JPH05105694A - Sialic acid derivative - Google Patents

Abstract

PURPOSE:To provide a new sialic acid derivative useful as a neuropathy therapeutic agent, cancer cell metastasis-inhibiting agent, antiinflammatory agent, demyelinating disease-therapeutic agent, etc., chemically and enzymatically stable, acting for a long time and capable of being readily handled. CONSTITUTION:A new sialic acid derivative having a group of the formula (X is H, lower alkyl, benzyl; Y is H, acetyl; AC is acetyl) and its salt. For example, 5-cholesteryl-3beta-yl 5-acetamido-5-deoxy-d-D-erythro-L-gluco-2-nonuropyranosidic acid. The compound is obtained by subjecting 5-acetamido-4,7,8,9-tetra-O- acetyl-2-halogeno-2,5-dideoxy-beta-D-erythro-L-gluco-2-nonuropyranosonate alkyl ester as a doner and a compound of formula R-OH as an acceptor to a glucoside-forming reaction in the presence of a catalyst such as trifluoromethane sulfonic acid silver salt and a neutralizing agent such as disodium phosphate.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a chemically and enzymatically stable novel sialic acid derivative which is useful as a drug such as a therapeutic agent for neurological diseases.

[0002]

BACKGROUND OF THE INVENTION Sialic acid contained in gangliosides and glycoproteins is present on the cell surface of cells or bacteria, and has recently been medically used as a substance involved in immunity, cancer, inflammation, virus infection, cell differentiation, hormone receptor and the like. Further, it is attracting attention pharmacologically, and various derivatives containing sialic acid have been synthesized. It has been reported that these physiologically active sialic acid derivatives have pharmacological actions such as a neuropathic disease treating action, a cancer metastasis inhibiting action, an anti-inflammatory action, and a demyelinating disease treating action.

[0003]

An object of the present invention is to provide a chemically and enzymatically stable novel sialic acid derivative having a hydroxyl group at the 3-position.

[0004]

The compound of the present invention is a sialic acid derivative containing a group represented by the following general formula (I).

[Chemical 2] In the above general formula, X is hydrogen, methyl, ethyl, n-
1 carbon atom such as propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl
To lower alkyl or benzyl, Y represents hydrogen or an acetyl group, preferably hydrogen, and Ac represents an acetyl group. The wavy line is meant to include both α-anomeric and β-anomeric forms.

Many substances containing sialic acid as a constituent, such as ganglioside, sialosyl cholesterol, sialosyl glycerolipids, sialosyl ceramides, and sialoglycoproteins, exist naturally or are chemically synthesized. The sialic acid contained in is a normal sialic acid having hydrogen at the 3-position. On the other hand, the sialic acid contained in the compound of the present invention has a hydroxyl group at the 3-position, and the sialic acid derivative composed of such 3-hydroxysialic acid is a novel compound.

The compounds of the present invention include all sialic acid compounds containing a group represented by the general formula (I). For example, the compound of the present invention can be represented by the following general formula (II).

[Chemical 3] In the formula, X is the same as the above general formula (I), R represents a moiety other than 3-hydroxysialic acid in the compound of the present invention, and examples thereof include an alkyl group, an allyl group, glucose, galactose, mannose, fucose and glucosamine. , Galactosamine, N-acetylglucosamine, N-acetylgalactosamine, sialic acid and other monosaccharides and sugars such as oligosaccharides to which these monosaccharides are bound, cerebroside, ganglioside and other sphingolipids and glyceroglycolipids and other glycolipids, ceramide A glycoprotein containing the saccharide as a constituent, a steroid such as cholesterol, a glycerolipid such as an alkylglycerol, a dialkylglycerol, an alkylacylglycerol and a diacylglycerol, a natural nucleoside such as an adenosine, a guanosine, an inosine, a cytidine and a uridine. Oside and azidothymidine such modified nucleosides of can include adenine, purine bases and cytosine guanine such as thymine, pyrimidine bases and acyclovir uracil etc., and modified bases 5-fluorouracil and the like.

The sialic acid derivative of the present invention includes a pharmaceutically acceptable salt of the compound represented by the above general formula (I), for example, an alkali metal such as sodium or potassium,
Alkaline earth metals such as calcium, magnesium and barium, and other metal salts with aluminum and the like, or addition salts with acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, citric acid and lactic acid, or ammonia. , Salts with organic bases such as organic amines. These salts can be produced from the free sialic acid derivative of the present invention by a known method, or can be converted into each other. When an optical isomer exists in the compound of the present invention, the present invention includes any isomer thereof.

Next, a method for producing the compound of the present invention will be described. For example, 5-acetamide-4,7,8,9-tetra-O-acetyl-2-halogeno-2,5-dideoxy-β-D-erythro-L-gluco-2-nonuropyranosonate alkyl or benzyl. The compound of the present invention can be produced by a glycosidation reaction using an ester as a donor. Examples of the alkyl ester include methyl, ethyl, n-propyl, iso-propyl, n-butyl,
Examples thereof include esters of lower alkyl groups having 1 to 4 carbon atoms such as iso-butyl, sec-butyl, t-butyl.
The halogen at the 2nd position is fluorine, chlorine, bromine, iodine, etc., with bromine being preferred. As the acceptor reacted with the glycosidation reaction donor, a compound having a hydroxyl group represented by the general formula R-OH (R is the same as in the general formula (II) above)
Can be used.

The glycosidation reaction can be carried out under the following reaction conditions. As the solvent, an appropriate solvent such as toluene, benzene or a mixed solvent of toluene and 1,2-dichloroethane which does not inhibit the reaction can be used. The catalyst is silver trifluoromethanesulfonate, the neutralizing agent is disodium phosphate, phosphoric acid. A dialkali phosphate such as dipotassium or silver carbonate is preferred. The reaction temperature can be appropriately set according to the intended product, because the production ratio of the α-anomer body and the β-anomer body changes depending on the temperature. If the reaction time is long, decomposition of the product or the like may occur due to a side reaction, so that 5 minutes to 1 hour is sufficient.

