Glycosidase inhibitors and methods of synthesizing same

Details Glycosidase inhibitors and methods of synthesizing same Glycosidase inhibitors and methods of synthesizing same

2000-07-28

2002-09-24

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S183000, C514S445000, C514S432000, C514S315000, C514S517000, C514S706000, C548S556000, C549S028000, C549S066000, C546S242000, C558S033000, C562S899000, C540S001000

Reexamination Certificate

active

06455573

ABSTRACT:

TECHNICAL FIELD
This application relates to methods for synthesizing Salacinol, its stereoisomers, and analogues thereof potentially useful as glycosidase inhibitors.
BACKGROUND
In treatment of non-insulin dependent diabetes (NIDD) management of blood glucose levels is critical. One strategy for treating NIDD is to delay digestion of ingested carbohydrates, thereby lowering post-prandial blood glucose concentration. This can be achieved by administering drugs which inhibit the activity of enzymes, such as glucosidases, which mediate the hydrolysis of complex starches to oligosaccharides in the small intestine. For example, carbohydrate analogues, such as acarbose, reversibly inhibit the function of pancreatic &agr;-amylase and membrane-bound intestinal &agr;-glucoside hydrolase enzymes. In patients suffering from Type II diabetes, such enzyme inhibition results in delayed glucose absorption into the blood and a smoothing or lowering of postprandial hyperglycemia, resulting in improved glycemic control.
Some naturally-occurring glucosidase inhibitors have been isolated from
Salacia reticulate,
a plant native to submontane forests in Sri Lanka and parts of India (known as
“Kotala himbutu”
in Singhalese).
Salacia reticulata
is a woody climbing plant which has been used in the Ayurvedic system of Indian medicine in the treatment of diabetes. Traditionally, Ayurvedic medicine advised that a person suffering from diabetes should drink water left overnight in a mug carved from Kotala himbutu wood. In an article published in 1997, Yoshikawa et al. reported the isolation of the compound Salacinol from a water-soluble fraction derived from the dried roots and stems of
Salacia reticulate.
1
Yoshikawa et al. determined the structure of Salacinol, shown below, and demonstrated its efficacy as an &agr;-glucosidase inhibitor.
Yoshikawa et al. later reported the isolation from the roots and stems of
Salacia reticulate
of Kotalanol which was also shown to be effective as an &agr;-glucosidase inhibitor.
2
Like Salicinol, Kotalanol contains a thiosugar sulfonium ion and an internal sulfate providing the counterion:
Kotalanol has been found to show more potent inhibitory activity against sucrase than Salicinol and acarbose.
2
The exact mechanism of action of Salacinol and other glucosidase inhibitors has not yet been elucidated. Some known glycosidase inhibitors, such as the indolizidine alkaloids castanospermine and swainsonine, are known to carry a positive charge at physiological pH.
It is believed that the mechanism of action of some known inhibitors may be at least partially explained by the establishment of stabilizing electrostatic interactions between the inhibitor and the enzyme active site carboxylate residues. It is postulated that the compounds of the present invention, which comprise postively charged sulfonium, ammonium, and selenonium ions, could function in a similar manner. It is also possible that Salacinol and other compounds of the same class may act by alteration of a transport mechanism across the intestinal wall rather than by directly binding to glucosidase enzymes.
Salacinol and Kotalanol may potentially have fewer long-term side effects than other existing oral antidiabetic agents. For example, oral administration of acarbose in the treatment of Type II diabetes results in undesirable gastrointestinal side effects in some patients, most notably increased flatulence, diarrhoea and abdominal pain. As mentioned above, Salacinol has been used as a therapy for diabetes in the Ayurvedic system of traditional medicine for many years with no notable side effects reported. Further, recent animal studies have shown that the oral ingestion of an extractive from a
Salacia reticulate
trunk at a dose of 5,000 mg/kg had no serious acute toxicity or mutagenicity in rats.
3
The
Salacia reticulate
plant is, however, in relatively small supply and is not readily available outside of Sri Lanka and India. Accordingly, it would be desirable if Salicinol, Kotalanol and analogues thereof could be produced synthetically.
Carbohydrate processing inhibitors have also been shown to be effective in the treatment of some non-diabetic disorders, such as cancer. While normal cells display characteristic oligosaccharide structures, tumor cells display very complex structures that are usually found in embryonic tissues. It is believed that these complex structures provide signal stimuli for rapid proliferation and metastasis of tumor cells. A possible strategy for therapeutic use of glucosidase inhibitors is to take advantage of the differential rates of normal vs cancer cell growth to inhibit assembly of complex oligosaccharide structures. For example, the indolizidine alkaloid swainsonine, an inhibitor of Golgi &agr;-mannosidase II reportedly reduces tumor cell metastasis, enhances cellular immune responses, and reduces tumor cell growth in mice.
4
Swainsonine treatment has led to significant reduction of tumor mass in human patients with advanced malignancies, and is a promising drug therapy for patients suffering from breast, liver, lung and other malignancies.
5,6
The compounds of the present invention may also find application in the treatment of Alzheimer's disease due to their stable, internal salt structure. Alzheimer's is characterized by plaque formation in the brain caused by aggregation of a peptide, &bgr;-amyloid, into fibrils. This is toxic to neuronal cells. One can inhibit this aggregation by using detergent-like molecules. It is believed that the compounds of the present invention, which are amphipathic, may demonstrate this activity.
The need has therefore arisen for a new class of glycosidase inhibitors which may be synthesized in high yields from readily available starting materials and which have potential use as therapeutics.
SUMMARY OF THE INVENTION
In accordance with the invention, a compound selected from the group consisting of non-naturally occurring compounds represented by the general formula (I), including stereoisomers and pharmaceutically acceptable salts thereof is disclosed,
where X is selected from the group consisting of S, Se, and NH. Such compounds include stereoisomers of Salicinol. The target compounds have a stable, internal salt structure comprising heteroatom cation X and a sulfate anion; the substituents may vary without departing from the invention. Preferably, R
1
, R
2
, R
3
, R
4
and R
5
are the same or different and are selected from the group consisting of H, OH, SH, NH
2
, halogens and constituents of compounds selected from the group consisting of cyclopropanes, epoxides, aziridines and episulfides; and R
6
is selected from the group consisting of H and optionally substituted straight chain, branched, or cyclic, saturated or unsaturated hydrocarbon radicals, such as alkyl, alkenyl, alkynyl, aryl, and alkoxy substituents containing any suitable functionality.
Processes for the production of compounds of the general formula (I) are also disclosed comprising reacting a cyclic sulfate having the general formula (II) with a 5-membered ring sugar having the general formula
where X is selected from the group consisting of S, Se, and NH; R
1
and R
2
are selected from the group consisting of H and a protecting group; R
3
is selected from the group consisting of H and optionally substituted straight chain, branched, or cyclic, saturated or unsaturated hydrocarbon radicals and their protected derivatives; and R
4
, R
5
and R
6
are the same or different and are selected from the group consisting of H, OH, SH, NH
2
, halogens and constituents of compounds selected from the group consisting of cyclopropanes, epoxides, aziridines and episulfides and their protected derivatives. Preferably the cyclic sulfate is a 2,4-di-O-protected-D-or L-erythritol-1,3-cyclic sulfate, such as 2,4-O-Benzylidene-D-or L-erythritol-1,3-cyclic sulfate (i.e. R
1
and R
2
comprise a benzylidene protecting group); R
3
is H or a protected polyhydroxylated alkyl chain; and R
4
, R
5
and R
6
are selected from the group consisting of OH and a protec

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