Anticonvulsants. I. An Investigation of N-R-α-R<sub>1</sub>-α-Phenylsuccinimides

Miller, C. A.; Long, Loren M.

doi:10.1021/ja01154a126

Cited by 129 publications

(56 citation statements)

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“…Subsequent reaction of 5a with benzyl amine gave the succinimic acid 6a, which was cyclized to succinimide 7a in refluxing acetic anhydride (Scheme 1). 4 Other succinimides 7b−h were also prepared following the above procedure. These were characterized by 1 H and 13 C NMR and were directly used for the reduction without further analytical characterization.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of 3,3-diarylpyrrolidines from diaryl ketones

Katritzky¹,

Nair²,

Witek³

et al. 2003

Arkivoc

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Section: Resultsmentioning

confidence: 99%

Synthesis of 3,3-diarylpyrrolidines from diaryl ketones

Katritzky¹,

Nair²,

Witek³

et al. 2003

Arkivoc

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“…It was decided to administer "C-methsuximide at a dosage known to be effective against both leptazol-and electrically-induced convulsions. A dose of 100 mg/kg was therefore chosen (Chen et al*, 1963;Miller & Long, 1951). Radioactivity measurement Radioactivity was measured by liquid scintillation counting with a Tracerlab Coru/Matic 100 Dual Channel Scintillation Spectrometer.…”

Section: Methodsmentioning

confidence: 99%

The physiological disposition of ¹⁴C‐methsuximide in the rat

Nicholls¹,

Orton²

1972

British J Pharmacology

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Summary1. "C-Methsuximide (N-methyl-"C-2-methyl-2-phenylsuccinimide) was rapidly absorbed from the small intestine of the rat (to 17A4 min). 2. The drug was rapidly and fairly evenly distributed throughout the body with peak blood and tissue levels occurring 1 h after oral administration. At all times, adrenals, body fat, kidneys and liver had higher levels of "Cmethsuximide than other tissues and the drug freely traversed the blood-brain barrier. However, radioactivity disappeared rapidly from most tissues after the initial phase of the distribution. 3. During 24 h, 26% of the orally administered radioactivity was recovered in urine and 29% appeared in expired air as "CO2. The excretion 'of-"CO2 indicated N-demethylation of "C-methsuximide to 2-methyl-2-phenylsuccinimide. 2-7% of an administered dose of methsuximide was excreted unchanged in 24 h urine and 2-7% appeared as 2-methyl-2-phenylsuccinimide. 2-Methyl-2-phenylsuccinimide was also detected as a urinary metabolite of methsuximide in man.4. 2-Methyl-2-phenylsuccinimide possesses anticonvulsant activity and it is suggested that this metabolite contributes to the overall anticonvulsant activity and toxicity of methsuximide. 5. Rat urine also contained a radioactive substance with similar chromatographic properties to one of the products of alkaline hydrolysis of methsuximide. This compound may arise from the spontaneous decomposition of the parent drug in vivo.

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“…The starting 2-benzhydryl-(1) and 2-isopropyl-succinic (2) acids were prepared according to the method described by Miller and Long 14 .…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and anticonvulsant activity of new N-mannich bases derived from benzhydryl- and isopropyl-pyrrolidine-2,5-dione

Rybka

Obniska

Rapacz

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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Synthesis and anticonvulsant properties of 26 new N-Mannich bases of 3-benzhydryl-(5-17) and 3-isopropyl-pyrrolidine-2,5-diones (18-30) have been described. Initial anticonvulsant screening for these compounds was evaluated in mice after intraperitoneal administration in the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizures tests. The acute neurological toxicity was determined by applying the rotorod test. The in vivo results in mice showed that the majority of 3-benzhydryl-pyrrolidine-2,5-dione derivatives revealed effectiveness, while 3-isopropyl-pyrrolidine-2,5-dione derivatives were practically devoid of activity. The quantitative evaluation in both tests revealed that the most active were N-[{4-(3-chlorophenyl)-piperazin-1-yl}-methyl]-3-benzhydryl-pyrrolidine-2,5-dione (9) with ED 5 0 value ¼42.71 mg/kg (MES), ED 5 0 value4150 mg/kg (scPTZ), and N-[{4-(3-trifluoromethylphenyl)-piperazin-1-yl}-methyl]-3-benzhydryl-pyrrolidine-2,5-dione (13) with ED 5 0 value ¼101.46 mg/kg (MES) and ED 5 0 value ¼72.59 mg/kg (scPTZ). These molecules showed higher potency and lower neurotoxicity than the reference antiepileptic drugs (ethosuximide and valproic acid). To explain the probable mechanism of action of selected active derivatives (9 and 13), their influence on Na v 1.2 and L-type calcium channel was evaluated in vitro.

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Anticonvulsants. I. An Investigation of N-R-α-R₁-α-Phenylsuccinimides

Cited by 129 publications

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Synthesis of 3,3-diarylpyrrolidines from diaryl ketones

Synthesis of 3,3-diarylpyrrolidines from diaryl ketones

The physiological disposition of ¹⁴C‐methsuximide in the rat

Synthesis and anticonvulsant activity of new N-mannich bases derived from benzhydryl- and isopropyl-pyrrolidine-2,5-dione

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Anticonvulsants. I. An Investigation of N-R-α-R1-α-Phenylsuccinimides

Cited by 129 publications

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Synthesis of 3,3-diarylpyrrolidines from diaryl ketones

Synthesis of 3,3-diarylpyrrolidines from diaryl ketones

The physiological disposition of 14C‐methsuximide in the rat

Synthesis and anticonvulsant activity of new N-mannich bases derived from benzhydryl- and isopropyl-pyrrolidine-2,5-dione

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Anticonvulsants. I. An Investigation of N-R-α-R₁-α-Phenylsuccinimides

The physiological disposition of ¹⁴C‐methsuximide in the rat