Further, 5-acetamide-4,7,8,9-tetra-O-acetyl-2,3-anhydro-5-deoxy-β-D-erythro-L-gluco-2-nonuropyranoso. Of the compounds of the invention by glycosidation reaction using nate alkyl or benzyl ester as a donor.
-The anomeric form can be selectively produced. Examples of the alkyl ester include lower alkyl esters similar to the above, and reaction conditions such as a solvent and a catalyst in the glycosidation reaction can be appropriately set according to the above method. Methods for producing these glycosidation reaction donors and the like are described in the literature. (Okamoto et al., Bull. Chem. Soc. Jpn., 60, 631−
636 (1987))

Deacetylation after the completion of the glycosidation reaction is carried out by a usual method in the presence of a basic catalyst such as an alkyl metal alkoxide such as potassium t-butoxide or sodium methoxide in a suitable solvent such as methanol or ethanol. Is available. It may be necessary to protect groups that do not participate in the reaction of the glycosidation reaction donor. For example, when glucose is used as the donor, it is preferable to protect a hydroxyl group other than the hydroxyl group that reacts with the acceptor with a benzyl group or the like. .. Other donors may be appropriately protected with a suitable protecting group, and the protecting group can be removed according to a usual method used in the art. For example, debenzylation may be carried out by catalytic reduction in the presence of palladium-carbon in a suitable solvent such as methanol.

The sialic acid derivative of the present invention in which X is lower alkyl or benzyl in the above general formula (I) can be easily converted to the compound of the present invention in which X is hydrogen by a conventional hydrolysis treatment. The compound produced in the present invention is purified by ordinary means such as distillation, chromatography, recrystallization, and the like, and is subjected to TLC, elemental analysis, melting point measurement, specific rotation (sodium D line), IR, NMR, UV, mass spectrum. Etc. were identified.

[0013]

【Example】

Example 1. (1) 6.6 g of methyl 5-acetamide-4,7,8,
9-Tetra-O-acetyl-2-bromo-2,5-dideoxy-β-D-erythro-L-gluco-2-nonuropyranosonate (raw material compound A), 5.0 g of 5-cholestene-3β -All, 6.6 g of anhydrous disodium hydrogen phosphate and 140 ml of dry benzene were mixed and stirred.
To this was added 3.1 g silver trifluoromethanesulfonate dissolved in 90 ml dry benzene at room temperature under an argon atmosphere. After stirring for 10 minutes, the insoluble matter was filtered off through a filter aid and washed with ethyl acetate. The filtrate and the washing solution were combined, washed with 5% aqueous sodium thiosulfate solution, 5% aqueous sodium hydrogen carbonate solution and saturated saline solution, and then evaporated to dryness to obtain a crude product in the form of a syrup, which was purified with a silica gel column to obtain methyl. (5-cholesten-3β-yl5-acetamide-4,7,8,9-tetra-O-acetyl-5-deoxy-D-erythro-L-gluco-2-nonuropyranoside) onate as α-anomeric body and β Obtained as a mixture of anomers (α: β = 6: 1). Yield: 61% Elemental analysis: As C ₄₇ H ₇₃ NO ₁₄

(2) 2.2 g of the above product and a catalytic amount of potassium t-butoxide were dissolved in 100 ml of anhydrous methanol, and the mixture was stirred at room temperature for 1 hour under an argon atmosphere. After the addition of a cation exchange resin for neutralization, the resin was filtered off and washed with methanol. The filtrate and the washing solution were combined and concentrated under reduced pressure, and the obtained solid crude product was chloroform-
Recrystallized from methanol-ether to give methyl (5-cholesten-3β-yl 5-acetamido-5-deoxy-
The α-anomeric form of D-erythro-L-gluco-2-nonuropyranoside) onate was obtained as white crystals. After the filtrate of recrystallization was concentrated, the β-anomer form and the remaining α-anomer form were separated and purified using a silica gel column. (Α-anomeric form) Yield: 80% Melting point: 229 −231 ℃ [α] ²⁵ : −23.7 ° (C = 0.65, chloroform / methanol = 5
/ 1) IR (KBr): 3470, 3400, 2950, 1730, 1620, 1548, 14
35, 1373, 1315, 1070, 1033 cm ^-1 Mass (SIMS): m / z 708 (M + H), 322 (M-cholesterol + 1) Elemental analysis: As C ₃₉ H ₆₅ NO ₁₀ ¹ H-NMR (CDCl ₃ / CD ₃ OD = 1/1, δ): cholesterol moiety
0.69 (s, 3H), 0.87 and 0.88 (2d, J = 6.6Hz, 2x3H), 0.93 (d,
J = 6.4Hz, 3H), 1.00 (s, 3H), 3.68-3.75 (m, 1H), 5.31-5.3
5 (m, 1H); Neu5Ac moiety 2.05 (s, 3H), 3.47 (dd, J = 1.2,
8.4Hz, 1H), 3.61 (d, J = 9.1Hz, 1H), 3.77 (dd, J = 8.2, 9.1H
z, 1H), 3.81 (s, 3H), 3.93 (dd, J = 1.2, 8.2Hz, 1H), 3.96 (d
(d, J = 8.2,8.2Hz, 1H) (β-anomer) Yield: 13% Melting point: 272 − 275 ℃ (α) ²⁵ : −53.7 ° (C = 0.51, chloroform / methanol = 5)
/ 1) IR (KBr): 3420, 2920, 1740, 1614, 1570, 1430, 13
80, 1315, 1095,1024 cm ^-1 Mass (SIMS): m / z 708 (M + H), 322 (M-cholesterol + 1) Elemental analysis: As C ₃₉ H ₆₅ NO ₁₀ ¹ H-NMR (CDCl ₃ / CD ₃ OD = 1/1, δ): cholesterol moiety
0.69 (s, 3H), 0.86 and 0.87 (2d, J = 6.6Hz, 2x3H), 0.93 (d,
J = 6.5Hz, 3H), 1.01 (s, 3H), 3.65-3.74 (m, 1H), 5.25-5.2
9 (m, 1H); Neu5Ac moiety 2.04 (s, 3H), 3.44 (dd, J = 0.5,
8.8Hz, 1H), 3.55 (d, J = 9.0Hz, 1H), 3.83 (s, 3H), 3.84 (d
d, J = 9.0,9.1Hz, 1H), 3.92 (dd, J = 0.5, 8.5Hz, 1H), 3.95
(dd, J = 8.5,9.1Hz, 1H)

