JPH07188205A - Alpha-glucosidase inhibitor - Google Patents

Abstract

PURPOSE:To obtain an alpha-glucosidase inhibitor containing a specific enopyranose derivative or its salt as an active ingredient, useful as a reagent for studying glucoprotein sugar chain processing and a medicine for treating viral diseases such as metastasis and AIDS, diabetes mellitus, etc. CONSTITUTION:This alpha-glucosidase inhibitor contains an enopyranose derivative of formula I (R<1> and R<2> each is H or an alkyl; R<3> is H or an acyl; R<4> is OH, an acyloxy or R<3> and R<4> together form a single bond; X is H or an acyl) or its salt as an active ingredient. As the compound of formula I as the active ingredient, especially, an enopyranose derivative expressed by formula II or formula III or its salt is preferably used. In the compound of formula I, a combination in which R<1> is H or an alkyl and R<2> is an alkyl and X us H or an acyl is preferable. Further, the compound of formula I in which X is furan carbonyl or thiophene carbonyl is preferable. This alpha-glucosidase inhibitor is useful as a medicine for treating hyperlipemia, inflammatory diseases, autoimmune diseases, rejection in organ transplantation, allergic diseases, etc., especially as metastasis inhibitor.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an α-glucosidase inhibitor. More specifically, the present invention is an inhibitor of an enzyme relating to in-vivo sugar chain processing, which is a research reagent for glycoprotein sugar chain processing, and further cancer metastasis, AID
It is useful as a therapeutic drug for viral diseases such as S, diabetes, hyperlipidemia, inflammatory diseases, autoimmune diseases, rejection upon organ transplantation and allergic diseases.

[0002]

2. Description of the Related Art Castanospermine, 1-deoxynojirimycin and the like are known as α-glucosidase inhibitors. However, the α-glucosidase inhibitors of the present invention differ from them in the chemical structure of the active ingredient.
As represented by castanospermine, which is an α-glucosidase inhibitor, inhibitors of enzymes involved in sugar chain processing are cancer metastasis suppressors (Humphries et al., Can).
cer Research 46, 5251-522
2, 1986), suppression of development in an autoimmune encephalomyelitis animal model (Willenburg et al., J. Neuro.
l. Sci, 90, 77-85, 1989), Suppression of development in animal models of arthritis (Willenburg et al.,
Immunol. Cell Biol. 70,369-
377, 1992), suppression of expression of major histocompatibility complex class I molecules on the cell membrane, which is important for immune response (Moore et al.,
J. Biologic. Chem. 268,3809-
3812, 1993) and the like. In addition, Japanese Patent Publication (A) Hei 4-5
00959 has an effect of improving the pathological condition in an autoimmune encephalomyelitis animal model, an adjuvant arthritis model, a tissue transplant rejection model, and a delayed hypersensitivity reaction model. Anti-inflammatory and / or immunosuppressive therapeutic methods have been proposed. Furthermore, the international patent specification WO 8703903 proposes the use of castanospermine as a therapeutic agent against retroviral pathogens such as the AIDS virus. Its action is described as interference of retroviral replication in infected cells resulting from inhibition of processing of sugar chains, and reduction of pathogenic effect associated with presentation of viral envelope glycoprotein on infected cells. In European Patent Specification No. 202661, use of castanospermine for prevention of hyperlipidemia and excessive lipid accumulation and treatment of diabetes is proposed. This is because of the inhibition of digestive enzymes, the inhibition of lipid biosynthesis,
This is due to the inhibition of glucose formation by hydrolysis of complex sugars.

[0003]

As described above, cancer metastasis, AIDS and other viral diseases, diabetes, hyperlipidemia,
In the treatment of inflammatory diseases, autoimmune diseases, rejection at the time of organ transplantation and allergic diseases, it is considered important to inhibit the enzymes involved in sugar chain processing. Based on such an idea, the development of a drug having an α-glucosidase inhibitory action is desired.

