JPH0324057A - Polyhydroxypiperidines and production thereof - Google Patents

Abstract

NEW MATERIAL:Compounds of formula I (R1 is H or methyl; One of R2 and R3 is H and the other is OH). EXAMPLE:2-O-Benzyl-3,4,6-tri-O-acetyl-5-O-trimethylsilyl-D-allononitrile. USE:A glycosidase inhibitor. PREPARATION:A ribofuranoside derivative of formula II [One of R4 and R5 is H and the other is alkoxy or formula III (X is R, CH3, OCH3 or Cl); One of R6 and R7 is H and the other is acyloxy, etc.; R8 is acyloxy, etc.; R9 is acyloxy, azide, etc.] and an arabinofuranoside derivative ire reacted with cyanotrimethylsilane in the presence of a Lewis acid and the resultant compound is then subjected to ring opening and carbon increase to obtain a compound of formula IV. The trimethylsilyl group of the resultant compound is substituted for a suitable elimination group and the cyano group thereof is subjected to ring closure by reduction to obtain a compound of formula V. Protective groups of the obtained compound of formula V are removed by a catalytic reduction, thus obtaining the objective compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to polyhydroxybiveridines and a method for producing the same, and more specifically to polyhydroxybiveridines having glycosidase inhibitory activity and their production method. It concerns the manufacturing method.

[Prior Art] Currently, enzyme inhibitors of the pseudosaccharide type (polyhydroxybiperidines) having a nitrogen atom (N) in the sugar ring include deoxynojirimycin, deoxymannonojirimycin, and castanosuber. Min. Swainsonine etc. are known. In particular, castanosvermine has been reported to inhibit the replication of the AIDS virus in cultured cells, and sweinsonine has been reported to reduce the ability of melanoma cancer cells to invade lung tissue [Fellers (L , E. Fe 1 1ows), Chemistry
In Preten (9). 842 (1987)].

These physiological activities are due to the fact that their structure is similar to that of the original substrate, so the enzymatic action is inhibited and the necessary sugar chains are not synthesized7.

In this way, pseudosaccharides containing a nitrogen atom in their rings are expected to have new physiological activities, specifically for diabetes. It is being considered as a treatment for cancer metastasis, AIDS, etc.

The biggest problem when synthesizing polyhydroxybiperidines from saccharides lies in the shape of the biperidine ring, and conventional methods can be broadly classified into the following three types.

I) Intramolecular substitution reaction with amino group or r of oxirane
Both methods using 5A'R reaction and 1-amino-5-0 derived from glucose
Deoxy-L-fuconojirimycin and deoxymannonojirimycin have been synthesized by ring-closing reactions of -mesyl-D-altritol derivatives and 2-amino-6-0-tosyl-D-mannofuranoside derivatives [Furih (G. W.J.Fleet), Chemical Communication, 841. (1985); Chemistry Letters, 1051 (1986)].

2) Method 1-Amino-5 by intramolecular reductive amination
- reductive ring closure of ketose or 5-aminoaldose derivatives. Deoxynojirimycin has been synthesized from D-glucose by the former method [Kinast (G.K.
inast), Angewante Hemyl 93,799
(1981)].

3) Those who use intramolecular amino merculation 6-
Promohexobiranoside to 1-pendylamino-5-
A hexenitol derivative is prepared, which is ring-closed with aminomercuricidin.

Deoxygalactonojirimycin has been synthesized from galactose [R.C.
s), Carbohydrate Research, 167, 3
05 (1987)].

[Problem to be Solved by the Invention 8] An object of the present invention is to provide novel polyhydroxypiveridines having enzyme inhibitory activity and a method for producing the same that is simpler than conventional methods.

[Means for Solving the Problems] The present inventors have made extensive studies regarding the above problems, and as a result, have arrived at the present invention.

That is, the present invention has the following general formula (1): H2 (wherein, R is hydrogen or a methyl group, and RR is 1
2I 3 One of which is hydrogen and the other is a hydroxyl group) is reacted with polyhydroxypiperidines represented by the following general formula (n) trimethylsilane (hereinafter referred to as TMSCN) to open the ring and increase carbon, The following general formula (m) (wherein, R
4 to R9 are the same as above), and then trimethylsilyl (hereinafter, TM
The following general formula (IV) C
H OCH or Cl), 3'
A ribofuranoside derivative or an arabinofuranoside derivative represented by 3' -X (wherein X is the same as above) or an azide group is treated with cyano (R4 to R9 are the same as above) in the presence of a Lewis acid. 1,5-dideoxy-1,5-
Claim 1 characterized in that it is an imino-L monotalitol derivative or a 1,5-dideoxy-1,5-imino-L-iditol derivative, and is subsequently deprotected by catalytic reduction.
) is a method for producing polyhydroxypiperidines described in .

