Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1991-07-17
1993-03-02
Brown, Johnnie R.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536119, 536120, 536115, 536116, 536 179, 536 53, 514 23, 514 25, 514 42, C07H 1100, C07H 1300, C07H 1302, A61K 3170
Patent
active
051910721
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to novel lipid A monosaccharide analogues which show lipid A-like activity and are useful as pharmaceutical drugs such as an immunopotentiator agent, and an anti-tumour agent.
BACKGROUND ART
Surface layers of Gram-negative bacteria are composed of cell membranes, cell wall peptide glucan surrounding the membrane, and outer membranes. The outer membrane contains lipopolysaccharide (hereinafter abbreviated LPS). LPS is a main ingredient of endotoxin which induces endotoxin shock, and consists of an acidic protein component, a high molecular polysaccharide component, and a phospholipid component.
LPS shows such functions as causing pyretogenesis, hemorrhage, arthritis, and encephalomyelitis. Moreover, LPS has been known to show immunopotentiating effect of a host-protecting mechanism such as macrophage activation, B cell blastogenesis, and cell-mediated immunity activation, as well as anti-tumor effect such as interferon induction, and TNF induction.
LPS expresses its activity mainly by the phospholipid part called lipid A among said three components. Lipid A comprises fatty acid residue and phosphoric acid both of which are combined with disaccharide amine, and has the following formula (Japanese Bacteriology Journal 40(1), 57(1985); Proc. Natl. Acad. Sci. USA. 80,4626 (1983)). ##STR2##
Recent study has revealed that either a nonreducing subunit or a reducing subunit as shown above alone is able to show lipid A-like activity. Based on this finding, various analogues have been synthesized concerning lipid A.
For example, Japanese Patent Disclosure No. 501259/85 discloses lipid A analogues which closely approximate to the reducing subunit and a method for producing the analogues. Japanese Patent Disclosure No. 146891/89 discloses monophosphoryl lipid A derivatives. Also, Japanese Patent Disclosure No. 246195/86 discloses novel disaccharide and trisaccharide derivatives of lipid A type. Japanese Patent Disclosure No. 275299/86 discloses deoxymuramyldipeptide derivatives. Further, Japanese Patent Disclosure Nos. 52793/89 and 179885/88 disclose glucopyranose derivatives obtained by converting a phosphoric acid residue of the non-reducing subunit in lipid A into sulphuric acid residue.
Inventors of the present invention have made extensive investigation in order to synthesize lipid A derivatives which show a stronger immunomodulating activity. Specifically, by changing substituents or substitutent-sites of a non-reducing subunit, many derivatives were synthesized. As a consequence, some of the derivatives synthesized as said have been found to show a strong immunopharmacological activity, and patent applications for them have already been filed (e.g., Japanese Patent Application Nos. 215613/88, 215612/88, and 172918/88, and Japanese Patent Disclosure Nos. 146892/89, 44588/88, 33391/88, 30495/88, 129292/87, 172867/86, 126094/86, and 126093/86).
As described above, extensive studies have been conducted in order to obtain lipid A analogues, specifically by modifying them with various substituents and by changing substituent sites introduced. However, such a problem has not yet overcome as obtaining different activities for different introduction sites of the same substituents, and thus lipid A analogues have not yet been developed which are applicable as pharmaceutical agents. Therefore compounds showing a more effective lipid A-like activity are earnestly expected to be developed.
SUMMARY OF THE INVENTION
An object of this invention is to provide novel lipid A monosaccharide analogues showing a strong immunomodulating activity analogous to lipid A.
The inventors of the present invention have energetically studied in order to solve the problem stated above by finding a smaller structure and substituent introduction sites for expressing characteristic biological activity specific to lipid A. Consequently, we have found compounds which show strong activities, even though varying strengths, such as limulus activity, mitogenic activity, tumor necrosis factor inducing activity
REFERENCES:
patent: 4746742 (1988-05-01), Hasegawa et al.
English abstract of Japanese Patent Application 61-275299.
English abstract of Japanese Patent Application 64-52793.
English abstract of Japanese Patent Application 63-179885.
English Abstract of Japanese Patent Application 2-62888.
English Abstract of Japanese Patent Application 61-126093.
English Abstract of Japanese Patent Application 61-126094.
English abstract of Japanese Patent Application 61-172867.
English abstract of Japanese Patent Application 62-129292.
English abstract of Japanese Patent Application 63-30495.
English abstract of Japanese Patent Application 2-25494.
English abstract of Japanese Patent Application 1-146892.
English abstract of Japanese Patent Application 63-44588.
English abstract of Japanese Patent Application 63-33391.
English abstract of Japanese Patent Application 2-62889.
Japanese Bacteriology Journal 40(1) 57 1985.
Proc. Natl. Acad. Sci., USA vol. 80, pp. 4624-4628, Aug. 1983.
Hasegawa Akira
Ishida Tomio
Kiso Makoto
Saito Yutaka
Suzuki Masanobu
Akira Hasegawa
Brown Johnnie R.
Japan Tobacco Inc.
White Everett
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