Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1991-12-12
1994-01-11
Brown, Johnnie R.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 552, 536115, 536117, C07H 1300, C07H 506, A61K 3170
Patent
active
052783006
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to novel 4,6-O-hydroxyphosphoryl-glucosamine derivatives and pharmaceutically-acceptable salts thereof.
The compounds of the present invention exhibit lipid A-like activity, and are useful as pharmaceutical drugs such as immunopotentiation agents and anti-tumour agents.
BACKGROUND ART
Surface layers of Gram-negative bacteria are composed of a cell membrane, a cell wall peptidoglycan, and an outer membrane. The outer membrane contains lipopolysaccharides (hereinafter abbreviated LPS). LPS is a main ingredient of endotoxin which induces endotoxin shock, and consists of an acidic protein component, a high-molecular weight polysaccharide component, and a phospholipid component.
LPS induces various morbid conditions such as pyrogenesis, bleeding, arthritis, and encephalomyelitis. LPS is also known to exhibit a host protection effect on immune-activating mechanisms such as macrophage-activation, B-cell blastogenesis activity, and cell-mediated immunity-activation, as well as antitumour effects such as IFN(interferon) induction and TNF(tumour necrosis factor) induction.
The main component of LPS which exhibits these activities among said three components is the phospholipid component, which is called lipid A. Lipid A comprises a fatty acid residue and phosphoric acid, both of which are combined with a disaccharide amine, and has the following formula [Japanese Bacteriology Journal 40(1), 57(1985) and Proc. Natl. Acad. Sci. U.S.A. 80, 4624(1983)]: ##STR2##
A recent study has revealed that either the non-reducing subunit or the reducing subunit alone as shown above can exhibit the lipid A-like activity, and various analogues have been synthesized based on this finding. Examples of such analogues are disclosed in European Patent Application Disclosure No. 224260, Japanese Patent Application Disclosure No. 62888/90, and Japanese Patent Application Disclosure No. 25494/90, etc.
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 introduced substituent sites. However, no lipid A analogue has been developed which is pharmaceutically applicable, mainly because the same substituent exhibits different activities depending on its introduced site, thus making the study of pharmaceutical applications of the lipid A-like analogues difficult. Therefore, lipid A analogues of higher activity and lower toxicity are expected to be developed.
DISCLOSURE OF INVENTION
The object of the present invention is to produce novel compounds which exhibit more effective lipid A-like activity and low toxicity.
The inventors of the present invention have been energetically studied lipid A derivatives in order to attain said object. As a result, the inventors have discovered novel compounds which exhibit strong lipid A-like activity such as mitogenic activity of varying strength depending on the analogue, TNF-inducing activity, and IFN-inducing activity, and which nevertheless exhibit low toxicity, and have completed the present invention based on these findings.
Novel 4,6-O-hydroxyphosphoryl-glucosamine compounds according to the present invention have the following general formula (I): ##STR3## wherein R.sub.1 and R.sub.2 represent a hydrogen atom or a hydroxy group; one of R.sub.3 and R.sub.4 is --OCO(CH.sub.2).sub.n CH.sub.3, --CH.sub.2 (CH.sub.2).sub.n CH.sub.3, or --O--CH.sub.2 (CH.sub.2).sub.n CH.sub.3, and the other is a hydrogen atom; l is an integer of 4-16; m is an integer of 4-16; and n is an integer of 6-18.
This invention also relates not only to said compounds but also to their pharmaceutically-acceptable salts. Examples of these salts are inorganic alkali metal salts, alkali-earth metal salts, and organic amine salts. Specifically, salts of the compounds with sodium, potassium, lithium, calcium, triethanolamine, diethanolamine, monoethanolamine, triethylamine, etc. are exemplified.
4,6-O-hydroxyphosphoryl-glucosamine derivatives (I) according to the present invent
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Hasegawa Akira
Ishida Tomio
Uesato Shin-ichi
Brown Johnnie R.
Hasegawa Akira
Japan Tobacco Inc.
White Everett
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