SYNTHESIS AND ANTINOCICEPTIVE ACTIVITY OF 1-METHYLPIPERIDYLIDENE-2-(PYRIDYL)SULFONAMIDES AND RELATED DIHYDROPYRIDYL ANALOGS

The regiospecific 1,3-dipolar cycloaddition reaction of 1-methyl-1,2-dihydropyridine 2 with 2-, 3- or 4-pyridylsulfonyl azide 3a-c yielded the respective 1-methyl-1,2,3,6-tetrahydropyridylidene-2-(2-, 3- or 4-pyridyl)sulfonamides 5a-c. Hydrogenation of 5a-c afforded the corresponding 1-methylpiperldylidene-2-(pyridyl)sulfonamides 1a-c. Compounds lb and 1c were elaborated to 1',6'- 6a-d and 1',4'- 7a-c, and 1',2'-dihydropyridines 8a-e, respectively by quaternization with phenyl chloroformate followed by in situ reaction with methyl-, n-butyl-, t-butyl- or phenylmagnesium chloride, or sodium borohydride. Antinociceptive activity was determined using the rat sodium chloride-induced writhing assay. The point of attachment of the pyridyl ring was a determinant of activity where the relative activity order was 2-pyridyl la greater-than-or-equal-to 4-pyridyl 1c > 3-pyridyl 1b (ED50) values of 6.2, 9.0 and 6.6 mg/kg sc, respectively), relative to the reference drug meperidine (EC50 = 0.6 mg/kg sc). The pyridyl compounds lb,1c were more potent than their dihydropyridyl derivatives 6a-d, 8a-e. The most active dihydropyridyl derivative, 1-methylpiperidylidene-2-(1',2'-dihydro-2'-t-butyl-1'-phenoxycarbonyl-4'-pyridyl)sulfonamide 8c was more active at 25 mg/kg sc (68% inhibition of writhing) than aspirin at 50 mg/kg sc (58% inhibition of writhing). In the dihydropyridyl series of compounds 6a-d, 8a-e, a t-Bu substituent at the alpha-position of the 1',6'- or 1',2'-dihydropyridyl ring provided superior antinociceptive activity relative to that of a H, Me. n-Bu or Ph substituent.