(3) 1.2 g of the above α-anomer, 1
After mixing 0 ml of a 1N sodium hydroxide aqueous solution and 200 ml of methanol and stirring at room temperature for 2 hours, a cation exchange resin was added at 0 ° C. for neutralization. The resin was filtered off, washed with methanol, and the filtrate and washing liquid were combined and concentrated. The obtained solid crude product was washed with ether and recrystallized from methanol-chloroform-hexane to give 5-
Cholesten-3β-yl 5-acetamido-5-deoxy-α-D-erythro-L-gluco-2-nonuropyranoside acid (Compound 1α) was obtained as white crystals. Yield: 97% Melting point: 191 − 193 ℃ [α] ²⁵ : −21.4 ° (C = 0.53, chloroform / methanol = 1
/ 1) IR (KBr): 3250, 2945, 1715, 1620, 1560, 1460, 13
68, 1103, 1066, 1021 cm ^-1 Mass (SIMS): m / z 694 (M + H), 308 (M-cholesterol + 1) Elemental analysis: as C ₃₈ H ₆₃ NO ₁₀ ¹ H-NMR (CD ₃ OD, δ): cholesterol moiety 0.71 (s, 3
H), 0.87 and 0.88 (2d, J = 6.5Hz, 2x3H), 0.94 (d, J = 6.4H
z, 3H), 1.02 (s, 3H), 3.67-3.76 (m, 1H), 5.33-5.37 (m, 1
H); Neu5Ac moiety 2.02 (s, 3H), 3.49 (dd, J = 1.5, 8.7H
z, 1H), 3.56 (d, J = 9.5Hz, 1H), 3.64 (dd, J = 6.3, 12.1Hz, 1
H), 3.70 (dd, J = 9.5, 10.2Hz, 1H), 3.81 (dd, J = 12.1Hz, 1
H), 3.82 (dd, J = 1.5, 10.3Hz, 1H), 3.82 (ddd, J = 6.3, 8.7
Hz, 1H), 3.93 (dd, J = 10.2, 10.3Hz, 1H)

Similarly, β-anomeric 5-cholesten-3β-yl 5-acetamido-5-deoxy-
β-D-erythro-L-gluco-2-nonuropyranoside acid (Compound 1β) was obtained. Yield: 97% Melting point: 193-195 ° C [α] ²⁵ : -56.9 ° (C = 0.54, chloroform / methanol = 1
/ 1) IR (KBr): 3400, 3260, 2920, 1757, 1618, 1578, 13
75, 1160, 1085, 1020 cm ^-1 Mass (SIMS): m / z 694 (M + H), 308 (M-cholesterol + 1) Elemental analysis: as C ₃₈ H ₆₃ NO ₁₀ ¹ H-NMR (CD ₃ OD, δ): cholesterol moiety 0.71 (s, 3
H), 0.87 and 0.88 (2d, J = 6.6Hz, 2x3H), 0.94 (d, J = 6.5H
z, 3H), 1.02 (s, 3H), 3.73-3.81 (m, 1H), 5.26-5.31 (m, 1
H); Neu5Ac moiety 2.00 (s, 3H), 3.43 (d, J = 9.1Hz, 1H),
3.48 (dd, J = 0.5, 9.0Hz, 1H), 3.64 (dd, J = 4.8, 11.0Hz, 1
H), 3.75 (ddd, J = 2.5, 4.8, 9.0Hz, 1H), 3.79 (dd, J = 2.5,
11.0Hz, 1H), 3.85 (dd, J = 9.1,9.2Hz, 1H), 3.96 (dd, J = 8.
5, 9.2Hz, 1H), 3.99 (dd, J = 0.5, 8.5Hz, 1H)

Embodiment 2. Raw material compound A and methyl 2,
3,4-tri-O-benzyl-α-D-glucoside,
Example 1 under silver trifluoromethanesulfonate catalyst
The same glycosidation reaction as in (1) was performed. Obtained α
-Anomeric form and β-anomeric form were respectively prepared in Example 1
After deacetylation as in (2), debenzylation was carried out by catalytic reduction according to a conventional method. Then Example 1
After hydrolyzing the methyl ester in the same manner as (3),
Neutralization with an acidic resin gave the following compound. Methyl 6-O- (5-acetamide-5-deoxy-α-
D-erythro-L-gluco-2-nonuropyranosylonate) -α-D-glucopyranoside (compound 2α) Melting point: 85-87 ° C [α] ²⁵ : + 26.8 ° (C = 1.1, H ₂ O) ) IR (KBr): 3350, 1735, 1640, 1555, 1370, 1030 cm
^-1 Mass (SIMS): m / z 502 (M + H), 308 (M-Glc) Elemental analysis: C ₁₈ H ₃₁ NO ₁₅・ 3H ₂ O ¹ H-NMR (D ₂ O / TSP, δ): Glc moiety 3.41 (s, 3H), 3.47
(dd, J = 9.2, 9.3Hz, 1H), 3.56 (dd, J = 3.7, 9.8Hz, 1H), 3.
64 (dd, J = 9.2, 9.8Hz, 1H), 3.76 (ddd, J = 9.3Hz, 1H), 3.98
(m, 2H), 4.78 (d, J = 3.7Hz, 1H); Neu5Ac moiety 2.03 (s, 3
H)

Methyl 6-O- (5-acetamido-5-deoxy-β-D-erythro-L-gluco-2-nonuropyranosylonate) -α-D-glucopyranoside (Compound 2β) Melting point: 79- 81 ℃ [α] ²⁵ : + 17.7 ° (C = 1.1, H ₂ O) IR (KBr): 3400, 1730, 1635, 1550, 1368, 1070, 10
28 cm ^-1 Mass (SIMS): m / z 502 (M + H), 524 (M + Na), 308 (M-Gl
c) Elemental analysis: As C ₁₈ H ₃₁ NO ₁₅・ 2H ₂ O ¹ H-NMR (D ₂ O / TSP, δ): Glc moiety 3.41 (s, 3H), 3.61
(dd, J = 3.8, 8.9Hz, 1H), 3.77 (ddd, J = 1.3, 3.5Hz, 1H),
3.85 (dd, J = 3.5, 10.6Hz, 1H), 3.92 (dd, J = 1.3, 10.6Hz, 1
H), 4.81 (d, J = 3.8Hz, 1H); Neu5Ac moiety 2.05 (s, 3H),
3.54 (d, J = 9.1Hz, 1H), 3.83 (m, 1H), 3.84 (d, J = 9.8Hz, 1
H), 3.90 (dd, J = 9.8, 10.3Hz, 1H), 3.98 (d, J = 10.6Hz, 1
H), 4.06 (dd, J = 10.3, 10.6Hz, 1H)

Example 3. Example 1 Raw material compound A and 1,2 (or 2,3) -di-O-alkyl-sn-glycerol under silver trifluoromethanesulfonate catalyst
The same glycosidation reaction as in (1) was performed to obtain a mixture of α-anomer and β-anomer. This mixture could not be separated by silica gel chromatography, but by reacting benzoyl chloride with pyridine in a pyridine solvent at room temperature by argon vaporization to benzoylate the hydroxyl group at the 3-position, both anomers were purified by silica gel chromatography. Could be separated. Separated α
-The anomeric form and the β-anomeric form were subjected to Zem according to a conventional method.
Example 1 after deacylation by the plen method
The methyl ester was hydrolyzed in the same manner as in (3) and then neutralized with an acidic resin to obtain the following compound.

