JPH0592991A - Thiosialic acid derivative - Google Patents

Abstract

PURPOSE:To provide the subject new compound effective for activating choline acetyltransferase activity in cholinergic nerve cell and useful as an agent for treating senile dementia, etc. CONSTITUTION:The thiosialic acid derivative of formula I (R1 is aglycon residue; R<2> is H or 1-4C alkyl; all of R<3> groups are H or acyl at the same time) or its salt, e.g. 5-acetamido-4,7,8,9-tetraO-acetyl-2-S-(3' alpha-cholestanyl)-3,5-dideoxy-2- thio-alpha-D-glycero-D-galacto-2-nonulopyranosonate. For example, the cr, isomer of the compound of formula I can be produced by reacting a compound of formula II (R<2>e is 1-4C alkyl; R<3> is acyl) with a compound of formula MSR''<1> (M is alkali metal) in a solvent (e.g. THF) at 0 deg.C to room temperature under anhydrous contidion.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel thiosialic acid derivative or a pharmaceutically acceptable salt thereof, which is useful for treating various diseases caused by disorders of cholinergic nerve cells.

[0002]

BACKGROUND ART Senile dementia including Alzheimer's disease is a disease showing progressive memory and cognitive impairment. In these diseases, the cholinergic nervous system, which projects from the basal forebrain to the cerebral cortex and hippocampus, has a prominent disorder, which is choline acetyltransferase (hereinafter, abbreviated as “ChAT”) that is an acetylcholine synthase activity. Therefore, it is considered that a drug that activates ChAT activity is effective as a therapeutic drug for senile dementia including Alzheimer's disease.

On the other hand, ganglioside, which is a glycosphingolipid containing sialic acid, is a constituent of biological membranes, and is abundantly contained in the brains of higher animals. For gangliosides,
Although various functions have been reported in recent years, their role in the nervous system has been attracting attention because they exist in the membranes of the nervous system quite specifically. Sialic acid is an important constituent of gangliosides, and various derivatives have been synthesized in relation to the function of gangliosides and from the viewpoint of medical application (Japanese Patent Laid-Open Nos. 55-89298 and 61-61). 2430
No. 96, No. 61-228390, No. 63-41492.
No. 63-41494, No. 63-63697, No. 63-68526, No. 64-52794, etc.), and some reports on the activity of the derivatives (JP-A-62-265229, JP-A-1-93529
No. Gazette, Brain Research, 438 , 2
77-285 (1988)) has not been known until now for a derivative that sufficiently activates ChAT activity.

[0004]

DISCLOSURE OF THE INVENTION The inventors of the present invention have conducted various studies for the purpose of providing a therapeutic drug for senile dementia including Alzheimer's disease. As a result, a specific thiocyanic acid derivative in cholinergic neurons has been identified. It has been found that by activating ChAT activity, it can be a drug for improving memory disorders and the like in senile dementia including Alzheimer's disease, and completed the present invention.

[0005]

That is, the gist of the present invention is the following general formula (I):

[0006]

[Chemical 2]

(Wherein R ¹ represents an aglycone residue,
R ² represents a hydrogen atom or a C ₁ -C ₄ lower alkyl group, and R ³ simultaneously represents a hydrogen atom or an acyl group. ), A thiosialic acid derivative or a pharmaceutically acceptable salt thereof.

The thiocyanic acid derivative of the present invention is represented by the above general formula (I).
The aglycone represented by R ¹ in the formula (I) is preferably a steroid, and particularly preferably

[0009]

[Chemical 3]

Examples of the lower alkyl group contained in R ² in the above general formula (I) include C _{1 to} C ₄ lower alkyl groups such as methyl group, ethyl group and n-propyl group. Examples of the acyl group contained in R ³ in the general formula (I) include acetyl group and benzoyl group.

Specific examples of preferred compounds represented by the above general formula (I) are shown in Tables 1, 2, 3 and 4 below.

[0012]

[Table 1]

[0013]

[Table 2]

[0014]

[Table 3]

[0015]

[Table 4]

[0016]

[Table 5]

[0017]

[Table 6]

[0018]

[Table 7]

[0019]

[Table 8]

The salts of the compound represented by the above general formula (I) are preferably pharmaceutically acceptable salts, for example salts with alkali metals such as sodium and potassium; ammonia, tris (hydroxymethyl) aminomethane, N ，
N-bis (hydroxyethyl) piperazine, 2-amino-2-methyl-1-propanol, ethanolamine,
Examples thereof include salts with organic amines such as N-methylglucamine and L-glucamine. Since the compounds of the general formula (I) and salts thereof may exist in the form of hydrates or solvates, these hydrates and solvates are also included in the scope of the present invention.

Next, a method for producing the compound of the present invention will be described. The compound of the present invention can be produced by the following method. (1) Production of α isomer

[0022]

[Chemical 4]

(In the above formula, R ¹ is as defined in the above general formula (I), R ² ′ represents a C _{1 to} C ₄ lower alkyl group, and R ³ ′ represents an acyl group. , M represents an alkali metal. That is, first, the compound (II) is reacted with the compound (III) (step (a)) to give the compound (I-α).
-A) is produced, and this is reacted with an alkoxide such as sodium methoxide for deacylation (step (b)) to produce a compound (I-α-b), which is then treated with an alkali such as sodium hydroxide. Compound (I-α-c) is produced by reacting with and hydrolyzing (step (c)).

In step (a), preferably 0.9 to 5 equivalents, more preferably 1.2 to 3 equivalents of compound (III) are used in the presence of a solvent such as tetrahydrofuran, dioxane, acetonitrile, dichloromethane and dichloroethane. The temperature is preferably 0 ° C to 50 ° C, more preferably 0 ° C to room temperature. At this time, the reaction operation and the reaction are more preferably performed under anhydrous conditions.

In step (b), in the presence of a solvent such as methanol, preferably 0.05 equivalent to 5 equivalents, more preferably 0.1 equivalent to 1 equivalent of alkoxide is used, preferably 0 ° C to 50 ° C. More preferably, it is carried out in the temperature range of 0 ° C to room temperature. At this time, the reaction operation and the reaction are more preferably performed under anhydrous conditions.