[0004]

Means for Solving the Problems The inventors of the present invention have conducted extensive studies using α-glucosidase inhibitory activity as an index, and as a result, found that a compound represented by the following general formula (I) has an excellent inhibitory action. Heading, completed the present invention. That is, the present invention has the general formula (I)

[0005]

[Chemical 3]

(Wherein R ¹ and R ² are each independently a hydrogen atom or a lower alkyl group, R ³ is a hydrogen atom or an acyl group, R ⁴ is an —OH group or an acyloxy group, and R ³ And R ⁴ may combine together to form a single bond, and X is a hydrogen atom or an acyl group), and an α-glucosidase containing an enopyranose derivative or a salt thereof as an active ingredient. Regarding inhibitors. The following three-dimensional structure is included in general formula (I).

[0007]

[Chemical 4]

(In the formula, R ¹ , R ² , R ³ , R ⁴ and X are as described above.) Here, when R ⁴ is a —OH group, (I-1) and (I
-2) is a tautomer. Similarly, (I-3)
And (I-4) are tautomers. The lower alkyl group for R ¹ or R ² means an alkyl group having 1 to 6 carbon atoms. They may be straight or branched chains, eg
Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like can be mentioned. The acyl group of R ³ or X or the acyl of the acyloxy group of R ⁴ means a group represented by RCO— contained in a carboxylic acid. Here, R is an optionally substituted chain hydrocarbon group, an optionally substituted monocyclic hydrocarbon group, an optionally substituted polycyclic hydrocarbon group, or an optionally substituted monocyclic heterocycle. A group or an optionally substituted polycyclic heterocyclic group.

In the general formula (I), examples of the chain hydrocarbon group contained in R include an alkyl group, an alkenyl group and an alkynyl group, and examples of the monocyclic hydrocarbon group include a cycloalkyl group and a cycloalkenyl group. Examples of the polycyclic hydrocarbon group include naphthyl group, tetrahydronaphthyl group, condensed polycyclic hydrocarbon group such as indanyl group or adamantyl group, noradamantyl group, norbornanyl group. Examples thereof include crosslinked polycyclic hydrocarbon groups such as norbornanonyl group, and the monocyclic heterocyclic group includes pyrrolyl group, furanyl group, thienyl group,
Pyrazolyl group, imidazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, thiadiazolyl group, pyrrolinyl group, pyrrolidinyl group, dihydrofuranyl group, tetrahizofuranyl group, dihydrothienyl group, tetrahydrothienyl group, pyradolinyl group,
Hydantoinyl group, oxazolinyl group, isoxazolinyl group, isoxazolidinyl group, thiazolinyl group, thiazolidinyl group, dioxolanyl group, dithialanyl group,
Pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, dihydropyridyl group, tetrahydropyridyl group, piperidinyl group, dihydrooxopyridazinyl group,
Tetrahydrooxopyridazinyl group, dihydrooxopyrimidinyl group, tetrahydrooxopyrimidinyl group, piperazinyl group, dihydropyranyl group, tetrahydropyranyl group, dioxanyl group, dihydrodithinyl group, dithianyl group, morpholinyl group and the like, As the polycyclic heterocyclic group, a thienothienyl group, a dihydrocyclopentathienyl group, an indolyl group, a benzofuranyl group,
Benzothienyl group, benzoxazolyl group, benzisoxazolyl group, benzothiazolyl group, benzimidazolyl group, tetrahydrobenzothienyl group, dihydrobenzofuranyl group, tetrahydrobenzisoxazolyl group, benzodioxolyl group, quinolinyl Examples thereof include condensed polycyclic heterocyclic groups such as group, isoquinolinyl group, benzodioxanyl group, quinoxalinyl group, and bridged polycyclic heterocyclic groups such as quinuclidinyl group.