3-O- (5-acetamido-5-deoxy-α-D-erythro-L-gluco-2-nonuropyranosylonic acid) -1,2-di-O-octyl-sn-glycerol (compound 3α) 3-O- (5-acetamido-5-deoxy-β-D-erythro-L-gluco-2-nonuropyranosylonic acid)-
1,2-di-O-octyl-sn-glycerol (compound 3β) 3-O- (5-acetamido-5-deoxy-α-D-erythro-L-gluco-2-nonuropyranosylonic acid)-
1,2-di-O-decyl-sn-glycerol (compound 4α) 3-O- (5-acetamido-5-deoxy-β-D-erythro-L-gluco-2-nonuropyranosylonic acid)-
1,2-di-O-decyl-sn-glycerol (compound 4β) 3-O- (5-acetamido-5-deoxy-α-D-erythro-L-gluco-2-nonuropyranosylonic acid)-
1,2-di-O-dodecyl-sn-glycerol (compound 5α) 3-O- (5-acetamido-5-deoxy-β-D-erythro-L-gluco-2-nonuropyranosylonic acid)-
1,2-di-O-dodecyl-sn-glycerol (compound 5β) 3-O- (5-acetamido-5-deoxy-α-D-erythro-L-gluco-2-nonulopyranosylonic acid)-
1,2-di-O-tetradecyl-sn-glycerol (compound 6α) 3-O- (5-acetamido-5-deoxy-β-D-erythro-L-gluco-2-nonuropyranosylonic acid)-
1,2-di-O-tetradecyl-sn-glycerol (compound 6β) 3-O- (5-acetamido-5-deoxy-α-D-erythro-L-gluco-2-nonuropyranosylonic acid)-
1,2-di-O-hexadecyl-sn-glycerol (compound 7α) 3-O- (5-acetamido-5-deoxy-β-D-erythro-L-gluco-2-nonuropyranosylonic acid)-
1,2-di-O-hexadecyl-sn-glycerol (compound 7β) 3-O- (5-acetamido-5-deoxy-α-D-erythro-L-gluco-2-nonuropyranosylonic acid)-
1,2-di-O-octadecyl-sn-glycerol (compound 8α) 3-O- (5-acetamido-5-deoxy-β-D-erythro-L-gluco-2-nonuropyranosylonic acid)-
1,2-di-O-octadecyl-sn-glycerol (compound 8β) 1-O- (5-acetamido-5-deoxy-α-D-erythro-L-gluco-2-nonuropyranosylonic acid)-
2,3-di-O-tetradecyl-sn-glycerol (compound 9α) 1-O- (5-acetamido-5-deoxy-β-D-erythro-L-gluco-2-nonuropyranosylonic acid)-
2,3-di-O-tetradecyl-sn-glycerol (compound 9β) 3-O- (5-acetamido-5-deoxy-α-D-erythro-L-gluco-2-nonuropyranosylonic acid)-
1,2-di-O-tetradecyl-rac-glycerol (compound 10α) 3-O- (5-acetamido-5-deoxy-β-D-erythro-L-gluco-2-nonuropyranosylonic acid)-
1,2-di-O-tetradecyl-rac-glycerol (compound 10β) 3-O- (5-acetamido-5-deoxy-α-D-erythro-L-gluco-2-nonuropyranosylonic acid) -1
-O-dodecyl-2-O-tetradecyl-sn-glycerol (compound 11α) 3-O- (5-acetamido-5-deoxy-β-D-erythro-L-gluco-2-nonuropyranosylonic acid)- 1
-O-dodecyl-2-O-tetradecyl-sn-glycerol (compound 11β) 3-O- (5-acetamido-5-deoxy-α-D-erythro-L-gluco-2-nonuropyranosylonic acid)- Two
-O-dodecyl-1-O-tetradecyl-sn-glycerol (compound 12α) 3-O- (5-acetamido-5-deoxy-β-D-erythro-L-gluco-2-nonuropyranosylonic acid)- Two
-O-dodecyl-1-O-tetradecyl-sn-glycerol (compound 12β)

Physical properties of the above compound obtained in Example 3 are shown in Tables 1 and 2.

[Table 1]

[Table 2]

Example 4. The raw material compound A and 3-O-alkyl-sn-glycerol were subjected to glycosidation reaction in the same manner as in Example 1 (1) under a silver trifluoromethanesulfonate catalyst to give a mixture of α-anomer and β-anomer. Obtained. This mixture was not separable by silica gel chromatography, but was
Both anomers could be separated by silica gel chromatography by treatment with dimethylaminopyridine and intramolecular lactonization. Separated α
-The anomeric form and the β-anomeric form were subjected to Zem according to a conventional method.
Example 1 after deacylation by the plen method
The methyl ester was hydrolyzed in the same manner as in (3) and then neutralized with an acidic resin to obtain the following compound. 1-O- (5-acetamido-5-deoxy-α-D-erythro-L-gluco-2-nonuropyranosylonic acid) -3
-O-dodecyl-sn-glycerol (compound 13α) 1-O- (5-acetamido-5-deoxy-β-D-erythro-L-gluco-2-nonuropyranosylonic acid) -3
-O-dodecyl-sn-glycerol (compound 13β) 1-O- (5-acetamido-5-deoxy-α-D-erythro-L-gluco-2-nonuropyranosylonic acid) -3
-O-tetradecyl-sn-glycerol (compound 14
α) 1-O- (5-acetamide-5-deoxy-β-D-erythro-L-gluco-2-nonuropyranosylonic acid) -3
-O-tetradecyl-sn-glycerol (compound 14
β) 1-O- (5-acetamide-5-deoxy-α-D-erythro-L-gluco-2-nonuropyranosylonic acid) -3
-O-hexadecyl-sn-glycerol (Compound 15
α) 1-O- (5-acetamide-5-deoxy-β-D-erythro-L-gluco-2-nonuropyranosylonic acid) -3
-O-hexadecyl-sn-glycerol (Compound 15
β) 1-O- (5-acetamide-5-deoxy-α-D-erythro-L-gluco-2-nonuropyranosylonic acid) -3
-O-octadecyl-sn-glycerol (compound 16
α) 1-O- (5-acetamide-5-deoxy-β-D-erythro-L-gluco-2-nonuropyranosylonic acid) -3
-O-octadecyl-sn-glycerol (compound 16
β) 1-O- (5-acetamide-5-deoxy-α-D-erythro-L-gluco-2-nonuropyranosylonic acid) -3
-O-icosyl-sn-glycerol (compound 17α) 1-O- (5-acetamido-5-deoxy-β-D-erythro-L-gluco-2-nonuropyranosylonic acid) -3
-O-icosyl-sn-glycerol (compound 17β) 1-O- (5-acetamido-5-deoxy-α-D-erythro-L-gluco-2-nonuropyranosylonic acid) -3
-O-docosyl-sn-glycerol (compound 18α) 1-O- (5-acetamido-5-deoxy-β-D-erythro-L-gluco-2-nonuropyranosylonic acid) -3
-O-docosyl-sn-glycerol (Compound 18β)

The physical properties of the above compound obtained in Example 4 are shown in Table 3.

