Glucohydrolase inhibitors useful as antidiabetic agents

Details Glucohydrolase inhibitors useful as antidiabetic agents Glucohydrolase inhibitors useful as antidiabetic agents

1993-12-09

1995-08-01

Redding, David A.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

514 23, 536 172, A61K 3100, A01N 4304, C07H 1500

Patent

active

054380693

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

Glycoprotein processing is a complex, poorly understood means by which the sugar groups of a previously glycosylated protein are "trimmed" or "processed" in a particular sequence to obtain a specific pattern of glycosylation. The specificity is important to a number of recognition processes and is the basis for cell-cell and cell-virus interactions. The trimming is accomplished by a set of highly specific enzymes which recognize particular sequences of sugars. One such enzyme, Glucosidase I, is responsible for cleaving the three terminal glucose residue in the oligosaccharide structure (Glc.sub.3 Man.sub.9 GlcNAc.sub.2). Clearly, inhibitors of such an enzyme could be useful in treating diseases and conditions in which glycoproteins are involved.
Certain viruses including the retroviruses have, in addition to the usual vital capsid, an outer membrane of lipid and glycoprotein, similar to the membrane of ordinary cells. Indeed, the lipid of the vital membrane is probably derived directly from the membrane of a previously infected host cell; however, the glycoprotein of the viral membrane is unique to the virus itself and is coded for by the viral genome. Infection of a host cell by a glycoprotein coated virus initially relies on the interaction of various receptors on the host cell surface with the glycoprotein membrane envelope of the virus. Subsequently, the virus and cell membranes fuse and the virion contents are released into the host cell cytoplasm. Thus the glycoprotein envelope of the coated viruses plays an important role in both the initial interaction of the virion and the host cell and in the later fusion of the viral and host cell membranes.
Interference with the formation of the viral envelope glycoprotein could prevent the initial virus-host cell interaction or subsequent fusion or could prevent viral duplication by preventing the construction of the proper glycoprotein required for the completion of the viral membrane. Inhibitors of Glucosidase I may be valuable agents in the treatment of membrane-coated viral disease and metastatic tumors. S. P. Sunkara et al., Biochem and Biophys Research Commun. 148(1), 206 (1987); A. Karpas et al., Proc. Natl. Acad. Sci. USA, 85, 9229 (1977); B. D. Walker et al., Proc. Natl. Acad. Sci. USA, 84, 8120 (1987).
Tumor metastasis is also a process which relies on the cell surface glycoproteins of a traveling tumor cell to bind to the cell surface of a distant tissue. The binding and subsequent cell fusion relies extensively on the cell surface glycoprotein and clearly interfering with the proper development of cell surface glycoproteins would prevent or reduce tumor metastasis. Glucosidase I inhibitors are known to be useful in preventing tumor metastasis and thus applicants' novel compounds are potential antimetastatic agents.


SUMMARY OF THE INVENTION

This invention relates to novel alpha glucohydrolase inhibitors of formula I ##STR1## wherein R is a hydrogen, a (C.sub.1 -C.sub.6)alkyl optionally substituted with one or two hydroxy groups, a glycosyl group, or a group of the formula --(CH.sub.2).sub.n --Ar wherein n is an integer of from 1 to 4 and Ar is a phenyl group optionally substituted with one or two groups selected from (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, F, Cl, Br, I, amino, mono(C.sub.1 -C.sub.4)alkyl- amino, or di(C.sub.1 -C.sub.4)alkylamino, and and are useful in the treatment of viral infections and metastatic tumors.


DETAILED DESCRIPTION OF THE INVENTION

The usual stereochemical conventions are used throughout to denote the relative spatial orientation of groups attached to the rings. Thus, a solid line diverging from the point of attachment to a ring, indicates that the attached group is in the beta-configuration, that is, the group is above the plane of the ring. Likewise, a dotted line indicates that the attached group is in the alpha-configuration, that is, the group is below the plane of the ring. Attachment of a group to a ring by a normal, not divergent or dotted, line indicates that the sp

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