JPH07316178A - Glycoaminooxazolines - Google Patents

Abstract

PURPOSE:To obtain new compounds having excellent saccharide hydroxidase- inhibiting activity and useful as antibestics, antidiabetics, insecticides and anti- HIV agents. CONSTITUTION:A compound of formula I (R<1> is H or a saccharide residue), e.g. 2-amino-[3aR-(3aalpha,5beta,6alpha,7',7alphabeta)]-5-(hydroxymethyl) 3a,6, 7,7a-tetrahydro-5H- pyrano[2,3-d]oxazole-6,7-diol. The compound is obtained by reacting a compound of formula II (R<2> is acetyl, benzoyl, etc.) with a compound of the formula R<1>aNCS (R<1a> is an amino group protecting group or a saccharide protected with an aralkyl) in an inert solvent (preferably benzene) to afford a compound of formula III, removing R<2> IN the compound of formula III, reacting the product with 2-chloro-3-ethylbenzooxazolium-tetrafluoroborate in an inert solvent (preferably nitriles) in the presence of a base (triethylamine).

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to sugar aminoxazolines which have an excellent sugar hydrolase inhibitory activity and are useful as antiobesity agents, antidiabetic agents, insecticides and anti-HIV agents.

[0002]

2. Description of the Related Art Sugar aminooxazolines which have an excellent sugar hydrolase inhibitory activity and are useful as antiobesity agents, antidiabetic agents, insecticides and anti-HIV agents have not been known.

[0003]

DISCLOSURE OF THE INVENTION The present inventors have synthesized a compound having an excellent sugar hydrolase inhibitory activity and useful as an antiobesity agent, an antidiabetic agent, an insecticide and an anti-HIV agent, and its synthesis. As a result of extensive research on pharmacological activity for many years, the inventors have found that the novel sugar aminoxazolines have excellent sugar hydrolase inhibitory activity, and completed the present invention.

[0004]

The novel sugar aminooxazolines of the present invention have the general formula

[0005]

[Chemical 3]

[In the formula, R ¹ represents a hydrogen atom or a sugar residue. ] Or a compound represented by the general formula

[0007]

[Chemical 4]

[In the formula, R ¹ represents a hydrogen atom or a sugar residue. ] It is a compound represented by.

In the above general formulas (I) and (II),
The sugar of R ¹ is preferably a monosaccharide such as D-glucose, D-mannose or D-galactose, and more preferably D-glucose.

The sugar bond is not particularly limited, but is preferably a bond at the 1-position (α or β) or the 5-position. In the compounds (1) and (2) of the present invention, when R ¹ is a hydrogen atom, it forms a salt, for example, hydrofluoric acid salt, hydrochloride, hydrobromide, hydroiodic acid. Inorganic acid salts such as hydrohalides, nitrates, perchlorates, sulfates, phosphates such as salts; lower alkanesulfonic acids such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate Organic salts such as salts, benzene sulfonates, aryl sulfonates such as p-toluene sulfonate, fumarate, succinate, citrate, tartrate, oxalate, maleate, etc. And amino acid salts such as glutamate and aspartate.

Among the compounds of the present invention, preferred compounds include 1) 2-amino- [3aR- (3aα, 5β, 6α, 7
β, 7aβ)]-5- (hydroxymethyl) -3a,
6,7,7a-Tetrahydro-5H-pyrano [2,3-
d] Oxazole-6,7-diol 2) [3aR- (3aα, 5β, 6α, 7β, 7a
β)]-5- (Hydroxymethyl) -3a, 6,7,7
a-Tetrahydro-2-[(1-deoxy-α-D-mannopyranosyl) amino] -5H-pyrano [2,3-
d] Oxazole-6,7-diol 3) [3aR- (3aα, 5β, 6α, 7β, 7a
β)]-5- (Hydroxymethyl) -3a, 6,7,7
a-Tetrahydro-2-[(1-deoxy-α-D-galactopyranosyl) amino] -5H-pyrano [2,3-
d] Oxazole-6,7-diol 4) [3aR- (3aα, 5β, 6α, 7β, 7a
β)]-5- (Hydroxymethyl) -3a, 6,7,7
a-Tetrahydro-2-[(1-deoxy-α-D-glucopyranosyl) amino] -5H-pyrano [2,3-
d] Oxazole-6,7-diol 5) 2-amino- [3aS- [3aα, 5α (S ^* ),
6α, 6aα]]-5-[(1,2-hydroxyethyl) -3a, 5,6,6a-tetrahydro-2-[(1
-Deoxy-α-D-glucopyranosyl) amino] -furo [2,3-d] oxazole 6) [3aS- [3aα, 5α (S ^* ), 6α, 6a
α]]-5-[(1,2-hydroxyethyl) -3a,
5,6,6a-Tetrahydro-2-[(1-deoxy-
α-D-mannopyranosyl) amino] -furo [2,3-
d] oxazole 7) [3aS- [3aα, 5α (S ^* ), 6α, 6a
α]]-5-[(1,2-hydroxyethyl) -3a,
5,6,6a-Tetrahydro-2-[(1-deoxy-
α-D-galactopyranosyl) amino] -furo [2,3
-D] oxazole 8) [3aS- [3aα, 5α (S ^* ), 6α, 6a
α]]-5-[(1,2-hydroxyethyl) -3a,
5,6,6a-Tetrahydro-2-[(1-deoxy-
α-D-glucopyranosyl) amino] -furo [2,3-
d] Oxazole.

