Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1995-05-05
1997-08-05
Kight, John
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514 62, 536 53, 536 552, 53612313, 536117, 536121, A61K 3173, C07H 506, C07H 1104, C07H 1312
Patent
active
056542895
DESCRIPTION:
BRIEF SUMMARY
DESCRIPTION
1. Technical Field
This invention relates to a novel disaccharide derivative, which has various biological activities and a low toxicity (i.e., extremely low lethal toxicity and pyrogenicity), and its salt.
2. Background Art
Lipopolysaccharide (LPS), which is contained in the outer membrane of the cell wall of various gram-negative bacteria, consists of a glycolipid called "lipid A" to which various saccharides are bonded. It has been known for a long time that LPS is the main component of endotoxins. It is also known that LPS accelerates various immune functions in vivo and its main activity expression site resides in lipid A. It is understood that LPS has various biological activities in addition to an immunomodulatory effect and an antitumor effect.
The chemical structure of lipid A has been clarified in various gram-negative bacteria including Escherichia coli ["Structure of the lipopolysaccharide from an E. coli Haprose-less Mutant", Marcha R. R., Jiunn-yann T., Israel B., and H. Gobind Khorana, The Journal of Biological Chemistry, vol. 254, No. 13, pp. 5906-5917 (1979)]. Among all, the chemical synthesis of lipid A originating in Escherichia coli has been completed and various derivatives thereof are also chemically synthesized. As a result, it is proven that some of chemically synthesized lipid A derivatives are comparable or even superior to the lipid A originating in Escherichia coli in the function of inducing tumor necrosis factor (TNF) and mitogen activity [Japanese Patent Application Laid-Open (Kokai) No. Sho-59-48497].
However, the lipid A originating in Escherichia coli and its derivatives exhibit some unfavorable properties such as pyrogenicity and necrotoxic activity. Thus attempts were made to synthesize lipid A derivatives over an extended range [Japanese Patent Application Laid-Open (Kokai) No. Sho-61-227586]. Further, detailed studies were conducted on compounds having a monosaccharide structure with lipid A-like activities, modification with the use of various substituents and substituent-introduction sites. Also various analogs were synthesized and the biological activities, immunological activities and toxicities of these substances were examined ["Ripido A Ruijitai no Seibutsu Kassei (Biological Activities of Lipid A Analogs)", Ogawa H., Kiso M. and Hasegawa A., Taisha (Metabolism), vol. 26, No. 5, pp. 15-27 (1989); and "Gosei Ripido A to sono Yudotai (Synthetic Lipid A and its Derivatives)", Honma Y., Meneki Yakuri (Immunopharmacology), vol. 8, No. 4, pp. 25-32 (1990)]. However, no reference has been made concerning a compound having free hydroxyl groups at the 3, 3' and 4'-positions and no compound practically available as a medicine has been developed so far.
DISCLOSURE OF THE INVENTION
Under these circumstances, it has been strongly desired to develop a lipid A analog which has a reduced toxicity and enhanced activities.
The present invention provides a novel disaccharide derivative which has various useful biological activities, for example, potent mitogen activity, adjuvant activity, nonspecific protective activity, antiviral activity, immuno-potentiation function, etc. but little adverse effects, for example, pyrogenicity, lethal toxicity, etc. and is highly useful as a medicine, etc.
The present inventors have found that LPS contained in the outer membrane of cell wall of Porphyromonas (Bacteroides) gingivalis, which is one of bacteria commonly found in human oral cavity and seemingly being causative of periodontal diseases, has mitogen activity, etc. but yet extremely low lethal toxicity and pyrogenicity. They have further prepared and purified the activity expression site of this LPS, analyzed its structure and effected extensive studies thereon. As a result, they have found that the active compound of the present invention has a glucosamine .beta.(1,6)-disaccharide structure having a phosphate group bonded to the 1-position as the basic skeleton and 3-hydroxy-15-methylhexadecanoic acid is bonded to the amino group at the 2-position thereof via an amide li
REFERENCES:
FEBS, vol. 332, No. 1.2, issued Oct. 1993, Ogawa, "Chemical Structure of Lipid a from Porphyromonas (Bacteroides) gingivalis Lipopolysaccharide", pp. 197-201.
Importance of Fatty Acid Substituents of Chemically Synthesized Lipid A-Subunit Analogs in the Expression of Immunopharmacological Activity, Infection and Immunity, Jan. 1988, vol. 56, No. 1, pp. 149-155.
Highly Purified Lipid X is Devoid of Immunostimulatory Activity, The Journal of Biological Chemistry, vol. 265, No. 16, pp. 9159-9164 (1990).
Structure of the Lipopolysaccharide from an E. coli Heptose-less Mutant, Marcha et al., The Journal of Biological Chemistry, vol. 254, No. 13, 5906-5917 (1979).
Ogawa et al., "Ripido A Ruijitai no Seibutsu Kassei (Biological Activiities of Lipid A Analogs)", Taisha (Metabolism), vol. 26, No. 5, pp. 15-27 (1989).
Honma Yudotai "(Synthetic Lipid A and its Derivatives)", Meneki Yakuri (Immunopharmacology), vol. 8, No. 4, pp. 25-32 (1990).
Kodama Tohru
Ogawa Tomohiko
Saitoh Masayuki
Kight John
Suntory Limited
White Everett
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