[Table 3]

Example 5. The raw material compound A and the alkyl alcohol were subjected to glycosylation, deacetylation and hydrolysis of the methyl ester in the same manner as in Example 1. In this reaction, α-anomeric form was predominantly synthesized, and the following compounds were obtained. Tetradecyl 5-acetamide-5-deoxy-α-D-
Erythro-L-gluco-2-nonuropyranosylonic acid (compound 19α) hexadecyl 5-acetamide-5-deoxy-α-D-
Erythro-L-gluco-2-nonuropyranosylonic acid (compound 20α)

Example 6. Uridine in which the 2 ', 3'-hydroxyl group is protected by a t-butyldimethylsilyl group and the starting compound A
Was subjected to glycosidation reaction in the same manner as in Example 1 (1).
The obtained mixture of α-anomeric body and β-anomeric body,
After acetylating with acetic anhydride in pyridine,
Both anomers were separated by silica gel chromatography. The separated α-anomer and β-anomer were deacylated by the Zemplen method according to a conventional method, and then desilylated by tetra-n-butylammonium fluoride. Then, the methyl ester was hydrolyzed in the same manner as in Example 1 (3) to obtain the following compound. 5'-O- (5-acetamide-5-deoxy-α-D-
Erythro-L-gluco-2-nonuropyranosylonic acid)-
Uridine (Compound 21α) 5′-O- (5-acetamido-5-deoxy-β-D-
Erythro-L-gluco-2-nonuropyranosylonic acid)-
Uridine (Compound 21β)

Example 7. (1) 1.0 g of Compound 1α was suspended in 100 ml of ethanol, and 121 mg of sodium hydrogen carbonate dissolved in 10 ml of water was added at room temperature. After stirring for 0.5 hour, the reaction solution became transparent and then concentrated to obtain a syrupy crude product. This was dissolved in 100 ml of water, filtered through a microfilter, the filtrate was concentrated to dryness, and sodium (5-cholesten-3β-yl 5-acetamide-5-
Deoxy-α-D-erythro-L-gluco-2-nonuropyranoside) onate (Compound 22α) was obtained as an amorphous powder. Yield: 95% Melting point: 201 −205 ℃ [α] ²⁵ : −14.9 ° (C = 0.2, CH ₃ OH) IR (KBr): 3380, 2930, 1615, 1555, 1460, 1430, 13
78, 1270, 1112, 1072, 1020 cm ^-1 Mass (SIMS): m / z 716 (M + Na) Elemental analysis: As C ₃₈ H ₆₂ NO ₁₀ Na ¹ H-NMR (CD ₃ OD, δ): cholesterol moiety 0.70 (s, 3
H), 0.87 and 0.88 (2d, J = 6.6Hz, 2x3H), 0.93 (d, J = 6.5H
z, 3H), 1.00 (s, 3H), 3.83-3.90 (m, 1H), 5.33-5.39 (m, 1
H); Neu5Ac moiety 2.04 (s, 3H), 3.37 (d, J = 9.6Hz, 1H),
3.52 (dd, J = 1.7, 8.9Hz, 1H), 3.54 (dd, J = 9.6, 9.6Hz, 1
H), 3.58 (dd, J = 1.7, 10.5Hz, 1H), 3.66 (dd, J = 5.2, 11.4
Hz, 1H), 3.81 (dd, J = 9.6,10.5Hz, 1H), 3.84 (dd, J = 2.5, 1
1.4Hz, 1H), 3.88 (ddd, J = 2.5, 5.2,8.9Hz, 1H)

(2) Similarly to sodium (5-cholesten-3β-yl 5-acetamido-5-deoxy-β-D-erythro-, using compound 1β instead of compound 1α.
L-gluco-2-nonuropyranoside) onate (compound 22β) was obtained. Yield: 92% Melting point: 226 − 229 ℃ (α) ²⁵ : −51.8 ° (C = 0.5, CH ₃ OH) IR (KBr): 3400, 2925, 1618, 1550, 1460, 1430, 13
75, 1160, 1063, 1030 cm ^-1 Mass (SIMS): m / z 716 (M + Na) Elemental analysis: As C ₃₈ H ₆₂ NO ₁₀ Na ¹ H-NMR (CD ₃ OD, δ): cholesterol moiety 0.71 (s, 3
H), 0.87 and 0.88 (2d, J = 6.5Hz, 2x3H), 0.93 (d, J = 6.4H
z, 3H), 1.00 (s, 3H), 3.65-3.72 (m, 1H), 5.27-5.32 (m, 1
H); Neu5Ac moiety 1.97 (s, 3H), 3.37 (d, J = 9.3Hz, 1H),
3.39 (dd, J = 0.5, 9.1Hz, 1H), 3.66 (dd, J = 4.7, 11.4Hz, 1
H), 3.77 (ddd, J = 3.0, 4.7, 9.1Hz, 1H), 3.80 (dd, J = 3.0,
11.4Hz, 1H), 3.85 (dd, J = 9.3.9.5Hz, 1H), 3.97 (dd, J =
0.5, 9.8Hz, 1H), 4.03 (dd, J = 9.5,9.8Hz, 1H)

