Spiro[4.5] and spiro[4.6] carboxylic acids: cyclic analogs of valproic acid synthesis and anticonvulsant evaluation

• Published in: Journal of medicinal chemistry 1985-04, Vol.28 (4), p.413-417
• Main Authors: Scott, K. R, Moore, Jacqueline A, Zalucky, Theodore B, Nicholson, Jesse M, Lee, Jo Ann M, Hinko, Christine N
• Format: Article
• Language: English
• Subjects: Alicyclic compounds; Alicyclic compounds, terpenoids, prostaglandins, steroids; Animals; Anticonvulsants - chemical synthesis; Anticonvulsants - pharmacology; Bicuculline; Carboxylic Acids - chemical synthesis; Carboxylic Acids - pharmacology; Chemistry; Exact sciences and technology; Male; Mice; Organic chemistry; Pentylenetetrazole; Picrotoxin; Preparations and properties; Spiro Compounds - chemical synthesis; Spiro Compounds - pharmacology; Structure-Activity Relationship; Valproic Acid - analogs & derivatives; Valproic Acid - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00382a004

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.