The present invention will be explained in detail below.

The novel compound polyhydroxybiperidine of the general formula (1) according to the present invention is a compound having a pseudosaccharide type structure having a nitrogen atom in the sugar ring, as shown in the formula. Because it has a similar structure to glycosides that are substrates for various glycosidases, it has an inhibitory effect on these enzymes.

This polyhydroxybiperidine (1) can be produced by the method of the present invention.

For production, first, a ribofuranoside derivative or an arabinofuranoside derivative represented by general formula (n) is reacted with TMSCN in the presence of a Lewis acid to form a cyano group and TM
A chain glyconitrile derivative (I[[) is obtained by simultaneously introducing an S group and a single steric configuration.

At this time, the amount of TMSCN used is not particularly limited, but TMSCN is preferably used in excess, more preferably about 5 equivalents, relative to 1 equivalent of general formula (■).

Examples of Lewis acids include boron trifluoride etherate and stannic chloride. The amount used is not particularly limited, but a catalytic amount is sufficient, and preferably 0.1 equivalent is used per equivalent of general formula (■).

The reaction is preferably carried out without a solvent at room temperature. The reaction temperature is
Although not particularly limited, it is generally carried out at about 0°C to 30°C.

The reaction time may vary depending on the reaction conditions, but when the reaction is carried out at about 0°C, it is about 0.5 to 2 hours.

The chain structure having a TMS group represented by the general formula (III) obtained as described above spontaneously undergoes TMS during the reaction.
The MS group is eliminated and a product with a free OH group is obtained.

However, since some products remain with the TMS group introduced, it is preferable to first perform a treatment to remove the TMS group. For example, ferrous chloride may be used in methylene chloride. It is preferable to proceed to the next step of the reaction after all TMS groups have been removed in this way.

Next, a leaving group is introduced by reacting with a suitable acid anhydride or acid chloride in the presence of a base in an organic solvent or in the absence of a solvent. The leaving group is a methanesulfonyl group (Ms in the figure).
), benzenesulfonyl group, toluenesulfonyl group, trifluoromethanesulfonyl group, etc.
An acid anhydride or acid chloride containing them may be used. The amount of acid anhydride or acid chloride to be used is not particularly limited, but is preferably at least equivalent to the chain structure, more preferably about 10 equivalents. Examples of the base include triethylamine and pyridine.

The amount of solvent is not particularly limited, but is generally 1 to 10 ml per mmol. Although the reaction temperature is not particularly limited, it is generally carried out around room temperature. The reaction time is not particularly limited as long as it is several hours or more, but is usually around 20 hours.

Next, the cyano group of the chain structure into which the leaving group has been introduced is reduced using a reducing agent to lead to an amino form. As a reducing agent,
Examples include lithium aluminum hydride and Raney nickel, but lithium aluminum hydride is preferably used. Ether solvents such as tetrahydrofuran are used as the solvent, but diethyl ether is usually used. There is no particular limitation on the reaction time, but one night is sufficient. The reaction temperature is not particularly limited as long as it is below room temperature, but is preferably -30°C.

The generated amino compound can proceed to the next step of the reaction without isolation or purification, and can be ring-closed at the same time as the leaving group is removed;
Obtained by heating under reflux in an ethanol solvent.

Finally, the protecting group is deprotected to obtain the desired polyhydroxypiperazines of general formula (1).

As a method for deprotection, for example, after converting into a hydrochloride form, catalytic reduction may be performed. Palladium on carbon is used as a reducing agent. Examples include palladium hydroxide, but palladium on carbon is preferably used.

As a reaction solvent, acetic acid, methanol with acetic acid added, methanol. Examples include ethanol, but ethanol is preferably used. The reaction time varies depending on the conditions, but is usually 5 to 10 hours.

[Example] Hereinafter, the present invention will be explained in more detail with reference to Examples.