In step (c), methanol, ethanol,
In the presence of a mixed solvent of water and a solvent such as 1-propanol, tetrahydrofuran or dioxane, preferably 1 to 3 equivalents, more preferably 1.1 to 2 equivalents of an alkali such as sodium hydroxide is used, and preferably 0 ℃ ~ 100
C., more preferably in the temperature range of 0.degree. C. to 50.degree. (2) Production of β isomer

[0027]

[Chemical 5]

(In the above formula, R ¹ , R ² 'and R ³ ' are as defined above.) That is, first, the compound (IV)
In the presence of a Lewis acid catalyst, compound (V) is reacted (step (d)) to produce compound (I-β-a), which is then reacted with an alkoxide such as sodium methoxide for deacylation. (Step (e)), compound (I-β-
b) is produced, and this is further reacted with an alkali such as sodium hydroxide to hydrolyze (step (f)) to produce the compound (I-β-c).

The compound (I-β-a) can also be produced by reacting the compound (VI) with the compound (V) in the presence of a Lewis acid catalyst as described below. ((G) step)

[0030]

[Chemical 6]

(In the above formula, R ¹ , R ² 'and R ³ ' are as defined above.)

In step (d), a solvent such as dichloromethane, dichloroethane, dioxane or ether is preferably used in an amount of 1 to 10 equivalents, more preferably 1 to 5 equivalents of B.
F _3, ZnCl _2, the presence of a Lewis acid catalyst such as AlCl _3, preferably 0.9 to 5 equivalents, more preferably 1 to 3
Preferably 0 ° C to 50 ° C, using an equivalent amount of compound (V),
More preferably, it is carried out in the temperature range of 0 ° C to room temperature. At this time, the reaction operation and the reaction are more preferably performed under anhydrous conditions.

The step (e) is carried out in the presence of a solvent such as methanol, preferably 0.05 to 5 equivalents, more preferably 0.
1 to 1 equivalent of alkoxide is used, preferably 0 ° C to 5
The temperature is 0 ° C., more preferably 0 ° C. to room temperature. At this time, the reaction operation and the reaction are more preferably performed under anhydrous conditions.

In step (f), methanol, ethanol,
In the presence of a mixed solvent of water with a solvent such as 1-propanol, tetrahydrofuran or dioxane, preferably 1 to 5 equivalents, more preferably 1.1 to 2 equivalents of an alkali such as sodium hydroxide is used, and preferably 0. C. to 100.degree. C., more preferably 0.degree. C. to 50.degree.

The step (g) is preferably carried out in a solvent such as dichloromethane, dichloroethane, dioxane and ethers in an amount of 1 to 10 equivalents, more preferably 1 to 5 equivalents of BF ₃ .
In the presence of a Lewis acid catalyst such as ZnCl ₂ or AlCl ₃ , preferably 0.9 to 5 equivalents, more preferably 1 to 3 equivalents of the compound (V) are used, preferably 0 ° C. to 50 ° C., further preferably 0 ° C. It is carried out in the temperature range of ℃ to room temperature. At this time, the reaction operation and the reaction are more preferably performed under anhydrous conditions.

Formula (II) as a starting material for the compound of the present invention
The compounds of (VI) to (VI) can be synthesized by the following methods. That is, the compounds (II) and (VI) are (a) Chem. Ber. , 99 , 611-617 (1
966), (b) Carbohydr. Res. , 11
0 , 11-18 (1982), (c) Carbohyd
r. Res. , 125 , 47-64 (1984), or the like, or a method analogous thereto.

The compound (IV) can be easily synthesized from the compound (II) by (d) the method described in JP-A-63-41492 or a method analogous thereto.

Further, the compounds (III) and (V) are d) Tetrahedron, 20 , 1265-126.
9 (1964), e) Chem. Lett. , 437-440 (197)
7), f) Tetrahedron Lett. , 22 (3
3), 3119-3122 (1981), g) Synthesis-Stuttgart,
(2), 137 to 139 (1989), or the like, or a method analogous thereto.

When the compound of the present invention is used as a therapeutic agent,
It is administered alone or in combination with a pharmaceutically acceptable carrier. Its composition is determined by the solubility of the compound, chemical characteristics, administration route, administration schedule and the like. For example, it may be orally administered in the form of granules, fine granules, powders, tablets, hard syrups, soft capsules, syrups, emulsions, suspensions or solutions, or intravenously as an injection. It may be administered intramuscularly, intramuscularly or subcutaneously.

It is also possible to prepare powder for injection and prepare it for use before use. Furthermore, a pharmaceutical organic or inorganic solid or liquid carrier or diluent suitable for oral, enteral, parenteral or topical administration can be used together with the compound of the present invention. Examples of the excipient used when producing the solid preparation include lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate and the like. Liquid preparations for oral administration, that is, emulsions, syrups, suspensions, solutions and the like, contain a generally used inert diluent such as water or vegetable oil. In addition to the inert diluent, the formulation may also contain auxiliary agents such as wetting agents, suspension auxiliary agents, sweetening agents, aromatic agents, coloring agents or preservatives. Liquid formulations may be included in capsules of absorbable material such as gelatin. Examples of the preparation for parenteral administration, that is, a solvent or suspending agent used for producing an injection or the like include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the like. The preparation of the preparation may be carried out by a conventional method.

When used by oral administration, the clinical dosage is generally 1 for the compound of the present invention for adults.
The daily dose is 1 to 1,000 mg, preferably 1 to 100
Although it is mg, it is more preferable to appropriately increase or decrease depending on the age, medical condition, symptom, and presence or absence of simultaneous administration. The above-mentioned daily dose of the compound of the present invention may be administered once a day or divided into two or three times a day at appropriate intervals, or may be administered intermittently.

When used as an injection, the daily dose of the compound of the present invention is 0.1 to 100 m for an adult.
g, preferably 0.1 to 50 mg.

[0043]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to the scope of these examples. Example 1 Methyl 5-acetamido-4,7,8,9-tetra-
O-acetyl-2-S- (3'α-cholestanyl)-
3,5-dideoxy-2-thio-α-D-glycero-D
-Galact-2-Nonuropyranosonate [Methy
l 5-acetamido-4,7,8,9-tet
ra-O-acetyl-2-S- (3'α-chol
estanyl) -3,5-dideoxy-2-th
io-α-D-glycero-D-galacto-
2-nonulopylanosonate] (Table-1
Compound No. Synthesis of 1) 700 mg of sodium salt of 3α-cholestanethiol
(1.64 mmol) of dry tetrahydrofuran 10 m
1 and dissolved under ice-cooling methyl 5-acetamide-4,
7,8,9-tetra-O-acetyl-2-chloro-2,
3,5-Trideoxy-β-D-glycero-D-galacto-2-nonulopyranosonate 864 mg (1.69
7 ml of a tetrahydrofuran solution of
Stir for 3 hours.