(3) The compounds (compounds 3α to 21β) obtained in Examples 3 to 6 were treated in the same manner as in the above method to obtain the following compounds. 3-O- (sodium 5-acetamide-5-deoxy-
α-D-erythro-L-gluco-2-nonuropyranosylonate) -1,2-di-O-octyl-sn-glycerol (compound 23α) 3-O- (sodium 5-acetamide-5-deoxy-
β-D-erythro-L-gluco-2-nonuropyranosylonate) -1,2-di-O-octyl-sn-glycerol (compound 23β) 3-O- (sodium 5-acetamide-5-deoxy-
α-D-erythro-L-gluco-2-nonuropyranosylonate) -1,2-di-O-decyl-sn-glycerol (compound 24α) 3-O- (sodium 5-acetamide-5-deoxy-
β-D-erythro-L-gluco-2-nonuropyranosylonate) -1,2-di-O-decyl-sn-glycerol (compound 24β) 3-O- (sodium 5-acetamide-5-deoxy-
α-D-erythro-L-gluco-2-nonuropyranosylonate) -1,2-di-O-dodecyl-sn-glycerol (compound 25α) 3-O- (sodium 5-acetamide-5-deoxy-
β-D-erythro-L-gluco-2-nonuropyranosylonate) -1,2-di-O-dodecyl-sn-glycerol (compound 25β) 3-O- (sodium 5-acetamide-5-deoxy-
α-D-erythro-L-gluco-2-nonuropyranosylonate) -1,2-di-O-tetradecyl-sn-glycerol (compound 26α) 3-O- (sodium 5-acetamide-5-deoxy-
β-D-erythro-L-gluco-2-nonuropyranosylonate) -1,2-di-O-tetradecyl-sn-glycerol (compound 26β) 3-O- (sodium 5-acetamide-5-deoxy-
α-D-erythro-L-gluco-2-nonuropyranosylonate) -1,2-di-O-hexadecyl-sn-glycerol (compound 27α) 3-O- (sodium 5-acetamide-5-deoxy-
β-D-erythro-L-gluco-2-nonuropyranosylonate) -1,2-di-O-hexadecyl-sn-glycerol (compound 27β) 3-O- (sodium 5-acetamide-5-deoxy-
α-D-erythro-L-gluco-2-nonuropyranosylonate) -1,2-di-O-octadecyl-sn-glycerol (Compound 28α) 3-O- (sodium 5-acetamide-5-deoxy-
β-D-erythro-L-gluco-2-nonuropyranosylonate) -1,2-di-O-octadecyl-sn-glycerol (compound 28β) 1-O- (sodium 5-acetamide-5-deoxy-
α-D-erythro-L-gluco-2-nonuropyranosylonate) -2,3-di-O-tetradecyl-sn-glycerol (Compound 29α) 1-O- (sodium 5-acetamide-5-deoxy-
β-D-erythro-L-gluco-2-nonuropyranosylonate) -2,3-di-O-tetradecyl-sn-glycerol (compound 29β) 3-O- (sodium 5-acetamide-5-deoxy-
α-D-erythro-L-gluco-2-nonuropyranosylonate) -1,2-di-O-tetradecyl-rac-glycerol (compound 30α) 3-O- (sodium 5-acetamide-5-deoxy-
β-D-erythro-L-gluco-2-nonuropyranosylonate) -1,2-di-O-tetradecyl-rac-glycerol (compound 30β) 3-O- (sodium 5-acetamide-5-deoxy-
α-D-erythro-L-gluco-2-nonuropyranosylonate) -1-O-dodecyl-2-O-tetradecyl-
sn-glycerol (compound 31α) 3-O- (sodium 5-acetamido-5-deoxy-
β-D-erythro-L-gluco-2-nonuropyranosylonate) -1-O-dodecyl-2-O-tetradecyl-
sn-glycerol (compound 31β) 3-O- (sodium 5-acetamide-5-deoxy-
α-D-erythro-L-gluco-2-nonuropyranosylonate) -2-O-dodecyl-1-O-tetradecyl-
Sn-glycerol (compound 32α) 3-O- (sodium 5-acetamide-5-deoxy-
β-D-erythro-L-gluco-2-nonuropyranosylonate) -2-O-dodecyl-1-O-tetradecyl-
sn-glycerol (compound 32β) 1-O- (sodium 5-acetamide-5-deoxy-
α-D-erythro-L-gluco-2-nonuropyranosylonate) -3-O-dodecyl-sn-glycerol (compound 33α) 1-O- (sodium 5-acetamide-5-deoxy-
β-D-erythro-L-gluco-2-nonuropyranosylonic acid) -3-O-dodecyl-sn-glycerol (compound 33β) 1-O- (sodium 5-acetamide-5-deoxy-
α-D-erythro-L-gluco-2-nonuropyranosylonate) -3-O-tetradecyl-sn-glycerol (compound 34α) 1-O- (sodium 5-acetamide-5-deoxy-
β-D-erythro-L-gluco-2-nonuropyranosylonate) -3-O-tetradecyl-sn-glycerol (compound 34β) 1-O- (sodium 5-acetamide-5-deoxy-
α-D-erythro-L-gluco-2-nonuropyranosylonate) -3-O-hexadecyl-sn-glycerol (compound 35α) 1-O- (sodium 5-acetamide-5-deoxy-
β-D-erythro-L-gluco-2-nonuropyranosylonate) -3-O-hexadecyl-sn-glycerol (compound 35β) 1-O- (sodium 5-acetamide-5-deoxy-
α-D-erythro-L-gluco-2-nonuropyranosylonate) -3-O-octadecyl-sn-glycerol (compound 36α) 1-O- (sodium 5-acetamide-5-deoxy-
β-D-erythro-L-gluco-2-nonuropyranosylonate) -3-O-octadecyl-sn-glycerol (compound 36β) 1-O- (sodium 5-acetamide-5-deoxy-
α-D-erythro-L-gluco-2-nonuropyranosylonate) -3-O-icosyl-sn-glycerol (compound 37α) 1-O- (sodium 5-acetamide-5-deoxy-
β-D-erythro-L-gluco-2-nonuropyranosylonate) -3-O-icosyl-sn-glycerol (compound 37β) 1-O- (sodium 5-acetamide-5-deoxy-
α-D-erythro-L-gluco-2-nonuropyranosylonate) -3-O-docosyl-sn-glycerol (compound 38α) 1-O- (sodium 5-acetamide-5-deoxy-
β-D-erythro-L-gluco-2-nonuropyranosylonate) -3-O-docosyl-sn-glycerol (compound 38β) sodium (tetradecyl 5-acetamido-5-deoxy-α-D-erythro-L -Gluco-2-nonuropyranoside) onate (compound 39α) sodium (hexadecyl 5-acetamido-5-deoxy-α-D-erythro-L-gluco-2-nonuropyranoside) onate (compound 40α) 5'-O- [sodium ( 5-acetamide-5-deoxy-α-D-erythro-L-gluco-2-nonuropyranosyl) onate] -uridine (compound 41α) 5′-O- [sodium (5-acetamide-5-deoxy-β-D- Erythro-L-gluco-2-nonuropyranosyl) onate] -uridine (Compound 41β)

