JPH092957A - Therapeutic and preventing agent for peripheral neuropathy - Google Patents

Abstract

(57) [Summary] [Constitution] The following general formula (I) R ¹ : steroid compound residue, R ² : H, alkyl group,
R ³ : an alkyl group, embedded image ^{(R 6, R 7: H} , alkyl group or the like, l: Less than six integer)
Etc., R ^4: H, an acyl ^{group, R 5: R 14 O- (} R 14: H,
Acyl ^{group), R 15 NH- (R 15} : acyl group, etc.), X:
A therapeutic or prophylactic agent for peripheral neuropathy, which comprises an sialic acid derivative represented by O or S, a salt thereof, a hydrate thereof or a solvate thereof as an active ingredient. [Effect] Since the sialic acid derivative of the present application has a protective action against a decrease in peripheral nerve conduction velocity in mammals, it can be used for the treatment of neuropathy.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a therapeutic or prophylactic agent for peripheral neuropathy, which comprises a sialic acid derivative having a specific amide bond, a salt thereof, a hydrate thereof or a solvate thereof as an active ingredient. It is about.

[0002]

BACKGROUND OF THE INVENTION In the treatment of neurological diseases, that is, central nervous system diseases and peripheral nervous system diseases, research and application of therapeutic agents for central nervous system diseases have been actively conducted. In comparison, there are relatively few types of therapeutic agents for peripheral nervous system diseases, especially for peripheral neuropathy. Decreased nerve conduction velocity has been reported in peripheral neuropathy (Disorders of Voluntary M
uschle, Churchill / Livingston
e, 973-1002 (1974); J Neuro.
1, neurosur, psych. , 58, 274-
283 (1995)), it is considered that protecting the decrease in nerve conduction velocity due to the disorder suggests its efficacy against peripheral neuropathy. At present, ganglioside (trade name: JP-A-52-34912), which is a natural glycolipid, mecobalamin (generic name), which is one of vitamins, and aldose reductase inhibitor (JP-A-60-156387). Is clinically used, but its effect is not yet sufficient, and a better therapeutic drug is expected to appear.

[0003]

Means for Solving the Problems As a result of various studies aimed at providing a therapeutic drug for peripheral nervous system disorders, the present inventors have found that a sialic acid derivative having a specific amide bond, a salt thereof, Their hydrates or solvates
The inventors have found that it can be a drug for improving peripheral nervous system disorders such as diabetic neuropathy, and completed the present invention.
That is, the gist of the present invention is the following general formula (I)

[0004]

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[In the above general formula (I), R ¹ represents a steroid compound residue, R ² represents a hydrogen atom or a C _{1 to} C ₄ alkyl group, and R ³ represents a C _{1 to} C ₁₅ alkyl group. ,

[0006]

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In the formula, R⁶And R⁷Are independent
Hydrogen atom, halogen atom, C₁ ~ C _Four An alkyl group of
Hydroxyl group, R⁸O- (wherein R⁸Is C₁ ~ C_Four of
Alkyl group, phenyl group or phenyl- (C₁ ~ C
_Three ) Represents an alkyl group), a nitro group, an amino group, C₁ ~
C_Four Alkylamino group of C_Two ~ C₈ Dialkylami
No group or

[0008]

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(Where R is⁹Is a hydrogen atom, C₁ ~ C_Four A
Alkyl group, phenyl group or phenyl- (C₁ ~ C_Three )
Represents an alkyl group), and l represents an integer of 0 to 6
S}, R^TenO (CH_Two )_m-(Where R^TenIs a hydrogen atom;
C₁ ~ C_Four An alkyl group of C₁ ~ C _Four Alkyl group of
Rogen atom, hydroxyl group, nitro group, amino group and
And one or more substituents selected from carboxyl groups
Optionally a phenyl group; or C₁ ~ C_Four The alkyl of
Group, halogen atom, hydroxyl group, nitro group, amino
One or more substituents selected from a group and a carboxyl group
Optionally having phenyl- (C₁ ~ C_Three ) Alkyl group
Represents, and m represents an integer of 2 to 6) or

[0010]

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[In the formula, R ¹¹ is a hydrogen atom or C _{1 to} C ₄
R ¹² represents a hydrogen atom; a C _{1 to} C ₄ alkyl group; a C _{2 to} C ₇ acyl group; a C _{1 to} C ₄ alkylsulfonyl group; a C _{1 to} C ₄ alkyl group, halogen A phenylsulfonyl group optionally having one or more substituents selected from an atom, a hydroxyl group, a nitro group, an amino group and a carboxyl group; or

[0012]

[Chemical 21]

(Wherein R ¹³ represents a C ₁ -C ₄ alkyl group, a phenyl group or a phenyl- (C ₁ -C ₃ ) alkyl group), and n represents an integer of 2-6} R ⁴ represents a hydrogen atom or a C _{2 to} C ₇ acyl group, R ⁵ represents R ¹⁴ O— (wherein R ¹⁴ represents a hydrogen atom or C ₂
An acyl group -C ₇₎ or R ¹⁵ NH- {in the formula, R
¹⁵ acyl group C ₂ -C _7;

[0014]

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(Wherein R ¹⁶ represents a hydrogen atom, a C _{1 to} C ₆ alkyl group, a phenyl group or a phenyl (C _{1 to} C ₃ ) alkyl group, and p represents an integer of 0 to 4); C _{1 to} C
₄ alkyl group, halogen atom, hydroxyl group, nitro group, amino group and C _{7 to} C ₁₁ aroyl group optionally having one or more substituents selected from carboxyl group; C _{1 to} C ₄ alkyl Group, a halogen atom, a hydroxyl group, a nitro group, an amino group and a phenyl (C ₁ -C ₃ ) alkylcarbonyl group which may have one or more substituents selected from a carboxyl group; C ₁ -C ₄ alkylsulfonyl Group; or a C ₁ -C ₄ alkyl group, a halogen atom, a hydroxyl group, a nitro group, an amino group and a phenylsulfonyl group which may have one or more substituents selected from a carboxyl group}. X represents an oxygen atom or a sulfur atom], and a therapeutic or prophylactic agent for peripheral neuropathy containing a sialic acid derivative, a salt thereof, a hydrate thereof or a solvate thereof as an active ingredient.

The present invention will be described in detail below. Departure
The clear drug is a sialic acid derivative represented by the general formula (I).
Body, its salts, their hydrates or their solvates
Use as an active ingredient. C defined by the general formula (I)₁ ~
C_Four Examples of the alkyl group include methyl group, ethyl group, n-
Propyl group, i-propyl group, n-butyl group, t-butyl
And a C group₁ ~ C_FifteenAs the alkyl group of
Methyl group, ethyl group, n-propyl group, i-propyl
Group, n-butyl group, t-butyl group, n-pentyl group, n
-Hexyl group, n-heptyl group, n-octyl group, n-
Decyl group, n-pentadecyl group and the like, and C₁~ C
₆Examples of the alkyl group include₁~ C _FifteenArchi
C in the radical₁~ C₆One. Halogen source
Examples of the child include a fluorine atom, a chlorine atom, and a bromine atom.
Phenyl- (C₁ ~ C_Three ) Benzo as an alkyl group
Examples thereof include a dil group and a phenethyl group. C_Two ~ C₇ A
Examples of silyl groups include acetyl group, propionyl group, butyryl
Group, valeryl group, benzoyl group, etc., and C₁ ~ C
_Four Methylsulfonyl as the alkylsulfonyl group of
Group, ethylsulfonyl group, n-propylsulfonyl group,
Examples thereof include n-butylsulfonyl group. Also, C₁ ~
C_Four The alkylamino group of is methylamino group, ethyl
Luamino group, butylamino group and the like, and C_Two ~ C₈ 
Examples of the dialkylamino group include dimethylamino group and diamine
Examples thereof include an ethylamino group and a dibutylamino group. C
₇~ C₁₁Examples of the aroyl group include
Group, naphthoyl group and the like, phenyl (C₁~ C
_Three) Alkylcarbonyl group is benzylcarbonyl
Group, phenylethylcarbonyl group, phenylpropylcarbonyl
Examples thereof include a rubonyl group. R in the formula (I)¹ Fixed by
Specific examples of the steroid compound residue that is meant include:
Examples include groups represented by the following formula.