[Production Method] The compounds (I) and (II) of the present invention are known compounds (III) (Tetra-hedron,
34 , 1427 (1978), Can. J. Chem., 58 , 2600 (1980)) and (IV) (Synthesis, 509 (1984)) in three steps.

[0013]

[Chemical 5]

In the above process chart, R ¹ has the same meaning as described above. R ^1a represents a sugar that is protected by an amino-protecting group or an aralkyl group (particularly a benzyl group),
R ² represents an aliphatic lower acyl group (especially acetyl group) or an aromatic acyl group (especially benzoyl group).

(Step 1) In this step, compound (III) is reacted with R ^1a -NCS (IV) in an inert solvent to obtain compound (V).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably, aromatic hydrocarbons such as benzene, toluene and xylene; Methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene,
Halogenated hydrocarbons such as dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether Such ethers can be mentioned.

The reaction temperature is usually 0 to 60 ° C., and the reaction time is 10 minutes to 7 days, preferably 1 hour to 3 days.

After completion of the reaction, the desired product of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, and the mixture is washed with water to form an organic layer containing the target compound. Separate and
It is obtained by drying over anhydrous magnesium sulfate or the like and then distilling off the solvent.

If necessary, the desired compound thus obtained is subjected to a conventional method,
It can be further purified by, for example, recrystallization, reprecipitation or chromatography.

(Step 2) In this step, R ² of compound (V) is removed in an inert solvent to obtain compound (VI).

The solvent used is not particularly limited as long as it can be used in a usual hydrolysis reaction, and water; alcohols such as methanol, ethanol and n-propanol. , Tetrahydrofuran, dioxane
An organic solvent such as tellurium or a mixed solvent of water and the above organic solvent is preferable. The base used is not particularly limited as long as it does not affect other parts of the compound,
Preferably metal alkoxides such as sodium methoxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide or ammonia. Water, ammonia such as concentrated ammonia-methanol is used. The reaction temperature and the reaction time vary depending on the starting material, the solvent, the base used and the like and are not particularly limited, but in order to suppress side reactions, they are usually 0.
To 150 ° C. (preferably 0 to 50 ° C.) for 5 minutes to 24 hours.

After completion of the reaction, the desired product of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, and the mixture is washed with water to form an organic layer containing the target compound. Separate and
It is obtained by drying over anhydrous magnesium sulfate or the like and then distilling off the solvent.

The desired compound thus obtained is, if necessary, used in a conventional method,
It can be further purified by, for example, recrystallization, reprecipitation or chromatography.

(Step 3) In this step, compound (VI) is reacted with 2-chloro-3-ethylbenzoxazolium tetrafluoroborate in the presence of a base in an inert solvent to give compound (Ia) or This is a step of obtaining (IIa).

As the solvent used, nitriles such as acetonitrile and isobutyronitrile are suitable.

The base used is not particularly limited as long as it is a tertiary organic amine, but triethylamine is preferred.

The reaction temperature is usually -20 to 30 ° C, and the reaction time is 10 minutes to 24 hours.

After completion of the reaction, the desired product of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, and the mixture is washed with water to form an organic layer containing the target compound. Separate and
It is obtained by drying over anhydrous magnesium sulfate or the like and then distilling off the solvent.

If necessary, the desired compound thus obtained is subjected to a conventional method,
It can be further purified by, for example, recrystallization, reprecipitation or chromatography.

(Step 4) In this step, the protecting group (aralkyl group) present in the compound (Ia) or (IIa) is removed in an inert solvent to obtain the compound (I) or (II). is there.

The aralkyl group is usually removed by contacting with a reducing agent in a solvent (preferably, catalytic reduction at room temperature under a catalyst). The solvent used in the removal by catalytic reduction is not particularly limited as long as it does not participate in this reaction, but methanol-
Alcohols such as alcohol, ethanol and isopropanol, ethers such as diethyl ether, tetrahydrofuran and dioxane, aromatic hydrocarbons such as toluene, benzene and xylene, hexane and cyclohexane. Suitable are aliphatic hydrocarbons, esters such as ethyl acetate and propyl acetate, fatty acids such as acetic acid, or a mixed solvent of these organic solvents and water.