After the reaction, the solvent was distilled off, the obtained syrup was dissolved in chloroform, washed with a saturated NaHCO ₃ aqueous solution and water, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the obtained syrup was subjected to silica gel column chromatography [Merck silica gel 60, developing solvent chloroform / methanol (100: 1 to 200:
3)], and 551 mg (38.
3%) was obtained.

[0045]¹H-NMR (CDCl₃) Δ (ppm) 0.60 (3H, s, 18'-CH₃), 0.74 (3
H, s, 19'-CH₃), 0.82 to 0.88 (9
H, 21'-CH₃, 26'-CH₃, 27'-C
H ₃), 1.84, 2.00, 2.01, 2.14 (1
5H, s × 5, Ac), 2.67 (1H, dd, J = 1)
2.8, 4.6 Hz, H-3eq, 3.46 (1H,
m, H-3 '), 3.75 (3H, s, -COOC
H ₃ ), 3.82 (1H, dd, J = 12.3, <2H)
z, H-6), 3.96 to 4.13 (2H, m, H-
5, H-9), 4.26 (1H, dd, J = 12.1,
<2 Hz, H-9), 4.80 (1H, ddd, J = 1
1.6, 10.4, 4.6 Hz, H-4), 5.18
(1H, d, J = 10.0Hz, NH), 5.25 ~
5.35 (2H, m, H-7, H-8)¹³ C-NMR (CDCl₃) Δ (ppm) 49.44 (-OMe), 52.85 (C-5), 6
2.14 (C-9), 67.46, 69.01, 69.
69, 74.22 (C-4, C-6, C-7, C-
8), 83.37 (C-2) 168.95, 170.15 (2), 170.18, 1
70.59, 170.97 (CO x 6)

Example 2 Methyl 5-acetamido-2-S- (3'α-cholestanyl) -3,5-dideoxy-2-thio-α-D-glycero-D-galacto-2-nonopyranosonate Synthesis of (Compound No. 5 in Table-1) 541 mg (0.62 mmo) of the compound obtained in Example 1
l) was dissolved in 15 ml of methanol and 4.9 N was added under ice cooling.
0.1 ml of sodium methoxide in methanol
(0.49 mmol) was added, and then the mixture was returned to room temperature and stirred for 7 hours. After the reaction, the precipitated solid was collected by filtration and washed with methanol to obtain the title compound (348 mg, 79.6%).

[0047]¹H-NMR [CDCl₃-CD₃OD
(1: 1)] δ (ppm) 0.66 (3H, s, 18'-CH₃), 0.78 (3
H, s, 19'-CH₃), 0.86 to 0.92 (9
H, 21'-CH₃, 26'-CH₃, 27'-C
H ₃), 2.02 (3H, s, Ac), 2.81 (1
H, dd, J = 13.0, 4.6 Hz, H-3eq),
3.83 (3H, s, -COOCH ₃ )¹³ C-NMR [CDCl₃-CD₃OD (1: 1)]
δ (ppm) 53.05 (-OMe), 53.41 (C-5), 6
4.00 (C-9), 68.20, 69.43, 71.
83, 76.59 (C-4, C-6, C-7, C-
8), 83.97 (C-2) 172.02, 174.73 (CO x 2)

Example 3 Sodium 5-acetamido-2-S- (3'α-cholestanyl) -3,5-dideoxy-2-thio-α-D
-Synthesis of glycero-D-galacto-2-nonupyranosonate (sodium salt of compound No. 8 in Table 1) 337 mg (0.47 mmo of the compound obtained in Example 2
l) is a mixed solvent of ethanol-dioxane (1: 1) 2
The solution was dissolved in 0 ml, and 9.4 ml (0.94 mmol) of 0.1N aqueous sodium hydroxide solution was added under ice cooling, and the mixture was stirred under ice cooling for 5 hours, then returned to room temperature and stirred for 40 hours. The reaction solution was neutralized with Dowex (50W-X8) (H ⁺ ) resin and then purified by chromatography (ODS, MCI GEL, developing solvent water / methanol), and 193 mg (56 mg of the title compound as a solid from methanol-ether. .6
%) Was obtained.

IR (KBr) ν_max(Cm^-1) 3350, 2920, 1600 (broad), 138
0¹ H-NMR [CDCl₃-CD₃OD (1: 1)]
δ (ppm) 0.66 (3H, s, 18'-CH₃), 0.78 (3
H, s, 19'-CH₃), 0.86 to 0.93 (9
H, 21'-CH₃, 26'-CH₃, 27'-C
H ₃), 2.05 (3H, s, Ac), 2.86 (1
H, dd, J = 13.0,4.4Hz, H-3eq)¹³ C-NMR [CDCl₃-CD₃OD (1: 1)]
δ (ppm) 53.45 (C-5), 63.53 (C-9), 68.
82, 69.43, 72.09, 76.01 (C-4,
C-6, C-7, C-8), 89.79 (C-2) 174.87, 174.96 (CO x 2)

Example 4 Methyl 5-acetamido-4,7,8,9-tetra-
O-acetyl-2-S- (5'-cholestene-3'α-
Yl) -3,5-dideoxy-2-thio-α-D-glycero-D-galacto-2-nonulopyranosonate (Compound No. 9 in Table 1) Synthesis of 3α-mercapto-5-cholestene Sodium salt 1.
02 g (2.41 mmol) was dissolved in 50 ml of dry tetrahydrofuran and, under ice cooling, methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-2-chloro-2,3,5-trideoxy-β. -D-glycero-D-
Galact-2-Nonuropyranosonate 1.23g
Tetrahydrofuran solution (2.41 mmol) 30 m
1 was added dropwise, and the mixture was stirred for 12 hours. After the reaction, the solvent was distilled off, the obtained syrup was dissolved in chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution and saturated saline, and dried over anhydrous magnesium sulfate. After distilling off the solvent,
The obtained syrup was subjected to silica gel column chromatography [Merck silica gel 60, developing solvent: chloroform /
Methanol (100: 1 to 50: 1)],
Obtained 524 mg (25%) of the title compound.

