Preliminary communication
Synthesis and structure–activity relationships of potential anticonvulsants based on 2-piperidinecarboxylic acid and related pharmacophores

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Abstract

Using N-(2,6-dimethyl)phenyl-2-piperidinecarboxamide (1) and N-(α-methylbenzyl)-2-piperidinecarboxamide (2) as structural leads, a variety of analogues were synthesised and evaluated for anticonvulsant activity in the MES test in mice. In the N-benzyl series, introduction of 3-Cl, 4-Cl, 3,4-Cl2, or 3-CF3 groups on the aromatic ring led to an increase in MES activity. Replacement of the α-methyl group by either i-Pr or benzyl groups enhanced MES activity with no increase in neurotoxicity. Substitution on the piperidine ring nitrogen led to a decrease in MES activity and neurotoxicity, while reduction of the amide carbonyl led to a complete loss of activity. Movement of the carboxamide group to either the 3- or 4-positions of the piperidine ring decreased MES activity and neurotoxicity. Incorporation of the piperidine ring into a tetrahydroisoquinoline or diazahydrinone nucleus led to increased neurotoxicity. In the N-(2,6-dimethyl)phenyl series, opening of the piperidine ring between the 1- and 6-positions gave the active norleucine derivative 75 (ED50=5.8 mg kg−1, TD50=36.4 mg kg−1, PI=6.3). Replacement of the piperidine ring of 1 by cycloalkane (cyclohexane, cyclopentane, and cyclobutane) resulted in compounds with decreased MES activity and neurotoxicity, whereas replacement of the piperidine ring by a 4-pyridyl group led to a retention of MES activity with a comparable PI. Simplification of the 2-piperidinecarboxamide nucleus of 1 into a glycinecarboxamide nucleus led to about a six-fold decrease in MES activity. The 2,6-dimethylanilides were the most potent compounds in the MES test in each group of compounds evaluated, and compounds 50 and 75 should be useful leads in the development of agents for the treatment of tonic–clonic and partial seizures in man.

Introduction

Epilepsy is a major neurological disorder in the United States and throughout the world [1], [2]. Although 70–80% of epileptics are currently controlled by a variety of drugs, seizure protection is frequently accompanied by numerous adverse effects [3].

Previously, the activity of several 2-piperidinecarboxamides in the maximal electroshock seizure (MES) test in mice was reported. Receptor binding studies indicated that these amides demonstrated weak binding affinity at the phencyclidine (PCP) site on the N-methyl-d-aspartate (NMDA) receptor complex; however, a correlation between binding affinity and seizure protection in the MES test was not observed [4]. As a continuation of this work, a structure–activity relationship (SAR) study of the 2-piperidinecarboxamide nucleus was initiated. The most active compound arising from this study, the 2,6-dimethylanilide (RS-1, figure 1), exhibited an ED50=5.8 mg kg−1 in the MES test and a TD50=33.2 mg kg−1 in the rotorod test to give a PI=5.7. The (R-1)-isomer exhibited similar MES activity as the racemate but was more neurotoxic, whereas the (S-1)-isomer was less active and less neurotoxic. Additionally, the N-(α-methylbenzyl)-2-piperidinecarboxamides 2 (figure 1) also exhibited activity in the MES test; however, the stereochemistry at the 2-position of the piperidine ring or at the α-position of the side chain did not significantly affect activity [5].

Although several new drugs such as vigabatrin, lamotrigine, gabapentin, tiagabine, felbamate, topiramate, fosphenytoin, and levetiracetam have appeared on the market, the development of novel agents, particularly compounds effective against complex partial seizures, remains a major focus of antiepileptic drug research [6]. A review on new structural entities having anticonvulsant activity has recently appeared [7]. Since the 2-piperidinecarboxamides represent a novel series of compounds that are active in the MES test in mice, further exploration of the SAR was of interest. Using compounds 1 and 2 as structural leads, the following modifications were explored: (1) substitution on the aromatic ring of compound 2, (2) replacement of the α-methyl substituent of 2 by other alkyl or aryl groups, (3) introduction of substituents on the piperidine ring nitrogen, (4) reduction of the side chain carbonyl, (5) movement of the carboxamide group to the 3- and 4-positions, (6) incorporation of the piperidine ring into a tetrahydroisoquinoline or diazahydrindanone nucleus, (7) opening of the piperidine ring, (8) replacement of the piperidine ring by cycloalkyl or pyridine, and (9) simplification of the 2-piperidinecarboxamide nucleus into a glycinecarboxamide moiety.

Section snippets

Chemistry

The synthesis of the N-[(α-alkyl or aryl-substituted)benzyl]-2-piperidine-carboxamides required the preparation of the precursor α-substituted-benzylamines which were prepared by the Leuckhart reaction (figure 2). The starting ketones were either commercially available or were prepared by Friedel–Crafts acylation of benzene with an appropriate acid chloride. In the case of solid ketones, the reaction of the ketone with a mixture of formic acid and formamide at 140°C usually required a reaction

2,6-Dimethylanilide series

The anticonvulsant activity and the neurotoxicity (table V) of the target compounds of this investigation were evaluated by the National Institutes of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health (NIH) using established procedures [5]. The ED50 in MES test and the TD50 in the rotorod test were calculated at the time of peak effect for the most active compounds according to a previously described method [4]. In the previous study, the 2,6-dimethylanilide (RS-1)

Conclusions

In agreement with previous findings on the N-(benzyl)piperidinecarboxamides, introduction of 3-Cl, 4-Cl, 3,4-Cl2, or 3-CF3 groups on the aromatic ring of N-(α-methylbenzyl)-piperidinecarboxamides led to an increase in MES activity. Replacement of the α-methyl group of α-methylbenzylamides with either i-Pr (42, ED50=22 mg kg−1) or benzyl (S,RS-45, ED50=22 mg kg−1) increased MES activity with no increase in neurotoxicity. In the piperidine series, movement of the carboxamide moiety to either the 3-

Chemistry

All chemicals were of reagent grade and were used without further purification. Melting points were determined on a Thomas Hoover melting point apparatus and were not corrected. The IR spectra were recorded as potassium bromide pellets or as liquid films on a Nicolet Impact 400D spectrometer. The NMR spectra were recorded on a JEOL FX 90Q spectrometer. Chemical shifts were recorded in parts per million (δ) relative to tetramethylsilane (1%). Optical rotations were recorded on a Perkin–Elmer 241

NMR data

Compound 6. 1H-NMR (CDCl3) δ 1.37 (d, 3H, J=6.4 Hz, CHCH3), 1.58 (s, 2H, CHNH2), 3.86 (s, 3 H, OCH3), 3.89 (s, 3H, OCH3), 4.09 (q, 1H, J=6.4 Hz, CHCH3), 6.87 (m, 3H, ArH); 13NMR (CDCl3) δ 25.8 (CHCH3), 51.1 (CHCH3), 56.2 (OCH3), 109.8, 111.9, 117.8, 140.9, 148.3, 149.5.

Compound 7. 1H-NMR (CDCl3) δ 1.49 (s, 2H, CHNH2), 2.90 (m, 2H, CHCH2), 4.18 (m, 1H, CHCH3), 7.26 (m, 10H, ArH); 13C-NMR (CDCl3) δ 46.7 (CHCH2), 57.7 (CHCH2), 126.4, 126.5, 127.1, 128.5, 129.4, 139.3, 145.9.

Compound 8. 1H-NMR (CDCl

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