Sulfonylurea

Systematic modification of the sulfanilamide molecule in order to maximize the hypoglycemic activity led to the observation that the sulfonamide is best replaced by a sulfonylurea function. Modification on both the aromatic ring and the substituent on the terminal nitrogen modulates the activity of the products.  

Sulfonylureas are accessible by the many methods that have been developed for the preparation of simpler ureas. For example, treatment of p-toluenesulfonamide (184) with butyl isocyanate (185) affords tolbutamide (186).  

Treatment of piperidine with nitrous acid affords the N-nitroso derivative (190) reduction gives the corresponding hydrazine (191). Condensation of this intermediate with the carbamate (192) obtained from p-toluenesulfonamide leads to the oral hypoglycemic agent tolazemide (193). In a similar vein, reaction of the hydrazine obtained by the same sequence from azepine (194) with the carbamate, 188, gives azepinamide (195).  

In another approach to the required functionality, the sodium salt of acetyl sulfanilamide (196) is condensed with butyl 

Inclusion of a para acetyl group requires a somewhat different approach to the preparation of these compounds. Reaction of the diazonium salt from p-aminoacetophenone with sulfur dioxide affords the sulfonyl chloride, 203 this is then converted to the sulfonamide, 204, Elaboration via the carbamate with cyclohexyl-amine affords acetohexamide (205).  

Biguanides Metformin (Glucophage) Act directly on the liver to decrease hepatic glucose production also increase sensitivity of peripheral tissues (muscle) to insulin Gastrointestinal disturbances lactic acidosis may also occur in rare cases, and this effect can be severe or fatal 

Thiazolidinediones Pioglitazone (Actos) Rosiglitazone (Avandia) Similar to the biguanides (metformin) Headache dizziness fatigue/weakness back pain rare but potentially severe cases of hepatic toxicity 

Benzoic acid derivatives Repaglinide (Prandin) Nateglinide (Starlix) Similar to the sulfonylureas Hypoglycemia bronchitis upper respiratory tract infections joint and back pain gastrointestinal disturbances headache 

Skeletal rearrangement with loss of S02 was also observed in the mass spectra of arenesulfonylthioureas, but alkanesulfonylthioureas failed to produce this fragmentation mode88 6. 

The important drugs belonging to eaeh of the above eategories shall now be diseussed individually in the sections that follows  

Salient Features The salient features of the sulfonylureas are as given below  

However, these agents are now divided into two sub-groups, namely  

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Herbicides also inhibit 5- (9/-pymvylshikiniate synthase, a susceptible en2yme in the pathway to the aromatic amino acids, phenylalanine, tyrosine and tryptophan, and to the phenylpropanes. Acetolactate synthase, or acetohydroxy acid synthase, a key en2yme in the synthesis of the branched-chain amino acids isoleucine and valine, is also sensitive to some herbicides. Glyphosate (26), the sulfonylureas (136), and the imida2oles (137) all inhibit specific en2ymes in amino acid synthesis pathways. 

The inhibitors of amino acid synthesis, sulfonylureas, imidazolinones, and glyphosate, were first recognized as general growth inhibitors that prevent mitotic entry (188,189). Whatever the mode of action, herbicides that inhibit amino acid synthesis also cause a rapid inhibition of cell growth, usually through inhibition of mitotic entry. 

Sulfonylurea herbicides ate weak acids and, in general, ate not strongly sorbed to soils. Sorption of chlotsulfuton and metsulfuron—methyl is inversely related to soil pH (407) and is positively correlated to soil organic matter (408). 

The EPA has not issued HAs for any of the sulfonylurea herbicides (269) and data on the occurrence of the sulfonylurea herbicides in SW or GW are not available. Additional sulfonylurea herbicides include bensulfuron [99283-01-9] and metsulfuron, methyl [74223-64-6]. 

Three classes of oral therapeutic agent are available for treating patients with diabetes mellitiis (NIDDM) the arylsulfonylureas (known simply as sulfonylureas), biguanides, and a-glycosidase inhibitors. Since 1977, only the sulfonylureas have been approved for use in the United States, although the other classes are used elsewhere. 

Sulfonylureas. The hypoglycemic effect of sulfonylureas was first noted in the early 1940s when several patients died in hypoglycemic coma after testing glyprothia2ole, a synthetic sulfonamide used to treat typhoid. Chemical modifications which enhanced activity and lowered toxicity led to the development of the first-generation sulfonylureas. Carbutamide [339-43-5] the first commercial sulfonylurea, came onto the European... 

Table 2. Sulfonylureas Used as Oral Hypoglycemic Agents...

The absorption of sulfonylureas from the upper gastrointestinal tract is faidy rapid and complete. The agents are transported in the blood as protein-bound complexes. As they are released from protein-binding sites, the free (unbound) form becomes available for diffusion into tissues and to sites of action. Specific receptors are present on pancreatic islet P-ceU surfaces which bind sulfonylureas with high affinity. Binding of sulfonylureas to these receptors appears to be coupled to an ATP-sensitive channel to stimulate insulin secretion. These agents may also potentiate insulin-stimulated glucose transport in adipose tissue and skeletal muscle. 

