Sulfonamides Antidiabetics

I became involved in carbodiimide chemistry in my research work on isocyanates at the former Donald S. Gilmore Research Laboratories of the Upjohn Company in North Haven, CT. Carbodiimides are readily synthesized from isocyanates using a phospholene oxide catalyst. This reaction can be conducted without a solvent, and the byproduct is carbon dioxide. We used this reaction in the manufacture of a liquid version of MDI (4,4 -diisocyanatodiphenylmethane), which today is sold in huge quantities worldwide. By reacting MDI with dicarboxylic acids in a vented extruder we manufactured a family of thermoplastic polyamide elastomers, which are sold today by the Dow Chemical Company. Also, N-sulfonylcarbodiimides were synthesized for the first time in our laboratories. They are the precursors of the antidiabetic sulfonamides, such as Upjohn s Tolbutamide (Orinase). Because of the close relationship of isocyanates with carbodiimides we studied many linear and cyclic carbodiimide reactions, especially their cycloaddition reactions. 

Of the 2,100,000 diagnosed diabetics in the United States today, 45% are on oral drugs, 33% are on insulin, and 22% are on diet alone. Approximately one million Americans take either tolbutamide or chlorpropamide every day as primary therapy for their diabetes mellitus. The sulfonylureas represent a very significant contribution to medical therapy. That guanidine bases depress blood sugar was first reported in 1918 by Watanabe (27). The real story of the antidiabetic sulfonamides began in 1942. 

The reduction in urinary elimination in untreated diabetic patients affects not only citric acid. Indeed, Osteux and Laturaze (07) have shown that the same holds true for the other acids of the tricarboxylic acid cycle treatment with insulin re-establishes a normal elimination of these acids. Treatment with antidiabetic sulfonamides also increases the urinary citrate in such patients (OlO). 

The more modest increase in AUC of rosiglitazone is less likely to be clinically important, but, until more experience is gained, some caution is warranted. No interaction would be expeeted between trimethoprim and tolbutamide, although note that co-trimoxazole has rarely caused hypogly-caemia alone or combined with various sulphonylureas, see Antidiabetics + Sulfonamides , p.506. 

Finally, attachment of a rather complex side chain to the para position of the benzene ring on the sulfonamide leads to the very potent, long-acting oral antidiabetic agent, glyburide (215). Preparation of this compound starts with the chlorosul-fonation of the acetamide of 3-phenethylamine (209). The resulting sulfonyl chloride (210) is then converted to the sulfonamide (211) and deacylated (212). Reaction with the salicylic acid derivative, 213, in the presence of carbodiimide affords the amide, 214. Condensation of that with cyclohexylisocyanate affords glyburide (215). ... 

The bioslurry treatment successfully removed several of the PhC to non-detectable levels after 26 days three histamine H2-receptor antagonists (ranitidine, famotidine, cimetidine), two (1-blockers (atenolol, sotalol), one barbiturate (butalbital) and one antidiabetic compound (glibenclamide). The elimination of the sulfonamide antibiotics sulfapyridine (100%), sulfamethazine (91.0%) and... 

The following are examples of substances that may increase the blood glucose-lowering effect and susceptibility to hypoglycemia oral antidiabetic products, ACE inhibitors, disopyramide, fibrates, fluoxetine, MAO inhibitors, pentoxifylline, propoxyphene, salicylates, and sulfonamide antibiotics. 

A series of esters of nuclear halogenated 3-carboxy-1,2,3-benzotriazin-4(3//)-ones show depressant activity, while the benzoate esters of substituted 3-(2-hydroxyethyl)-l,2,3-benzotriazin-4(3f0-one are reported to function as coronary dUating agents," as do certain other compounds of this type." 3-(o-Haloaryl)-l,2,3-benzotriazin-4(3i/> ones are claimed to have antisecretory," anoretic, anticonvulsant, and hypoglycemic activity, and a variety of other 3-aryl derivatives are stated to be relaxants, tranquilizers, sedatives, hypnotics, or cramp inhibitors. A number of derivatives of 10, R = H, in which the 3-substituent is a long alkyl chain containing a terminal sulfonamide group have been claimed to act. as antidiabetics. ... 