[0017]

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(The broken line represents no bond or single bond.)
(The configuration of 3-position of the steroid skeleton includes α-form and β-form.) Preferred R ¹ is

[0019]

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And the like. Further, the groups not specifically described in the above groups are selected from the above-mentioned atoms and groups in any combination or in accordance with the commonly known common sense. R ₂ is preferably a hydrogen atom or a methyl group, and most preferably a hydrogen atom. R ³ is C _{1 to} C
₈ alkyl groups,

[0021]

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(In the formula, R ⁶ and R ⁷ are each independently a hydrogen atom, a halogen atom or

[0023]

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(In the formula, R⁹Is a hydrogen atom or C₁~ C_Four
Represents an alkyl group), and l represents an integer of 0 to 3.
S}, R^TenO (CH_Two)_m-(Where R^TenIs a hydrogen atom,
C₁~ C _FourAlkyl group, phenyl group or phenyl
(C₁~ C_Three) Represents an alkyl group, m is an integer of 2 to 4
Represent) or

[0025]

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[In the formula, R ¹¹ represents a hydrogen atom, R ¹² represents a hydrogen atom, a C _{2 to} C ₇ acyl group, a C _{1 to} C ₄ alkylsulfonyl group, or

[0027]

Embedded image

(Wherein R ¹³ represents a phenyl (C ₁ -C ₃ ) alkyl group), n represents an integer of 2-4}, and a C ₁ -C ₈ alkyl group or

[0029]

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(Wherein l represents an integer of 0 to 3) is more preferable, and a C _{1 to} C ₃ alkyl group is most preferable. R
₄ is preferably a hydrogen atom or an acetyl group, and most preferably a hydrogen atom. R ⁵ is R ¹⁴ O— (in the formula, R 5
¹⁴ represents a hydrogen atom or an acetyl group) or R ¹⁵ NH
-{Wherein R ¹⁵ is a C ₂ -C ₅ acyl group,

[0031]

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(In the formula, R ¹⁶ represents a hydrogen atom, a C ₁ -C ₄ alkyl group or a phenyl (C ₁ -C ₃ ) alkyl group, and p represents an integer of 0-4), C ₇ -C ₁₁ Aroyl group, a C ₁ -C ₃ alkylsulfonyl group or a phenylsulfonyl group)} is preferred, and R ¹⁴ O— (in the formula,
R ¹⁴ represents a hydrogen atom) or R ¹⁵ NH- {in the formula, R ¹⁵
Acyl group C ₂ -C _5,

[0033]

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(Wherein R ¹⁶ represents a hydrogen atom and p represents 1)} is more preferable, and R ¹⁵ NH— (in the formula, R ¹⁵ represents an acetyl group) is most preferable. Most preferably, X is an oxygen atom. The most preferable compound is
3α- [N- (3-deoxy-2-O-methyl-α-D
-Glycero-D-galacto-2-nonulopyranosonyl) amino] cholestane (Compound No. 367 of Table-5)
Α-form), 3α- [N- (3-deoxy-2-O-methyl-α-D-glycero-D-galacto-2-nonulopyranosonyl) amino] -5-cholestene (Table 7 Compound α of Compound No. 507), 3α- [N- (5-acetamido-3,5-dideoxy-2-O-methyl-α-D-
Glycero-D-galacto-2-nonulopyranosonyl)
Amino] cholestane (α of compound No. 4 in Table-1)
Body), 3α- [N- (5-acetamido-3,5-dideoxy-2-O-phenyl-α-D-glycero-D-galacto-2-nonulopyranosonyl) amino] cholestane (Table-1) Α-form of compound No. 19) of 3), 3α- [N-
(5-acetamido-3,5-dideoxy-2-O-benzyl-α-D-glycero-D-galacto-2-nonulopyranosonyl) amino] cholestane (α-form of compound No. 21 in Table-1) ) 3α- [N- (5-acetamido-3,5-dideoxy-2-O-methyl-α-D-glycero-D-galacto-2-nonulopyranosonyl) amino] -5-cholestene (Table -1 compound No. 234 α-), 3α- [N- (5-acetamido-3,5-dideoxy-2-S-phenyl-2-thio-α-D-glycero-D-galacto-2- Nonuropyranosonyl) amino] cholestane (α of compound No. 260 in Table 2)
Body), 3α- [N- (5-acetamido-3,5-dideoxy-2-O-methyl-β-D-glycero-D-galacto-2-nonulopyranosonyl) amino] cholestane (Table-3 Α-form of compound No. 268), and 3α-
[N- (5-acetamido-3,5-dideoxy-2-
O-benzyl-β-D-glycero-D-galact-2-
Nonuropyranosonyl) amino] cholestane (α-form of compound No. 281 in Table 3).

Specific examples of peripheral neuropathy include inflammatory or allergic neuropathy (Guillain-Barre syndrome, viral neuropathy such as AIDS, chronic relapsing neuropathy, multiple neuropathy, clofkase syndrome, collagen disease or vasculitis. Neuropathy associated with it, neuropathy associated with malignant tumor, abnormal glybrinemia etc.), toxic neuropathy (due to organic solvent,
Drugs such as anti-cancer agents, heavy metals such as mercury, bacterial toxins such as botulinum, etc.), metabolic neuropathy (diabetic neuropathy, alcoholic neuropathy, neuropathy due to uremia, etc.), hereditary neuropathy, facial nerves Paralysis, sciatic nerve palsy, spinal muscular atrophy, muscular dystrophy, myasthenia gravis, Shy-Drager syndrome, SMON, rheumatism, dyskinesia and the like can be mentioned. Specific examples of preferred compounds represented by the above general formula (I) are shown below.
1, 2, 3, 4, 5, 6, 7 and 8.

[Table 1]

[0036]

[Table 2]

[0037]

[Table 3]

[0038]

[Table 4]

[0039]

[Table 5]

[0040]

[Table 6]

[0041]

[Table 7]

[0042]

[Table 8]

[0043]

[Table 9]

[0044]

[Table 10]

[0045]

[Table 11]

[0046]

[Table 12]

[0047]

[Table 13]

[0048]

[Table 14]

[0049]

[Table 15]

[0050]

[Table 16]

[0051]

[Table 17]

[0052]

[Table 18]

[0053]

[Table 19]

[0054]

[Table 20]

[0055]

[Table 21]

[0056]

[Table 22]

[0057]

[Table 23]

[0058]

[Table 24]

[0059]

[Table 25]

[0060]

[Table 26]

[0061]

[Table 27]

[0062]

[Table 28]

[0063]

[Table 29]

[0064]

[Table 30]

[0065]

[Table 31]

[0066]

[Table 32]

[0067]

[Table 33]

[0068]

[Table 34]

[0069]

[Table 35]

[0070]

[Table 36]

[0071]

[Table 37]

[0072]

[Table 38]

[0073]

[Table 39]

[0074]

[Table 40]

[0075]

[Table 41]

[0076]

[Table 42]

[0077]

[Table 43]

[0078]

[Table 44]

[0079]

[Table 45]

[0080]

[Table 46]

[0081]

[Table 47]

[0082]

[Table 48]

[0083]

[Table 49]

[0084]

[Table 50]

[0085]

[Table 51]

[0086]

[Table 52]

[0087]

[Table 53]

[0088]

[Table 54]

[0089]

[Table 55]

[0090]

[Table 56]

[0091]

[Table 57]

[0092]

[Table 58]

[0093]

[Table 59]

[0094]

[Table 60]

[0095]

[Table 61]

As the salt for the carboxyl group of the compound represented by the general formula (I), a pharmaceutically acceptable salt is preferable, for example, a salt with an alkali metal such as sodium or potassium; ammonia, tris (hydroxymethyl). Aminomethane, N, N-bis (hydroxyethyl)
Examples thereof include salts with organic amines such as piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine and L-glucamine.

As the salt for the amino group of the compound represented by the above general formula (I), pharmaceutically acceptable salts are preferable, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, Inorganic acid salts such as phosphates, and oxalates,
Maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate,
Organic acid salts such as camphor sulfonate may be mentioned.

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.
Examples of the solvent of the solvate include methanol, ethanol, isopropanol, acetone, ethyl acetate, methylene chloride and the like. The compound of the general formula (I) has an asymmetric carbon atom, and many isomers exist. These isomers are also included in the scope of the present invention.

Next, a method for producing the sialic acid derivative will be described. The compound can be produced, for example, by the following method. 1. R ⁵ is

[0100]

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In the case of (a) A method for producing a compound in which the 2-position of sialic acid is an α isomer (i) When X is an oxygen atom

[0102]

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[0103]

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(In the above formula, R ¹ , R ² and R ³ are as defined in the above general formula (I), and R ⁴ ′ is C ₂ to
Represents a C ₇ acyl group. That is, first, compound (II) is reacted with compound (III) [(1) step] to give compound (IV), which is chlorinated [(2) step], compound (V), and then compound The compound (I-α-
a) is produced, and then this is reacted with an alkoxide such as sodium methoxide to deacylate [step (4)].
Compound (I-α-b) is produced. The compound (I-α
-A) can also be manufactured as follows.

