Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-08-18
2003-12-16
Ponda, Kathleen K. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S017200, C536S017900, C536S018200, C536S018300, C536S018400
Reexamination Certificate
active
06664235
ABSTRACT:
TECHNICAL FIELD
The present invention relates to medicaments comprising a sialic acid derivative as an active ingredient.
BACKGROUND ART
Viruses including influenza virus proliferate depending on the biosynthcsis mechanism of the host. Therefore, it is difficult to develop medicaments which can exert sufficient antiviral action specifically on viruses, and only a few medicaments which can exert clinically high effectiveness are known. For the treatment of viral infections, vaccines have been used as the most effective means so far. However, there are problems that vaccines cannot be prepared and used when a causal virus is not identified, and that effectiveness of a prepared vaccine can hardly be expected against a virus with rapid variation.
There are types A, B and C of influenza viruses, and the virus type A is known to drastically change the structure of the antigen protein and pass through the immune mechanism of a human as a host, so that a problem arises that vaccine treatment fails to achieve sufficient effectiveness.
Influenza viruses have two spike glycoproteins, trimer hemagglutinin (HA) and tetramer sialidase (NA). They form infection through polyvalent specific action of the hemagglutinin (HA) and the sialoglycoside chain receptor of host cells. The viruses, after proliferation by destruction of the virus receptor by sialidase (NA), are released from the host cells. These two proteins recognize the sialoglycoside chain as ligands which exist on the surface of the host cell. Accordingly, it can be considered that the infection of influenza viruses can be inhibited by interference of the interaction of these two proteins and the sialoglycoside chain.
Recently, a highly effective antiviral agent has been developed on the basis of analysis of the crystal structure of sialidase which is one of the two viral membrane proteins of influenza viruses (von Itzstein, M. et al., Nature, 363, 1993). However, this antiviral agent cannot inhibit the formation of infection, per se, since sialidase does not participate in the first stage of the infection. Therefore, it is necessary to develop antiviral agents which can exert potent inhibitory action against both of the two membrane proteins, i.e., sialidase and hemagglutinin.
It has been reported so far that a sialyl-lactose-containing polymer has potent inhibitory activity against type H1 virus HA (Japanese Patent Unexamined Publication (KOKAI) (Hei) No.11- 147951/1999), and a polymer binding to sialic acid monosaccharide to form C- or S-glycoside has potent inhibitory action on type H3 virus HA.
However, no compound has been reported so far which is a sialic acid derivative having a low molecular weight and can exert potent inhibitory action against the two membrane proteins (sialidasc and hemagglutinin).
The inventors of the present invention succeeded in synthesizing sialic acid derivatives having a substituent on the carbon atom in the 3-position on the basis of studies conducted so far to provide a compound which can be expected to exert excellent antiviral activity on viruses including influenza viruses (Japanese Patent Unexamined Publication (KOKAI) No.(Hei)11-343295/1999; The 20th Carbohydrate Symposium, July 1998). However, these sialic acid derivatives have not been verified to have antiviral activity on influenza viruses.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide novel medicaments comprising a sialic acid derivative, especially a sialic acid derivative having a low molecular weight. More specifically, the object is to provide medicaments for preventive and/or therapeutic treatment of viral diseases such as influenza virus infectious diseases.
Another object of the present invention is to provide novel medicaments comprising a sialic acid derivative having resistance against hydrolysis by sialidase, more specifically, medicaments for preventive and/or therapeutic treatment of viral diseases such as influenza virus infectious diseases.
The inventors of the present invention conducted intensive studies to solve the aforementioned problems. As a result, they found that sialic acid derivatives which may be substituted on the carbon atom in the 3-position have resistance to hydrolysis and inhibitory action against the membrane binding proteins of influenza viruses, and another membrane enzyme sialidase. The present invention was achieved on the basis of these finding.
The present invention thus provides medicaments which comprise as an active ingredient a compound represented by the following formula (I) or its pharmaceutically acceptable salt, or a hydrate thereof or a solvate thereof
wherein R
1
represents hydrogen atom or a C
1-6
alkyl group; R
2
represents an optionally substituted phenyl group, a C
1-20
alkyl group, a C
1-20
alkenyl group, or —(CH
2
)
k
—[NH—(CH
2
)
m
—NH]
n
—Y or —(CH
2
)
k
—[NH—(CH
2
CH
2
O)
m−1
—CH
2
CH
2
NH]
n
—Y in which Y represents phosphatidylethanolamine residue or polyglutamic acid residue, k and m independently represent an integer of from 2 to 10, n represents 0 or 1, provided that when n represents 1, Y represents phosphatidylethyl group; R
3
represents hydrogen atom or an optionally substituted hydroxyl group; R
4
represents hydrogen atom, a halogen atom, azide group, an optionally substituted amino group, or an optionally substituted hydroxyl group; and R
5
, R
6
, R
7
and R
8
independently represent an optionally substituted hydroxyl group.
Preferably, the medicaments of the present invention are those for preventive and/or therapeutic treatment of viral diseases.
More preferably, the medicaments of the present invention are those for preventive and/or therapeutic treatment of influenza virus infectious diseases.
More specifically, the medicaments of the present invention have inhibitory action against infection and/or proliferation of influenza viruses.
Preferably, in the formula (I), R
2
represents —(CH
2
)
k
—[NH—(CH
2
)
m
—NH]
n
—Y or —(CH
2
)
k
—[NH—(CH
2
CH
2
O)
m−1
—CH
2
CH
2
NH]
n
—Y in which Y represents phosphatidylethanolamine residue or polyglutamic acid residue, k and m independently represent an integer of from 2 to 10, n represents 0 or 1, provided that when n represents 1, Y represents phosphatidylethyl group.
Further preferably, in the formula (I), R
2
represents —(CH
2
)
k
—Y wherein Y represents phosphatidylethanolamine residue, and k represents an integer of from 2 to 10.
Preferably, one of R
3
and R
4
is hydrogen atom, and the other is a halogen atom or an optionally substituted hydroxyl group.
Further preferably, R
3
is hydrogen atom, and R
4
is a halogen atom or an optionally substituted hydroxyl group.
Preferably, R
1
is hydrogen atom.
From another aspect of the present invention, there are provided use of a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof for the manufacture of a medicament, in particular, a medicament for preventive and/or therapeutic treatment of viral infectious disease such as influenza viral infections; and a method for preventive and/or therapeutic treatment of viral infectious diseases such as influenza viral infections which comprises the step of administering to a mammal including human an effective amount of a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solvate thereof.
BEST MODE FOR CARRYING OUT THE INVENTION
The meanings of the terms used herein are as follows. The alkyl group or an alkyl moiety of a functional groups containing the alkyl moiety may be linear, branched, or cyclic alkyl groups, or a combination thereof. Examples include methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, n-butyl group, sec-butyl group, tert-butyl group, cyclopropylmethyl group, and cyclobutyl group.
When the phenyl group represented by R
2
is substituted, the number of the substituent and the substituting position arc not particularly limited. Examples include subs
Kanie Osamu
Suzuki Yasuo
Wong Chi-Huey
Maier Leigh C.
Ponda Kathleen K.
Riken
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