We recently reported the potent anticonvulsant activity of (R,S)-alpha-acetamido-N-benzyl-alpha-phenylacetamide (2b). Selectively substituted derivatives of this compound have now been prepared (23 examples) and evaluated in the maximal electroshock seizure (MES) and horizontal screen (tox) tests in mice. In several key cases, replacement of the alpha-phenyl substituent in 2b by a relatively small, electron-rich, heteroaromatic moiety led to a substantial improvement in the anticonvulsant potency of the drug candidate. The most active compounds were (R,S)-alpha-acetamido-N-benzyl-2-furanacetamide (2g) and (R,S)-alpha-acetamido-N-benzyl-2-pyrroleacetamide (2i). After ip administration, the MES ED50 values for 2g (10.3 mg/kg) and 2i (16.1 mg/kg) compared well with phenytoin (9.50 mg/kg). Evaluation of the two individual enantiomers of 2g demonstrated that the anticonvulsant activity resided in the R stereoisomer. The low ED50 value (3.3 mg/kg) for (R)-2g contributed to the large protective index (TD50/ED50) observed for this drug candidate, which approached that of phenytoin.
Potent anticonvulsant activity has been reported for (R,S)-2-acetamido-N-benzyl-2-methylacetamide (2a). Select alpha-heteroatom substituted derivatives of 2a have been prepared (26 examples) in which the alpha-methyl group has been replaced by nitrogen (3a-q), oxygen (3r-u), and sulfur (3v-z) containing moieties. The functionalized amino acid derivatives were evaluated in the maximal electroshock seizure (MES) and horizontal screen (tox) tests in mice. The most active compounds were (R,S)-2-acetamido-N-benzyl-2-(methoxyamino)acetamide (31), and (R,S)-2-acetamido-N-benzyl-2-(methoxymethylamino)acetamide (3n). After ip administration, the MES ED50 values for 31 (6.2 mg/kg) and 3n (6.7 mg/kg) compared favorably with phenytoin (9.50 mg/kg).
Synthetic routes have been developed for the preparation of functionalized amino acid derivatives in which the α‐substituent at carbon 2 is either an aromatic or a heteroaromatic group. The α‐substituent was introduced using an amidoalkylation reaction using boron trifluoride etherate and proceeded in moderate yield with excellent regioselectivity. This protocol permitted the employment of the acid sensitive heterocycles: pyrrole, benzofuran, and indole. The scope and limitations of this procedure have been evaluated.
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ChemInform Abstract Two different synthetic approaches to amino acid amides bearing a (hetero)aryl substituent in the α-position are examined. Treatment of the 2-acetamido-2-methoxyacetate (I) with furan (II) or pyrrole (IV) in the presence of boron trifluoride etherate gives the functionalized α-amino esters (III) or (V) and (VI). (III) is converted to the benzylamide (VIIIc) by conventional methods. Better results are achieved when the acetamidoethoxyacetate (IX) is first transformed into the benzamide (X) and the (het)aryl substitutent is introduced in the second step, producing (VIII).
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