Sialic acid derivatives

Details Sialic acid derivatives Sialic acid derivatives

1997-12-19

2001-09-11

Badio, Barbara P. (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S172000, C536S029100, C540S106000

Reexamination Certificate

active

06288041

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel sialic acid derivatives which are useful for therapeutic and/or preventive treatment of various diseases caused by disorders of the cholinergic nerve cells.
BACKGROUND ART
Senile dementia including Alzheimer's disease is a disease with progressive memory disorder or cognition disorder. In the disease, remarkable disturbance is observed in the cholinergic nervous system which transmits signals from forebrain basal ganglia to cerebral cortex and hippocampus. This disturbance is caused by significant decrease of choline acetyltransferase (hereinafter abbreviated as “ChAT”) activity, therefore, it is considered that agents that activate ChAT activity are effective medicament for therapeutic treatment of senile dementia including Alzheimer's disease. In addition, medicaments having such activity are also considered to be useful as therapeutic medicaments for peripheral nervous disorder.
Gangliosides, i.e., sphingoglycolipids containing sialic acid, are components for constituting biomembranes, and abundant in brains of higher animals. In recent years, various functions of gangliosides have been reported, and in particular, their roles in nervous systems have been focused because they almost specifically exist in membranes of nervous systems. Sialic acid is an important constituting element of gangliosides, and accordingly, various derivatives have been synthesized from viewpoints of relations with functions of gangliosides and medical applicability (Japanese Patent Unexamined Publication Nos. (Sho)55-89298/1980, (Sho)61-243096/1986, (Sho)61-282390/1986, (Sho)63-41492/1988, (Sho)63-41494/1988, (Sho)63-63697/1988, (Sho)63-68526/1988, (Sho)64-52794/1989, (Hei)1-190693/1989, and (Hei)3-151398/1991, and WO93/10134, WO94/03469 or other). Some articles report biological activities of the derivatives (Japanese Patent Unexamined Publication No. (Sho)62-265229/1987, (Hei)1-93529/1989, (Hei)3-77898/1992, and (Hei)3-81287/1992, and Brain Research, 438, pp.277-285, 1988). However, any derivatives that can sufficiently activate ChAT activity have not yet been known to date.
DISCLOSURE OF THE INVENTION
The present inventors conducted various researches to provide medicament for therapeutic treatment of disturbance of central nervous system such as senile dementia including Alzheimer's disease and disturbance of peripheral nervous system. As a result, they found that sialic acid derivatives having a specific type of amide bond can activate ChAT activity in the cholinergic nerve cells, and accordingly, the derivatives can be used as medicaments for improving disturbance of central nervous system such as memory disorder accompanied with senile dementia including Alzheimer's disease and peripheral nervous disorder such as diabetic neuropathy. The present invention was achieved on the basis of these findings.
The present invention provides sialic acid derivatives represented by the following general formula (1AA) or their salts, or hydrates or solvates thereof:
wherein R
1
represent a residue of a steroid compound excluding cholestane residue and cholestene residue,
R
2
represents hydrogen atom or methyl group,
R
3
represents a C
1
-C
6
alkyl group, a group of formula:
[wherein R
6
and R
7
independently represent hydrogen atom, a halogen atom, a C
1
-C
4
alkyl group, hydroxyl group, a group of formula R
8
O— (wherein R
8
represents a C
1
-C
4
alkyl group, phenyl group, or a phenyl-(C
1
-C
3
alkyl) group), nitro group, amino group, a C
1
-C
4
alkylamino group, a C
2
-C
8
dialkylamino group, or a group of formula R
9
O—CO— (wherein R
9
represents hydrogen atom, a C
1
-C
4
alkyl group, phenyl group, or a phenyl-(C
1
—C
3
alkyl) group), and l represents an integer of 0-6]; a group of R
10
O(CH
2
)
m
— (wherein R
10
represents hydrogen atom; a C
1
-C
4