Example 8. Raw material compound A and 1,2-di-O
-Acyl-sn-glycerol was subjected to glycosidation reaction in the same manner as in Example 1 (1). Then, the mixture was treated with acetic anhydride in pyridine for acetylation, and separated into α-anomer and β-anomer by silica gel chromatography to obtain the following compounds. 3-O- [methyl 5-acetamide-3,4,7,8,9
-Penta-O-acetyl-5-deoxy-α-D-erythro-L-gluco-2-nonuropyranosyl) oate]
-1,2-di-O-dodecanoyl-sn-glycerol (Compound 42α) 3-O- [methyl 5-acetamide-3,4,7,8,
9-penta-O-acetyl-5-deoxy-β-D-erythro-L-gluco-2-nonuropyranosyl) oate] -1,2-di-O-dodecanoyl-sn-glycerol (Compound 42β) 3-O- [Methyl 5-acetamide-3,4,7,8,9
-Penta-O-acetyl-5-deoxy-α-D-erythro-L-gluco-2-nonuropyranosyl) oate]
-1,2-Di-O-tetradecanoyl-sn-glycerol (compound 43α) 3-O- [methyl 5-acetamide-3,4,7,8,9
-Penta-O-acetyl-5-deoxy-β-D-erythro-L-gluco-2-nonuropyranosyl) oate]
-1,2-Di-O-tetradecanoyl-sn-glycerol (compound 43β) 3-O- [methyl 5-acetamide-3,4,7,8,9
-Penta-O-acetyl-5-deoxy-α-D-erythro-L-gluco-2-nonuropyranosyl) oate]
-1,2-Di-O-hexadecanoyl-sn-glycerol (compound 44α) 3-O- [methyl 5-acetamide-3,4,7,8,9
-Penta-O-acetyl-5-deoxy-β-D-erythro-L-gluco-2-nonuropyranosyl) oate]
-1,2-Di-O-hexadecanoyl-sn-glycerol (Compound 44β)

Physical properties of the above compounds obtained in Examples 5 to 8 are shown in Tables 4 to 7.

[Table 4]

[Table 5]

[Table 6]

[Table 7]

Example 9. 500 mg of methyl 5-acetamide-4,7,8,9-tetra-O-acetyl-2,3
-Anhydro-5-deoxy-β-D-erythro-L
-Gluco-2-nonuropyranosonate, 470 mg of 5
-Cholesten-3β-ol, 500 mg of anhydrous disodium hydrogen phosphate and 10 ml of dry 1,2-dichloroethane were mixed and stirred. To this was added 0.2 ml of trimethylsilyl trifluoromethanesulfonate at 5 ° C under an argon atmosphere. After stirring for 12 minutes, the mixture was diluted with benzene and washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over sodium sulfate, the crude product obtained by evaporation to dryness under reduced pressure was purified on a silica gel column to give methyl (5-cholesten-3β-yl 5-acetamide-4,7,8,9- Tetra-O-acetyl-5-
Deoxy-β-D-erythro-L-gluco-2-nonuropyranoside) onate was obtained in a yield of 37%. Then
Deacetylation and hydrolysis of the methyl ester were carried out in the same manner as in Examples 1 (2) and (3) to obtain compound 1β. The physical property values were the same as those obtained in Example 1.

Example 10 0.350 mg of 7-hydroxy-4-methylcoumarin sodium salt and 500 mg of the starting compound A were stirred in 5 ml of dry dimethylformamide under an argon atmosphere at room temperature for 1 hour. After the solvent was distilled off under reduced pressure, water and chloroform were added to the residue for partition extraction. The separated chloroform layer was washed with water, saturated saline and dry sodium sulfate and then concentrated. After purification with a silica gel column, hexane-ethyl acetate was added to crystallize and methyl (4-methylcoumarin-7yl5-acetamide-4,7,8,9-tetra-O-acetyl-5-deoxy-α was used. -D-erythro-L-gluco-2-nonulopyranoside) onate was obtained as a white powder. This was deacetylated as in Example 1 (2), then Example 1
After hydrolyzing the methyl ester in the same manner as (3),
It is neutralized with an acidic resin and 4-methylcoumarin-7yl 5-acetamido-5-deoxy-α-D-erythro-L-gluco-2-nonuropyranoside acid (4MU-3β-OH-
NeuAc) was obtained. Yield: 90% Melting point: 145-147 ° C [α] ²⁵ : + 43.2 ° (C = 1.1, H ₂ O) IR (KBr): 3400, 1720, 1700, 1603, 1552, 1380, 13
60, 1275, 1068, 1015 cm ^-1 Mass (SIMS): m / z 484 (M + H), 308 (M-4MU) Elemental analysis: As C ₂₁ H ₂₅ NO ₁₂

Example 11. (1) Methyl 5-acetamide-4,7,8,9-tetra-O-acetyl-2,3,5-trideoxy-D-glycero-D-galacto-2-nonuropyranosonate (25
To a dichloromethane solution (4 ml) of 0 mg) was added dimethyldioxirane (1.2 mol) dissolved in acetone.
Added at ° C. The reaction mixture was stirred at 0 ° C. for 1 hour and then at room temperature for 1 hour. Concentration under reduced pressure gave a solid, which was recrystallized from hexane-ethyl acetate to give 25
2 mg of methyl 5-acetamide-4,7,8,9-tetra-O-acetyl-2,3-anhydro-5-deoxy-β-D-erythro-L-gluco-2-nonuropyranosonate Obtained as white crystals. According to the present method using a dialkyldioxirane such as dimethyldioxirane, the target substance can be obtained in high yield and the purification step by chromatography or the like can be omitted.

(2) 1,2-of the above product (7.5 g)
To the dichloroethane solution (150 ml) was added 30% hydrobromic acid acetic acid solution (3.8 ml) at room temperature. 1 reaction solution
After stirring for 0 minutes, the mixture was concentrated. The obtained residue was dissolved in ethyl acetate and washed with sodium hydrogen carbonate and saturated brine. After drying over sodium sulfate, evaporate to dryness,
8.7 g of methyl 5-acetamide-4,7,8,9-tetra-O-acetyl-2-bromo-2,5-dideoxy-β-D-erythro-L-gluco-2-nonuropyranosonate Got Any of the compounds obtained in (1) and (2) above can be used as a glycosidation reaction donor for producing the compound of the present invention.