However, the present invention is not limited to these examples.

(Major Example 1) Synthesis of 2-0-benzyl-3.4.6-1-O-acetyl-5-0-trimethylsilyl-D-alononitrile Benzyl-2.3.5-tri-10-acetyl-β-D −
TM to ribofuranoside 500mg (1.3mmol)
13.5 equivalents of SCN and BF3'OEtO.
1 equivalent was added and the reaction was allowed to proceed at room temperature for 2 hours. The reaction solution was poured into a saturated heavy distilled aqueous solution and extracted with 21 terres. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The product was separated and purified by silica gel column chromatography (hexane:ethyl acetate-4:1) to obtain the desired product in a yield of 78.2%.

[α]D-+60.2" 1H-NMR (C6D6) 67.04 (s, Ph), 5.63 (t
, H-3. J3. 4”3.6).5.54 (t,H
-4. J, 5=3.6). 4.62 (d, H-2
．． J2, 3-3.6). 4. 2 9 , 4
．． 5 8 (ABq, CH2)
,4. 10-3. 90 (m, H-5, H-
6a, H-6b). 1.84, 1. 69. 1. 67 (
s, OAc), elemental analysis: calculated value C-56.75, H-
6.71, N-3. 01 Actual measurement value C-56.53, H-6.71. N-3.01 This can be used to produce the corresponding polyhydroxypiveridines. Furthermore, the structures of the reactants and products in this example are shown in FIG.

(Example 2) Combination of 2,3,4,6-tetra0-penzyl-D-alononitrile or benzyl-2.3.5-}-101benzyl-β-D-
Ribofuranoside 3g (6mmo 1), TMSCN3
．． 8ml (30mmol), boron trifluoride etherate 70μl (0.6mmol 1)
were mixed and allowed to react at room temperature for 30 minutes.

The product was separated and purified by silica gel chromatography to obtain three components. That is, 0.93 g (25%) of 2,3,4,6-tetra-0-benzyl-5-0-trimethylsilyl-D-alononitrile, 2,3,4.6
-Tetler 0-benzyl-D-alononitrile 1.6
8 g (52%), and 0.4 g (
19%) yield.

2.3,4.6~Tetler 0-benzyl-510-trimethylsilyl-D-alononitrile'H-NMR (C
DC1 3) 63.36 (dd, H-6a). 3. 46 (dd, H-6b), 3. 7
0 (t, H-4). 4. 04 (m,
H-3, H-5). 4. 56, 4.
80 (ABq, Bn). 4. 60. 4
．． 84 (ABq, Bn), 4. 40
(s, Bn). 4. 60 (s, B
n), 7. 26-7. 30 (Ph). "C.
-NMR (CDCl3) 6 138.212, 137.728,135
．． 87, 116.89, 79.649.
78.673,78. 43,
77. 013,? 5.599. 73,9
4,73,792. 73.257.72.
62, 71. 839.70.
716. Elemental analysis two calculated values C-72.92, H-7.06, N-
2.30 Measured value C-73.08. H-7.01, N-2. 4
6. 2.3,4.6-tetra 0-benzyl-D-alononitrile゜[α] −+59.6°(8-1.71 CHCI
3) D 1H-NMR (CDCI3) 62.45 (d,H-2). 3.48 (d, 2H, H-6a, 6b), 3.70
(dd, H-3). 4.10 (dd, H-4). ~3.94 (m, H-5). 4.41 (s, 2H, Bn). 4.46, 4.64 (ABq, Bn). 4.5
8, 4.82 (ABq, Bn). 4.64,
4.86 (ABq, Bn), 7.26 (s, P
h) "C-NMR (CDC1 3) 6137.77, 137.53, 137.38
, 135.681, 117.135,
78.77, 78.62, 78.43, 77.02, 75.60, 74. 19, 73. 79.73.
307, 72.573, 70.866,
70.132,69. 793. Elemental analysis: Calculated values C-75.95, H-6.56, N-
2.61 Measured values C-75.76, H-6.39. N-2. 4
0. 2,3.5-1-0-benzyl-β-D-ribofuranosyl cyanide [α] D- +1 7.1@(c-1.3 CHC
l3) IH-NMR (CDCl3) 64. 44-4. 60 (3XCH Bn and H-1), 2 4.0 (dd, H-2.J1, 2-4.2, J2,
3-5), 4.28 (t, H-3, J3, 4-5). 4.
24 (m, H-4). 3. 50 (dd
d, H-5a, 5b) 13C-NMR (CDC1
3) 6 137. 77, 137.
33,136.75 (aromatic CH), 127. 72-128. 60 (m + aromatic CM), 117.67 (CN). 83.16,81.
07, 77. 70, 73.
65, 73. 11,72.
67, 69. 45,68
．． 96. (Example 3) Synthesis of 2,3,4.6-tetra-O-benzyl-D-alononitrile 2,3,4.6-tetra-O-benzyl-5-0-}limethylsilyl-D-alononitrile synthesized in Example 2 .9g (1.5mmol) in 5m methylene chloride
Add 0.1 g of ferrous chloride and stir at room temperature for 30 min.
Stir for a minute. The resulting reaction mixture was subjected to silica gel column chromatography (hexane:ethyl acetate-2:1).
Separate and refine the target product to 0.71g (1.3mmo
l) Obtained.