IR (KBr) ν_max(Cm^-1) 3350, 2920, 1740, 1220¹ H-NMR (CDCl₃) Δ (ppm) 0.66 (3H, s, 19'-CH₃), 0.85
0.95 (9H, 21'-CH₃, 26'-CH₃, 2
7'-CH ₃), 0.98 (3H, s, 18'-C
H₃), 1.87, 2.02.2.04, 2.13
2.17 (15H, s × 5, Ac), 2.66 to 2.7
5 (2H, m, H-3eq, H-4 '), 3.50 (1
H, m, H-3 '), 3.80 (3H, s, -COOC
H ₃), 3.86 (1H, d, J = 6.9Hz, H-
6), 3.95 to 4.16 (2H, m, H-5, 9),
4.28 (1H, d, J = 11.5Hz, H-9),
4.83 (1H, m, H-4), 5.13 (1H, d,
J = 10.0 Hz, NH), 5.26-5.35 (3
H, m, H-7, H-8, H-6 ')

Example 5 Methyl 5-acetamido-2-S- (5'-cholesten-3'α-yl) -3,5-dideoxy-2-thio-
Synthesis of α-D-glycero-D-galacto-2-nonopyranosonate (Compound No. 13 in Table-1) Compound 449 mg (0.512 mm) obtained in Example 4
20 ml of methanol and 10 ml of tetrahydrofuran.
It was dissolved in ml, 0.1 ml (0.49 mmol) of a 4.9N sodium methoxide methanol solution was added under ice-cooling, and then the mixture was returned to room temperature and stirred for 12 hours. After the reaction
The precipitated solid was collected by filtration and washed with methanol and ether to give the title compound (275 mg, 75%).

IR (KBr) ν _max (cm ⁻¹ ) 3450, 3400, 3300, 2910, 1735,
1720, 1620, 1040 ¹ H-NMR (CD ₃ OD) δ (ppm) 0.75 (3 H, s, 19′-CH ₃ ), 0.91
1.02 (9H, s, 21'- CH 3, 26'-C
_{H 3, 27'-CH 3)} , 1.05 (3H, s, 18 '
_{-CH 3), 1.81 (1H,} dd, J = 11.2H
z, 12.7 Hz, H-3ax), 2.03 (3H,
s, Ac), 2.70 to 2.83 (2H, m, H-3e)
q, H-4 '), 3.88 (3H, s, -COO C
_{H 3), 5.30 (1H,} m, H-6 ')

Example 6 Sodium-5-acetamido-2-S- (5'-cholesten-3'α-yl) -3,5-dideoxy-2-thio-α-D-glycero-D-galacto-2 -Synthesis of nonuropyranosonate (sodium salt of Compound No. 16 in Table 1) 200 mg (0.282 mm) of the compound obtained in Example 5
was dissolved in 15 ml of methanol, 0.5 ml (2.5 mmol) of a 5N sodium hydroxide aqueous solution was added under ice cooling, the mixture was cooled to room temperature for 1 hour and then stirred at room temperature for 48 hours. The reaction solution is Dowex (50W-X8, H ⁺ type)
After neutralizing with resin, chromatography (ODS, MC
IGEL, developing solvent: water / methanol) and the title compound 84m as a solid from methanol-ether.
g (41%) was obtained.

IR (KBr) ν_max(Cm^-1) 3350 (broad), 2900, 1600 (bro
ad), 1385¹ H-NMR (CD₃OD) δ (ppm) 0.75 (3H, s, 19'-CH₃), 0.91
1.00 (9H, 21'-CH₃, 26'-CH₃, 2
7'-CH ₃), 1.03 (3H, s, 18'-C
H₃), 2.04 (3H, s, Ac), 2.70 (1
H, m, H-4 '), 2.90 (1H, dd, J = 4.
2 Hz, 12.7 Hz, H-3 eq), 5.30 (1
H, d, J = 4.4 Hz, H-6 ')¹³ C-NMR (CD₃OD) δ (ppm) 54.04 (C-5), 64.50 (C-9), 69.
70, 70.34, 73.12, 76.60 (C-4,
C-6, C-7, C-8), 87.81 (C-2), 1
22.80 (C-6 '), 140.80 (C-5'),
175.40, 175.50 (CO x 2)

Example 7 Methyl 5-acetamido-4,7,8,9-tetra-
O-acetyl-2-S- (3'β-cholestanyl)-
3,5-dideoxy-2-thio-α-D-glycero-D
-Synthesis of galacto-2-nonopyranosonate (Compound No. 17 of Table-2) Sodium salt of 3β-cholestanethiol 974 mg
(2.28 mmol) of dry tetrahydrofuran 50 m
suspended in 1, methyl 5-acetamide-4,7,8,
9-tetra-O-acetyl-2-chloro-2,3,5-
Trideoxy-β-D-glycero-D-galacto-2-
1.40 g (2.74 mmo) of non-neuropyranosonate
30 ml of a tetrahydrofuran solution of 1) was added dropwise at room temperature and stirred for 18 hours.

After the reaction, the solvent was distilled off, the resulting syrup was washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent, the obtained syrup was subjected to silica gel column chromatography [Merck silica gel 60, developing solvent.
Chloroform / methanol (200: 1-100:
1)] and 897 mg (44.
9%).

IR (KBr) ν_max(Cm^-1) 3300, 2950, 1750, 1220¹ H-NMR (CDCl₃) Δ (ppm) 0.61 (3H, s, 18'-CH₃), 0.72 (3
H, s, 19'-CH₃), 0.82 to 0.88 (9
H, 21'-CH₃, 26'-CH₃, 27'-C
H ₃), 1.85, 2.00, 2.02, 2.11
2.14 (15H, s × 5, Ac), 2.67 (1H,
dd, J = 12.8, 4.6 Hz, H-3 eq), 2.
95 (1H, m, H-3 '), 3.76 (3H, s,-
COOCH ₃), 3.82 (1H, dd, J = 10.
8, <2 Hz, H-6), 3.95-4.15 (2H,
m, H-5, H-9), 4.29 (1H, dd, J = 1)
2, <2 Hz, H-9), 4.80 (1H, ddd, J
= 11.6, 10.4, 4.6 Hz, H-4), 5.1
5 (1H, d, J = 10 Hz, N-H), 5.25-
5.30 (2H, m, H-7, H-8)

Example 8 Methyl 5-acetamido-2-S- (3'β-cholestanyl) -3,5-dideoxy-2-thio-α-D-glycero-D-galacto-2-nonopyranosonate Synthesis of (Compound No. 21 in Table 2) 828 mg (0.94 mmo) of the compound obtained in Example 7
1) was dissolved in 40 ml of a mixed solvent of methanol-tetrahydrofuran (1: 1), and 0.1 ml of a methanol solution of 4.9N sodium methoxide (0.49 mm) under ice cooling.
ol) was added, and then the mixture was returned to room temperature and stirred for 7 hours. After the reaction, the precipitated solid was collected by filtration and washed with methanol to give the title compound (604 mg, 90.3%).

