Sulfathiazole derivatives

Table XIa and b shows the effect of altering the. V -substituent on the biliary excretion of some sulfonamides in the rat. The extent of biliary excretion of the succinyl (Table XIa) and phthalyl (Table Xlb) derivatives of sulfanilamide, sulfacetamide, and sulfathiazole was measured for 24 hours in biliary-cannulated rats. All the compounds are found unchanged in the bile and, therefore, any differences in their biliaiy excnitioii must reflect their affinity for hepatobiliary elimination. In both the succinyl and phthalyl series, the biliary excretion of the sulfathiazole derivative Avas much higher than either tlie corresponding sulfanilamide or sulfacetamide...

The effect of varying the A -substituent of the sulfonamide was studied with a scries of sulfathiazole derivatives, which are excreted mainly unchanged in the bih (Table XII), Sulfathiazole and its A -acetyl derivative have molecular weights below 300 and are not metabolized to polar con-... 

The reactivity of sulfathiazoles has been reviewed (65). Methylation in alkaline solution with dimethyl sulfate gives only the ring methylated derivative (85). Mixtures of products are obtained with diazomethane as alkylating agent (see p. 37). Other alkyl halides in aqueous alkali lead also to ring-alkylated products (85. 251, 650. 669-671). 

However, the sulfathiazoles have now been superseded by penicillin derivatives. 

Sulfathiazole is advised as an hair lotion additive defatting the hair and reducing formation of dandruff (1024). The polymeric 2-aminothiazoles derivatives (427) exhibit good thermal stability with decomposition in air starting at 350°C (1025). 

Aminothiazole itself (104a), R, = R2 = H (an intermediate in the preparation of sulfathiazole), was synthetized as early as 1888 from a,p-dihalogenoethylethers, which give chloroacetaldehyde in addic medium (8). Many other derivatives have now been used for this synthesis, and they are listed in Table IT12. All give excellent yields. 

A variation of this procedure is used for sulfisomidine because of the different character of the amino group in the 4-position of a pyrimidine ring. Two moles of the sulfonyl chloride are condensed with one mole of 4-amino-2,6-dimethy1pyrimidine in the presence of triethylamine. The resulting bis(acetylsulfanilyl) derivative is readily hydrolyzed to the product. The formation of the bis(acetylsulfanilyl) derivative has also been employed for other heterocycHc amines, eg, for synthesis of sulfathiazole and sulfamoxole (44), but the 1 1 reaction is probably preferable. 

A/ -HeterocycHc derivatives can be formed in some cases by a ring closure to give the heterocycle. Sulfadiazine, sulfamethazine, sulfamerazine, and sulfathiazole have been prepared in this fashion, but also by the usual procedure from the sulfonyl chloride and heterocycHc amine. The synthesis of sulfamethazine from sulfaguanidine is an example of the ring closure method. 

The large importance of the sulfonamides for chemotherapeutics, and specially the high activity of sulfathiazole toward bacterial infections, indicated that sulfonamido derivatives of selenazole should also be investigated. Backer and de Jonge used for this purpose 2-amino-... 

Much of the development of the chemistry of sulfanilamidoselenazole derivatives is a result of the important role played by sulfonamides in chemotherapy and more particularly the good activity of sulfathiazole against bacterial infections. Backer and De Jonge (44) prepared these derivatives by reaction of 2-amino-4-methvl- and 2-amino-4-phenvl-selenazoles with N-acetvlsulfanilic acid chloride in pyridine. Alkaline... 

Levulinic acid is fairly easily converted into thiazole derivatives by the intermediate formation of an a-halogenated ketone such as the /3-bromo derivative (XL) or /3-chloro derivative, which reacts with thiourea to form 2-amino-4-methyl-5-thiazoleacetic acid (XLI) or with thioformamide to give 4-methyl-5-thiazoleacetic acid (XLII). The aminothiazole (XLI) and its ethyl ester (XLIII) have been converted into their corresponding sulfanilamide derivatives, (XLIV) and (XLV). These sulfanilamides, particularly the acid XLIV, have considerable chemotherapeutic activity moreover the acid possesses distinct solubility advantages over sulfathiazole itself. 

