Sulfonamide groupings

Cyclothia2ide [2259-96-3] is another example of a duorine-free pharmaceutical (diuretic, antihypertensive) based on y -chloroduoroben2ene [625-98-9] where duorine activation is subsequentiy provided by two sulfonamide groups (156). 

Sulfonamide groups can be introduced into phthalocyanines to make them soluble in alcohols and glycol ethers. Their main appHcations are transparent paints, flexo and gravure printing inks, wood stains, plastics, and ballpoint inks. This includes products Hke Solvent Blue 24 (Cl 74380),... 

Developing agents must also be soluble in the aqueous alkaline processing solutions. Typically such solutions are maintained at about pH 10 by the presence of a carbonate buffer. Other buffers used include borate and, less frequendy, phosphate. Developer solubiUty can be enhanced by the presence of hydroxyl or sulfonamide groups, usually in the A/-alkyl substituent. The solubilization also serves to reduce developer allergenicity by reducing partitioning into the lipophilic phase of the skin (46). 

A second approach utilizes the oxidation of alow mobiUty substituted 4-hydroxydiphenylamine to which an image dye is linked through a sulfonamide group. Oxidation and hydrolysis result in ting closure and release of the alkaU-soluble dye (eq. 2). 

Protective group chemistry for these amines has been separated from the simple amines because chemically they behave quite differently with respect to protective group cleavage. The increased acidity of these aromatic amines makes it easier to cleave the various amide, carbamate, and sulfonamide groups that are used to protect this class. A similar situation arises in the deprotection of nucleoside bases (e.g., the isobutanamide is cleaved with methanolic ammonia ), again, because of the increased acidity of the NH group. 

Another point for structural diversification is the sulfonamide group. Imai had already shown that a wide variety of groups could be introduced at this position to optimize the reaction. Since a wide variety of sulfonyl chlorides are commercially available, a number of different types of groups could be examined (Scheme 3.34). Testing of a variety of aryl and alkyl groups on the 1,2-cyclohexanediamine backbone demonstrates that the simple methanesulfonamide 122 is clearly superior or equal to many other analogs in the cyclopropanation of cinnamyl alcohol (Table 3.11). Another concern which was directly addressed by this survey was the question of catalyst solubility. 

Since the ring nitrogen at 3 is now comparable in reactivity to the amine at 4, acylation with one equivalent of 88 gives a mixture of products. The desired product, sulfaisodimidine (109), can be obtained by acylation with an excess of the sulfonyl chloride (140) followed by alkaline hydrolysis. The rate of saponification of the sulfonamide group attached to the ring nitrogen is sufficiently greater to cause it to be lost selectively. 

Diuretic activity can be retained in the face of replacement of one of the sulfonamide groups by a carboxylic acid or amide. Reaction of the dichlorobenzoic acid, 174, with chlorsulfonic acid gives the sulfonyl chloride, 175 this is then converted to the amide (176). Reaction of that compound with furfuryl ine leads to nucleophilic aromatic displacement of the highly activated chlorine at the 2 position. There is thus obtained the very potent diuretic furosemide (177). ... 

Chlorthalidone (49) is another thiazide-like diuretic agent that formally contains an isoindole ring. Transformation of the amine in benzophenone, 47, to a sulfonamide group by essentially the same process as was outlined for chlorexolone (46) affords Intermediate 43. This product cyclizes to the desired pseudoacid 1-ketoisoindole (49) on successive treatments with thionyl... 

The sulfonamide group has been used successfully to confer diuretic activity to both aromatic and simple heterocyclic compounds. 

Replacement of the sulfonamide group at the 7 position by chlorine markedly diminishes the diuretic effect in this series. One such compound, diazoxide (169), exhibits instead potent anti-... 

Alkylated sulfonamide groups have proven useful additions to the phenothiazine nucleus. The same seems to hold true in the thioxanthene series. Chlorosulfonation of the benzoic acid, 38, followed by displacement with dimethylamine affords the sulfonamide, 39. This is then taken on to the substituted thioxanthone (41) by the sequence of steps shown above Grignard condensation followed by dehydration gives thiothixine (42). 

It was found, furthermore, that the substituent on the sulfonamide group of the chiral hgand strongly influenced the enantiofacial selectivity. Hence, ligand 81 bearing a tosyl substituent delivered the endo-(2il)-cycloadduct, whereas a trifluoromethanesulfonamide group afforded its enantiomer. The authors proposed that the latter substituent should increase the Lewis acid-... 

Changing the substitution pattern on the carbo-cyclic ring of the benzothiadiazine diuretics is well known to have a marked effect on the qualitative biological activity. Thus, the direct analogue of the diuretic chlorothiazide (199) in which chlorine replaces one sulfonamide group, diazoxide (200), shows negligible diuretic activity instead the compound is a potent antihypertensive vasodilator. 

Aromatic heterocycles can also be mercurated. For example, iV-acetylpyrrole and Ar- p h e n y 1 s u 1 fo n y I p y no 1 e react with HgCl2/NaOAc to form the monomercurated products 79 and 80, respectively (Equations (30) and (31)). The amide or sulfonamide group provides an oxygen donor atom that coordinates with the incoming mercuric ion, ultimately directing mercuration at the 2-position.100... 

COX-2 selectivity was evaluated in vitro by using the human whole blood assays of COX isoenzyme activity. Three compounds, not bearing the sulfonamide group present in valdecoxib, have been found to be selective COX-1 inhibitors. 

TMS group and the Suzuki cross-coupling reaction is again repeated. This sequential process allows for the introduction of different aromatic groups at positions 3 and 4 of the pyrrole system. The synthesis of the Furstner intermediate (6) is completed by removal of the sulfonamide group. 

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