Relative potency alone does not determine dmg selection because maximal effectiveness is similar for all agents. A single daily dose of any sulfonylurea, except tolbutamide, is sometimes adequate to control blood glucose in NIDDM patients. 

Generally, the untoward effects associated with tola2amide are the same as those noted with the other sulfonylureas the incidence is low and reactions are reversible when tola2amide is discontinued. Hypoglycemia has been reported occasionally. 

Tolbutamide. Tolbutamide (l-but5l-3-(p-tolylsulfonyl)urea), with mol wt 270.35, is known as Orinase. It is a white to off-white practically ododess crystalline powder having a slightly bitter taste, mp 126—132°C. It is practically insoluble in water, and soluble in alcohol and chloroform. The toxicity of tolbutamide appears to be low, and reactions are similar to those observed with other sulfonylureas. 

Extensive reviews have been pubUshed, covering the Hterature to about 1967 (1 3). Pyrazoles and the benzopyrazoles have been well reviewed in References 4 and 5. More up-to-date reviews, though much narrower in scope, have been pubUshed on pyrazole oxides (6), dihydropyrazoles as insecticides (7), the anticancer dmgs anthrapyrazoles (8,9), and pyrazole sulfonylureas as herbicides (10). 

Carboxyhc acid ester, carbamate, organophosphate, and urea hydrolysis are important acid/base-catalyzed reactions. Typically, pesticides that are susceptible to chemical hydrolysis are also susceptible to biological hydrolysis the products of chemical vs biological hydrolysis are generally identical (see eqs. 8, 11, 13, and 14). Consequentiy, the two types of reactions can only be distinguished based on sterile controls or kinetic studies. As a general rule, carboxyhc acid esters, carbamates, and organophosphates are more susceptible to alkaline hydrolysis (24), whereas sulfonylureas are more susceptible to acid hydrolysis (25). 

Extensive use of two more recendy developed classes of herbicides will further dramatically reduce the amount of appHed to control weeds. The sulfonylurea herbicides are extremely active compounds first discovered in the mid-1970s at DuPont they have been discussed extensively (78). Sulfonjiurea herbicides have experienced a rapid and widespread success since thek commercial introduction in 1982 with chlorsulfuron (Table 5). The sulfonylureas are appHed at rates of 2—75 g/ha. The chemistry of the sulfonylurea molecule permits the synthesis of a very large number of useful analogues, consequentiy many new herbicides are anticipated for crop production. As of this writing (1996), over 350 patents have been issued to about 27 agricultural companies covering tens of millions of stmctures known or expected to be herbicidaHy active. 

Table 5. Application Rates of Sulfonylurea and Imidazoline Herbicides...

Another class of herbicides, the imida zolines, was discovered at American Cyanamid in the early 1980s. Extensive research has led to the development of four commercial compounds imazapyr, imazamethahenz-methyl, imazethapyr, and imazaquin (see Table 5). Like the sulfonylureas, the imidazolines are extremely active at low rates. 

Pharmaceuticals and Agrochemicals. Thioglycohc acid and its esters are useful as a raw material to obtain biologically active molecules. In cephalosporine syntheses, (4-pyridyl)thioacetic acid [10351 -19-8] (65) and trifluoromethane (ethyl) thioglycolate [75-92-9] (66) are used as intermediates. Methyl-3-ainino-2-thiophene carboxylate can be used as intermediate for herbicidal sulfonylureas (67) and various thiophenic stmctures (68). 

Agrochemical Products. The principal thiophene derivative in herbicidal protection, one of a range of sulfonylurea herbicides, is Harmony [79277-27-3] (Du Pont) (60), based on the intermediate methyl 3-aminothiophene-2-carboxylate (9). The product is characterized by a rapid biodegradabHity in the soil. Many other thiophene derivatives have been shown to have agrochemical activity, but few of these have been developed to the commercial level. 

A multiresidue analytical method based on sohd-phase extraction enrichment combined with ce has been reported to isolate, recover, and quantitate three sulfonylurea herbicides (chlorsulfuron, chlorimuron, and metasulfuron) from soil samples (105). Optimi2ation for ce separation was achieved using an overlapping resolution map scheme. The recovery of each herbicide was >80% and the limit of detection was 10 ppb (see Soil chemistry of pesticides). 

Yet another example of a so-called pharmacophoric group is the biguanide functionality, a grouping associated with oral antidiabetic activity (see the section on sulfonylureas for a fuller discussion of this activity). Condensation of 2-phenethylamine with dicyanamide affords directly the orally active hypoglycemic agent phenformin (88). ... 

BENZENESULFONIC ACID DERIVATIVES As has been discussed previously, substituted -alkylbenzene-sulfonylureas often possess the property of releasing bound insulin, thus sparing the requirement for insulin injections in adult-onset diabetes. A pyrimidine moiety, interestingly, can serve as a surrogate for the urea function. 

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