The catalyst used is not particularly limited as long as it is usually used in a catalytic reduction reaction, but preferably palladium carbon, Raney-nickel, platinum oxide,
Platinum black, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride, palladium-barium sulfate are used.

The pressure is not particularly limited, but is usually 1 to 1
It is carried out at 0 atm. The reaction temperature and reaction time will differ depending on the starting materials, solvent, type of catalyst, etc., but they are usually carried out at 0 to 100 ° C. for 5 minutes to 24 hours.

After completion of the reaction, the desired product of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, and the mixture is washed with water to form an organic layer containing the target compound. Separate and
It is obtained by drying over anhydrous magnesium sulfate or the like and then distilling off the solvent.

If necessary, the desired compound thus obtained is subjected to a conventional method,
It can be further purified by, for example, recrystallization, reprecipitation or chromatography.

[0036]

INDUSTRIAL APPLICABILITY The compound of the present invention exhibits an excellent sugar hydrolase inhibitory activity. Therefore, they are useful as antiobesity agents, antidiabetic agents, insecticides and anti-HIV agents.

Hereinafter, the present invention will be described more specifically with reference to examples.

[0038]

【Example】

[0039]

Example 1 (1a) N- (1-deoxy-2,3,4,6-tetra
-O-acetyl-β-D-glucopyranosyl) -N'-
(1-deoxy-2,3,4,6-tetra-O-benzyl
1-amino-1-deoxy-2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (347 mg) and 10-ml of -α-D-glucopyranosyl) thiourea tetrahydrofuran (THF). 2,3,4,6-O-tetrabenzyl-1-deoxy-
β-D-glucopyranosyl isothiocyanate (586
mg) was added and the mixture was allowed to stand at room temperature for 2 days. After the reaction,
The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (eluted with n-hexane: ethyl acetate = 5: 3) to obtain 585 mg of the target compound as a powdery substance.

Infrared absorption spectrum ν _max (CHCl ₃ ):
1750, 1620 cm ^-1 Nuclear magnetic resonance spectrum 270MHz, (CDCl ₃ ) δ: 2.01 (3H, s), 2.20 (3H, s), 2.04 (3H, s), 2.13 (3H, s), 3.
65-3.84 (7H, m), 4.15 (1H, dd, J = 1,11Hz), 4.29 (1H, dd, J =
4,11Hz), 4.46-4.94 (9H, m), 5.08 (1H, t, J = 9.2-9.9Hz),
5.11 (1H, bs), 5.37 (1H, t, J = 9.2-9.9Hz), 5.95 (1H, t, J =
9.2Hz), 6.75 (1H, d, J = 2.6Hz), 7.11-7.14 (2H, m), 7.26-
7.37 (19H, m) (1b) N- (1-deoxy-β-D-glucopyranosi
) -N '-(1-deoxy-2,3,4,6-tetra
-O-benzyl-α-D-glucopyranosyl) thioure
A compound (430 mg) obtained in (1a) was added to 99.5
% Ethanol (27 ml), potassium hydroxide 27 mg was added there, and it stirred at room temperature for 10 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography (methanol: ethyl acetate = 5:
(Eluted at 95) to obtain 288 mg of the target compound as a powdery substance. Infrared absorption spectrum ν _max (Nujol): 3300 cm ^-1 Nuclear magnetic resonance spectrum 270MHz, (CDCl ₃ ) δ: 3.2-3.9 (12H, m), 4.25-4.90 (9H, m), 5.58 (1H, bs) , 7.06
(2H, bs), 7.2-7.3 (19H, m), 7.68 (1H, bs, NH) (1c) [3aR- (3aα, 5β, 6α, 7β, 7a
β)]-5- (Hydroxymethyl) -3a, 6,7,7
a-tetrahydro-2-[(1-deoxy-2,3,
4,6-Tetra-O-benzyl-α-D-glucopyrano
Syl) amino] -5H-pyrano [2,3-d] oxazo
The compound (206 mg) obtained with diol-6,7-diol (1b) was dissolved in acetonitrile (14 ml), and 2-chloro-3-ethylbenzoxazole tetrafluoro was then dissolved under ice cooling under a nitrogen atmosphere. Borate (206 mg) was added and stirred. After 2 hours, triethylamine (206 mg) was added, and the mixture was further stirred for 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (eluted with methanol: ethyl acetate = 5: 95) to obtain 131 mg of the target compound as a powdery substance.