(Example 4) Synthesis of 2,3.4.6-tetra O-benzyl-5-0-methanesulfonyl-D-alononitrile 2,3,4.6-tetra O-benzyl obtained in Examples 2 and 3 D-Arononitrile 3.35g (6.2mmo 1)
was dissolved in 20 ml of pyridine, 5 ml (62 mmol) of methanesulfonyl chloride was added, and the mixture was stirred at room temperature overnight.

The reaction solution was poured into ice-cooled saturated sodium bicarbonate solution and stirred for 30 minutes. The precipitate was filtered through Celite, and the filtrate was diluted with chloroform for 3
Extracted twice. After drying over magnesium sulfate, the residue was concentrated under reduced pressure, and separated and purified by silica gel chromatography (hexane:ethyl acetate-4:1) to obtain 3.6 g (96.8%) of the desired product as a yellow syrup.

1H-NMR (CDC1 3) 64.55 (d, H-2, J 1. 2-3.82
). 3.97 (dd, H-3.J2, 3-6.72)
3. 89 (dd. H-4. J
Simple 3. 05)3. 4 5. 07 (ddd, H-5, J, 5-7
．． 33, 3.36). 3, 6 7 (dd, H-6 a, J,
5-11.2), 3. 58 (dd, H-6b), 2. 9
3 (s, Ms), 4.71, 4.68, 4.63,
4. 39 (CH Bn)2 13C-NMR (CDCl3) δ 80.665, 78.03, 77.
72, 70. 87,74. 1
0, 74. 25,73. 77,
73. 73,69. 73,
42. 489,112.34,
131.41, 130.96, 130.7
4,129. 69 Elemental analysis: Calculated value C-68.30, H-6.01N-2
．． 28 Measured values C-68.99, H-6.29, N-2. 2
3 (Example 5) Synthesis of 2,3,4.6-tetra,10-benzyl-1,5-dideoxy-1,5-imino-L-talitol 2,3.4.6-obtained in Example 4 280 mg (0.45 mmo!) of Tetra 0-benzy-5-0-methanesulfonyl-D-alononitrile was dissolved in 8 ml of ether, and this was dissolved in 28 m of lithium aluminum hydride.
g (0.74 mmol) in 5 ml ether at -78°C.

The temperature was gradually raised to -30°C, and the mixture was stirred for 20 hours. After the reaction was completed, 0.1 ml of water was added, filtered through Celite, dried over magnesium sulfate, dissolved in saturated sodium acetate ethanol solution, and heated under reflux for 6 hours. It was concentrated under reduced pressure, dissolved in chloroform, and washed three times with water. After drying with magnesium sulfate and concentration under reduced pressure, silica gel column chromatography (chloroform:acetone-8=
Purification was performed in step 1) to obtain 110 mg of the target product (46%).

This compound was acetylated to confirm its structure.