alkyl group; phenyl group which may optionally have one or more substituents selected from the group consisting of a C
1
-C
4
alkyl group, a halogen atom, hydroxyl group, nitro group, amino group, and carboxyl group; or a phenyl-(C
1
-C
3
alkyl) group which may optionally have one or more substituents selected from the group consisting of a C
1
-C
4
alkyl group, a halogen atom, hydroxyl group, nitro group, amino group, and carboxyl group, and m represents an integer of 2-6); or a group of (R
11
)(R
12
)N(CH
2
)
n
— [wherein R
11
represents hydrogen atom or a C
1
-C
4
alkyl group, and R
12
represents hydrogen atom; a C
1
-C
4
alkyl group; a C
2
-C
7
acyl group; a C
1
-C
4
alkylsulfonyl group; phenylsulfonyl group which may optionally have one or more substituents selected from the group consisting of a C
1
-C
4
alkyl group, a halogen atom, hydroxyl group, nitro group, amino group, and carboxyl group; or a group of R
13
O—CO— (wherein R
13
represents a C
1
-C
4
alkyl group, phenyl group, or a phenyl-(C
1
-C
3
alkyl) group), and n represents an integer of 2-6],
R
4
represents hydrogen atom or a C
2
-C
7
acyl group,
R
5
represents a group of R
14
O— (wherein R
14
represents hydrogen atom or a C
2
-C
7
acyl group) or a group of R
15
NH— [wherein R
15
represents a C
2
-C
7
acyl group, a group of R
16
O(CH
2
)
p
—CO— (wherein R
16
represents hydrogen atom, a C
1
-C
6
alkyl group, phenyl group, or a phenyl-(C
1
-C
3
alkyl) group, and p represents an integer of 0-4); a C
7
-C
11
aroyl group which may optionally have one or more substituents selected from the group consisting of a C
1
-C
4
alkyl group, a halogen atom, hydroxyl group, nitro group, amino group, and carboxyl group; or a phenyl-(C
1
-C
3
alkyl)carbonyl group which may optionally have one or more substituents selected from the group consisting of a C
1
-C
4
alkyl group, a halogen atom, hydroxyl group, nitro group, amino group, and carboxyl group, and
X represents oxygen atom or sulfur atom.
According to another aspect of the present invention, there are also provided sialic acid derivatives represented by the following general formula (1BB) or their salts, or hydrates or solvates thereof:
wherein R
101
represents a residue of a steroid compound,
R
102
represents hydrogen atom or methyl group,
R
103
represents a C
1
-C
6
alkyl group, a group of:
[wherein R
106
and R
107
independently represent hydrogen atom, a halogen atom, a C
1
-C
4
alkyl group, hydroxyl group, a group of R
108
O— (wherein R
108
represents a C
1
-C
4
alkyl group, phenyl group, or a phenyl-(C
1
-C
3
alkyl) group), nitro group, amino group, a C
1
-C
4
alkylamino group, a C
2
-C
8
dialkylamino group, or a group of R
109
O—CO— (wherein R
109
represents hydrogen atom, a C
1
-C
4
alkyl group, phenyl group, or a phenyl-(C
1
-C
3
alkyl) group), and l represents an integer of 0-6]; a group of R
110
O(CH
2
)
m
— (wherein R
110
represents hydrogen atom; a C
1
-C
4
alkyl group; phenyl group which may optionally have one or more substituents selected from the group consisting of a C
1
-C
4
alkyl group, a halogen atom, hydroxyl group, nitro group, amino group, and carboxyl group; or a phenyl-(C
1
-C
3
alkyl) group which may optionally have one or more substituents selected from the group consisting of a C
1
-C
4
alkyl group, a halogen atom, hydroxyl group, nitro group, amino group, and carboxyl group, and m represents an integer of 2-6); or a group of (R
111
)(R
112
)N(CH
2
)
n
— [wherein R
111
represents hydrogen atom or a C
1
-C
4
alkyl group, R
112
represents hydrogen atom; a C
1
-C
4
alkyl group; a C
2
-C
7
acyl group; a C
1
-C
4
alkylsulfonyl group; phenylsulfonyl group which may optionally have one or more substituents selected from the group consisting of a C
1
-C
4
alkyl group, a halogen atom, hydroxyl group, nitro group, amino group, and carboxyl group; or a group of R
113
O—CO— (wherein R
113
represents a C
1
-C
4
alkyl group, phenyl group, or a phenyl-(C
1
-C
3
alkyl) group), and n represents an integer of 2-6],
R
104
represents hydrogen atom or a C
2
-C
7
acyl group,
R
105
represents a group of R
114
O— (wherein R
114
represents hydrogen ato

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