IR (KBr) ν_max(Cm^-1) 3500, 3400, 2950, 2850, 1710,
1630, 1550, 1440, 1380, 1280,
1020¹ H-NMR [CDCl₃-CD₃OD (1: 1)]
δ (ppm) 0.66 (3H, s, 18'-CH₃), 0.78 (3
H, s, 19'-CH₃), 0.86 to 0.93 (9
H, 21'-CH₃, 26'-CH₃, 27'-C
H ₃), 2.03 (3H, s, Ac), 2.80 (1
H, dd, J = 13.0, 4.6 Hz, H-3eq),
2.89 (1H, m, H-3 '), 3.86 (3H,
s, -COOCH ₃)

Example 9 Sodium 5-acetamido-2-S- (3'β-cholestanyl) -3,5-dideoxy-2-thio-α-D
-Synthesis of glycero-D-galacto-2-nonulopyranosonate (sodium salt of compound No. 24 in Table 2) 198 mg of the compound obtained in Example 8 (0.28 mmo
l) was dissolved in 50 ml of tetrahydrofuran, and 0.11 ml (0.55 m
mol) was added and the mixture was stirred at room temperature for 5 days. Do the reaction solution
After neutralizing with wex (50W-X8) (H ⁺ ) resin, the product was purified by chromatography (ODS, MCI GEL, developing solvent water / methanol), and 65.3 mg (32.7) of the title compound as a solid from methanol-ether. %) Was obtained.

IR (KBr) ν_max(Cm^-1) 3350, 2940, 2850, 1600 (broa
d), 1380¹ H-NMR [CDCl₃-CD₃OD (1: 1)]
δ (ppm) 0.71 (3H, s, 18'-CH₃), 0.82 (3
H, s, 19'-CH₃), 0.90 to 0.98 (9
H, 21'-CH₃, 26'-CH₃, 27'-C
H ₃), 2.05 (1H, s, Ac), 2.89 (1
H, dd, J = 12.7, 4.3 Hz, H-3eq),
3.10 (1H, m, H-3 ')

Example 10 Methyl 5-acetamido-4,7,8,9-tetra-
O-acetyl-2-S- (5'-cholestene-3'β-
Yl) -3,5-dideoxy-2-thio-α-D-glycero-D-galacto-2-nonopyranosonate (Compound No. 25 in Table 2) Synthesis of 3β-mercapto-5-cholestene Sodium salt 1.
02 g (2.41 mmol) was dissolved in 50 ml of dry tetrahydrofuran, and methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-2-chloro-2,3,5-trideoxy-β was dissolved under ice cooling. -D-glycero-D-
Galact-2-Nonuropyranosonate 1.23g
Tetrahydrofuran solution (2.41 mmol) 30 m
1 was added dropwise, and the mixture was stirred for 2 hours.

After the reaction, the solvent was distilled off, the obtained syrup was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the resulting syrup was subjected to silica gel column chromatography [Merck silica gel 60, developing solvent: chloroform / methanol (100:
1-50: 1)] and the title compound 968m
g (46%) was obtained.

IR (KBr) ν_max(Cm^-1) 3400, 2950, 1740, 1220¹ H-NMR (CDCl₃) Δ cm^-1 0.66 (3H, s, 19'-CH₃), 0.82
0.92 (9H, 21'-CH₃, 26'-CH₃, 2
7'-CH ₃), 0.96 (3H, s, 18'-C
H₃), 1.87, 2.02, 2.03, 2.13
2.14 (15H, s × 5, Ac), 2.73 (1H,
dd, J = 4.5 Hz, 12.5 Hz, H-3 eq),
2.89 (1H, m, H-3 '), 3.81 (3H,
s, -COOCH ₃), 3.86 (1H, d, J = 1
0.5 Hz, H-6), 4.03 (1H, q, J = 1
0.5Hz, H-5), 4.18 (1H, m, H-
9), 4.36 (1H, d, J = 11.6Hz, H-
9), 4.82 (1H, m, H-4), 5.19 (1
H, d, J = 9.6 Hz, NH), 5.30 to 5.40
(3H, m, H-7, H-8, H-6 ')

Example 11 Methyl 5-acetamido-2-S- (5'-cholesten-3'β-yl) -3,5-dideoxy-2-thio-
Synthesis of α-D-glycero-D-galacto-2-nonopyranosonate (Compound No. 29 in Table-2) 826 mg (0.943m) of the compound obtained in Example 10
3. mol) in 20 ml of methanol, and under ice cooling, 4.
Methanol solution of 9N sodium methoxide 0.15m
1 (0.74 mmol) was added, followed by returning to room temperature,
Stir for 6 hours. After the reaction, the precipitated solid was collected by filtration and washed with methanol and ether to give the title compound (539 mg)
(80%) was obtained.

IR (KBr) ν_max(Cm^-1) 3350, 2920, 1710, 1625, 1020¹ H-NMR [CDCl₃-CD₃OD (1: 1)]
δ (ppm) 0.69 (3H, s, 19'-CH₃), 0.85
0.95 (9H, 21'-CH₃, 26'-CH₃, 2
7'-CH ₃), 0.98 (3H, s, 18'-C
H₃), 2.03 (3H, s, Ac), 2.77 (1
H, m, H-3 '), 2.80 (1H, dd, J = 4.
5 Hz, 13.1 Hz, H-3 eq), 3.85 (3
H, s, -COOCH ₃), 5.39 (1H, m, H-
6 ')

Example 12 Sodium-5-acetamido-2-S- (5'-cholesten-3'β-yl) -3,5-dideoxy-2-thio-α-D-glycero-D-galacto-2 -Synthesis of nonuropyranosonate (sodium salt of compound No. 32 in Table 2) 295 mg (0.417 m) of the compound obtained in Example 11
(mol) was dissolved in 20 ml of tetrahydrofuran, and 0.48 ml of 5N sodium hydroxide aqueous solution (2.4
mmol) was added, and the mixture was stirred under ice-cooling for 1 hour, then returned to room temperature and stirred for 48 hours. The reaction solution is Dowex (50W-X
(8, H ⁺ type) resin, followed by purification by chromatography (ODS, MCI GEL, developing solvent: water / methanol), and 182 mg (61%) of the title compound was obtained as a solid by methanol-ether. ..

