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Synthesis and structure activity study of N‐1 substituted (S)‐(+)‐5‐n‐propyl‐2‐iminohydantoins as potential anticonvulsant agents

A series of (S)‐(+)‐5‐n‐propyl‐2‐iminohydantoins with various N‐1 substituents were synthesized and tested for anticonvulsant activity to better understand the structure–activity relationship (SAR) of 2‐iminohydantoins. Compounds with N‐1 phenoxycarbonyl (2), ethoxycarbonyl (6), t‐butoxycarbonyl (7), propoxycarbonyl (12), and p‐methyl phenoxycarbonyl (14) groups provided the most substantial anticonvulsant activity against the maximal electroshock seizure (MES) test with ED50 values in the range of 72–124 mg/kg. All of the above compounds except 7 also showed activity against the pentylenetetrazol (PTZ) test with ED50 values in the range of 65–178 mg/kg. Compound 6 provided the highest protective index (PI) value against the PTZ test, while 7 provided the highest PI value against the MES test. All significantly active compounds against the MES test (1, 2, 6, 7, 12, and 14) possessed aliphatic hydrocarbon chains of relatively small carbon length or aryl/arylalkyl groups not greater than benzyl in the carbamate moiety. Longer or larger than a benzyl group (3, 5, 8, 9, 10, and 11) or a saturated six‐member ring (4) destroyed the activity. In addition, N‐1 methoxycarbonyl substituted compound (13) was also devoid of significant activity. These results suggest that steric size of the substituent at N‐1 oxycarbonyl sidechain in the 2‐iminohydantoin molecule plays an important role in providing anticonvulsant activity, and that an alkyl substituent with a proper size further enhances PTZ anticonvulsant activity while maintaining MES activity. Drug Dev. Res. 47:17–26, 1999. © 1999 Wiley‐Liss, Inc.