1,5-dideoxy-1,5-((2-hydroxyethyl)imino)-D-glucitol

개요Miglitol was introduced in Germany as an auxiliary treatment for non-insulin dependent diabetes (NIDDM). A simple two-step synthesis of Miglitol consists of converting 6-desoxy-6-aminosorbose into desoxynojirimycin by reductive cyclization, then selectively hydroxyethylating the cyclic nitrogen. Miglitol is a short-acting intestinal alpha-D-glucosidase inhibitor, reducing postprandial glucose excursions by helping to delay absorption of complex carbohydrates. Acarbose and voglibose are the previous compounds marketed in this class. At low doses, orally administered miglitol was shown to be rapidly and completely absorbed then removed by renal excretion.

용도An inhibitor of alpha-glucosidases.

일반 설명Miglitol is (2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl)-3,4,5-piperidinetriol, or N-hydroxyethyl-1-deoxynorjirimycin. The drug is available as 25-, 50-, and100-mg tablets (Glyset), for administration 25 to 100 mgt.i.d. with meals. In contrast to acarbose, miglitol is highlyabsorbed from a 25-mg oral dose, although absorption is reportedto be saturable, and accordingly less complete athigher doses. Binding to plasma proteins is minimal, andthe volume of distribution (0.18 L/kg, corresponding to12–13 L in a 70-kg adult) is characteristic of compoundsdistributed only to blood and extracellular fluids. Practicallyno systemic biotransformation of miglitol occurs in humans;essentially 100% of an orally administered dose is excretedintact in urine.

생산 방법Miglitol requires 1-deoxynojirimycin as a precursor which can be obtained via three different routes: extraction from plants such as the mulberry tree, fermentation using various bacterial strains, and a complete chemical synthesis. Industrially feasible production of miglitol was, however, restricted by expensive purification steps or low yields. Hence, a new approach was adopted in which a combination of biochemical and chemical synthesis was employed (Schedel, 2000). In this approach, D-glucose is converted to 1-amino-D-sorbitol by reduction with suitable amines and hydrogen, with nickel as catalyst, and then further reaction of products with appropriate acid esters (Kinast and Schedel, 1979). The oxidation of 1-amino-D-sorbitol to 6-amino-L-sorbose is then carried out in a fermenter using Gluconobacter oxydans grown at temperatures between 20 and 45 C, preferably at roomtemperature and maintaining thepHbetween 2.0 and 9.0. At this pH, 6-amino-L-sorbose is present in the medium as piperidinose, which is reduced to 1-desoxy-nojirimycin in the presence of inert solvents and by choosing the appropriate pH. After this, miglitol is obtained by first centrifuging the biomass followed by clarification using active charcoal. Next, separation of catalyst, evaporation of solvents, and isolation of any remaining salts in the medium is carried out (Kinast and Schedel, 1979). An important modification necessary in this process is the addition of protection groups before feeding 1-amino-D-sorbitol to the G. oxydans cultures and their subsequent removal before the ring-closure reaction. This is necessary since1-amino-D-sorbitol is readily oxidized by G. oxydans strains to form 3-hydroxy-2-hydroxymethyl-pyridine at near-neutral pH as a result of spontaneous ring closure (Schedel, 2000).