Abstract
A series of novel stereochemically pure derivatives of the investigative broad-spectrum anticonvulsant ADD408003 was designed and synthesized. Five-center four-component (U-5C-4CR) and four-center three-component (U-4C-3CR) variants of Ugi reaction were used in the key step of the synthetic pathways. The compounds obtained were evaluated for the anticonvulsant activitiy in the maximal electroshock seizure (MES), subcutaneous Metrazole (scMET) and minimal clonic seizure (6 Hz) animal models of epilepsy. The efficacies of most derivatives in the 6 Hz model of pharmacoresistant partial seizures were markedly higher than in the ‘classical’ MES and scMET models. The most active compounds, (4R,8aR)-3a, and (4S,8aS)-6 displayed median effective doses (ED50) of 47.90 and 126.19 mg/kg, respectively, for the 6 Hz test.
Highlights
According to epidemiological studies, epilepsy affects approximately 1% of the world’s population [1]. significant advances have been achieved in pharmacotherapy of this disorder, currently available anticonvulsant drugs (AEDs) produce satisfactory seizure control only in 60%–70% of patients
Since our previous studies on the stereochemistry-activity relationship of structurally related pyrido[1,2-a]pyrazines revealed interesting activity of (R,R) stereoisomers, we focused on synthesizing both (R,R) and (S,S) enantiomers of the new ADD408003 derivatives [8]
The appropriate (S)-amino acids were condensed with aldehydes or aliphatic ketones, tert-butyl isocyanide and methanol in the presence of catalytic amount of FeCl3 or TiCl4 to give Ugi adducts 1a–g with chemical yields ranging from 17% to 64% (Table 1)
Summary
Epilepsy affects approximately 1% of the world’s population [1]. Significant advances have been achieved in pharmacotherapy of this disorder, currently available anticonvulsant drugs (AEDs) produce satisfactory seizure control only in 60%–70% of patients. A preliminary structure–activity relationship (SAR) study revealed that several structural patterns are necessary for the high anticonvulsant activity: the (S,S) absolute configuration on the stereogenic centers, the presence of the annulated pyrrolidine ring, the presence of imide moiety and the benzene ring in C-4 position of the pyrrolo[1,2-a]pyrazine core. To complement our previous extensive SAR investigations in this group of active compounds [7,8,9,10], we synthesized and pharmalogically evaluated a new series of ADD408003 derivatives. Since our previous studies on the stereochemistry-activity relationship of structurally related pyrido[1,2-a]pyrazines revealed interesting activity of (R,R) stereoisomers, we focused on synthesizing both (R,R) and (S,S) enantiomers of the new ADD408003 derivatives [8]
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