Synthesis and anticonvulsant activity of new fluorinated N-phenyl- and N-benzyl-2-azaspiro[4.4]nonane- and [4.5]decane-1,3-dione derivatives: Part III Jolanta Obniska a, * , Krzysztof Kaminski a , Agnieszka Zagorska a , Agnieszka Dzierzawska-Majewska b , Janina Karolak-Wojciechowska b a Department of Pharmaceutical Chemistry, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland b Institute of General and Ecological Chemistry, Technical University, Zwirki 36, 90-924 Lodz, Poland Received 25 October 2005; received in revised form 23 January 2006; accepted 31 January 2006 Available online 23 February 2006 Abstract A series of N-phenyl- and N-benzyl-2-azaspiro[4.4]nonane- and [4.5]decane-1,3-diones containing a fluoro or trifluoromethyl substituents at the aryl ring was synthesized and tested for their anticonvulsant activity in the maximal electroshock (MES) and subcutaneous metrazole (sc.Met) tests. Among them, the most active were N-benzyl derivatives with fluoro and trifluoromethyl substituents especially at position-2 of the aryl moiety. The introduction of the phenyl ring at the imide nitrogen atom resulted in less active compounds. The results obtained showed that incorporation of fluoro or trifluoromethyl substituents increased the anticonvulsant activity in comparison to respective chloro, methoxy or methyl analogues. Crystallographically obtained conformation for one active and two inactive derivatives with trifluoromethyl substituents at position-2 or -3 of phenyl ring were initially used for molecular electrostatic potentials (MEP) calculation. The MEP distribution at carbonyl oxygen atoms was different for active and inactive molecules. # 2006 Elsevier B.V. All rights reserved. Keywords: Fluorinated spirosuccinimides; Anticonvulsant activity; X-ray structures; Molecular electrostatic potential (MEP) 1. Introduction Azaspirane derivatives of succinimides are a well-known group of anticonvulsant active compounds [1–3]. In our earlier research we described anticonvulsant properties of many N- phenyl- and N-benzyl-2-azaspiro[4.4]nonane- and [4.5]decane- 1,3-diones, containing chloro, methoxy and methyl substituents at the aryl moiety. The pharmacological evaluation in this series of compounds revealed moderate protection against both maximal electroshock (MES) and subcutaneous metrazole (sc.Met) tests [4,5]. The properties of fluorine such as its small size, combined with the high electronegativity may modulate electronic, lipophilic and steric parameters crucial for biological activity [6,7]. Additionally, an enhancement of activity as well as a decrease of toxicity has been reported in many cases for fluorine containing derivatives [8,9]. Thus, fluorinated com- pounds are the focus of much interest in modern pharmaceu- tical chemistry, and the incorporation of fluoro or fluoroalkyl substituents plays a significant role in development of drugs, including anticonvulsant active molecules [10,11]. In view of this and our earlier chemical and pharmacological investigations in a group of differently 1,3-substituted pyrrolidine-2,5-diones [4,5,12–15], in the current study we designed and synthesized a new series of fluorinated N-phenyl- and N-benzyl-2-azaspiro[4.4]nonane- and [4.5]decane-1,3- diones, containing the fluoro or trifluoromethyl substituents at the aryl moiety, in order to examine the influence of such substitution on anticonvulsant activity. The compounds were evaluated for their anticonvulsant and neurotoxic properties within the Antiepileptic Drug Development (ADD) program (Epilepsy Branch, Neurological Disorders Program, National Institute of the Neurological and Communicative Disorders and Stroke (NINCDS), Bethesda). The previous structure–activity relationship studies per- formed in a group of succinimide derivatives with different substitutents at the nitrogen atom and at position-3 of pyrrolidine-2,5-dione ring, indicated that their anticonvulsant www.elsevier.com/locate/fluor Journal of Fluorine Chemistry 127 (2006) 417–425 * Corresponding author. Tel.: +48 12 6570560; fax: +48 12 6570262. E-mail address: mfobnisk@cyf-kr.edu.pl (J. Obniska). 0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jfluchem.2006.01.009