[0105]

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(In the above formula, R ¹ , R ² , R ³ and R ⁴ ′ are as defined above, and M represents an alkali metal or quaternary ammonium ion.) The compound (I-α-a) is produced by reacting (VII) with [(5) step]. The compound (I-α-a) can also be produced as follows.

[0107]

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[0108]

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[0109] (In the above ^{formulas, R 1, R 2, R} 3, R 4 ' are as previously defined.) That first compound (VIII) and chlorinated [(6) step], the compound (IX) And then reacting it with compound (VI) [(7) step] to give compound (X-α), and then reducing this [(8) step] to give compound (XI-α), and then Compound (III) is reacted [step (9)] to produce compound (I-α-a).

The step (1) is carried out in a solvent such as tetrahydrofuran, dioxane, acetonitrile, dichloromethane, dichloroethane or the like in an amount of 0.9 to 10 equivalents, preferably 1.0.
To 5.0 equivalents of chlorocarbonic acid esters such as ethyl chlorocarbonate and isobutyl chlorocarbonate and 0.9 to 10 equivalents, preferably 1.0 to 5.0 equivalents of tertiary amines such as N-methylmorpholine and triethylamine. -50 ° C to 50
C, preferably in the temperature range of -20 ℃ ~ room temperature,
After the corresponding mixed acid anhydride of the compound (II), 0.9 to 10 equivalents, preferably 1.0 to 5.0 equivalents of the compound (III) or a salt such as a hydrochloride of the compound (III) is subsequently obtained. It is carried out in the temperature range of −50 ° C. to 50 ° C., preferably −20 ° C. to room temperature, using the same amount of the tertiary amine. Alternatively, in a solvent such as tetrahydrofuran, dioxane, acetonitrile, dichloromethane, dichloroethane, etc., 0.9-10
An equivalent amount, preferably 1.0 to 5.0 equivalents of chlorides such as thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, and the like.
9 to 20 equivalents, preferably 1.0 to 10 equivalents of a base such as pyridine are added at -50 ° C to 50 ° C, preferably -20 ° C.
After reacting in the temperature range of from room temperature to the corresponding acid chloride of compound (II), 0.9 to 10 equivalents, preferably 1.0 to 5.0 equivalents of compound (III) or compound (II
Using a salt such as the hydrochloride salt of I) and 0.9 to 100 equivalents, preferably 1.0 to 50 equivalents of a tertiary amine, -50 ° C to
It is carried out at a temperature of 50 ° C, preferably -20 ° C to room temperature. At this time, the reaction operation and the reaction are more preferably carried out under anhydrous conditions.

In step (2), acetyl chloride, propionyl chloride, butyryl chloride, valeryl chloride,
-20 ° C to 50 in acid chloride such as benzoyl chloride
C., preferably in the temperature range of 0.degree. C. to room temperature. At this time, it is preferable to saturate the reaction solution with hydrogen chloride gas because the yield is improved. Further, the reaction operation and the reaction are more preferably carried out under anhydrous conditions.

The step (3) is carried out in a solvent such as benzene, toluene, dichloromethane or dichloroethane in an amount of 0.1 to 10
In the presence of an equivalent, preferably 0.9 to 5.0 equivalents of a silver catalyst such as silver trifluoromethanesulfonate, silver salicylate, silver carbonate, silver oxide, etc., 0.9 to 200 equivalents, preferably 1.
0 to 50 equivalents using compound (VI)
C., preferably in the temperature range of 0.degree. C. to room temperature. At this time, it is preferable to coexist with 0.1 to 10 equivalents, preferably 0.9 to 5.0 equivalents of a base such as 2,4,6-trimethylpyridine or pyridine, because the yield is improved. Also,
The reaction operation and the reaction are more preferably carried out under anhydrous conditions.

In step (4), in a solvent such as methanol,
0.05-5.0 equivalents, preferably 0.1-2.0 equivalents of alkoxide are used and 0 ° C-50 ° C, preferably 0 ° C.
~ It is performed in the temperature range of room temperature. At this time, the reaction operation and the reaction are more preferably carried out under anhydrous conditions. In the step (5), acetonitrile, tetrahydrofuran,
In a solvent such as dioxane, dimethylformamide, dimethyl sulfoxide, etc., 0.9 to 200 equivalents, preferably 1.
Using 0 to 100 equivalents of compound (VII), 0 ° C to 50
C., preferably in the temperature range of 0.degree. C. to room temperature. At this time, it is preferable to coexist with 0.1 to 10 equivalents, preferably 0.9 to 5.0 equivalents of a silver catalyst such as silver trifluoromethanesulfonate, silver salicylate, silver carbonate, and silver oxide because the yield is improved. . Further, the reaction operation and the reaction are more preferably carried out under anhydrous conditions.

The step (6) is performed under the same conditions as the step (2). In the step (7), benzene, toluene, dichloromethane,
0.1 to 10 in a solvent such as dichloroethane or in the absence of solvent
In the presence of 10 equivalents, preferably 0.9 to 5.0 equivalents of a silver catalyst such as silver trifluoromethanesulfonate, silver salicylate, silver carbonate, silver oxide, etc., 0.9 to 500 equivalents, preferably 1.0 to 200 equivalents. Using an equivalent amount of compound (VI), 0 ° C-5
It is carried out in a temperature range of 0 ° C, preferably 0 ° C to room temperature. At this time, it is preferable to coexist with 0.1 to 10 equivalents, preferably 0.9 to 5.0 equivalents of a base such as 2,4,6-trimethylpyridine or pyridine, because the yield is improved. Further, the reaction operation and the reaction are more preferably carried out under anhydrous conditions.

In step (8), methanol, ethanol,
0.1 to 0.1 in a solvent such as tetrahydrofuran or dioxane
200% by weight, preferably 1.0 to 100% by weight of palladium black, palladium-carbon, etc., in the presence of a catalyst, in a hydrogen atmosphere, at 0 ° C to 50 ° C, preferably 0 ° C.
It is carried out in a temperature range from ℃ to room temperature. The step (9) is performed under the same conditions as the step (1). (Ii) When X is a sulfur atom

[0116]

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[0117] (In the above formulas, are as ^{R 1, R 2, R 3} , R 4 ' is previously defined, M ¹ is. An alkali metal) That First, compound compound (V) to (XII) Reaction [(10) step] to produce compound (I-α-a-1), which is reacted with an alkoxide such as sodium methoxide to deacylate [(11) step] compound (I-α
-B-1) is manufactured. The compound (I-α-a-1)
Can also be manufactured as follows.

[0118]

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[0119] (In the above ^{formulas, R 1, R 2, R} 3, R 4 ' are as previously defined.) In other words, the presence compound of a Lewis acid catalyst to the compound (IV) (XI
II) is reacted [(12) step], and the compound (I-α-a
-1) is manufactured. The compound (I-α-a-1) can also be produced as follows.

[0120]

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[0121] (In the above ^{formulas, R 1, R 2, R} 3, R 4 ' are as previously defined.) That is, by reacting the compound (XIV) to the compound (IV) [(1
3) step], and the compound (I-α-a-1) is produced. In the step (10), 0.9 to 200 equivalents, preferably 1.0 to 100 equivalents of the compound (XII) are used in a solvent such as acetonitrile, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide and the like, and 0 ° C to 5 ° C.
It is carried out in a temperature range of 0 ° C, preferably 0 ° C to room temperature. At this time, 0.1 to 10 equivalents, preferably 0.9 to 5.0 equivalents of silver trifluoromethanesulfonate, silver salicylate,
Coexistence of a silver catalyst such as silver carbonate or silver oxide is preferable because the yield is improved. Further, the reaction operation and the reaction are more preferably carried out under anhydrous conditions.

The step (11) is performed under the same conditions as the step (4). In the step (12), 0.9 to 10 equivalents in a solvent such as dichloromethane, dichloroethane, dioxane, ethers,
Preferably 1.0 to 5.0 equivalents of BF ₃ , ZnCl ₂ ,
In the presence of a Lewis acid catalyst such as AlCl ₃ , 0.9-10 equivalents, preferably 1.0-5.0 equivalents of compound (XIII) are used, and the reaction temperature is 0 ° C-50 ° C, preferably 0 ° C-room temperature. It is carried out in the temperature range. At this time, the reaction operation and the reaction are more preferably carried out under anhydrous conditions.