[α] = 1 3. 5@(c -1.5
CHC 1 3) D IH-NMR (CDCl3) 6 2. 88 (dd, H-1, J1,
1b-12.0. J1, 2-12.0), 3. 25 (ddd, H-1b, Jeb,
2-5.0. J1, 3-2.1). 4. 72
(dd, H-2). 4.09 (dd, H
3=J3,4-2.2),3. 38 (
dd, H-4. J-6. 0
). 4. 5 4. 19 (ddd, H-5.J5, 6
a-11.0. J5, 6, -2.1)3. 89
(dd. H-6a, J6a, 6, -11.0). 4. 00 (H-6b). 2.1 0 (S, CH3CO), 4.35-4.85 (q.CH2) 13C-NMR (CDCl3) δ 34.701, 75.161.76.8
68, 56,908, 67.158.
71,011.71.159. 73.20
9.74.283, 21.91B, 138.
96, 138.19.137.598,
170.767 elemental analysis: calculated value C-76.43,
H-6.95, N-2. 48 Measured values C-76.21, H-6.99, N-2.41 (Implementation fIJ6) Synthesis Example 5 of 1.5-Iminol-L monotalitol hydrochloride
2.3.4.6-tetra O-benzyl-1 obtained in
．． 5-dideoxy-1,5-imino L-talitol 3
60 mg (6.69 mmol) was dissolved in 6 ml of ethanol, 3 ml of a 4M methanol solution of hydrogen chloride was added, and the mixture was concentrated under reduced pressure. Dissolve in 15ml ethanol, 10%
150 mg of palladium activated carbon was added, and hydrogen gas was passed through the mixture while stirring for about 8 hours. After the reaction was completed, it was filtered through Celite and concentrated under reduced pressure. The residue was subjected to short force chromatography using chloroform:ethanol:water (1:4:2), concentrated, dissolved in 20 m of water and purified with activated carbon 300 m
mg was added. Activated carbon was filtered off, and the mixture was concentrated while azeotropically distilled with ethanol several times to obtain the desired product as a hydrochloride (yield: 97 mg, 70%).

3. 21 (t, IH, H-2, J,
3-3.4), 3. 6 Cb d, I H. H-3, J 3.
4-0) ,3.52 (s,IH,H-4,J,,
5=O). 2. 77 (t, IH, H
-5, J5, 6a-7.02), 3. 24 (d, 2H, H-6a, 6b) 13C
-NMR (CDCl3) δ49. 585, 6, 1. ．． 628,
67. 821, 68.406.68.
844. 60. 361 The structures of the reactants and products in each reaction of Examples 2 to 6 are shown in FIG.

'H-NMR (D20) 6 2. 63 (d. IH, H-1, J
1, 15-14). 2. 89 (dd, IH, H-1b,'
1b,2=3-4), (Example 7) Synthesis of 3,4.6-tri10-benzyl-5-0-trimethylsilyl-2-0-methyl-D-glucononitrile Methyl-2.3 .5-tri-10-benzyl-β-101 arabinofuranoside 630 mg (1.4 mmol). T
MSCN O. 96ml (7.2mmo 1),
Boron trifluoride etherate 1 7.8u 1
(0.14 mmol 1) and reacted at room temperature for 2 hours. The raw material was separated and purified by silica gel column chromatography, and the next three portions were obtained as syrup. That is, 3.4.6-tri-10-benzyl-5-0
110 mg (15%) of -trimethylsilyl-2-0-methyl-D-glucononitrile, 90 mg (14%') of 3,4.6-tri101benzyl-2-0-methyl-D-glucononitrile, 2 ,3.5-tri-10-
100 mg (23%) of benzyl-β(α)-D-arabinofuranosyl cyanide was obtained.

