.alpha.-glucosidase inhibitors

Details .alpha.-glucosidase inhibitors .alpha.-glucosidase inhibitors

1992-12-07

1996-04-02

Geist, Gary

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

546207, 536 173, A61K 31445, C07H 1500

Patent

active

055040780

DESCRIPTION:

BRIEF SUMMARY
This invention relates to novel polyglycosidyl derivatives of 1-deoxy-nojirimycin, to the processes for their preparation and to their end-use applications, particularly as to their use in the treatment of diabetes.
More specifically this invention relates to novel polyglycosyl derivatives of 1-deoxy-nojirimycin, to the chemical processes for their preparation, to their .alpha.-glucosidase inhibiting properties, and to their end-use application in the treatment of diabetes, obesity and those diseases associated with retroviruses, particularly the HIV virus reported to be causative of acquired immune deficiency syndrome (AIDS).
UK Patent Application GB 2 088 365 A discloses a bisglucosylmoranoline derivative useful as a remedy for diabetes mellitus.
European Patent Application Number 87112480.6 discloses glucosylmoranoline derivatives useful as a remedy for diabetes.
Still more specifically this invention relates to the novel 1-deoxy nojirimycin derivatives of the formula I ##STR1## and the-pharmaceutically acceptable acid addition salts thereof wherein
n is zero, 1 or 2,
R is a glycosyl moiety containing 1 to 3 hexose or pentose units, said units optionally bearing an ether or acyl radical at the anomeric carbon atom of the terminal hexose or pentose unit, and one of R.sub.1 and R.sub.2 is H and the other is .alpha.-D-glucopyranosyl. The glycosyl moiety represented by "R" in Formula I are radicals which contain from 1 to 3 hexose or pentose units which optionally bear an ether or an acyl radical at the anomeric carbon atom of the terminal hexose or pentose moiety.
Acid addition salts are those salts forms with such inorganic acids as, for example, hydrochloric, hydrobromic, sulfuric, phosphoric and like acids; with organic carboxylic acids such as, for example, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, maleic, tartaric, citric, ascorbic, maleic, hydroxymaleic and dihydroxymaleic, benzoic, 2-acetoxybenzoic, mandelic and like acids; and with organic sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid.
In general, the mono-, di- or trisaccharide moiety (i.e., the glycosyl moiety defined by R) may be attached directly -- or thru a (CH.sub.2).sub.n alkylene bridge -- to the nitrogen atom of the 1-deoxynojirimycin moiety thru either an exocyclic or ring carbon atom of the pentose or hexose ring thereby forming a variety of position isomers for each individual glycosyl moiety. Also, similar or dissimilar pentose or hexose moieties may be linked to each other thru a glycosidic oxygen bridge wherein the bridging oxygen atom is attached to an exocylic and/or endocyclic carbon atom of the pentose or hexose moiety of which the glycosyl radical is comprised; again the position isomers all being contemplated as being within the scope of this invention.
Exemplary of glycosyl radicals contemplated by the "R" designation in Formula I are such monosaccharides as 6- or 4-glucosyl, 6- or 4-galactosyl, 4-fucosyl, 1-, 2- or 6-fructosyl, 6- or 4-mannosyl, 4-ribosyl, 4-arabinosyl, 4-xylosyl, 6- or 4-allosyl, 6- or 4-altrosyl, 6- or 4-gulosyl, 6- or 4-idosyl, 6- or 4-talosyl and 4-1-yxosyl, such disaccharides as 4- or 6-isomaltosyl, 4- or 6-trehalosyl, .beta.4- or 6-cellobiosyl, maltosyl, and such trisaccharides as maltotriosyl and cellotriosyl. Preferred glycosyl radicals are 6- or 4-glucosyl, 1- or 6-fructosyl, 6- or 4-maltosyl and 6- or 4-isomaltosyl. Ether derivatives are those derivatives wherein the hydroxyl group attached to the anomeric carbon atom is etherified and include the C.sub.1-8 alkyl derivatives, preferably methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclohexyl, cyclohexylmethyl, t-butyl, isobutyl, isopropyl and aromatic derivatives such as phenyl and benzyl and the like. Acyl derivatives, such as those formed at the anomeric carbon atom by reaction of the free hydroxy radical with C.sub.1-8 alkanoic acids or benzoic acids, are also contemplated even though such acylated moieties may easily be removed from the glycosyl radical. Preferred acyl radicals are those

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