In step (13), 0.1 to 10 equivalents in a solvent such as dichloromethane, dichloroethane, ethers,
Preferably in the presence of 1.0 to 5.0 equivalents of a catalyst such as trimethylsilyl trifluoromethanesulfonate, 0.9
It is carried out in a temperature range of 0 ° C to 50 ° C, preferably 0 ° C to room temperature, using 10 to 10 equivalents, preferably 1.0 to 5.0 equivalents of the compound (XIV). At this time, the reaction operation and the reaction are more preferably carried out under anhydrous conditions. (B) Production of a compound in which the 2-position of sialic acid is a β isomer (i) When X is an oxygen atom

[0124]

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[0125] (In the above ^{formulas, R 1, R 2, R} 3, R 4 ' are as previously defined.) That First, the compound (VI) is reacted to the compound (V) [(14) step] , Compound (I-β-a), and then reacting this with an alkoxide such as sodium methoxide to deacylate [step (15)] to give compound (I-
β-b) is produced. The compound (I-β-a) can also be produced as follows.

[0126]

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[0127] (In the above ^{formulas, R 1, R 2, R} 3, R 4 ' are as previously defined.) That First, the compound (VI) is reacted to the compound (IX) [(16) step] , Compound (X-β), which is reduced [(17) step] to give compound (XI-β), which is then reacted with compound (III) [(18) step], compound (I- β-a) is produced. In addition, the compound (X-β)
Can also be manufactured as follows.

[0128]

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[0129] (In the above formulas, R ^3, R 4 ^'is as previously defined, M ² represents an alkali metal.) That First, hydrolysis by reacting the compound (XV) with an alkali such as sodium hydroxide [(19) step] to give compound (XVI), which is reacted with benzyl bromide and the like [(2
Step 0)] to give compound (XVII), which is then acylated [step (21)] to give compound (X-β).

The step (14) is performed under the same conditions as the step (3). The step (15) is performed under the same conditions as the step (4). The step (16) is performed under the same conditions as the step (3). Process (17) is performed under the same conditions as process (8). The step (18) is performed under the same conditions as the step (1).

Step (19) is carried out in a solvent such as water, methanol or ethanol in an amount of 0.9 to 10 equivalents, preferably 1.0 to
It is carried out in a temperature range of 0 ° C to 50 ° C, preferably 0 ° C to room temperature using 5.0 equivalents of a base such as sodium hydroxide or potassium hydroxide. The step (20) is performed in a solvent such as dimethylformamide or tetrahydrofuran in an amount of 0.9 to 10 equivalents, preferably 1.0.
~ 5.0 equivalents of benzyl chloride, benzyl bromide and the like are used in the temperature range of 0 ° C to 50 ° C, preferably 0 ° C to room temperature. At this time, the reaction operation and the reaction are more preferably carried out under anhydrous conditions.

In step (21), in a solvent such as pyridine,
Using an acid anhydride such as acetic anhydride or an acid chloride such as acetyl chloride, propionyl chloride, butyryl chloride, valeryl chloride or benzoyl chloride in an amount of 4.0 to 200 equivalents, preferably 4.4 to 100 equivalents at 0 ° C. ~ 8
It is carried out in a temperature range of 0 ° C, preferably 0 ° C to 50 ° C.
At this time, it is preferable to coexist with 0.1 to 1 equivalent, preferably 0.1 to 0.5 equivalent of a base such as 4-dimethylaminopyridine because the yield is improved. Further, the reaction operation and the reaction are more preferably carried out under anhydrous conditions. (Ii) When X is a sulfur atom

[0133]

Embedded image

[0134] (In the above ^{formulas, R 1, R 2, R} 3, R 4 ' are as previously defined.) That First, the presence the compound of Lewis acid catalyst and (XIII) is reacted to the compound (IV) [(22) step], Compound (I-β
-A-1) is produced, and this is reacted with an alkoxide such as sodium methoxide to deacylate [step (23)] to produce a compound (I-β-b-1). Process (22) is performed under the same conditions as process (12). The step (23) is performed under the same conditions as the step (4).

[0135] 2. R ⁵ is R ¹⁵ NH— (R ¹⁵ is as defined in the above general formula (I), provided that R ¹⁵ is C
Except for H ₃ CO-. In the case of (a) a method for producing a compound in which the 2-position of sialic acid is an α isomer (i) when X is an oxygen atom

[0136]

Embedded image

(In the above formula, R ¹ , R ² , R ³ , R ^{4 '} , R
¹⁵ is as defined above, R ^{3 ′} represents a C ₁ -C ₆ alkyl group, and M ³ represents an alkaline earth metal. That is, first, the compound (VI) is reacted with the compound (XVIII) [(24) step] to obtain the compound (XIX), which is then deacylated by reacting with an alkoxide such as sodium methoxide [(25) step] , Compound (XX), and then hydrolyzed by reacting with an alkali such as barium hydroxide [(2
6) step], a compound (XXI), which is N-acylated,
N-oxycarbonylation or N-sulfonylation [step (27)] to give compound (XXII), and then acylation [step (28)] to give compound (XXIII),
This is reacted with compound (III) [step (29)] to produce compound (I-α-a-2), which is then reacted with an alkoxide such as sodium methoxide to deacylate [(30)]. Step] A compound (I-α-b-2) is produced. In addition, by substituting the amine residue containing R ¹⁵ of the compound (I-α-a-2) with another amine residue ((I-α
-A-2 ') can also be produced.

[0138]

Embedded image

(In the above formula, R ¹ , R ² , R ³ , R ^{4 '} , R
¹⁵ is as defined above, but here (I-α-a-
R ¹⁵ in 2) in the ^{R 15 (I-α-a} -2 ')
Do not represent the same group. That is, first, compound (I-α-a-2) is N-deprotected [step (31)] to give compound (XXIV-α), which is then N-acylated, N-oxycarbonylated or N-
Sulfonylation [(32) step] to give compound (I-α-
a-2 ') is produced.

The step (24) is performed under the same conditions as the step (7). The step (25) is performed under the same conditions as the step (4). In step (26), a base such as barium hydroxide is used in an amount of 0.9 to 10 equivalents, preferably 1.0 to 5.0 equivalents in a solvent such as water, methanol or ethanol, and 0 ° C to 100 ° C, preferably Is performed in a temperature range of 50 ° C to 100 ° C.

In the step (27), in a solvent such as water, methanol, ethanol, dioxane or tetrahydrofuran,
0.9 to 10 equivalents, preferably 1.0 to 3.0 equivalents of acid anhydrides such as acetic anhydride and propionic anhydride or acid chlorides such as acetyl chloride, propionyl chloride and benzoyl chloride and 0.9 to 10 equivalents , Preferably 1.0
To 3.0 equivalents of N-acylation using tertiary amines such as triethylamine or 0.9 to 10 equivalents, preferably 1.0 to 3.0 equivalents of di-t-butyl dicarbonate. , Carbobenzoxylchloride and the like, 0.9 to 10 equivalents,
Preferably, N-oxycarbonylation is carried out using tertiary amines such as triethylamine in an amount of 1.0 to 3.0 equivalents, or 0.9 to 10 equivalents, preferably 1.0 to
3.0 to 10 equivalents of methanesulfonyl chloride, benzenesulfonyl chloride and the like, and 0.9 to 10 equivalents, preferably 1.
N-sulfonylation is carried out with 0 to 3.0 equivalents of tertiary amines such as triethylamine. At this time, the reaction is 0 ° C to 8
It is carried out in a temperature range of 0 ° C, preferably 0 ° C to 50 ° C.

The step (28) is performed under the same conditions as the step (21). Process (29) is performed under the same conditions as in process (1). Process (30) is performed under the same conditions as process (4).

In step (31), methanol, ethanol,
0.1-2 in a solvent such as tetrahydrofuran or dioxane
00 weight percent, preferably 1.0 to 100 weight percent, in the presence of a catalyst such as palladium black, palladium-carbon, etc., under a hydrogen atmosphere, 0 ° C. to 50 ° C., preferably 0 ° C.
~ N-deprotection in the temperature range of room temperature, or 0.9 equivalent to 1 in a solvent such as dioxane, ethyl acetate, acetic acid
00 equivalent, preferably 1.0 equivalent to 20 equivalents of hydrogen chloride, hydrogen bromide and the like, 0 ° C to 50 ° C, preferably 0 ° C
~ N-deprotection is performed in the temperature range of room temperature.

