compounds, [23,24] such as N,N'-methyleno-didemnin A, [25] which is cytotoxic against human colon tumor cells;s piroimidazolidinone,w hich exhibits anticonvulsant activity; [26] Ro 64-6198, an agonist for the nociceptin/orphanin FQ opioid peptide (NOP) receptor; [27] and ML298, as elective inhibitor of phospholipase D (PLD) [28] (Figure 1c).…”

Crystal structure of 2,3-diphenyl-1-(morpholin-4-ylacetyl)-1,3-diazaspiro[4.5]decan-4-one, C26H31N3O3

“…The title molecule, displayed a good anticonvulsant activity (83% protection) against subcutaneous pentylenetetrazole induced convulsions at dose level 0.025 mmol/kg. Whereas, it exhibited mild anticonvulsant activity (66% protection) against maximal electric shock induced convulsions, at the same dose level [1]. The asymmetric unit of the title compound contains one molecule.…”

“…The crude product was re-crystallized from a mixture of petroleum ether (40-60) and ethyl acetate to afford white crystals (m.p. 441-443 K) in 60% yield [1]. Crystals were obtained by slow evaporation of its ethyl acetate solution.…”

Crystal structure of 2,3-diphenyl-1-[(dipropylamino)acetyl]-1,3-diazaspiro[4.5]decan-4-one, C28H37N3O2

“…The organic phase was washed with water, dried (Na 2 SO4) and evaporated under vacuum to yield the title compound as a viscous oil. The crude oil was purified by column chromatography using silica gel as a stationary phase and a mixture of petroleum ether (40-60°C): ethyl acetate (7:3) as a mobile phase to give the title compound as a white [4]. The title compound was re-crystallized from ethyl acetate to afford colorless single crystals.…”