Diuretics 1.2.4- benzothiadiazine dioxides

A general account of prototropic tautomerism has been given in Chapter 2.01. The situation in the non-aromatic polyheteroatom systems is generally quite complicated particularly if the system has more than one nitrogen atom to provide extra sites for the tautomeric proton. Only the important diuretic benzothiadiazine dioxides (46) (47) have... 

Drugs. Ttifluoromethyl-based pharmaceuticals had been limited to phenothiatine tranquilizers and benzothiadiazine 1,1-dioxide diuretics (qv). However, new dmgs have been developed (Table 11). One of the key properties of the CF group is its high lipophilicity it increases the Hpid solubiUty of the pharmaceutical and thus accelerates absorption and transport within the host organism. 

Chlorothiazide Chlorothiazide, 1,1-dioxide 6-chloro-2//-l,2,4-benzothiadiazin-7-sulfon-amide (21.3.3) is synthesized in the exact same manner, is aU thiazide diuretics. 3-Chloroanihne (or 3-trifluoromethylaniline) undergoes sulfoylchlorination by chlorosulfonic acid, forming 4,6-sntfonochloride-3-chloroanihne (21.3.1), the reaction of which with ammonia gives 4,6-sutfonylamido-3-chloroaniline (21.3.2). Heating this with formamide leads to formation of chlorothiazide (21.3.3) [9-11]. 

A great advance in potency was achieved with the 1,2,4-benzothiadiazine 1,1-dioxide chlorothiazide (190), a cyclized aniline-2,4-disulfonamide which is a weaker inhibitor of carbonic anhydrase than acetazolamide, but a more powerful diuretic. The major contribution to diuretic activity in these compounds must come from some factor other than the inhibition of carbonic anhydrase since a ten-fold increase in activity was seen in the reduced compound hydrochlorothiazide (191 R1 = R2 = H, R3 = CI) which has only one-tenth of... 

The 1,2,3-benzothiadiazine 1,1-dioxide (7, R = OEt) has diuretic and antihypertensive activity (62HCA996)—pharmacological features more common to a number of 1,2,4-benzothiadiazine 1,1-dioxides (see Section III.D). 

The only compound of note is the 4-hydrazino-2//-l,2,3-benzothiadiazine 1,1-dioxide (43) which, like the 1,2,4-thiadiazine 1,1-dioxides (see Chapter 6.14), is reported to have diuretic and antihypertensive activity <62HCA996>. 

The UV spectra of the major 3,4-dihydro-2/7-l,2,4-benzothiadiazine 1,1-dioxide diuretics (e.g.,... 

The HPLC characterization of the major 3,4-dihydro-2i/-l,2,4-benzothiadiazine 1,1-dioxide diuretics has been discussed in detail <85JC395>, and their racemic mixtures have been resolved into the pure enantiomers by liquid chromatography on a variety of stationary phases including chiral polyacrylamides (1 1 toluene-dioxan as eluant) <85JPS438>, (R)(-l-)-camphanic acid and V-(IS)-... 

Benzothiadiazine 1,1-dioxides have been shown to be useful antihypertensive agents and diuretics and many such compounds have been prepared <62AG(E)235>. 

Thiazide diuretics are found to be weakly acidic in nature having a benzothiadiazine 1,1-dioxide nucleus. 

NB See Whitehead CW, Traverse JJ, Sullivan HR and Morrison DE, Diuretics. IV. 6-Chloro-3-substituted-7-sulfamoyl-l,2,4-benzothiadiazine-l,l-dioxides, /OC, 26, 2809-2813 (1961). 

Synonyms 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide Chlorosulthiadil Chlorzide Dihydrochlorothiazide Empirical C7H8CIN3O4S2 Properties Wh. or pract. wh. cryst. powd., odorless sol. in sodium hydroxide sol n., dimethylformamide, dil. ammonia, NaOH insol. in water, chloroform, ether, dil. min. acids m.w. 297.75 m.p. 273-275 C Toxicology LD50 (oral, mouse) 2830 mg/kg poison by IP and IV routes mod. toxic by ing. and subcutaneous routes mutagenic data diuretic TSCA listed... 

Benzothiadiazines such as hydrochlorothiazide (Fig. 3.10, 3), which are also referred to as thiazides, represent one of the most commonly prescribed and observed classes of diuretic agents. They consist of a common nucleus of l,2,4-benzothiadiazine-l,l-dioxide with a sulfon-... 

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