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The synthesis and pharmacological evaluation of novel 1-substituted-1,2-dihydro-pyridazine-3,6-diones (4a-l, 5a-j) as potential anticonvulsant agents are described. The compounds were tested in vivo for the anticonvulsant activity. The compound which have maximum protection against MES induced seizures is 1-[3-(2-aminophenylamino)-2-hydroxypropyl)-1,2-dihydro-pyridazine-3,6-dione 4h (ED 50 ‫7.44؍‬ mg · kg ؊1 i.p.) 1-[2-hydroxy-3-piperazin1-yl-propyl)-1,2-dihydro-pyridazine-3,6-dione 4c (ED 50 ‫27؍‬ mg · kg ؊1 i.p.) and 1-[2-hydroxy-3-imidazol-1-yl-propyl)-1,2-dihydro-pyridazine-3,6-dione 4d (ED 50 ‫97؍‬ mg · kg ؊1 i.p.) were also found to have maximum protection against MES induced seizures. Whereas all these compounds failed to protect the animals from subcutaneous pentylenetetrazole (Metrozol) seizure threshold test (sc-Met).

Enzymatic syntheses of water-soluble alpha-tocopheryl glycosides were carried out in di-isopropyl ether using amyloglucosidase from Rhizopus mold or beta-glucosidase isolated from sweet almond. Optimum conditions for the amyloglucosidase were: alpha-tocopherol 0.5 mmol, D-glucose 0.5 mmol, 400 activity unit (AU) amyloglucosidase, 0.2 mM pH 7 phosphate buffer and 72 h; and for the beta-glucosidase: alpha-tocopherol 0.5 mmol, D: -glucose 0.5 mmol, 110 AU beta-glucosidase, 0.1 mM pH 6 phosphate buffer and 72 h. Out of 11 carbohydrates employed, amyloglucosidase reacted only with D-glucose to give 50% of 6-O-(alpha-D-glucopyranosyl)alpha-tocopherol. However, the beta-glucosidase gave 6-O-(beta-D-glucopyranosyl)alpha-tocopherol, 6-O-(alpha-D-galactopyranosyl)alpha-tocopherol, 6-O-(beta-D-galactopyranosyl)alpha-tocopherol, 6-O-(alpha-D-mannopyranosyl)alpha-tocopherol and 6-O-(beta-D-mannopyranosyl)alpha-tocopherol in yields ranging from 10-25%. Water solubility of 6-O-(alpha-D-glucopyranosyl)alpha-tocopherol was 26 g/l at 25 degrees C. alpha-Tocopheryl glycosides showed antioxidant activities with IC(50) values from 0.5 to 1 mM and angiotensin-converting enzyme (ACE) inhibitory activity with IC(50) values from 1.3 to 2.6 mM.

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Pyridines were reported to possess anticonvulsant, 1,2) cardiotonic, 3) antihypertensive, 4) b-adrenergic blocking activity.5) Aryloxypropanolamines were reported to be associated with b-adrenergic blocking, 6,7) CNS depressant 8) and hypotensive 9) activities. In view of this potential nature of these moieties, it was thought worthwhile to study the effects of two pharmacophoric moieties like pyridine and propanolamine/ethanediamine in a single molecule. We have reported the potential anticonvulsant activity of arylaminopropanolamine 10) of pyridine and arylaminopropanolamine/ aryloxyaminopropane, [11][12][13] to continue our work with the same intention, it was envisaged that, chemical entities with both pyridine and arylaminopropanolamine/ethanediamine moieties would result in compounds of interesting biological activities.In the present study, we report the synthesis, the pharmacological evaluation, and structure-activity relationship of 2-(3Ј-substituted-2Ј-hydroxypropylamino/2Ј-substituted-ethylamino)-pyridine. The compounds were characterized by IR, 1 H-NMR spectral and elemental analysis. The compounds were investigated for anticonvulsant activity, the decrease in the elevated motor activity by introceptive chemical stimuli (amphetamine antagonistic activity) at the dose level of 25 and 50 mg/kg, cardiac activity on isolated frog heart and antihistaminic on guinea pig ileum. ChemistryMelting points were determined in open capillary tubes and are uncorrected. IR spectra were recorded (in KBr) on Bomem FT-IR spectrophotometer M.B Serial II. 1 H-NMR and IR spectra were consistent with the assigned structures. Synthesis of 2-(2-Chloroethylamino)-6-aminopyridine 2,6-Diaminopyridine was reacted with 1,2-dichloroethane, using the previously reported procedure.10) A solution of sodium methoxide (0.113 mol of sodium and 75 ml of methanol) was added to 0.113 mol of 2,6-diaminopyridine and refluxed for 1 h. Then the methanol was completely removed from the medium and 10 ml of anhydrous dimethyl formamide (DMF) was added to the dry residue. A solution of 1,2-dichloroethane (0.113 mol) in 10 ml anhydrous dimethyl formamide was then added dropwise to the reaction mixture with continuous stirring. The mixture was stirred for 1 h at room temperature. The product was filtered, dried in vacuum and recrystallised by using chloroform-diethylether (1 : 1). Yieldϭ56%, mp 175°C. , 49.12; H, 5.84; N, 24.56. Found: C, 49.36; H, 5.58; N, 24.34.General Method of Synthesis of 1a to m 2-(2-Chloroethylamino)-6-aminopyridine was reacted with various amines, using the previously reported procedure.10) A solution of 2-(2-chloroethylamino)-6-aminopyridine (0.013 mol) and the appropriate amine (0.013 mol) in 40 ml of methanol was refluxed for 24 h. The product obtained was filtered, vacuum dried and recrystallized using 1 : 1 acetone-diethylether (1c, 1e, 1f, 1l), 1 : 1 ethanol-diethylether (1a, 1h, 1k, 1m), 1 : 1 chloroform-diethylether (1b, 1g) and 1 : 1 methanol-diethylether (1d, 1i, 1j).2-(2-Morpholinoethylamino)-6-aminopyridine 1a:...