VOL. 25The major constituent of the ketone was established as the 6 rather than the 7-keto derivative by formation of a monobenzal derivative, no dibenzal derivative being isolated.The ketone, 470 mg. (3.17 mmol.) was dissolved in 5 ml. of 5% potassium hydroxide in methanol9 and 1.1 ml. of benzaldehyde was added. After 20 hr. the mixture was diluted with 11 ml. of water and extracted with 10 ml. of hexane. The hexane layer was dried over magnesium sulfate and concentrated. Excess benzaldehyde was removed by maintaining the residue a t 60' (0.25 mm.) for several hours. The cooled semicrystalline residue was recrystallized twice from 3 ml. portions of hexane to give 0.151 g. (0.639 mmol., 20.1%) of pale yellow monobenzal derivative, m.p. 74.0-77.0'. Anal.Calcd. for C17H160: 0, 6.77. Found: 0, 6.63.The infrared spectra of all compounds encountered in this (9) K. Alder, K. Heimbach, and R. Reubke, Chem. BeT., 91, 1516 (1958); K. Alder and R. Reubke, Chem. Ber., 91, 1525 (1958). investigation were measured routinely and supported the proposed structures. In particular, these nortricyclene derivatives absorbed a t 12.3-12.4 microns, as first noted by Roberts and co-workers.10

The synthesis of the isomeric series 6-chloro-7-sulfamoyl- and 7-chloro-6-sulfamoyl-1(2H)-phthalazinones (1 and 2) and 6-chloro-7-sulfamoyl- and 7-chloro-6-sulfamoyl-3,4-dihydo-1(2H)-phthalazinones (3 and 4), combining structural features characteristic to furosemide and hydralazine, is described, the mechanism of the formation of 1 and 2 is discussed, and their structure-activities relationships are studied. Preliminary screening in the rat shows that series 1 and 3 exhibit diuretic and saluretic activity similar to that of chlorothiazide with, however, Na+/K+ ratios more favorable than chlorothiazide and furosemide. The compounds of series 2 and 4 are practically inactive. All four series show initial antihypertensive activity lower than that of hydralazine. However, compounds 1a, 1c, and 4a show a higher activity at 8 and/or 24 h after administration and thus may offer a unique combination of a "loop" diuresis with direct long-acting peripheral vasodilating effects.

No abstract

The synthesis of a new series of N,N'-disubstituted 6,7-diazabicyclo[3.2.2]nonane derivatives is described. The antimuscarinic potency of these drugs was evaluated in the guinea pig ileum and compared to that of atropine sulfate. All the drugs tested competitively inhibited the acetylcholine-induced contractions. Kd values were calculated and, in several cases, compared to those obtained by direct binding to the muscarinic receptor from mouse brain. The order of potencies followed that which is known for various tropine and pseudotropine esters; that is, the 3alpha configuration is more potent than the 3beta configuration, and the quaternary analogues are more potent than the tertiary ones. The antimuscarinic activity of the drugs is dicussed in terms of their acetylcholine-like molecular arrangement that gives rise to a characteristic interaction pharmacophore.

The structure activity correlation of several groups of anthranilic acid derivatives was studied. 59 compounds, most of them possessing the anthranilic acid moiety, were synthesized and tested for diuretic and saluretic activities. Equations correlating the biological activities of these compounds with their physicochemical constants suggest positive dependence of the diuretic activity on log P (octanol: water partition coefficient). It is concluded that, within limits, the variation in biological activity is primarily governed by the lipophilicity of the molecule, and further increase in log P value will not enhance this activity.