[(Aminomethyl)arloxy]acetic acid esters. A new class of high-ceiling diuretics. 3. Variation in the bridge between the aromatic rings to complete mapping of the receptor.

Continued structural evaluation of the [(aminomethyl)aryloxy]acetic ester diuretics has produced a series of compounds in which the functional group that bridges the two aromatic rings has been varied. Diuretic screening of these analogues in rats indicates that the keto group can be effectively replaced with an ether or thio ether function with a slight increase in potency, whereas the methylene and sulfoxide linking groups lead to diminished saluretic potency. Replacement with either -SO2-, -COCO-, -CH2O-, -CONH- or direct bond results in a loss of activity. Although the series was designed according to QSAR criteria, the traditional linear free-energy properties of these compounds do not correlate with diuretic potency. However, conformational analysis of the series by potential energy calculations indicates that all active compounds have an accessible conformation that matches the bridge atom-carboxylate distance of the very potent dihydrobenzofuran analogue 56. Conformational calculations of several compounds in which the aminomethyl group was varied suggests that the active conformation is probably a low-energy conformation. Consideration of rotation about the bridge could not distinguish between two possible orientations of the aminomethyl ring in the active conformation. However, there is a quantitative negative linear correlation between diuretic potency and the protrusion into space of the group that bridges the two aromatic rings.

[(Aminomethyl)aryloxy]acetic acid esters. A new class of high-ceiling diuretics. 1. Effects of nitrogen and aromatic nuclear substitution.

A series of Mannich bases and aminomethyl derivatives of ethyl [2,3-dichloro-4-(4-hydroxybenzoyl)phenoxy]acetate were synthesized and tested for saluretic and diuretic activities. The effects of nitrogen and aromatic nuclear substitution, reorientation of the aminomethyl group relative to that of the phenolic hydroxyl group, and replacement of either the phenolic hydroxyl or the aminomethyl group by other functional groups are described. Ethyl [2,3-dichloro-4-[3-(aminomethyl)-4-hydroxybenzoyl]phenoxy]acetate (27) was found to be a very potent, high-ceiling diuretic.

Local anesthetic activity and acute toxicity of N-substituted 1,2,3,4-tetrahydro-1- and 2-naphthylamines.

Seven N-substituted 1,2,3,4-tetrahydro-1- and three 2-naphthylamines were prepared and tested for local anesthetic activity in the rabbit corneal reflex test and the mouse sciatic nerve block test. At 0.1 and 1%, three 1-alkylamino compounds had durations of action comparable to that of tetracaine in the rabbit corneal reflex test and were considerably more potent than lidocaine. The other four 1-alkylamino derivatives were inactive or at best minimally active. The durations of action of 1% concentrations of the three 2-alkylamino compounds were equivalent to that of 1% lidocaine in the corneal reflex test. In the mouse sciatic nerve block test, the three active 1-alkylamino compounds were considerably longer acting than either tetracaine or lidocaine. Three 1-alkylamino and the three 2-alkylamino compounds showed toxicity equal to or greater than lidocaine, while two 1-alkylamino and two 2-alkylamino compounds showed toxicity equal to or greater than tetracaine by the intraperitoneal route in mice. N-Heptyl-1,2,3,4-tetrahydro-6-methoxy-1-naphthylamine methanesulfonate was the most promising local anesthetic in these series.

Dimethylpropynylbenzamides: a new group of herbicides.

N-(1,1-Dimethylpropynyl)-3,5-dichlorobenzamide is representative of a group of benzamides that are herbicidally active on annnual and perennial grasses with potential agricultural uitility in forage legumes, certain turf grasses, and clultivated crops.