IR (KBr) ν_max(Cm^-1) 3400, 2920, 1600 (broad), 137
5¹ H-NMR (CD₃OD) δ (ppm) 0.74 (3H, s, 19'-CH₃), 0.90
1.00 (9H, 21'-CH₃, 26'-CH₃, 2
7'-CH ₃), 1.02 (3H, s, 18'-C
H₃), 2.05 (3H, s, Ac), 2.28 (1
H, t, J = 14.1 Hz, H-4 '), 2.69 (1
H, dd, J = 2.3 Hz, 14.1 Hz, H-
4 '), 2.91 (1H, dd, J = 3.4Hz, 1
2.3 Hz, H-3 eq), 3.06 (1 H, m, H-
3 '), 5.44 (1H, d, J = 4.8Hz, H-
6 ')¹³ C-NMR (CD₃OD) δ (ppm) 54.03 (C-5), 64.54 (C-9), 69.
72, 70.30, 73.07, 76.81 (C-4,
C-6, C-7, C-8), 88.42 (C-2) 121.73 (C-6 '), 140.80 (C-
5 '), 175.12, 175.50 (CO x 2)

Example 13 Methyl 5-acetamido-4,7,8,9-tetra-
O-acetyl-2-S- (3'α-cholestanyl)-
3,5-dideoxy-2-thio-β-D-glycero-D
-Synthesis of galacto-2-nonulopyranosonate (Compound No. 33 in Table 3) Methyl 5-acetamido-4,7,8,9-tetra-
787 mg (1.60 mmol) of O-acetyl-2-fluoro-2,3,5-trideoxy-α-D-glycero-D-galacto-2-nonopyranosonate and 3α
-Cholestanthiol 811 mg (2.00 mmol)
Was dissolved in 18 ml of dry dichloromethane, and BF was cooled with ice.
₃ · OEt ₂ 0.60 ml of (4.86 mmol) was added, followed by stirring for 23 hours to return to room temperature. The reaction solution was washed with saturated aqueous NaHCO ₃ solution and water, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the obtained syrup was subjected to silica gel column chromatography [Merck silica gel 60, developing solvent chloroform / methanol (20
0: 1)], and 631 mg (4
5.1%) was obtained. At the same time, the compound 1 obtained in Example 1
40 mg (10.0%) was obtained.

[0071]¹H-NMR (CDCl₃) Δ (pp
m) 0.61 (3H, s, 18'-CH₃), 0.74 (3
H, s, 19'-CH₃), 0.82 to 0.88 (9
H, 21'-CH₃, 26'-CH₃, 27'-C
H ₃), 1.85, 2.00, 2.03, 2.05
2.10 (15H, s × 5, Ac), 2.50 (1H,
dd, J = 13.9, 4.9 Hz, H-3 eq), 3.
32 (1H, m, H-3 ′), 3.75 (3H, s, −
COOCH ₃), 4.01 to 4.18 (1H, m, H-
5, H-9), 4.33 (1H, dd, J = 10.5,
2.3 Hz, H-6), 4.89 (1H, dd, J = 1)
2.2, 2.0 Hz, H-9), 5.02 (1H, dd
d, J = 8.3, 2, <2 Hz, H-8), 5.27.
(1H, ddd, J = 13.0, 11.1, 4.9H
z, H-4), 5.37 (1H, d, J = 10.4H)
z, NH), 5.40 (1H, m, H-7)¹³ C-NMR (CDCl₃) Δ (ppm) 49.60 (-OMe), 52.82 (C-5), 6
2.86 (C-9), 68.98, 69.39, 72.
73, 73.45 (C-4, C-6, C-7, C-
8), 84.91 (C-2) 168.74, 170.15 (2), 170.40, 1
70.95,171.02 (CO x 6)

Example 14 Methyl 5-acetamido-4,7,8,9-tetra-
O-acetyl-2-S- (3'α-cholestanyl)-
3,5-dideoxy-2-thio-β-D-glycero-D
-Synthesis of galacto-2-nonulopyranosonate (Compound No. 33 in Table 3) Methyl 5-acetamido-2,4,7,8,9-penta-O-acetyl-3,5-dideoxy-β -D-glyceto-D-galacto-2-nonulopyranosonate 2.
75 g (5.15 mmol) and 3.18 g (7.86 mmol) of 3α-cholestanethiol were dissolved in 30 ml of dry dichloromethane to prepare powder molecular sieve 4A.
2.6 g was added. BF ₃ · OEt ₂ 2.0m under ice cooling
1 (16.2 mmol) was added, followed by returning to room temperature and
Stir for 0 hours. After the reaction solution was filtered through Celite, the filtrate was washed with saturated aqueous NaHCO ₃ solution and water, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the obtained syrup was subjected to silica gel column chromatography [Merck silica gel 60, developing solvent chloroform / methanol (20
0: 1)] and 2.72 g (6%) of the title compound.
0.0%) was obtained.