[0035]

The chemical and enzymatic stability and physiological activity of the novel sialic acid derivative of the present invention will be described below. (1) Chemical stability The sialic acid derivative of the present invention having a hydroxyl group at the 3-position (compound 2
The chemical stability of α and 2β) and a known compound having no hydroxyl group was compared. As a target compound for comparison with the compound 2α of the present invention, methyl 6-O- (5-acetamide-
3,5-dideoxy-α-D-glycero-D-galacto-nonuropyranosylonate) -α-D-glucopyranoside, and methyl 6-O-as the target compound of compound 2β
(5-acetamide-3,5-dideoxy-β-D-glycero-D-galacto-nonulopyranosylonate) -α-
D-glucopyranoside was used. 250 μg / ml of each test compound solution (water or 0.01N sulfuric acid) was placed in a water bath at 80 ° C., 5 μl was taken over time, separated by HPLC using a strongly acidic resin column, and detected by UV 205 nm measurement. The amount of sialic acid produced was determined. An example of the result
And shown in FIG.

[Figure 1]

[Fig. 2]

(2) Enzymatic Stability Sialidase is known as an enzyme that hydrolyzes a sialic acid glycoside compound such as ganglioside. There 3
The stability of the compound of the present invention containing sialic acid having a hydroxyl group at sialidase was examined. Specifically, 4M
405n of 4-MU (4-methylumbelliferone) produced by allowing sialidase to act on U-3β-OH-NeuAc and 4MU-NeuAc whose 3rd position is hydrogen
Stability to sialidase was analyzed by measuring the fluorescence value at m. Since sialidase has considerably different substrate specificity depending on its origin, a test was conducted using 3 types of sialidase derived from bacteria and 4 types of sialidase derived from bovine brain known to use most of human gangliosides in human brain as substrates. went. Table 8 shows an example of the results.

[Table 8]

(3) Nerve growth promoting action Neuro2a cells (mouse neuroblastoma) purchased from ATCC were cultured in a medium containing 10% (V / V) fetal calf serum in Dulbecco's modified MEM. Neuro2a cells dispersed by trypsin treatment were diluted with the above medium to 2 × 10 ³ cells / ml, and the diluted 2
1 ml aliquots were dispensed to a 4-well plate and cultured at 37 ° C in 5% carbon dioxide-95% air for 2 days. The medium of the cultured cells was removed by suction, 0.9 ml of a complete serum-free medium and 0.1 ml of an aqueous solution of the test compound were added, and the cells were cultured overnight under the same conditions. After culturing, five photographs were taken per well using a phase contrast microscope, and the ratio of cells having protrusions of 50 μm or more was calculated. The ratio of cells having protrusions in the control (control) was set to 1, and the nerve growth promoting action (mean ± standard error) of the test compound was expressed as a ratio. In addition, the measurement result was judged by T test, and a significant difference from the control was obtained. (*: P <0.05, **: P <0.01, *
**: P <0.005)

Table 9 shows an example of the results.

[Table 9]

Further, by comparing the nerve growth promoting action of the compound (target compound) in which the 3-position of sialic acid of compound 13α is hydrogen, the difference due to the presence or absence of hydroxyl group at the 3-position was examined. An example of the results is shown in Table 10.

[Table 10]

In general, glycosides of sialic acid are chemically unstable and difficult to handle, and particularly natural α-glycosides are easily hydrolyzed chemically and enzymatically (sialidase). On the other hand, the compound of the present invention containing sialic acid having a hydroxyl group at the 3-position is an extremely stable compound chemically and enzymatically. As shown in FIG. 1 and FIG. 2, α-glycoside and β-glycoside, which normally have sialic acid as a constituent, are hydrolyzed with the passage of time. The compound of the present invention is chemically very stable and hardly decomposed even after 6 hours.

As shown in Table 8, 4MU-3β-OH-NeuAc containing 3-hydroxysialic acid was hardly hydrolyzed by sialidases such as sialidase derived from bacteria and sialidase derived from bovine brain, and 4MU of sialidase. It did not inhibit the hydrolytic action on NeuAc. Thus, it was revealed that the compound of the present invention containing sialic acid having a hydroxyl group at the 3-position is very stable enzymatically.

Up to now, various known sialic acid derivatives have been known to have pharmacological actions such as a neuropathic disease treating action, a cancer metastasis inhibiting action, an anti-inflammatory action and a demyelinating disease treating action. Also, as shown in Table 10, it was revealed that the sialic acid derivative of the present invention in which the 3-position is substituted with a hydroxyl group also exhibits the same nerve growth action as the target compound in which the 3-position is hydrogen. Moreover, 3-hydroxy sialic acid that is substantially the same conformation as the sialic acid was confirmed from the coupling constants in the ¹ H-NMR spectrum in the acetyl protecting body, which the present invention the sialic acid derivative 3-position is a hydroxyl group Affirmatively suggests the above test results showing that the compound has physiological activity similar to that of a normal sialic acid-containing compound.

As described above, since the sialic acid derivative of the present invention having a hydroxyl group at the 3-position has the same physiological activity as that of the conventional physiologically active sialic acid derivative, dementia, Alzheimer's syndrome, facial nerve palsy, and sciatic nerve palsy. , Spinal muscular atrophy, muscular dystrophy, myasthenia gravis, multiple sclerosis,
Amyotrophic lateral sclerosis, acute disseminated encephalomyelitis, Guillain-Barre syndrome (polyneuropathy), post-vaccination encephalitis, encephalitis sequelae, sequelae of head trauma, cerebral ischemic disease, cerebral infarction, sequelae of cerebral hemorrhage, Compounds useful as pharmaceuticals such as therapeutic agents for peripheral / central nervous system diseases such as autonomic imbalance, diabetic neuropathy, and SMON, or cancer metastasis inhibitors, anti-inflammatory agents, demyelinating disease therapeutic agents, antirheumatic agents, etc. Is. In addition, since the compound of the present invention is chemically stable, it can be stored for a long time, is easy to handle, and is not metabolized by sialidase. And has very high utility.

[Brief description of drawings]

FIG. 1 is a diagram showing test results comparing the chemical stability of a sialic acid derivative of the present invention having a hydroxyl group at the 3-position (α-anomer form) with a compound having no hydroxyl group.

FIG. 2 is a view showing the test results comparing the chemical stability of the β-anomer of the sialic acid derivative of the present invention and the compound having no hydroxyl group at the 3-position, as in FIG. 1.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location C07H 7/02 7822-4C // C07J 9/00 7180-4C

Claims (1)

[Claims] 1. A sialic acid derivative containing a group represented by the following general formula (I) and a pharmaceutically acceptable salt thereof. [Chemical 1] [In the formula, X represents hydrogen, lower alkyl or benzyl, Y represents hydrogen or an acetyl group, and Ac represents an acetyl group. ]