3,4.6-}-O-benzyl-5-0-trimethylsilyl-2-0-methyl-101 glucononitrile IH-NMR (CDC1 3) 60.12 (s, TMS). 3. 43 (s, -OMe), 3. 69
(dd, H-6a, J-4. 5, 9.
9), 3. 47 (dd, H-6b, J-4.
8. 9. 9), 3. 84-4. 05 (m + II-3 + K-4 + H-5
) +4. 26 (d, H-2. J
-4. 5). 4. 45 (s, CH
Bn). 2 4. 63 (s, CH Bn). 2 4. 70 (s, CH Bn), 2 7. 25 (s, Ph) 3,4.6-}-O-benzyl-2-0-methyl 101 glucononitrile [α] o − + 3 0′ (c − 0
．． 8 8 , C H C l 3 ) IH-N
MR (CDC1 3) 6 7. 3 (15H), 4. 7. 4. 56 (CH Bn). 2 4. 5 (CH Bn). 2 4.3 (d, IH, H-2, 72. 3-6). 4
．． 04 (dd. IH, H-3, J3. 4-3) 3.
84 (dd.IH,H 4,J4.5■8)3.
9-4. 0 (IH), 3. 6 (d,
2H, H-6a, 6b), 3. 5
(s, 3H, Me) 13C-NMR (CDCl
3) δ 79. 06, 72. 2
3,70. 72, 69. 94
(CH). 78. 04, 75
．． 26, 74.28, 73.50 (
CH2), 58. 52, 116.
79 (CN). 140, 31, 137.68 (Aromatic) Elemental analysis two calculated values C-72.89, H-6.72, N-
3. 04 Measured value C-72.29, H-6.59. N-2. 9
4. 2,3.5-tri-101benzyl-β(α)D-arabinofuranosylcyanide'H-NMR (CDCl3) 64.68 (d,H-1,J t, 2-2.1)
．． 4.03 (dd, H-2, J-4.5),
2,3 4.20-4.40 (m, H-3, H-4), 3.5
2 (d, H-5a, 5b, “H-NMR (CDC1 3) δ 86.629, 83.73.353,
72. 72.038, 70. 69.109, 116, 1 37. 727, 137, 136. 4
07 5 5 6, 3 77, 3 78, 589 (CN), 1 89. (Example 8) Synthesis of 3,4.6-tri10-benzyl-2-0-methyl101 glucononitrile 3,4.6-}-O-benzyl-2 obtained in Example 7 0.7 g (1.2 mmol) of -0-methyl-5-0-trimethylsilyl-D-glucononitrile was dissolved in 5 ml of methylene chloride, 0.1 g of ferrous chloride was added, and the mixture was stirred at room temperature for 30 minutes. The resulting reaction mixture was separated and purified by silica gel column chromatography (hexane:ethyl acetate-2=1) to obtain 0.59 g (1.
0 mmol I) was obtained.

(Example 9) Synthesis of 3,4.6-1-O-benzyl-5-0-methanesulfonyl-210-methyl-D-glucononitrile 3,4.6-1 obtained in Examples 7 and 8. 6-Tri10-benzyl-2-0-methyl-D-glucononitrile 180m
Dissolve g (0.39 mmol) in 3 ml of pyridine, and add 1 ml of methanesulfonyl chloride (1 ml) under water cooling.
3 mmol) was added. After stirring overnight, the reaction solution was poured into ice-cooled saturated sodium bicarbonate solution, stirred for 7 hours, and extracted three times with chloroform. After drying with magnesium sulfate, it was concentrated under reduced pressure, and filtrated with silica gel short column (hexane:ethyl acetate-4:
Purify in step 1) and use the target product as syrup to produce 160 mg (
74%).

1H-NMR (CDC1 3) 6 7. 3 (15H), 4. 9 (m, IH, H-5). 4,7
, 4.68, 4.24(each
s, 2H, CH2). 3. 7-4. 24 (m. 5H, H-2
+ 3+ 4+ 6a, 6b), 3. 4
4 (s, 3H. Me). 2. 96
(s, 3H, Me) (Example 10) 3.4.6-tri10-benzyl-2-0-methyl-1
．． Synthesis of 5-dideoxy-1,5-imino-L-iditol 160 mg of 3.4.6-tri-O-benzy-510-methanesulfonyl-2-0-methyl-D-glucononitrile obtained in Example 9 ( 0.3 mmo 1) to 7.
The mixture was dissolved in 5 ml of ether and added dropwise to a suspension of 17 mg (0.45 mmol) of lithium aluminum hydride in 3 ml of ether while cooling with water. After 40 minutes, 0. 1 m
1 of water was added and filtered through Celite. After drying over magnesium sulfate and concentration under reduced pressure, the mixture was dissolved in a saturated ethanol solution of sodium acetate, heated under reflux overnight, and concentrated under reduced pressure. Dissolved in chloroform and washed with water. Dry with magnesium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (chloroform:acetone 8:1).
26 mg (20%) of the desired product was obtained.

