Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-07-06
2002-03-19
Low, Christopher S. F. (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S345000, C530S395000, C530S402000, C536S055100, C536S055200, C536S069000
Reexamination Certificate
active
06358919
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a medicament. More specifically, the present invention relates to a polymer compound comprising a saccharide-conjugated sphingosine, and a medicament comprising the polymer compound as an active ingredient.
BACKGROUND ART
Vaccines are generally used for the prevention of viral infections. However, vaccines fail to achieve sufficient preventive effects against viruses which rapidly develop variations, such as influenza virus and AIDS virus. Accordingly, it has been desired to develop antiviral agents having satisfactory effects against the viruses developing rapid variations.
For example, it is known that the two distinct proteins that are possessed by influenza virus, i.e., sialidase and hemagglutinin, have different roles. Sialidase is an enzyme which engages in the cleavage of sialic acid residues from sialyloligosaccharides on cellular surfaces when viruses germinate from cells. Recently, a sialic acid derivative having inhibitory activity against sialidase has been developed, and a clinical application as an anti-influenza viral agent is being studied.
Hemagglutinin, a trimer protein, has a key role in the introduction of a viral genome RNA into host cells by recognizing a sialyloligosaccharide, that has a specific binding mode upon infection to impart a host specificity to viruses, and by invading inside cells through endocytosis, and then changing its conformation and inducing the fusion of membranes. As to inhibitors of hemagglutinin, researches were conducted only from fundamental standpoints by using compounds comprised of a polyacrylamide bound by sialic acid (Mammen, M., et al., J. Med. Chem., 38, pp.4179-4190, 1995).
It is known that cholera toxin produced by Vibrio parahaemolyticus causes severe diarrhea. The toxin is composed of subunit A and subunit B. The subunit B, as a pentamer, acts as a receptor for a ligand, and has a role in introducing the subunit A as a toxic body, per se, into cytoplasm.
DESCRIPTION OF THE INVENTION
The object of the present invention is to provide a compound which exerts antiviral activity against variety of viruses and is useful as an active ingredient of a medicament. The inventors of the present invention conducted various studies to achieve the foregoing object, and as a result, found that a compound composed of a polymer containing a saccharide-conjugated sphingosine exhibited strong antiviral effect against viruses including influenza virus, for example. The present invention was achieved on the basis of these findings.
The present invention thus provides a polymer compound and a salt thereof which comprises a biodegradable polymer containing a glycosphingolipid. According to preferred embodiments of the present invention, the aforementioned polymer compound or a salt thereof wherein the glycosphingolipid is a lysoglycosphingolipid, more preferably lysoganglioside, and most preferably lysoganglioside GM
3
is provided. According to further preferred embodiments, the aforementioned polymer compound or a salt thereof wherein the glycosphingolipid and the biodegradable polymer are bound by means of a spacer; and the aforementioned polymer compound or a salt thereof wherein the biodegradable polymer is a polyglutamic acid, more preferably a polyglutamic acid acetylated at N-terminal thereof are provided. Sodium salts may preferably be used as the salt of the compound.
According to the most preferred embodiment of the present invention, it is provided a polymer compound represented by the following formula (I) and a salt thereof:
wherein R
1
represents hydrogen atom or acetyl group; R
2
represents hydrogen atom or a fluorescent functional group, and m and n independently represents an integer of from 10 to 40. According to a preferred embodiment of the aforementioned polymer compound and a salt thereof, there is provided the polymer compound and sodium salt thereof wherein R
1
is acetyl group, R
2
is a fluorescent functional group such as BODIPY group, m is an integer of from 15 to 25, n is an integer of from 20 to 40, and the amount of conjugated lysoganglioside GM
3
is from 1 to 10 molar percent. Among them, the polymer compound and sodium salt thereof wherein m is 19, n is 27, and the amount of the conjugated lysoganglioside GM
3
is 5 molar percent are most preferred.
According to another aspect of the present invention, there is provided a medicament comprising the aforementioned polymer compounds. According to preferred embodiment of the aforementioned invention, the medicament used as an antiviral agent and/or antidote is provided. According to further aspects of the present invention, there are provided a method for the treatment of an infectious disease caused by a virus or a microorganism, which comprises the step of administering a therapeutically effective amount of the aforementioned polymer compound to a patient; and lysoganglioside GM
3
derivatives represented by the following formula (II):
wherein R
3
represents hydrogen atom or an amino protective group; and R
4
represents hydrogen atom or a fluorescent functional group. The compound represented by the formula (II) is useful as a synthetic intermediate for the aforementioned polymer compound.
BEST MODE FOR CARRYING OUT THE INVENTION
The polymer compounds of the present invention are characterized in that they comprise a biodegradable polymer containing a residue of a glycosphingolipid. As glycosphingolipids from which the residue of a glycosphingolipid is derived, any glycolipids may be used so long as they contain a long chain amino alcohol having 16 to 20 carbon atoms (sphingoid). Glycolipids containing a sphingosine may preferably be used, and most preferably, a naturally occurring sphingosine [D(+)-erythro-1,3-dihydroxy-2-amino-4-trans-octadecene] may be used. As the residue of the glycolipid, which corresponds to a partial structure of the glycosphingolipid, for example, a residue of a glycolipid formed by the conjugation of a sialic acid residue and a saccharide residue, and a residue of a glycolipid formed by the conjugation of a sialic acid residue and a nonreducing terminal of an oligosaccharide residue composed of two or more saccharide residues may preferably be used.
As the residues of glycosphingolipids, for example, lysoglycosphingolipid residues may preferably be used. Among them, a lysoganglioside residue (the term “lysoganglioside” used herein means a ganglioside whose ceramide is deacylated, namely, a compound comprising a sialic acid-containing oligosaccharide chain bound to a sphingosine by means of a glycosidic linkage) is more preferred, and lysoganglioside GM
3
(Lyso GM
3
) residue is most preferred.
Types of the biodegradable polymer are not particularly limited so long as they are readily degraded by enzymes existing in a living body, preferably in a human living body, and are substantially free from antigenicity and low toxic to a living body. Numbers of such biodegradable polymers are known, and an appropriate polymer is readily obtainable and used by one of those skilled in the art. For example, synthetic polymers as well as polypeptides, polynucleotides, polysaccharides and other may be used. When a serum half-life of the biodegradable polymer is too short, desired antiviral effects may sometimes be insufficiently achieved. On the other hand, if a serum half-life is too long, accumulation in a body may sometimes be a problem. Therefore, it is desired that a suitable type of biodegradable polymer may be chosen depending on the type of the glycosphingolipid, a desired biological action and other factors.
For example, polypeptides such as polyglutamic acid may preferably be used as the biodegradable polymer. When polyglutamic acids are used as the biodegradable polymer, for example, those having the degree of polymerization of about 100 to 1,000, preferably about 300 to 700, and most preferably about 500 to 600 can be used. In the polymer compounds represented by the general formula (I) mentioned above, it is preferred that m is an integer of from 15 to 25, n is an i
Kamitakahara Hiroshi
Kanie Osamu
Wong Chi-Huey
Greenblum & Bernstein P.L.C.
Low Christopher S. F.
Mohamed Abdez A.
The Institute of Physical and Chemical Research
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