1.2.4- Benzothiadiazine 1.1- dioxides

B) A solution of BB g of 5-chloro-2,4-disulfamylaniline in 1.1 liters of BB% formic acid was heated under reflux for 2 hours. After removal of 200 ml of solvent by distillation, one liter of water was added and the product collected, washed with water and dried. Crystallization from dilute alcohol afforded 6-chloro-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide as colorless needles, MP 342.5° to 343°C, as described in U.S. Patent 2,BOB,194. 

Chemical Name 7-chloro-3-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide Common Name —... 

A mixture of 2.9 grams of 5-chloro-2,4-disulfamvl-aniline in 20 ml of anhydrous diethylene-glycol dimethylether, 0.44 gram of propionaldehyde and 0.5 ml of a solution of hydrogen chloride in ethyl acetate (109.5 grams hydrogen chloride per 1,000 ml) Is heated to 80° to 90°C and maintained at that temperature for 1 hour. The reaction mixture is concentrated under reduced pressure on addition of water, the product separates and is then recrystal-lized from ethanol or aqueous ethanol to yield the desired 6-chloro-3-ethvl-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide, MP 269° to 270°C. 

As described in U.S. Patent 3,025,292, the desired product may be made by hydrogenation of chlorothiazide. Three grams of 6-chloro-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide (chlorothiazide) is suspended in 100 ml of methanol. Then 1.0 gram of a 5% ruthenium on charcoal catalyst is added, and the mixture is reduced at room temperature and at an initial hydrogen pressure of 39 psig. The theoretical amount of hydrogen to form the 3,4-dihydro derivative is absorbed after a period of about 10 hours. 

C) Preparation of 2-Methyl-3-(2,2,2-Trifluoroethyl)Thiomethyl-6-Chloro-7-Sulfamyl-3,4-Dihydro-1,2,4-Benzothiadiazine-1,1-Dioxide To 4.6 g (0.015 mol) of 4-amino-2-chloro-5-(methylsulfamyl)benzenesulfonamide in 30 ml of the dimethyl ether of ethylene glycol is added 4.08 g (0.02 mol) of 2,2,2-trifluoroethylmercaptoacetaldehyde dimethylacetal followed by 1 ml of ethyl acetate saturated with hydrogen chloride gas. The resulting solution is refluxed for 1.5 hours, cooled and then slowly added to cold water dropwise with stirring. The crude product is filtered, dried and recrystallized from isopropanol (3.2 g), MP 202° to 202.5°C. A second recrystallization from isopropanol raised the MP to 202°... 

A mixture of 5.7 grams (0.02 mol) of 5-chloro-2,4-disulfamylaniline and 4.9 grams (0.04 mol) of dichloroacetaldehyde in 25 ml of dimethyl formamide was heated at the boiling temperature and under reflux for 30 minutes. The reaction mixture was thereafter poured into a mixture of ice and water to precipitate the desired 6-chloro-7-sulfamyl-3-dichloro-methyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide as a crystalline solid melting at 250° to 270°C with decomposition. 

N- 4H-1,2,4-Benzothiadiazine 1,1 -dioxide-3-yl)aminomethylenemalo-nates (86) were prepared in 90-92% yields in the reactions of 3-amino-4//-1,2,4-benzothiadiazine 1,1-dioxides and EMME at 170-180°C for 2 hr (89JHC473). 

Benzothiadiazines (492 X = S) are prepared by cyclization of (491 X = S, Y = Br or NOz) (80JOC3677), and analogous compounds result from cyclization of the chlorohydrazones (496) with triethylamine (81JCS(P1)2245). Intramolecular aromatic sulfonation gives 1,2,4-benzothiadiazine 1,1-dioxides (498) from (497) and aluminum trichloride (79JCS(P1)1043). 

Aminobenzenesulfonamides are ring closed directly to AH- 1,2,4-benzothiadiazine 1,1-dioxides (500) with a variety of carboxylic acids, employing polyphosphoric acid trimethylsilyl ester as the cyclization agent (83S851, 85JAP(K)6025984, 90JMC172l). 

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). 

Because of the lipophilic nature of the biological membrane and the importance of size and charge distribution, the formal charge at position 7 of the 1,2,4-benzothiadiazine 1,1-dioxide systems and two other parameters, Hansch s hydrophobic 1r parameter and the van der Waals volume (as calculated by Bondi s method), are included in a structure-activity rela-... 

DIHYDRO-6-CHLOROA-SULF AMYL-1,2,4-BENZOTHIADIAZINE-1,1-DIOXIDE see CFYOOO DIHYDROCHLOROTHIAZID see CFYOOO DIHYDROCHLOROTHIAZIDE see CFYOOO... 

Whitehead ec al.5 assign the intense absorption band at approximately 6.2 p, (1600 cm-1) as characteristic for 3,4-dihydro-3-substituted 7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxides. 

Whitehead et al.5 report that in aqueous 66% N,N-dimethylformamide, 3,4-dihydro-3-substituted-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxides are characterized by two pKa s of 11.0-11.4 and 13,0-13.3. Novello and Sprague12 reported pKa s of 9.1 and 10.5 for cyclothiazide. In the latter case the pKa represents the pH at half neutralization in 30% aqueous ethanol determined potentiometrically. 

---