Some compounds are stored in the body in specific tissues. Such storage effectively removes the material from circulation and thus decreases the toxicity of the compound. Repeated doses of a toxic substance may be taken up and subsequently stored without apparent toxicity until the storage receptors become saturated then toxicity suddenly occurs. In some cases, the stored compound may be displaced from its storage receptor by another compound that has an affinity for the same receptor. Examples of this phenomenon are the displacement of antidiabetic sul-fonylureas by sulfonamides and the ability of antimalarial drugs such as quina-crine (atabrine) and primaquine to displace each other (Loomis, 1978). A special danger in such cases is that compounds may have escaped detoxifying metabolism while stored in the body, and that their toxicity may be potent and prolonged when released. 

Another very prominent example of the development of dmgs for new indications, from the fortuitous observation of side effects, is that of the sulfonamides. Several sulfonamides of the first generation had, in addition to their antibacterial effect, either diuretic or hypoglycemic activities. Correspondingly, specific diuretics, antiglaucomics, antihypertensives, and antidiabetics could be developed in this group of compounds [11,14,16]. 

Figure 2.7 N-lsopropyl-thiadiazolyl sulfanilamide (IPTD) 19 was the first sulfonamide that showed antidiabetic properties in the clinics. Carbutamide 20 and tolbutamide 21 are also antidiabetics tolbutamide 21 has a shorter biological half-life than carbutamide 20, due to its methyl group instead of the chlorine atom in addition, tolbutamide does not show antibacterial activity. Glibendamide 22 is an antidiabetic drug with improved therapeutic properties.

Clinically important, potentially hazardous interactions with anticoagulants, antidiabetics, barbiturates, chlorpheniramine, corticosteroids, digoxin, gliclazide, lithium, methotrexate, methylphenidate, phenytoin, rifampin, sulfonamides... 

Several Cr111 complexes with activated amido donor ligands (e.g., amides of carboxylic or sulfonic acids) have been described, but none of them have been crystallographically characterized.132,479 Complexes of Cr111 with 2-sulfonamide-1,3,4-thiadiazol derivatives act as potent inhibitors of carbonic anhydrases and may have potential use as anti-inflammatory or antidiabetic drugs.479,480... 

A further example is provided by the antidiabetic agent tolbutamide (Fig. 7.30) which was developed from a sulfonamide structure. Most sulfonamides are used as antibacterial agents, but some proved unsatisfactory since they led to convulsions brought on by hypoglycaemia (low glucose levels in the blood). Structural alterations were made to eliminate the antibacterial activity and to enhance the hypoglycaemic activity and this led to tolbutamide. 

Sulfonamides may adversely affect the level of some medications causing a toxic effect. Avoid using sulfonamides with anticoagulants such as coumarin or indanedione derivatives and anticonvulsants (hydantoin) as well as oral antidiabetic agents and methotrexate. 

Oral Antidiabetic Agents The oral hypoglycemics were developed fijom the observation that sulfonamides had hypoglycemic activity. 

The sulphonylurea and other sulfonamide-related compounds such as chlorpropamide and tolbutamide were the first synthetic compounds used in medicine as antidiabetics. Among their actions they stimulate the remaining beta-cells of the pancreas to grow and secrete insulin which, with a restricted diet, controls blood glucose levels and permits normal metabolism to occur. Clearly they can only be effective in those diabetics whose pancreas still has the capacity to produce some insulin, so their use is confined to type 2 diabetes. 

Table 13.3 , (p.508) summarises the information on the interactions between sulphonylureas and sulfonamides. For a report of the combined use of co-trimoxazole and fluconazole causing hypoglycaemia with gli-clazide, see Antidiabetics + Azoles Fluconazole , p.479. 

Table 13.3 Interactions between antidiabetics and sulfonamides (continued)...

When a sulfonamide reacts with aqueous acid or aqueous hydroxide, the amine (or ammonia) is released along with the parent sulfonic acid. Butanesulfonamide (191), for example, reacts with aqueous hydroxide (followed by an acid neutralization step) to give butanesulfonic acid (190) and ammonia. Sulfonamides are quite stable molecules and they are used in a variety of applications, particularly those sulfonamides derived from benzene derivatives (see Chapter 21). Sulfanilamide (192), for example, is a potent antibacterial agent and isobuzole (193), with the formal name of JV-(5-isobutyl-l,3,4-thiadiazol-2-yl)-p-methoxy-benzenesulfonamide, has hypoglycemic (antidiabetic) properties. 

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