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Spiro[4.5] and spiro[4.6] carboxylic acids: cyclic analogues of valproic acid. Synthesis and anticonvulsant evaluation.

Authors
  • Scott, K R
  • Moore, J A
  • Zalucky, T B
  • Nicholson, J M
  • Lee, J A
  • Hinko, C N
Type
Published Article
Journal
Journal of medicinal chemistry
Publication Date
Apr 01, 1985
Volume
28
Issue
4
Pages
413–417
Identifiers
PMID: 3920394
Source
Medline
License
Unknown

Abstract

Spiro[4.5]decane-2-carboxylic acid (12a), spiro[4.5]decane-2,2-dicarboxylic acid (11a), spiro[4.6]undecane-2-carboxylic acid (12b), spiro[4.6]undecane- 2,2-dicarboxylic acid (11b), and spiro[4.6]undecane-2-acetic acid (13) were synthesized by an improved method and evaluated for anticonvulsant activity. These analogues were synthesized to evaluate the role of the carboxylic acid group as an essential substituent in valproic acid (di-n-propylacetic acid, 1). Carbocyclic spiranes are known to resist metabolic alteration so that any activity elicited by these compounds would be due to the carboxylic acid function and not to any metabolic change. Spiro[4.6]undecane-2-carboxylic acid (12b) was the most active analogue tested and the pentylenetetrazol and picrotoxin evaluations of 12b compared favorably to 1. However, 12b failed to provide adequate protection against maximal electroshock seizures, bicuculline, or strychnine in mice. Possible reasons for these results are discussed.

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