In step (32), 0.9 to 10 equivalents, preferably 1.0 to 3.0 equivalents of acetic anhydride, propionic anhydride, etc. are used in a solvent such as methanol, ethanol, dioxane, tetrahydrofuran, dichloromethane and dichloroethane. Acid anhydrides or acid chlorides such as acetyl chloride, propionyl chloride and benzoyl chloride,
N-acylation is carried out using tertiary amines such as triethylamine in an amount of 0.9 to 10 equivalents, preferably 1.0 to 3.0 equivalents, or 0.9 to 10 equivalents, preferably 1.0 to 3 equivalents. ．
0 to 10 equivalents of di-t-butyl dicarbonate, carbobenzoxylcolide and the like and 0.9 to 10 equivalents, preferably 1.0
N-oxycarbonylation with ~ 3.0 equivalents of tertiary amines such as triethylamine, or 0.9
10 to 10 equivalents, preferably 1.0 to 3.0 equivalents of methanesulfonyl chloride, benzenesulfonyl chloride and the like and 0.9 to 10 equivalents, preferably 1.0 to 3.0 equivalents of tertiary amines such as triethylamine. Is used to perform N-sulfonylation. In this case, the reaction is 0 ° C to 80 ° C, preferably 0 ° C.
It is performed in a temperature range of 50 ° C to 50 ° C. At this time, the reaction operation and the reaction are more preferably performed under anhydrous conditions. (Ii) When X is a sulfur atom

[0145]

Embedded image

(In the above formula, R ¹ , R ² , R ³ , R ^{4 '} , R
¹⁵ , R ^{3 ′} , M ¹ and M ³ are as defined above. ) That is, first, the compound (XVIII) is reacted with the compound (XII) [(33) step] to obtain the compound (XXV), which is reacted with an alkoxide such as sodium methoxide to deacylate the [(34) step] compound (XXVI), then hydrolyze by reacting with alkali such as barium hydroxide [(35)
Step] As a compound (XXVII), this is N-acylated, N-
Oxycarbonylation or N-sulfonylation [[3
Step 6)] Compound (XXVIII), which is then acylated to give [(37) Step] Compound (XXIX), which is reacted with Compound (III) [Step (38)] Compound (I-α
-A-4) was prepared, and then this was reacted with an alkoxide such as sodium methoxide to deacylate [[3
9) Step] A compound (I-α-b-4) is produced.

The step (33) is performed under the same conditions as the step (10). The step (34) is performed under the same conditions as the step (4). Process (35) is performed under the same conditions as process (26). Process (36) is performed under the same conditions as process (27). The step (37) is performed under the same conditions as the step (21). The step (38) is performed under the same conditions as the step (1). The step (39) is performed under the same conditions as the step (4).

(B) Method for producing compound in which 2-position of sialic acid is β isomer (i) When X is oxygen atom

[0149]

Embedded image

(In the above formula, R ¹ , R ² , R ³ , R ^{4 '} , R
¹⁵ and M ³ are as defined above. ) That is, first, the compound (XV) is hydrolyzed by reacting it with an alkali such as barium hydroxide [Step (40)] Compound (XXX)
And N-acylating, N-oxycarbonylating, or N-sulfonylating this to give [(41) step] compound (XX
XI) and then acylate this [Step (42)]
Compound (XXXII), and this is reacted with compound (III) [Step (43)] to produce compound (I-β-a-2),
Then, this is reacted with an alkoxide such as sodium methoxide for deacylation to give a compound (I-
β-b-2) is produced.

Process (40) is performed under the same conditions as process (26). The step (41) is performed under the same conditions as the step (27). The step (42) is performed under the same conditions as the step (21). The step (43) is performed under the same conditions as the step (1). Process (44) is performed under the same conditions as process (4).

(Ii) When X is a sulfur atom

[0153]

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(In the above formula, R ¹ , R ² , R ³ , R ^{3 '} , R
^{4 ′} , R ¹⁵ and M ³ are as defined above. That is, first, the compound (XXXIII) is reacted with the compound (XIII) [(45) step] to obtain the compound (XXXIV), and this is reacted with an alkoxide such as sodium methoxide to deacylate the [(46) step] compound. (XXXV), then reacted with alkali such as barium hydroxide to hydrolyze [(4
7) Step] As a compound (XXXVI), this is N-acylated,
N-oxycarbonylated or N-sulfonylated to give [(48) step] compound (XXXVII), and then acylated to [(49) step] compound (XXXVIII),
This is reacted with compound (III) [step (50)] to produce compound (I-β-a-4), which is then reacted with an alkoxide such as sodium methoxide to deacylate [step (51). ] The compound (I-β-b-4) is produced.

Step (45) is performed under the same conditions as step (12). Process (46) is performed under the same conditions as process (4). Process (47) is performed under the same conditions as process (26). The step (48) is performed under the same conditions as the step (27). Process (49) is performed under the same conditions as process (21). The step (50) is performed under the same conditions as the step (1). The step (51) is performed under the same conditions as the step (4).

3. When R ⁵ is R ¹⁴ O— (R ¹⁴ is as defined in the above general formula (I).) (A) Method for producing a compound in which the 2-position of sialic acid is an α isomer (i) X is an oxygen atom If

[0157]

Embedded image

[0158] (In the above formula, ^'is as already ^{defined, R 14' R 1, R} 2, R 3, R 4 represents an acyl group of C ₂ ~C _7.) That First, Compound (XXXIX ) Is chlorinated to give [(52) step] compound (XL), which is reacted with compound (VI) to give [(53) step] compound (XLI-α), and then reduced to [(54) Step] As compound (XLII-α), and then reacting this with compound (III) [Step (55)] As compound (I-α-a-5), then reacting this with an alkoxide such as sodium methoxide Deacylation is performed [Step (56)] to produce a compound (I-α-b-5). The compound (I-α-a-5) can also be produced as follows.

[0159]

Embedded image

(In the above formula, R ¹ , R ² , R ³ , R ^{4 '} , R
^{14 '} is as defined above. That is, first, compound (III) is allowed to act on compound (XLIII) to give compound (XLIV), which is chlorinated to give compound (XLV) [step (58)]. VI) is reacted [(59) step] Compound (I-
α-a-5) is produced.

Step (52) is performed under the same conditions as step (2). The step (53) is performed under the same conditions as the step (3). Process (54) is performed under the same conditions as process (8). The step (55) is performed under the same conditions as the step (1). The step (56) is performed under the same conditions as the step (4). The step (57) is performed under the same conditions as the step (1). The step (58) is performed under the same conditions as the step (2). The step (59) is performed under the same conditions as the step (3). (Ii) When X is a sulfur atom

[0162]

Embedded image

(In the above formula, R ¹ , R ² , R ³ , R ^{4 '} , R
^{14 '} and M ¹ are as defined above. That is, first, compound (XLV) is reacted with compound (XII) [step (60)] to give compound (I-α-a-6), which is reacted with an alkoxide such as sodium methoxide for deacylation. [Step (61)] Compound (I-α-b-
6) is manufactured. The compound (I-α-a-6) can also be produced as follows.

[0164]

Embedded image

(In the above formula, R ¹ , R ² , R ³ , R ^{4 '} , R
^{14 '} is as defined above. ) That is, the compound (XLIV) is reacted with the compound (XIV) [(6
Step 1)] The compound (I-α-a-6) is produced. The compound (I-α-a-6) can also be produced as follows.

[0166]

Embedded image

(In the above formula, R ¹ , R ² , R ³ , R ^{4 '} , R
^{14 '} is as defined above. That is, the compound (XLIV) in the presence of a Lewis acid catalyst (XI
II) is reacted [(63) step] Compound (I-α-a-
6) is manufactured. Process (60) is performed under the same conditions as process (10). The step (61) is performed under the same conditions as the step (4). The step (62) is performed under the same conditions as the step (13). The step (63) is performed under the same conditions as the step (12).

(B) Method for producing compound in which 2-position of sialic acid is β isomer (i) When X is oxygen atom

[0169]

Embedded image

(In the above formula, R ¹ , R ² , R ³ , R ^{4 '} , R
^{14 '} and M ² are as defined above. That is, first, the compound (XLVI) is reacted with an alkali such as sodium hydroxide and hydrolyzed to obtain [(64) step] compound (XLVII), which is reacted with benzyl bromide and the like [(65) step compound ( XLVIII), which is then acylated to give a compound (XLI-β) [step (66)],
Then, the compound (XLII-
β) and then reacting it with compound (III) [(6
Step 8)] A compound (I-β-a-5) is obtained, which is then reacted with an alkoxide such as sodium methoxide to deacylate the compound to give a compound (I-β-b-).
5) is manufactured.

The step (64) is performed under the same conditions as the step (19). Process (65) is performed under the same conditions as process (20). Process (66) is performed under the same conditions as process (21). Process (67) is performed under the same conditions as process (8). Step (68) is performed under the same conditions as in step (1). The step (69) is performed under the same conditions as the step (4). (Ii) When X is a sulfur atom

[0172]

Embedded image

(In the above formula, R ¹ , R ² , R ³ , R ^{4 '} , R
^{14 '} is as defined above. That is, the compound (XLIV) is reacted with the compound (XIII) in the presence of a Lewis acid catalyst [step (70)] compound (I-β-
a-6), and then this is reacted with an alkoxide such as sodium methoxide to deacylate to produce compound (I-β-b-6) [step (71)]. Process (70) is performed under the same conditions as process (12). The step (71) is performed under the same conditions as the step (4).