[0073]¹H-NMR (CDCl₃) Δ (pp
m) 0.61 (3H, s, 18'-CH₃), 0.74 (3
H, s, 19'-CH₃), 0.82 to 0.88 (9
H, 21'-CH₃, 26'-CH₃, 27'-C
H ₃), 1.85, 2.00, 2.03, 2.05
2.10 (15H, s × 5, Ac), 2.50 (1H,
dd, J = 13.9, 4.9 Hz, H-3 eq), 3.
32 (1H, m, H-3 ′), 3.75 (3H, s, −
COOCH ₃), 4.01 to 4.18 (1H, m, H-
5, H-9), 4.33 (1H, dd, J = 10.5,
2.3 Hz, H-6), 4.89 (1H, dd, J = 1)
2.2, 2.0 Hz, H-9), 5.02 (1H, dd
d, J = 8.3, 2, <2 Hz, H-8), 5.27.
(1H, ddd, J = 13.0, 11.1, 4.9H
z, H-4), 5.37 (1H, d, J = 10.4H)
z, NH), 5.40 (1H, m, H-7)¹³ C-NMR (CDCl₃) Δ (ppm) 49.60 (-OMe), 52.82 (C-5), 6
2.86 (C-9), 68.98, 69.39, 72.
73, 73.45 (C-4, C-6, C-7, C-
8), 84.91 (C-2) 168.74, 170.15 (2), 170.40, 1
70.95,171.02 (CO x 6)

Example 15 Methyl 5-acetamido-2-S- (3'α-cholestanyl) -3,5-dideoxy-2-thio-β-D-glycero-D-galacto-2-nonopyranosonate Synthesis of (Compound No. 37 in Table 3) Compound 631 obtained in Example 13 or Example 14
mg (0.72 mmol) was dissolved in 30 ml of methanol, 0.1 ml (0.49 mmol) of a 4.9N sodium methoxide methanol solution was added under ice-cooling, and then the mixture was returned to room temperature and stirred for 7 hours. After the reaction, the precipitated solid was collected by filtration and washed with methanol to give the title compound (387 mg)
(75.9%) was obtained.

[0075]¹H-NMR [CDCl₃-CD₃OD
(1: 1)] δ (ppm) 0.66 (3H, s, 18'-CH₃), 0.78 (3
H, s, 19'-CH₃), 0.86 to 0.93 (9
H, 21'-CH₃, 26'-CH₃, 27'-C
H ₃), 2.03 (3H, s, Ac), 2.52 (1
H, dd, J = 13.8, 4.8 Hz, H-3 eq),
3.41 (1H, m, H-3 '), 3.52 (1H, d
d, J = 9.3, <2 Hz, H-7), 3.77 (3
H, s, -COOCH ₃), 4.07 to 4.18 (2
H, m)¹³ C-NMR [CDCl₃-CD₃OD (1: 1)]
δ (ppm) 53.01 (OMe), 53.51 (C-5), 64.
86 (C-9), 67.69, 69.86, 70.6
7, 72.28 (C-4, C-6, C-7, C-8),
85.04 (C-2) 171.3, 174.5 (CO x 2)

Example 16 Sodium 5-acetamido-2-S- (3'α-cholestanyl) -3,5-dideoxy-2-thio-β-D
-Synthesis of glycero-D-galacto-2-nonulopyranosonate (sodium salt of compound No. 40 in Table 3) 360 mg (0.51 mm) of the compound obtained in Example 15
ol) was dissolved in 300 ml of a mixed solvent of methanol-tetrahydrofuran (1: 1), 12.0 ml (1.2 mmol) of 0.1N sodium hydroxide aqueous solution was added under ice cooling, and then the mixture was returned to room temperature and stirred for 7 days. did. After the reaction, the solid was collected by filtration and washed with methanol. The obtained solid was suspended and washed with chloroform-methanol (1: 2) to obtain 160 mg (44.0%) of the title compound.

IR (KBr) ν_max(Cm^-1) 3400, 2950, 1610 (broad), 138
0¹ H-NMR [CD₃OD-DMSO-d₆(1:
1)] δ (ppm) (measured at 40 ° C) 0.81 (3H, s, 18'-CH₃), 0.92 (3
H, s, 19'-CH₃), 1.01 to 1.08 (9
H, 21'-CH₃, 26'-CH₃, 27'-C
H ₃), 2.06 (3H, s, Ac), 2.53 (1
H, dd, J = 13.8, 4.7 Hz, H-3 eq),
4.00 (1H, ddd, J = 13.0, 11.0,
4.7 Hz, H-4)¹³ C-NMR [CD₃OD-DMSO-d₆(1:
1)] δ (ppm) (measured at 40 ° C.) 54.46 (C-5), 65.10 (C-9), 68.
96, 70.49, 72.77 (2) (C-4, C-
6, C-7, C-8), 88.97 (C-2) 172.77, 174.56 (CO x 2)

Example 17 Methyl 5-acetamido-4,7,8,9-tetra-
O-acetyl-2-S- (3'β-cholestanyl)-
3,5-dideoxy-2-thio-β-D-glycero-D
-Synthesis of galacto-2-nonulopyranosonate (Compound No. 49 of Table-4) Methyl 5-acetamido-4,7,8,9-tetra
1.70 g (3.45 mmol) of O-acetyl-2-fluoro-2,3,5-trideoxy-α-D-glycero-D-galacto-2-nonupyranosonate and 3β
-Cholestanthiol 1.54 g (3.81 mmol)
Is dissolved in 25 ml of dry dichloromethane, and BF is added under ice cooling.
₃ · OEt ₂ 1.3ml the (10.5mmol) was added,
Then, it returned to room temperature and stirred for 24 hours. The reaction solution is saturated with N
It was washed with an aqueous aHCO ₃ solution and water, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the obtained syrup was subjected to silica gel column chromatography [Merck silica gel 60, developing solvent chloroform / methanol (200:
1)] to obtain 608 mg (20.1%) of the title compound as a solid from methanol.

[0079]¹H-NMR (CDCl₃) Δ (pp
m) 0.61 (3H, s, 18'-CH₃), 0.74 (3
H, s, 19'-CH₃), 0.82 to 0.88 (9
H, 21'-CH₃, 26'-CH₃, 27'-C
H ₃), 1.85, 1.99, 2.06 (2), 2.1
1 (15H, s × 5, Ac), 2.48 (1H, dd,
J = 13.9, 4.9 Hz, H-3 eq), 2.70.
(1H, m, H-3 '), 3.77 (3H, s, -CO
OCH ₃), 4.00-4.24 (2H, m, H-5,
H-9), 4.39 (1H, dd, J = 10.5, 2.
3 Hz, H-6), 4.90 (1H, dd, J = 12.
3, <2 Hz, H-9), 4.98 (1H, m, H-
8), 5.20 (1H, m, H-4), 5.36-5.
40 (2H, m, H-7, NH)¹³ C-NMR (CDCl₃) Δ (ppm) 63.11 (C-9), 69.19, 69.25, 7
2.80, 73.87 (C-4, C-6, C-7, C-
8), 85.17 (C-2) 168.88, 170.19 (2), 170.28, 1
70.90, 171.18 (CO x 6)

Example 18 Methyl 5-acetamido-2,5- (3'β-cholestanyl) -3,5-dideoxy-2-thio-β-D-glycero-D-galacto-2-nonopyranosonate (Synthesis of Compound No. 53 in Table 4) 481 mg (0.55 mm) of the compound obtained in Example 17
ol) was dissolved in 18 ml of a mixed solvent of methanol-tetrahydrofuran (5: 4), and 0.1 ml of a methanol solution of 4.9N sodium methoxide (0.49 m) under ice cooling.
mol) was added, and then the mixture was returned to room temperature and stirred for 24 hours. The reaction mixture was neutralized with Dowex (50W-X8, H ⁺ ) resin, the solvent was evaporated, and 199 mg (51.2%) of the title compound was obtained as a solid from methanol.

