Hypoglycemic

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...

Sulfonamides derived from sulfanilamide (p-arninoben2enesulfonainide) are commonly referred to as sulfa dmgs. Although several dmg classes are characterized by the presence of a sulfonamide function, eg, hypoglycemics, carbonic anhydrase inhibitors, saluretics, and tubular transport inhibitors, the antibacterial sulfonamides have become classified as the sulfa dmgs. Therapeutically active derivatives are usually substituted on the N nitrogen the position is generally unsubstituted. These features are illustrated by the stmctures of sulfanilamide (1) and sulfadiazine (2)... 

A number of 4-pyrazolylpyridinium salts (687) have been found to have hypoglycemic activity in several animal models (68JMC981). The possibility that the corresponding 4-pyrazolylpyridine I-oxides might also exhibit this type of activity was investigated without success (69JMC945). 

Azaquinolizinium tetrafluoroborate, 2-ethoxy-synthesis, 2, 573 1 -Azaquinolizin-2-one dipolar character, 2, 572 synthesis, 2, 575 UV spectra, 2, 572 1 - Azaquinolizin-4-one hypoglycemic activity, 2, 575 reactions, 2, 574 synthesis, 2, 575 UV spectra, 2, 572... 

Meguro and co-workers described the synthesis and hypoglycemic activity of 4-oxazoleacetic acid derivatives." For example, cyclization of 18 was performed by using phosphorus oxychloride in refluxing toluene to provide 5-methyI-2-(l-methylcyclohexyl)-4-oxazoleacetate in 73% yield and the subsequent hydrolysis gave 19. 

Development of hypoglycemic agent troglitazone (CS-045). 6-hydroxy-2-[p-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2,5,7,8-tetramethylchro-mane 97YZ597. 

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). ... 

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. ... 

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). ... 

It is of note that hypoglycemic activity is maintained even when the aromatic ring is fused onto a carbocyclic ring. Chlor-sulfonation of hydrindan gives chloride, 206. Reaction of the sulfonamide (207) obtained from that intermediate with cyclohexyl isocyanate leads to glyhexamide (208). ... 

Hypoglycemic agent. A drug that lowers glucose concentrations in the blood. 

A related agent, g1 icetanile sodium (42), is made b / a variant of this process. Methyl phenyl acetate is reacted with chlorosulfonic acid to give 38, which itself readily reacts with aminopyrimidine derivative 39 to give sulfonamide Saponification to acid 4 is followed by conversion to the acid chloride and amide formation with 5-chloro-2-methoxyaniline to complete the synthesis of the hypoglycemic agent glicetanile (42). ... 

Perhaps surprisingly, the p-methyl benzenesulfonylurea analogue called tosi fen (45), which is structurally rather close to the oral hypoglycemic agents, is an anti anginal agent... 

---