1H-NMR (CDCl3) 62. 83 (dd. H-1g, J1,
, 5-13. J1, 2-6.4), 3. 00
(dd, H-1b, Jeb, 2-3.83) 3.21 (dt, H-2, J, 3-6.20) 3
．． 57 (t, H-3, J, 4-6.20), 3.3
9 (dd, H-4, J, 5-3.40) 3.34
(ddd, H-5, J, 6a-8.85, J, 6
, -5.45)3. 64 (t, H-6a,
J-9. 2) 5, 6 b 3. 51 (dd, H-6b), 4.64.
4.56. 4.52 (CH2)13C-
NMR (CDC13) δ79.066, 77.047, 76.67
2, 73.794, 73.353,
72.57, 67.594, 57.737
, 54.663, 43.827 This was deprotected in the same manner as in Example 6 to obtain 2-0-methyl-1,5-imino-L-iditol hydrochloride.

The structures of the reactants and products in each reaction of Examples 7 to 10 are shown in FIG. 3.

(Example 11) Enzyme inhibitory activity An enzyme inhibitory activity experiment was conducted on the 1,5-imino-L monotalitol thus synthesized.

As a substrate, p(0)-nitrophenyl glycoside corresponding to each enzyme was used, and 200 μl of a substrate solution (2-4 mM) was used.
Inhibitor (l,5-imino-L-tally 2-6 toll) solution (1.6X10~10 M) 20
Add 0 μl of each enzyme solution (1 μg/m 1 to
7ug/ml)2001tI was added to start the reaction. Incubate at 25°C, and after a certain period of time add 1ml of 0.05M glycine-sodium hydroxide buffer (PH1
0.1), and the color development of p(0) ditrophenol produced by hydrolysis in alkalinity was
The reaction rate was determined by determining the absorbance at nm as 7lνj. Inhibition constant Ki was determined by Dixon-plot.

The enzymes (origins) used are as follows. That is, ■α−
Glucosidase (brewer's yeast) ■β-glucosidase (almond) ■α-galactosidase (coffee bean) ■β-galactosidase (black mold) ■α-mannosidase (jack bean) ■α-fucosidase (cow accessory testis) ■α-fucosidase (cow kidneys), etc.

The inhibitory activities determined in this way are shown in the table below.

Enzyme 50% inhibition (M) [K. [1. IXIO] ■α-fucosidase 8. OX10'-6 [7X10]-3 NI: No inhibitory activity (>5xlO) [Effects of the invention] As is clear from the above explanation, the polyhydro-oxybiperidines of the present invention are effective against glycosidases such as α-glucosidase and α-fucosidase. Inhibitory activity was observed.

The polyhydroxybiperidines of the present invention could be easily produced by the method of the present invention, in which a bofuranoside derivative or an arabinoside derivative is ring-opened with TMSCN, the cyano group is reduced to an amino group, and the ring is closed.

[Brief explanation of drawings]

FIG. 1 is a diagram showing the structures of reactants and products in each reaction of Example 1, FIG. 2 is of Examples 2 to 6, and FIG. 3 is of Examples 7 to 10.

Claims (2)

[Claims] (1) The following general formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) Polyhydroxypiperidines represented. (2) General formula (II) below ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, one of R_4 and R_5 is hydrogen and the other is an alkoxy group, or ▲There are mathematical formulas, chemical formulas, tables, etc.) (in the formula, X represents H, CH_3, OCH_3, or Cl),
Either one of R_6 and R_7 is hydrogen and the other is an acyloxy group, or there are numerical formulas, chemical formulas, tables, etc.▼ (in the formula,
X is the same as above), R_8 is an acyloxy group or ▲ there is a mathematical formula, chemical formula, table, etc. ▼ (in the formula, X is the same as above), R_9 is an acyloxy group, ▲ there is a mathematical formula, chemical formula, table, etc. ▼ A ribofuranoside derivative or arabinofuranoside derivative represented by -X (wherein X is the same as above) or an azide group is reacted with cyanotrimethylsilane in the presence of a Lewis acid to open the ring and increase the carbon content. After forming a chain structure represented by the following general formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) (in the formula, R_4 to R_9 are the same as above), a trimethylsilyl group is added to an appropriate It is converted into a leaving group, and then the cyano group is reduced and ring-closed, resulting in the following general formula (IV) ▲ Numerical formula, chemical formula, table, etc. ▼ (IV) (R_4 to R_9 are the same as above) 1,5
-dideoxy-1,5-imino-L-talitol derivative or 1,5-dideoxy-1,5-imino-L-iditol derivative, followed by deprotection by catalytic reduction (claim 1) ) The method for producing polyhydroxypiperidines described in .