[0081]¹H-NMR [CDCl₃-CD₃OD
(1: 1)] delta (ppm) 0.67 (3H, s, 18'-CH₃), 0.78 (3
H, s, 19'-CH₃), 0.87 to 0.94 (9
H, 21'-CH₃, 26'-CH₃, 27'-C
H ₃), 2.04 (3H, s, Ac), 2.51 (1
H, dd, J = 13.7, 4.8 Hz, H-3 eq),
2.88 (1H, m, H-3 '), 3.53 (1H, d
d, J = 8.7, <2 Hz, H-7), 3.68-3.
91 (7H, m), 4.03 to 4.17 (2H, m)¹³ C-NMR [CDCl₃-CD₃OD (1: 1)]
δ (ppm) 53.08 (-OMe), 53.11 (C-5), 6
4.88 (C-9), 67.81, 70.14, 71.
23,72.57 (C-4, C-6, C-7, C-
8), 85.57 (C-2) 171.87, 174.70 (CO x 2)

Example 19 Sodium 5-acetamido-2-S- (3'β-cholestanyl) -3,5-dideoxy-2-thio-β-D
-Synthesis of glycero-D-galacto-2-nonopyranosonate (sodium salt of compound No. 56 in Table 4) 179 mg (0.25 mm) of the compound obtained in Example 18
ol) was dissolved in 50 ml of tetrahydrofuran and 0.08 ml (0.4 m of 5N aqueous sodium hydroxide solution was added under ice cooling).
mol) was added, and then the mixture was returned to room temperature and stirred for 24 hours. After the reaction, the solvent was distilled off, and the solid was made into methanol to obtain 130 mg (71.4%) of the title compound.

IR (KBr) ν_max(Cm^-1) 3400, 2920, 1610 (broad), 138
0¹ H-NMR (CD₃OD) δ (ppm) 0.71 (3H, s, 18'-CH₃), 0.82 (3
H, s, 19'-CH₃), 0.90 to 0.98 (9
H, 21'-CH₃, 26'-CH₃, 27'-C
H ₃), 2.03 (3H, s, Ac), 2.56 (1
H, dd, J = 13.6, 4.6 Hz, H-3 eq),
2.91 (1H, m, H'-3), 3.52 (1H, d
d, J = 8.3, <2 Hz, H-7), 4.02 (1
H, m, H-4), 4.24 (1H, m)¹³ C-NMR (CD₃OD) δ (ppm) 54.21 (C-5), 65.10 (C-9), 69.
26, 70.55, 72.30, 72.73 (C-4,
C-6, C-7, C-8), 88.39 (C-2) 174.39, 176 (CO x 2)

Test Example 1 Effect on acetylcholine synthase (choline acetyltransferase; ChAT) activity of postnatal rat-derived cultured septal area corinadic neurons The primary culture method of septal area neurons from postnatal rats is the method of Hatanaka et al. Hatanaka et al. Dev. Brain.
Res. 39 , 85-95, 1988). That is, the septal area was removed from the 14-day-old rat brain,
Shred and enzymatically (treated with papain in the presence of DNase I)
The cells were dispersed mechanically (pipetting). About 5 x 10 of the obtained isolated cells were placed on a 48-well plate in which astroglial cells were grown on a sheet in advance.
^The cells were seeded at ⁵ cells / cm ² and cultured in DF medium containing 5% quasi-fetal bovine serum and 5% non-immobilized bovine serum (equivalent mixture of Dulbecco's modified Eagle medium and Ham's F12 medium). Astroglial cells were prepared from the cerebral cortex of rat embryo E20, propagated for several generations, and then used. The day after the start of culture, the test compound was replaced with the same medium containing a predetermined concentration,
After culturing for 1 week, the cells were diluted with 0.1% Triton X.
The cells were disrupted by sonication in 5 mM Tris-HCl buffer containing -100. Using this as a crude enzyme preparation, [ ¹⁴ C]
Add Acetyl Coenzyme A (0.3KBq) to 37 ℃
And incubated for 1 hour. After the reaction was stopped, it was generated [
¹⁴ C] Acetylcholine was extracted into toluene scintillator and measured with a liquid scintillation counter. The ChAT activity value of the control group is usually about 1.5 pmol
/ Min / culture well, and the ChAT activity of the test compound is a ratio (%) when the activity value of the control group is 100.
It showed with. The test results are shown in Table 5 below.

[0085]

[Table 9]

[0086]

[Chemical 7]

[0087]

[Chemical 8]

The compounds (A) and (B) are both compounds described in JP-A-63-63697.

[0089]

EFFECTS OF THE INVENTION Since the compound of the present invention activates ChAT activity in cholinergic nerve cells, senile dementia including Alzheimer's disease; cerebral vascular dementia associated with stroke (cerebral hemorrhage, cerebral infarction), cerebral arteriosclerosis, etc .; head It is considered to be useful for treating memory disorders associated with partial trauma, encephalitis sequelae, cerebral palsy, etc., and also for treating peripheral neuropathy such as diabetic neuropathy and alcoholic neuropathy.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Michiyo Yokota 1000 Kamoshida-cho, Midori-ku, Yokohama-shi, Kanagawa Sanryoh Kasei Co., Ltd. (72) Inventor Akihiro Tobe, 1000, Kamoshida-cho, Midori-ku, Yokohama-shi, Kanagawa San Ryokasei Co., Ltd.

Claims (1)

[Claims] 1. The following general formula (I): (In the formula, R ¹ represents an aglycone residue, R ² represents a hydrogen atom or a C _{1 to} C ₄ lower alkyl group, and R ³ represents simultaneously a hydrogen atom or an acyl group.)
A thiosialic acid derivative represented by or a pharmaceutically acceptable salt thereof.