When R ³ has an ester group, it is hydrolyzed to give a carboxylic acid derivative. Also, R
^{If a} benzyl ether group was present at ³ or R ⁵ , it was reduced to the hydroxy derivative. When R ³ has a benzyloxycarbonylamino group, it is reduced to give an amino derivative.
Acylation to acylamino derivatives and sulfonylation to sulfonylamino derivatives. Separation / purification of the compound produced by the method detailed in the above 1, 2 and 3 from the reaction mixture is carried out by a known and commonly used method such as extraction,
It can be easily performed by recrystallization, chromatography and the like.

The compound of formula (I
I), (III), (VIII), (XV), (XVIII), (XXXII
I), (XXXIX), (XLIII) and (XLVI) compounds are
It can be synthesized by the method described in the following documents. That is, the compounds (II), (VIII), (XV), (XVIII), (XXXIII),
(XXXIX), (XLIII) and (XLVI)

(A) Carbohydr. Res. , 1
25 , 47-64 (1984). (B) Chem. Pharm. Bull. , 35 , 36
09-3614 (1987). (C) Chem. Ber. , 99 , 611-617 (1
966). (D) Chem. Pharm. Bull. , 36 , 48
07-4813 (1988). In addition, the compound (III) can be prepared by using the method described in (e) J. Org. Chem. , 27 , 2925-29
27 (1962). Can be easily synthesized by the method described in 1) or a method analogous thereto.

When the compound is used as a therapeutic or prophylactic 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, granules,
Fine granules, powders, tablets, hard syrups, soft capsules, syrups, emulsions, suspensions, liposomes or solutions may be orally administered, or may be administered intravenously as an injection. It may be administered intramuscularly or subcutaneously.

Further, it may be used by making powder for injection and preparing it at the time of use. Further, a pharmaceutical organic or inorganic solid or liquid carrier 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 commonly used inert diluent such as water or vegetable oil. This preparation contains, in addition to the inert diluent, auxiliary substances such as wetting agents, suspending aids, sweeteners,
Fragrances, colorants or preservatives may also be included. Liquid formulations may be included in capsules of absorbable material such as gelatin. Formulations for parenteral administration, that is, solvents or suspending agents used in the production of injections and the like include, for example, water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate,
Examples include lecithin and the like. Preparation of the preparation may be performed by a conventional method.

When used by oral administration, the clinical dose is generally 0.1 to 1,000 mg / day, preferably 1 to 200 mg / day, as the above compound for adults.
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 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 for an adult is 0.1 to 100 mg, preferably 0.1 to 50 mg.

[0180]

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.

Synthesis Example 1 3α- [N- (5-acetamido-2,4,7,8,9
-Penta-O-acetyl-3,5-dideoxy-β-D
-Glycero-D-galacto-2-nonuropyranosoni
Le) amino] cholestane [3α- [N- (5-acetamido-2,4,
7,8,9-penta-O-acetyl-3,5-
dideoxy-β-D-glycero-D-gal
acto-2-nonulopyranosonyl)
amino] cholestane] [of compound (IV)
R¹: 3α-cholestane, R^Two: Hydrogen, R ^Four′: Asset
]] Synthesis

5-acetamido-2,4,7,8,9-
Penta-O-acetyl-3,5-dideoxy-β-D-
5.59 g (11.5 mmol) of glycero-D-galacto-2-nonulopyranosonic acid was dissolved in 50 ml of dry tetrahydrofuran, and 1.4 ml (12.7 mmol) of N-methylmorpholine under cooling at -10 ° C, chloro. Add 1.6 ml (12.5 mmol) of isobutyl carbonate and add 2
Stir for 0 minutes. Subsequently, 5.40 g (12.7 mmol) of 3α-aminocholestane hydrochloride and 30 ml of a tetrahydrofuran suspension of 1.4 ml (12.7 mmol) of N-methylmorpholine were added, stirred for 40 minutes, and then returned to room temperature for 15 minutes. Stir for hours.

After the reaction, the solvent was distilled off, ethyl acetate was added to the obtained syrup, and the mixture was washed with saturated aqueous sodium hydrogencarbonate solution, 0.2N hydrochloric acid, water, saturated aqueous sodium hydrogencarbonate solution and water to give anhydrous sulfuric acid. It was dried with magnesium. The syrup obtained after distilling off the solvent was subjected to silica gel column chromatography [Merck silica gel 60, developing solvent:
Chloroform / methanol (250: 1 to 25: 1)]
5.19 g (yield 50.4 g) of the title compound.
%) Was obtained.

¹ H-NMR (CDCl ₃ ) δ (pp
m): 0.61 (3H, s , 18'-CH 3), 0.7
_{9~0.88 (12H, 19'-CH 3} , 21'-CH
_{3, 26'-CH 3, 27'} -CH 3), 1.90,
2.01, 2.03, 2.09, 2.13 (18H, s
× 6, Ac), 2.58 (1H, dd, J = 4.9H
z, 13.6 Hz, H-3 eq), 3.98-4.18.
(4H, m, H-3 ', 5, 6, 9), 4.36 (1
H, dd, J = 2.7 Hz, 12.3 Hz, H-9),
5.10 (1H, ddd, J = 2.7Hz, 6.2H
z, 8.9 Hz, H-8), 5.29 (2H, m, H-
4, 7), 5.48 (1H, d, J = 8.9Hz, Ac
NH ), 6.85 (1H, d, J = 8.0Hz, NH)

Synthesis Example 2 3α- [N- (5-acetamido-4,7,8,9-tetra-O-acetyl-2-chloro-2,3,5-trideoxy-β-D-glycero-D- Galact-2-nonulopyranosonyl) amino] cholestane [Synthesis of R ¹ : 3α-cholestane of compound (V), R ² : hydrogen, R ^{4 ′} : acetyl] 6.40 g of the compound obtained in Synthesis Example 1 (7.20mmo
75 ml of acetyl chloride saturated with hydrogen chloride gas
It was dissolved in 1 l, tightly capped and left at room temperature for 16 hours. After the reaction, the solvent was distilled off, followed by azeotropic distillation with benzene to obtain 6.20 g (yield 99.5%) of the title compound.

¹ H-NMR (CDCl ₃ ) δ (pp
m): 0.63 (3H, s , 18'-CH 3), 0.7
_{9~0.89 (12H, 19'-CH 3} , 21'-CH
_{3, 26'-CH 3, 27'} -CH 3), 1.90,
2.01, 2.02, 2.10, 2.14 (15H, s
× 5, Ac), 2.25 (1H, dd, J = 11.4H
z, 14.3 Hz, H-3ax), 2.80 (1H, d
d, J = 4.8 Hz, 14.3 Hz, H-3 eq),
3.98-4.24 (5H, m, H-3 ', 5, 6,
9, 9), 5.31 to 5.45 (4H, m, H-4,
7,8, AcN H), 6.91 ( 1H, d, J = 7.0
Hz, NH)

Synthesis Example 3 3α- [N- (5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-2-O-methyl-α-D-glycero-D- Galact-2-Nonuropyranosonyl) amino] cholestane (Compound N in Table 1
o. Synthesis of α-form 1) 6.20 g (7.20 mmo) of the compound obtained in Synthesis Example 2
l) was dissolved in 75 ml of dry benzene, 10 g of anhydrous calcium sulfate was added, and the mixture was stirred at room temperature for 45 minutes. Subsequently, 18.0 ml (444 mmol) of methanol was added and the mixture was stirred for 15 minutes, and then 2.60 g (10.1 mmol) of silver trifluoromethanesulfonate and 2,4,6 under light-shielding under ice cooling.
-Trimethylpyridine 1.15 ml (8.75 mmo
l) Nitromethane 15 ml and diethyl ether 20 m
1 of the mixed solution was added, and then the mixture was returned to room temperature and stirred for 15 hours. Chloroform was added to the reaction solution and filtered through Celite, and then the filtrate was 0.2N sodium thiosulfate aqueous solution, 0.1N
The extract was washed with hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the obtained syrup was purified by silica gel column chromatography [Merck silica gel 60, developing solvent: chloroform / methanol (100: 1 to 50: 1)] to give 4.13 g of the title compound (yield 66.9%).

