Steroidal glycosides

Details Steroidal glycosides Steroidal glycosides

1996-06-19

1997-12-16

Ivy, C. Warren

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

514173, 536 6, A61K 31705

Patent

active

056985266

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

This invention relates to steroidal glycosides and methods of using the same, particularly as hypocholesterolemic agents and antiatherosclerosis agents, in mammals.
Many known products possessing hypocholesterolemic activity are cross-linked synthetic polymer derivatives. For example, cross-linked, water-insoluble, bile-acid-binding polystyrene-based resins, e.g., Cholestyramine.RTM. agents, have a gritty "mouth-feel", and thus have poor palatability. In addition, these resin beads typically have a low in vivo efficiency. Thus, the effective hypocholesterolemic dose of these materials is excessive, typically 18-24 grams of formulated product per day. Other known polymers having hypocholesterolemic activity include the natural product chitosan and chitosan derivatives as described in European Application pub. no. 0212145. However, the effective hypocholesterolemic dose of these materials is also high.
Other known hypercholesterolemia controlling agents include plant extracts such as "alfalfa saponins". However, these plant extracts are of variable composition and contain significant amounts of non-useful chemical substances. Due to the variations in composition, it is difficult to set a standard dosage or predict the impurities present. Thus, such extracts are not well suited for use by humans. Furthermore purification of these extracts would be expensive. As an alternative certain synthetically produced, pure "sapogenin-derived" compounds e.g., substances compounded from spirostane, spirostene or sterol-derived compounds depress cholesterol absorption more effectively than alfalfa extracts on a weight basis and thus can be administered in reasonable sized doses. Because the chemical compositions of these substances are known and because they can be synthesized at a high degree of purity, they are suitable for use by any warm-blooded animal, including humans.
However, unless administered in massive amounts, pure sapogenins do not significantly inhibit cholesterol's absorption. It is only when compounded with another moiety that sapogenins have the desired effect. Examples of such sapogenin compounds are compounds of tigogenin and diosgenin, particularly glycosides thereof. P. K. Kintia, Iu. K. Vasilenko, G. M. Gorianu, V. A. Bobeiko, I. V. Suetina, N. E. Mashchenko, Kim. Pharm. Zh., 1981, 15(9), 55 discloses 3-O-(.beta.-D-galactopyranosyl)hecogenin and its use as a hypocholesterolemic agent. U.S. Pat. Nos. 4,602,003 and 4,602,005 disclose certain steroidal glycosides, in particular 3-O-(.beta.-D-glucopyranosyl)tigogenin and 3-O-(.beta.-D-cellobiosyl)tigogenin and their use for the control of hypercholesterolemia. 3-O-(.beta.-D-cellobiosyl)tigogenin has superior hypocholesterolemic activity when compared to, for example, cholestyramine. PCT publication WO 93/07167 discloses several steroidal glycosides in particular 3-O-(5-C-hydroxymethyl-L-arabino-hexopyranosyl)-tigogenin and 3-O-(5-C-hydroxymethyl-L-arabino-hexopyranosyl)-diosgenin and their use in the control of hypercholesterolemia.
Recently commonly assigned PCT publication WO 93/11150 has disclosed a number of steroidal glycosides including 11-ketotigogenyl-beta-O-cellobioside, hecogenin-beta-O-cellobioside, diosgenin-beta-O-cellobioside and their use as antihypercholesterolemic agents. Also commonly assigned PCT publication WO 94/00480 the disclosure of which is hereby incorporated by reference, discloses a variety of steroidal glycosides and their use as antihypercholesterolemic agents.
Although the hypocholesterolemic compounds described above make a significant contribution to the art there is a continuing search in this field of art for improved hypocholesterolemic pharmaceuticals.


SUMMARY OF THE INVENTION

This invention is directed to steroidal glycosides, particularly spirostanyl glycosides, that are useful as hypocholesterolemic agents and antiatherosclerosis agents. The compounds of this invention have the formula ##STR2## and the pharmaceutically-acceptable salts and hydrates thereof wherein ##STR3## R.sub.1, R

REFERENCES:
patent: 4265886 (1981-05-01), Pegel
Protective Groups in Organic Synthesis; Greene, T.W., 1981, Wiley and Sons Inc., pp. 16, 39-50, 61, 69, 70, and 72-82, Feb. 1982.

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