Infrared absorption spectrum ν _max (Nujol): 33
25, 1640 cm ^-1 Nuclear magnetic resonance spectrum 270MHz, (CDCl ₃ ) δ: 1.5-2.4 (4H, broad), 3.30-4.00 (12H, m), 4.37-4.880 (9
H, m), 5.40 (1H, bs), 7.08-7.11 (2H, m), 7.22-7.32 (20H,
m) (1d) [3aR- (3aα, 5β, 6α, 7β, 7a
β)]-5- (Hydroxymethyl) -3a, 6,7,7
a-Tetrahydro-2-[(1-deoxy-α-D-g
Rucopyranosyl) amino] -5H-pyrano [2,3-
The compound (158 mg) obtained with [ d] oxazole-6,7-diol (1c) was dissolved in methanol (30 ml), and Pd (OH) ₂ / C (3.
0 g) was added, and the mixture was stirred at 60 ° C. for 30 minutes in a hydrogen stream. After completion of the reaction, the catalyst was filtered off and then Amberlite CG-
25 ml of 50 (NH ₄ ⁺ type: H ⁺ type = 3: 2) was used and eluted with water to obtain a fraction of the desired product. This was freeze-dried to obtain 39 mg of the desired product. Infrared absorption spectrum ν _max (KBr): 3700-2800, 1752, 1656, 1563 cm ^-1 High resolution MS spectrum: Measured value: m / z 367.1355 Theoretical value: 367.1352 (m + 1) C ₁₃ H ₂₃ N ₂ O ₁₀ [α] ²⁴ _D : + 18.5 ° (c = 0.83, H ₂ O)

[0042]

Example 2 (2a) N- (1-deoxy-2,3,4,6-tetra
-O-acetyl-α-D-glucopyranosyl) -N'-
(1-deoxy-2,3,4,6-tetra-O-benzyl
L- α-D-glucopyranosyl) thiourea 1-amino-1-deoxy-2,3,4,6-tetra-
Instead of O-acetyl-β-D-glucopyranoside, 1-amino-1-deoxy-2,3,4,6-tetra-O-acetyl-α-D-glucopyranoside was used, Reaction and treatment were carried out in the same manner as in 1a to obtain the target compound.

Infrared absorption spectrum ν _max (Nujol): 33
10, 1740 cm ^-1 mass spectrum m / z 929 (M + 1) ⁺ (2b) N- (1-deoxy-α-D-glucopyranosy
) -N '-(1-deoxy-2,3,4,6-tetra
-O-benzyl-α-D-glucopyranosyl) thioure
A compound (2a) was used and reacted and treated in the same manner as in 1b to obtain the target compound. Infrared absorption spectrum ν _max (Nujol): 3300 cm ^-1 Nuclear magnetic resonance spectrum 270MHz, (CDCl ₃ ) δ: 3.2-3.9 (12
H, m), 4.25-4.90 (9H, m), 5.58 (1H, bs), 7.06 (2H, bs),
7.2-7.3 (19H, m), 7.68 (1H, bs, NH) (2c) [3aS- [3aα, 5α (S ^* ), 6α, 6
aα]]-5-[(1,2-hydroxyethyl) -3
a, 5,6,6a-tetrahydro-2-[(1-deoxy
Ci-2,3,4,6-tetra-O-benzyl-α-D-
Glucopyranosyl) amino] -furo [2,3-d] oxy
The compound of Sazole (2b) was used and reacted and treated in the same manner as in 1c to obtain the target compound. Infrared absorption spectrum ν _max (Nujol): 3600-3200, 1645
cm ^-1 Nuclear magnetic resonance spectrum 270MHz, (CDCl ₃ ) δ: 3.40
-3.87 (14H, broad), 4.45-4.92 (10H, m), 5.40 (1H, bs),
5.67 (1H, d, J = 5.9Hz), 7.06-7.09 (2H, m), 7.22-7.27 (18H,
m) (2d) [3aS- [3aα, 5α (S ^* ), 6α, 6
aα]]-5-[(1,2-hydroxyethyl) -3
a, 5,6,6a-tetrahydro-2-[(1-deoxy
Ci-α-D-glucopyranosyl) amino] -furo [2,
Using a compound of 3-d] oxazole (2c), the reaction and treatment were performed in the same manner as in 1d to obtain the target compound. Infrared absorption spectrum ν _max (KBr): 3370, 1656, 1553,
1428, 1350, 1236,1092, 1031 cm ^-1 High resolution MS spectrum: Measurement: m / z 367.1361 Theoretical: 367.1353 (m + 1) C ₁₃ H ₂₃ N ₂ O ₁₀

Claims (2)

[Claims] 1. A general formula: [In the formula, R ¹ represents a hydrogen atom or a sugar residue. ] The compound represented by these. 2. A general formula: [In the formula, R ¹ represents a hydrogen atom or a sugar residue. ] The compound represented by these.