No abstract

The thiazide-type1 of sulfonamide diuretics offered the first useful departure from the mercurial agents. The clinical success as well as the shortcomings of the many drugs of this class has stimulated an intensive search for improved agents. This search has extended to new chemical classes of diuretics. More recent efforts in our laboratory have been directed toward compounds that are neither mercurials nor sulfonamides. One such class of compounds that exhibits a high order of activity in laboratory animals and in man is ,ßunsaturated ketone derivatives of aryloxyacetic acids of the general structure I.

Pyrazine Diuretics. I. N-Amiclino-3-aniino-6-halopyrazinecarboxa~iiides . I series of S-amidiiio-B-aiuiiio-ti-lialop~rr.aziiiecarboxuiiiides WIJ prepared pi'iitc,ipr.ally try the reaction of iiiethyl 3-ar~iitio-6-halop~ra~iiie~a~bor;3.lates with yiiariidirie or siihstitiited giiatiidiiies. A iiiiriiber of 1 hew compounds reverse the electrolyte excretion effects of deox!co~ti~oEteroiie in the adreiialec,toniizetl rat and cause iiatriiuesis in the intact rat, arid dog while leaving unaffected or eveii repressing K + excretion.

No abstract

A series of O-acyl derivatives of 6-hydroxybenzothiazole-2-sulfonamide (4, L-643,799) was prepared and the potential utility of each series member as a topically active inhibitor of ocular carbonic anhydrase was determined. In vitro studies showed these esters to be substrates for ocular esterases which liberate 4 during corneal translocation. The most interesting series member, 2-sulfamoyl-6-benzothiazolyl 2,2-dimethylpropionate (22, L-645,151), acting as a prodrug form of 4, was found to enhance delivery through the isolated albino rabbit cornea by 40-fold when compared to the parent phenol 4. Studies in rabbits revealed that 22 is a potent topically active ocular hypotensive carbonic anhydrase inhibitor.