IR (KBr) (cm ^-1 ) 3380,2
_{^{940,2870,1750,1690 1 H-NMR (CDCl 3}} ) δ (ppm): 0.62
(3H, s, 18'-CH 3), 0.77~0.89
_{(12H, 19'-CH 3,} 21'-CH 3, 26'-
_{CH 3, 27'-CH 3)} , 1.86,1.99,2.
01, 2.04, 2.11 (15H, s × 5, Ac),
2.18 (1H, dd, J = 5.3Hz, 13.0H
z, H-3eq), 3.40 (3H, s, OCH 3),
3.99-4.17 (3H, m, H-3 ', 5,9),
4.36 (1H, dd, J = 1.5Hz, 11.8H
z, H-9), 4.47 to 4.52 (1H, m, H-
6), 5.25 to 5.27 (2H, m, H-7, 8),
5.31 to 5.42 (2H, m, H-4, AcN H ),
5.79 (1H, d, J = 7.7Hz, NH)

Synthesis Example 4 Benzyl 5-acetamide-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-2-O-methyl-α-D-glycero-D-galact-2-no Nuropyranosonate [R ³ : methyl of compound (X-α), R ^{4 ′} :
Acetyl] Synthesis Benzyl 5-acetamido-2,4,7,8,9-penta-O-acetyl-3,5-dideoxy-β-D-glycero-D-galacto-2-nonulopyranosonate 2
After 6.5 g (43.5 mmol) was dissolved in 200 ml of acetyl chloride saturated with hydrogen chloride gas, the container was tightly sealed and left at room temperature for 15 hours, and then the solvent was distilled off.
It was azeotropically distilled twice with 100 ml of toluene. Silver carbonate 1 in the residue
4.6 g and anhydrous calcium sulfate 26 g were added, further 300 ml of methanol was added, and the mixture was stirred under ice cooling for 1 hour and then stirred at room temperature for 3 hours. The reaction solution was filtered through Celite, the solvent of the filtrate was evaporated, the residue was dissolved in 500 ml of ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give the title compound 25. 0.4 g (yield 100%)
I got

Melting point 97-103 ° C. (decomposition) IR (KBr) (cm ⁻¹ ) 3290,1750,16
60 ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.87,
2.02, 2.04, 2.13, 2.15 (15H, s
× 5, Ac), 2.62 (1H, dd, J = 4.6H
z, 12.7 Hz, H-3eq), 3.26 (3H,
s, OCH ₃ ), 4.31 (1H, dd, J = 2.6H)
z, 12.4 Hz, H-9), 4.83 (1H, m, H
-4), 5.23 (2H, s, COOC H ₂ C
₆ H ₅ ), 7.30 to 7.40 (5 H, m, COOCH
₂ C ₆ H ₅ )

Synthesis Example 5 5-Acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-2-O-methyl-α-D-
Glycero-D-galacto-2-nonulopyranosonic acid [R ³ : methyl of compound (XI-α), R ^{4 ′} : acetyl]
14.18 g (24.38 m) of the compound synthesized in Synthesis Example 4
(mol) was dissolved in 250 ml of ethanol, 1.40 g of 5% palladium-carbon was added, and the mixture was stirred in a hydrogen stream for 3 hours. After removing the catalyst by filtration, the solvent was evaporated, and the residue was recrystallized from hexane-ethyl acetate to give 10.22 g of the title compound (yield 8
5%).

Melting point 189 to 190 ° C. (decomposition) IR (KBr) (cm ⁻¹ ) 3380, 2990, 17
40, 1660, 1540 ¹ H-NMR (CD ₃ OD) δ (ppm): 1.79
(1H, t, J = 12.4 Hz, H-3ax), 1.8
7, 2.02, 2.04, 2.13, 2.14 (15
H, s × 5, Ac), 2.65 (1H, dd, J = 4.
7 Hz, 12.4 Hz, H-3 eq), 3.37 (3
_{H, s, OCH 3),} 3.99 (1H, t, J = 10.
5 Hz, H-5), 4.11 (1H, dd, J = 5.0)
Hz, 12.4 Hz, H-9), 4.26 (1H, d
d, J = 2.1 Hz, 10.8 Hz, H-6), 4.3
4 (1H, dd, J = 2.5Hz, 12.4Hz, H-
9), 4.93 (1H, m, H-4), 5.37 (1
H, dd, J = 2.1 Hz, 9.1 Hz, H-7),
5.45 (1H, ddd, J = 2.5Hz, 5.0H
z, 9.1 Hz, H-8)

Synthesis Example 6 3α- [N- (5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-2-O-methyl-α-D-glycero-D- Galact-2-Nonuropyranosonyl) amino] cholestane (Compound N in Table 1
o. Synthesis of α-form 1) Compound 1 synthesized in Synthesis Example 5
0.10 g (20.55 mmol) was dissolved in 500 ml of tetrahydrofuran and cooled to -10 ° C, 3.15 ml of triethylamine, isobutyl chlorocarbonate 2.94.
After adding ml, the mixture was stirred for 1 hour, and then a solution of 7.98 g (20.55 mmol) of 3α-aminocholestane dissolved in 30 ml of tetrahydrofuran was added over 10 minutes. Allow the temperature of the reaction solution to rise to room temperature over 3 hours, and
Stir for 2 hours. The precipitated triethylamine hydrochloride was filtered off, the solvent was distilled off, the residue was dissolved in 500 ml of ethyl acetate, washed successively with 0.1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. It was dried and 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)] and 15.77 g of the title compound (yield 89
%) Was obtained.

Synthesis Example 7 3α- [N- (5-acetamido-3,5-dideoxy-2-O-methyl-α-D-glycero-D-galacto-
2-Nonuropyranosonyl) amino] cholestane (Table-
Compound No. 1 4. α-form of 4) 4.13 g of the compound obtained in Synthesis Example 3 or Synthesis Example 6
(4.80 mmol) is dissolved in 70 ml of methanol,
Under ice-cooling, 0.3 ml (1.47 mmol) of a 4.9 N sodium methoxide methanol solution was added, and then the mixture was returned to room temperature and stirred for 15 hours. After the reaction, about half the amount of the solvent was distilled off, and then the solid was collected by filtration and washed with methanol. The obtained solid is washed with methanol by suspension to give 2.53 g of the title compound.
(Yield 76.2%) was obtained. Hereinafter, this compound is abbreviated as “the compound of the present invention”.

Melting point 269 to 280 ° C. (decomposition) IR (KBr) (cm ⁻¹ ) 3450, 3340, 29
60,1670,1620 ¹ H-NMR [CDCl ₃ -CD ₃ OD (1: 1)] δ
(Ppm): 0.69 (3H, s, 18'-CH 3),
_{0.84~0.95 (12H, 19'-CH 3} , 21 '
_{-CH 3, 26'-CH 3,} 27'-CH 3), 2.0
4 (3H, s, Ac), 2.82 (1H, dd, J =
4.5 Hz, 12.7 Hz, H-3eq), 3.38
_{(3H, s, OCH 3)} , 4.02 (1H, m, H-
3 ')

Example 1 Effect on peripheral neuropathy in streptozotocin-induced diabetic rats Streptozotocin (ST
Z) was intravenously administered at 50 mg / kg, and one week later, the blood glucose levels were grouped. 0.1, 0.3, 1.0 of the compound of the present invention
Oral administration of mg / kg once a day was performed to measure sensory nerve conduction velocity (SCV). Nerve conduction velocity can be determined by the method of Miyoshi et al. (Fukuoka Medical Journal, 62 (7), 588-603 (197)
1)) and Stanley's method (Experime
ntal Neurology 71, 497-506
(1981)). That is, the recording electrode and the stimulating electrode are placed at the rostral side of the recording electrode at the tip of the tail, and the distance between them is measured. The conduction velocity was calculated from the difference in the latency of the H wave peaks induced by two stimulations and the distance between the stimulation electrodes. The results are shown in FIG. From the results shown in FIG. 1, the compound of the present invention showed a protective effect against diabetic decrease in peripheral nerve conduction velocity. This indicates that the compound of the present invention can be used for treating neurological disorders.

[0197]

As described above, it was revealed that the sialic acid derivative of the present invention is useful as an agent for improving and / or treating nervous system diseases such as peripheral neuropathy in mammals. Typical examples of these nervous system diseases include various neuropathies. For example, inflammatory or allergic neuropathy (Guillain-Barre syndrome, viral neuropathy such as AIDS, chronic relapsing neuropathy, multiple neuropathy, cleft-case syndrome, neuropathy associated with collagen disease or vasculitis, neuropathy associated with malignant tumor, abnormal globulin. , Etc.), toxic neuropathy (due to organic solvents, drug-based drugs such as anticancer drugs, due to heavy metals such as mercury, due to bacterial toxins such as botulinum), metabolic neuropathy (diabetic neuropathy, alcoholic neuropathy) , Neuropathy due to uremia, etc.), hereditary neuropathy and the like. Further, facial nerve palsy, sciatic nerve palsy, spinal muscular atrophy, muscular dystrophy, myasthenia gravis, Shy-Drager syndrome, SMON, rheumatism, dyskinesia and the like can be mentioned. The above are merely examples, and it goes without saying that the indication diseases are not limited to these exemplified diseases.

