Synthesis and Anticonvulsant Properties of New Benzylpyridazine Derivatives

Abstract

Several 3-substituted pyridazines and a series of imidazo- and triazolopyridazines were synthesized and tested for anticonvulsant activity against maximal electroshock-induced seizures in mice. The most active derivatives, 3-ureidopyridazine 7 and triazolopyridazines 16, 18, 21, and 25 with oral ED50's that ranged from 6.2 to 22.0 mg/kg, were more extensively investigated by evaluating their ability to prevent chemically induced seizures and were compared with phenytoin, phenobarbital, sodium valproate, carbamazepine, and diazepam. 3-amino-7-(2,6-dichlorobenzyl)-6-methyltriazolo-[4,3-b]pyridazine (25) was also protective in the pentylenetetrazole-induced seizures test (ED50 = 76 mg/kg per os) and blocked strychnine-induced tonic extensor seizures (ED50 = 34.5 mg/kg per os). Furthermore, derivative 25 showed anticonvulsant effects on bicuculline- and yohimbine-induced seizures tests in mice. All these results suggest that the pharmacological activity of 25 is partly due to modifications of glycinergic and GABAergic transmission. Moreover, molecular modeling studies based on the antiepileptic drug lamotrigine and the most stable conformer of 25 show structural similarities between these two molecules. This conformer also agrees with the electronic tolerances and volume of benzodiazepine pharmacophore models.

5-(2-Chlorobenzyl)-6-methyl-3(2H)-pyridazinone

“…The structure determination of 5-( 2-chlorobenzyl )-6-methyl-3(2H)-pyridazinone was undertaken to confirm that 5-benzylpyridazine derivatives satisfy pharmacophore requirements (Villar et al, 1989;Brandau, Bourguignon & Wermuth, 1991) of central benzodiazepine receptors, as suggested by previous molecularmodelling studies (Moreau et al, 1994). Table 2).…”

“…The structure determination of 5-( 2-chlorobenzyl )-6-methyl-3(2H)-pyridazinone was undertaken to confirm that 5-benzylpyridazine derivatives satisfy pharmacophore requirements (Villar et al, 1989;Brandau, Bourguignon & Wermuth, 1991) of central benzodiazepine receptors, as suggested by previous molecularmodelling studies (Moreau et al, 1994). The structure of the title compound determined by X-ray diffraction corroborates the aromatic structure of the pyridazine ring suggested by recent NMR spectroscopic data (Bebot, Coudert & Couquelet, unpublished work), contrary to former results (Rubat et al, 1990) describing a dihydro skeleton with a 5-arylidene moiety.…”

“…The carbonyl O atom O(16) and the N(2)--H(2) amino group form an intermolecular hydrogen bond, the details of which are given in Table 2. tor (Villar et al, 1989;Brandau, Bourguignon & Wermuth, 1991) when they are substituted by an electronrich group, such as an acetamido side chain at N(2) (Rubat et al, 1990), or fused with a triazole ring (Moreau et al, 1994). …”

Synthesis, NMR, IR spectroscopic and X-ray study of novel [pyridazin-3(2H)-one-6-yl]ferrocenes and related ferrocenophane derivatives. Study on ferrocenes. Part 14

“…For many years considerable attention has been paid to the chemistry and biological activity of pyridazines [2][3][4][5][6][7][8][9]. It has been shown, e.g., that 1,3-and 1,4-bis[pyridazin-3(2H)-one-6-yl]benzenes, 4,4 0 -bis[pyridazin-3(2H)-one-6-yl]biphenyl and 2,5-bis[pyridazin-3(2H)-one-6-yl]thiophene and some of their partly saturated derivatives display generally stronger phosphodiesterase (PDE-III) inhibition than the corresponding mono-pyridazinone and this enhanced biological activity originates from the closer to optimal separation of two interacting polar heterocyclic moieties [5].…”

Current Research on Antiepileptic Compounds

“…The compound 200 was also protective in the PTZ-induced seizure test (ED 50 = 76 mg/kg per os) and blocked strychnine-induced tonic extensor seizures (ED 50 = 34.5 mg/kg per os). Furthermore, derivative 200 showed anticonvulsant effects on bicuculline-and yohimbine-induced seizure tests in mice [158].…”