SYNTHETIC STUDIES OF COMPOUNDS RELATED TO CHLOROTHIAZIDE

6-Chloro-7-sulfamyl-l,2,4-benzothiadiazine-1,1-dioxide (chlorothiazide) is an orally effective diuretic and is being employed for the treatment of hypertension. Many workers have reported the chemistry and pharmacology of this compound and its analogs. But the mechanism of the antihypertensive action has not been fully elucidated. It seemed to be of interest to us to analyse the structural features conducive to diuretic and antihypertensive activities. Five types of compounds have been prepared for the purpose of studying the relationship between chemical structure and biological activities and of searching for a better antihypertensive agent. Physical data of these compounds were assembled in tables 1 to 12 in the Chinese text. Most of the compounds prepared were derived from 4-amino-6-chloro-l,3-benzenedisulfonamide, but compounds containing trifluoromethyl were also made. The intermediate disulfonamides were prepared by chlorosulfonation of m-chloroaniline with chlorosulfonic acid in large excess (ocassionally with added phosphorus trichloride or sodium chloride), followed by treatment with ammonia or with simple aliphatic and aromatic amines. The sulfonamides were condensed with aldehydes and ketones to give substituted 1,2,4-benzothiadiazine-1,1-dioxide. Pharmacologic studies will be reported elsewhere.