Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-10-03
2002-09-17
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S024000, C514S053000, C514S054000, C514S459000, C514S460000, C530S807000, C536S017200, C549S013000, C549S028000, C549S417000, C549S419000, C549S420000, C549S423000, C549S424000
Reexamination Certificate
active
06451766
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a series of new neuraminic acid derivatives which have excellent sialidase inhibitory activity and which are therefore useful for the treatment and prevention of influenza and other viral diseases where the replication of the virus is susceptible to sialidase inhibitors. The invention also provides methods and compositions using these compounds for the treatment or prevention of influenza and similar viral infections, as well as processes for the preparation of these compounds.
The compounds of the present invention have a 2-deoxy-2,3-didehydro-N-acylneuraminic acid structure. Sialic acid is N-acetylneuraminic acid.
The influenza virus, as well as a number of other types of virus, have sialidase on the surface of the virus particles. As one of the processes by which such viruses proliferate, subviruses that have budded on the cell surface dissociate from the cell. Such subviruses are coupled to sialic acid on the cell surface mediated by hemagglutinin of the subvirus surface. Subviruses dissociate from the cell as a result of sialidase on the subvirus surface breaking down the sialic acid, thereby resulting in secondary infection of surrounding cells. Thus, inhibition of sialidase would make it possible to inhibit dissociation of subviruses from the cell surface, thereby preventing secondary infection. Accordingly, a substance that has the effect of inhibiting sialidase is considered to be effective in treating or preventing (but preferably treating) influenza.
A number of compounds having a sialidase inhibitory activity and a 2-deoxy-2,3-didehydro-N-acylneuraminic acid backbone are known from WO91/16320 (equivalent to Japanese Patent Publication (Kokoku) No. Hei 5-507068). Other such compounds are known from WO96/26933. These compounds (described in WO91/16320 (Japanese PCT Application (Kokai) No. Hei 5-507068)) include Compound A (GG-167), represented by the following formula which is being developed as a drug for the treatment of influenza.
We have now discovered a series of new compounds having a 2-deoxy-2,3-didehydro-N-acylneuraminic acid backbone which have excellent sialidase inhibitory activity, which is significantly greater than that of the prior art compounds referred to above, and which can thus be used for the treatment and prevention of influenza and other diseases caused by sialidase-bearing viruses.
BRIEF SUMMARY OF INVENTION
It is, therefore, an object of the present invention to provide a series of novel compounds having sialidase inhibitory activity.
Other objects and advantages of the present invention will become apparent as the description proceeds.
The compounds of the present invention are those compounds of formula (I):
wherein:
R
1
represents an alkyl group having from 1 to 4 carbon atoms or a haloalkyl group having from 1 to 4 carbon atoms;
R
2
and R
3
are the same as or different from each other and each represents a hydrogen atom or an aliphatic acyl group having from 2 to 25 carbon atoms;
X represents a hydroxy group, a halogen atom, an alkoxy group having from 1 to 4 carbon atoms, or a group of formula R
a
O—, where R
a
represents an aliphatic acyl group having from 2 to 25 carbon atoms;
Y represents a group of formula R
b
R
c
N— or R
b
R
c
N—O—, where R
b
and R
c
are the same as or different from each other and each represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms; and
Z represents an oxygen atom or a sulfur atom;
and pharmaceutically acceptable salts and esters thereof.
The invention also provides a pharmaceutical composition for the treatment or prevention of infections in a mammal, which may be human, caused by sialidase-bearing viruses, such as viruses of the influenza family, which composition comprises a sialidase inhibitory compound in admixture with a pharmaceutically acceptable carrier or diluent, wherein the sialidase inhibitory compound is at least one compound selected from the group consisting of compounds of formula (I) and pharmaceutically acceptable salts and esters thereof.
The invention still further provides a method of treating or preventing an infection in a mammal, which may be human, caused by a sialidase-bearing virus, such as a virus of the influenza family, which method comprises administering to said mammal an effective amount of a sialidase inhibitory compound, wherein the sialidase inhibitory compound is at least one compound selected from the group consisting of compounds of formula (I) and pharmaceutically acceptable salts and esters thereof.
The invention also provides processes for the preparation of the compounds of the present invention which processes are described in greater detail hereafter.
DETAILED DESCRIPTION OF THE INVENTION
In a first embodiment, there is provided a compound of formula (I):
wherein:
R
1
represents an alkyl group having from 1 to 4 carbon atoms or a haloalkyl group having from 1 to 4 carbon atoms;
R
2
and R
3
are the same as or different from each other and each represents a hydrogen atom or an aliphatic acyl group having from 2 to 25 carbon atoms;
X represents a hydroxy group, a halogen atom, an alkoxy group having from 1 to 4 carbon atoms, or a group of formula R
a
O—, where R
a
represents an aliphatic acyl group having from 2 to 25 carbon atoms;
Y represents a group of formula R
b
R
c
N— or R
b
R
c
N—O—, where R
b
and R
c
are the same as or different from each other and each represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms; and
Z represents an oxygen atom or a sulfur atom;
PROVIDED THAT, when Y represents an amino group and Z represents an oxygen atom, then X represents a halogen atom or an alkoxy group;
and pharmaceutically acceptable salts and esters thereof.
The compounds of the present invention are named on the basis of saccharide terminology, in which the main positions are numbered as shown in the following formula:
The compounds are named as derivatives of the unsaturated sugar non-2-enopyranosoic acid, of formula:
The configurations of the carbon atoms at the 4 to 7 positions are D-galacto, while that of the carbon atom at the 8 position is D-glycero, as can be seen from the following partial formula:
In the compounds of the present invention, where R
1
represents an alkyl group, this may be a straight or branched chain group having from 1 to 4 carbon atoms, and examples of such groups include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl groups, of which we prefer the methyl group.
Where R
1
represents a haloalkyl group, the halogen atom may be a fluorine, chlorine, bromine or iodine atom, preferably a fluorine, chlorine or bromine atom, and more preferably a fluorine atom. The alkyl part of this haloalkyl group may be any of the alkyl groups having from 1 to 4 carbon atoms listed above. Specific examples of such haloalkyl groups include the fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1-fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, 4-fluorobutyl, chloromethyl, 1-chloroethyl, 2-chloroethyl, 1-chloropropyl, 2-chloropropyl, 3-chloropropyl, bromomethyl, 1-bromoethyl, 2-bromoethyl, 1-bromopropyl, 2-bromopropyl, and 3-bromopropyl groups, of which we prefer a methyl group substituted with at least one fluorine atom, particularly the fluoromethyl or difluoromethyl groups.
More preferably R
1
represents a methyl group or a halomethyl group, particularly a methyl, fluoromethyl or difluoromethyl group, more preferably a methyl group.
Where R
2
, R
3
or R
a
represents an aliphatic carboxylic acyl group having from 2 to 25 carbon atoms, this may be a straight or branched chain group, and is preferably an alkanoyl (alkylcarbonyl) group having from 2 to 25 carbon atoms. Specific examples of such groups include the acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl, isovaleryl, octanoyl, nonylcarbonyl, decylcarbonyl, 3-methylnonylcarbonyl, 8-methylnonylcarbonyl, 3-ethyloctylcarbonyl, 3,7-dimethyloctylcarbonyl, undecylcarbonyl, dodecylcarbonyl, tridecylcarbonyl, tetradecylcarbonyl, p
Honda Takeshi
Kobayashi Yoshiyuki
Yamashita Makoto
Covington Raymond
Frishauf, Holtz Goodman, Langer & Chick, P.C.
Rotman Alan L.
Sankyo Company Limited
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