[Brief description of drawings]

FIG. 1 is a drawing showing the action of the compound synthesized in Synthesis Example 7 on sensory nerve conduction velocity in diabetic model rats.

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Haruyuki Chaki 1000 Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa Mitsubishi Chemical Corporation Yokohama Research Institute (72) Inventor Naoko Ando 1000, Kamoshita-cho, Aoba-ku, Yokohama, Kanagawa Mitsubishi Chemical Co., Ltd. Yokohama Research Institute

Claims (21)

[Claims] 1. A compound represented by the following general formula (I)[In the above general formula (I), R¹ Is a steroid compound residue
Represent, R^Two Is a hydrogen atom or C₁ ~ C_Four The alkyl group of
Represent, R^Three Is C₁ ~ C_FifteenAn alkyl group of中 where R⁶And R⁷Are each independently a hydrogen atom,
Halogen atom, C₁ ~ C _Four The alkyl group of hydroxyl
Group, R⁸O- (wherein R⁸Is C₁ ~ C_Four An alkyl group of
Phenyl group or phenyl- (C₁ ~ C_Three ) Alkyl group
Represents), a nitro group, an amino group, C₁ ~ C_Four The alkyl of
Amino group, C_Two ~ C₈ A dialkylamino group of or(Where R⁹Is a hydrogen atom, C₁ ~ C_Four The alkyl group of
Phenyl group or phenyl- (C₁ ~ C_Three ) Alkyl group
Represents, and 1 represents an integer of 0 to 6}, R^TenO (C
H_Two )_m-(Where R^TenIs a hydrogen atom; C₁ ~ C_Four Al
Kill group; C₁ ~ C _Four Alkyl group, halogen atom, hydr
Roxyl group, nitro group, amino group and carboxyl group
A phenyl optionally having one or more substituents selected from
Or a C group₁ ~ C_Four Alkyl group, halogen atom,
Hydroxyl, nitro, amino and carboxy
Group optionally having one or more substituents selected from the group
Phenyl- (C₁ ~ C_Three ) Represents an alkyl group, m is 2 to 6
Represents the integer) or中 where R¹¹Is a hydrogen atom or C₁ ~ C_Four Alkyl group
Represents R¹²Is a hydrogen atom; C₁ ~ C_Four An alkyl group of C
_Two ~ C₇ An acyl group; C₁ ~ C_Four Alkylsulfonyl
Group; C₁ ~ C_Four Alkyl group, halogen atom, hydroxy
From sil, nitro, amino and carboxyl groups
Phenyls optionally having one or more substituents selected
A sulfonyl group; or(Where R¹³Is C₁ ~ C_Four Alkyl group, phenyl group
Or phenyl- (C₁ ~ C_Three ) Represents an alkyl group)
, N represents an integer of 2 to 6}, and R^Four Is a hydrogen atom
Or C_Two ~ C₇ Represents an acyl group of R^FiveIs R¹⁴O-
(Where R¹⁴Is a hydrogen atom or C_Two~ C₇The acyl group of
Represents) or R^FifteenNH- {in the formula, R^FifteenIs C_Two~ C₇A
Sil group;(Where R¹⁶Is a hydrogen atom, C₁~ C₆The alkyl group of
Phenyl group or phenyl- (C₁~ C_Three) Alkyl group
, P represents an integer of 0 to 4); C₁~ C_FourArchi
Group, halogen atom, hydroxyl group, nitro group, amine
One or more substituents selected from the group
C which may have₇~ C₁₁Aroyl group; C₁~ C
_FourAlkyl group, halogen atom, hydroxyl group, nit
1 or more selected from a group b, an amino group and a carboxyl group
Phenyl which may have the above substituent (C₁~ C_Three)
Alkylcarbonyl group; C₁~ C_FourAlkylsulfonyl
Group; or C₁~ C_FourAlkyl group, halogen atom,
Droxyl group, nitro group, amino group and carboxyl
A group which may have one or more substituents selected from the group
Represents an nylsulfonyl group}, and X is an oxygen atom or
Representing a sulfur atom] represented by a sialic acid derivative, a salt thereof,
The hydrate or solvate thereof is the active ingredient.
A therapeutic or preventive drug for peripheral neuropathy. 2. R ₁ is The therapeutic or prophylactic agent according to claim 1, wherein the broken line represents no bond or a single bond. 3. R ₁ is The therapeutic or prophylactic drug according to claim 1, which is 4. R ₁ is The therapeutic or prophylactic drug according to claim 1, which is 5. The therapeutic or prophylactic agent according to claim 1, wherein R ² is a hydrogen atom or a methyl group. 6. The therapeutic or prophylactic agent according to claim 1, wherein R ² is a hydrogen atom. 7. R^ThreeIs C₁~ C₈An alkyl group of中 where R⁶And R⁷Are each independently a hydrogen atom,
Halogen atom or(Where R⁹Is a hydrogen atom or C₁~ C_FourAlkyl group
Represents, and 1 represents an integer of 0 to 3}, R^TenO
(CH_Two)_m-(Where R^TenIs a hydrogen atom, C₁~ C _Fourof
Alkyl group, phenyl group or phenyl- (C₁~
C_Three) Represents an alkyl group, and m represents an integer of 2 to 4).
Or中 where R¹¹Represents a hydrogen atom, R¹²Is a hydrogen atom, C_Two
~ C₇Acyl group of C₁~ C_FourAlkylsulfonyl group of
Or [Chemical 13](Where R¹³Is phenyl- (C₁~ C_Three) Alkyl group
Represents, and n represents an integer of 2 to 4}.
The therapeutic or prophylactic drug according to any one of 1 to 6. 8. R ³ is a C ₁ -C ₈ alkyl group or (In the formula, 1 represents an integer of 0 to 3).
The therapeutic or prophylactic drug according to any one of 1. 9. The therapeutic or prophylactic agent according to claim _{1, wherein} R ³ is a C _{1 to} C ₃ alkyl group. 10. The therapeutic or prophylactic agent according to claim 1, wherein R ⁴ is a hydrogen atom or an acetyl group. 11. The therapeutic or prophylactic agent according to claim 1, wherein R ⁴ is a hydrogen atom. 12. R^FiveIs R¹⁴O- (wherein R¹⁴Is hydrogen
Child or acetyl group) or R^FifteenNH- {wherein
R^FifteenIs C_Two~ C₇An acyl group of(Where R¹⁶Is a hydrogen atom, C₁~ C_FourThe alkyl group of
Is phenyl (C₁~ C_Three) Represents an alkyl group, and p is 0 to
Represents the integer of 4), C₇~ C₁₁Aroyl group of C ₁~ C
_ThreeAlkylsulfonyl group or phenylsulfonyl group
Represents)).
Medical and preventive drugs. 13. R^FiveIs R¹⁴O- (wherein R¹⁴Is hydrogen
Represents a child) or R ^FifteenNH- {in the formula, R^FifteenIs C_Two~ C_Five
An acyl group of(Where R¹⁶Represents a hydrogen atom and p represents 1)}
The therapeutic or prophylactic drug according to any one of claims 1 to 11. 14. The therapeutic or prophylactic agent according to claim 1, wherein R ⁵ is R ¹⁵ NH— (wherein R ¹⁵ represents an acetyl group). 15. The therapeutic or prophylactic agent according to claim 1, wherein X is an oxygen atom. 16. α- [N- (5-acetamide-
3,5-Dideoxy-2-O-methyl-α-D-glycero-D-galacto-2-nonupyranosonyl) amino] cholestane, a hydrate or a solvate thereof as an active ingredient. The therapeutic or prophylactic drug according to 1. 17. The therapeutic or prophylactic agent according to claim 1, wherein the peripheral neuropathy is inflammatory or allergic neuropathy. 18. The therapeutic or prophylactic agent according to claim 1, wherein the peripheral neuropathy is toxic neuropathy. 19. The therapeutic or prophylactic agent according to claim 1, wherein the peripheral neuropathy is metabolic neuropathy. 20. The therapeutic or prophylactic agent according to claim 1, wherein the peripheral neuropathy is hereditary neuropathy. 21. Peripheral neuropathy is facial paralysis,
The therapeutic or prophylactic drug according to any one of claims 1 to 16, which is sciatic nerve palsy, spinal muscular atrophy, muscular dystrophy, myasthenia gravis, Shy-Drager syndrome, SMON, rheumatism, and dyskinesia.