Rx with prednisolone (Blephamide, Dioptimyd, Metamyd, Vasocidin, Isopto Ceta-pred) with sulfur (Sulfacet-R) with sulfabenzamide (Sulfathiazole, Sulfa-Gyn, Sulnac, Trysul) with phenylephrine (Vasosulf) with fluorometholone (FML-S) Cfiemical Class Sulfonamide derivative... 

Interference with transport characteristics can serve many purposes. The introduction of a hydrophilic disposable moiety can restrict a drug to the gastrointestinal tract and prevent its absorption. Such a type of drug is represented by the intestinal disinfectant succinyl-sulfathiazole (3.27). On the other hand, lipophilic groups can ensure peroral activity, as in the case of the penicillin derivative pivampicillin (3.28), which enters the circulation and then slowly releases the antibiotic in its free acid form, producing high blood levels of the latter. 

The structure of sulfonamides is shown for representative purposes. Among the several thousand compounds in existence, about 25-30 have found widespread use. Sulfanilamide itself is, by present-day standards, very inactive. It was the development of heterocyclic derivatives that produced the highly potent sulfathiazole (9.90). When a succinyl or phthalyl group is attached to the aniline nitrogen, the inactive acylanilide derivatives will not be absorbed from the intestinal tract. Slow deacylation by intestinal... 

Sulfathiazole is available for oral use and is also included in some parenteral formulations in combination with other sulfonamides. It is also used as a feed additive for growth promotion purposes. It is more toxic than sulfamethazine and sulfadimethoxine but is safe when used as the phthalyl derivative. 

Derivatives of 2-aminothiazolines are important pharmacological compounds and precursors in the synthesis of medications [37], such as the antibiotic sulfathiazole and the anthelmintic thiabedazole. Moreover, recent research indicates that they are also inhibitors of enzymes, such as kinurenin 3-hydroxylase [38]. On the other hand, derivatives of 4-hydroxy-chromen-2-one are known as anti-coagulants and antitumor compounds [39-41], The 2-aminothiazolines are obtained by means of the Hantzsch reaction [42-44], which is the reaction of a-haloketones with thioureas. 

Uses, aminothiazoles derivatives, 132-172 hydroxythiazole derivatives, 438-442 mercaptothiazole derivatives, 438-442 UV spectra, 21 of alkylaminothiazoles. 38 and amino-imino equilibrium, 19, 20 and charge transfer, 21 of iminothiazolines, 38 and PPP calculations, 21 and potentiometric measurements, 21 representative data, 22 of Schiff bases, 41 and solvent effects, 21 and substituent effects, 22 of sulfathiazoles, 20 -of sulfonamidothiazoles, 116 of A-2-thiazoline-4-one, 422 pKa determination, 423 of A-4-thiazoline-2-one, in relation with protomerism, 387 representative data, 389 of A-4-thiazoline-2-thiones, 380. 381 in relation with protomerism. 378 of thiazolylcarbamates, 97 of thiazolyl-2-oxides, 409 of thiazolyl-4-oxides, 426 of 2-thiazolylthioethers, 404 of thiazolylthioureas, 94, 96 of thiazolylureas, 93... 

The mass spectra of sulfonamides derived from heterocyclic bases, e.g., sulfathiazole (306) (Fig. 10), show mainly fragments corresponding to a stepwise degradation of the sulfanilamide moiety, (306)—>[307]—>[308]—>[309]—>[49].178... 

Investigations into drugs suspected of causing cancer in humans have included aryl amine derivatives such as Paracetamol (17a)61 and phenacetin (17b). Metabolism of acetanilide (17c) yields aniline, and of 17b A-hydroxyphenacetin (18)62, in accord with views on mechanisms of toxicity as discussed in the next section. Tumor formation was induced in rats at excessively high dose levels and only under certain conditions. Drugs found to cause methemoglobinemia include antipyrine, acetanilide, sulfanilamide, sul-fapyridine, sulfathiazole, sulfonal and thional. 

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