The substituent of the optionally substituted chain hydrocarbon group contained in R is a halogen atom, an alkoxy group, a haloalkoxy group, an alkylthio group, a cycloalkyl group,
Cycloalkoxy group, cycloalkenyl group, cycloalkenyloxy group, alkoxycarbonyl group, carboxyl group, alkylcarbonyl group, alkylcarbonyloxy group, aryl group, aryloxy group, arylthio group, amino group, amino group substituted with an alkyl group The number of the substituents or the substituents attached to the substituents may be 1 or 2 or more, and in the case of 2 or more, the substituents are the same. Or they may be different. Further, an optionally substituted monocyclic hydrocarbon group contained in R, an optionally substituted polycyclic hydrocarbon group,
The substituents of the optionally substituted monocyclic heterocyclic group and the optionally substituted polycyclic heterocyclic group include a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkylthio group and a cycloalkyl group. , A cycloalkoxy group, a cycloalkenyl group, a cycloalkenyloxy group, an alkoxycarbonyl group, an alkylcarbonyl group,
Examples include an alkylcarbonyloxy group, an aryl group, an aryloxy group, an arylthio group, an amino group, an amino group substituted with an alkyl group, a cyano group, a nitro group, and a hydroxyl group, which are attached to these substituents or their substituents. The number of the substituents may be one, or two or more, and in the case of two or more, the substituents may be the same or different.

The alkyl group and alkyl moiety contained in R have 1 to 18 carbon atoms, for example, a methyl group,
Examples thereof include an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a decyl group, a nonadecyl group, and the like, which also include structural isomers having a linear or branched fatty chain. Examples of the alkenyl group contained in R include those having 2 to 18 carbon atoms, such as a vinyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a decenyl group, a nonadecenyl group, and the like. It also includes structural isomers of branched fatty chains. Examples of the alkynyl group contained in R include those having 2 to 18 carbon atoms, such as an ethynyl group, a propynyl group, a butynyl group, a pentynyl group, a hexynyl group, a decynyl group, and a nonadecynyl group. It also includes structural isomers of branched fatty chains. The cycloalkyl group and the cycloalkyl moiety contained in R include those having 3 to 8 carbon atoms, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclooctyl group and the like. Examples of the cycloalkenyl group and the cycloalkenyl moiety contained in R include those having 5 to 8 carbon atoms, for example, a cyclopentenyl group, a cyclohexenyl group, a cyclooctenyl group and the like. Further, examples of the halogen atom contained in R include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Examples of the aryl group and aryl moiety contained in R include a phenyl group, a thienyl group, a furanyl group, a pyridyl group, a naphthyl group, a benzothienyl group, a benzofuranyl group and a quinolinyl group.

Examples of the salt of the enopyranose derivative represented by the general formula (I) include acid addition salts with mineral acids such as hydrochloric acid and sulfuric acid. The enopyranose derivative which is the active ingredient of the present invention is preferably the following compound group. (1) In the stereostructure of the general formula (I-1) or (I-3), R ¹ and R ² are each independently a hydrogen atom or a lower alkyl group, and R ³ and R ⁴ are together. To form a single bond, and X is a hydrogen atom or an acyl group. (2) A three-dimensional structure of general formula (I-1) or (I-2) or a three-dimensional structure of general formula (I-3) or (I-4),
R ¹ and R ² are each independently a hydrogen atom or a lower alkyl group, R ³ is a hydrogen atom or an acyl group, and R ⁴
Is an —OH group or an acyloxy group, and X is a hydrogen atom or an acyl group.

In the above (1), R ¹ is a hydrogen atom or a lower alkyl group, R ² is a lower alkyl group,
A combination in which X is a hydrogen atom or an acyl group is more desirable. Further, in the above (1), it is more preferable that the acyl group as X is a substituted or unsubstituted furancarbonyl group or a substituted or unsubstituted thiophenecarbonyl group. The enopyranose derivative represented by the general formula (I) or a salt thereof is described in European Patent Application Publication EP056.
It can be obtained by the method described in 0055A. In addition, it can be obtained by the synthesis examples of the representative compounds described below or according to the synthesis examples.

Synthesis Example 1 1,6-anhydro-3,4-
Synthesis of dideoxy-3,4-dimethyl-β-D-threo-hex-3-enopyranose (Compound No. 19)

[0015]

[Chemical 5]

(1) Synthesis of 1,6-anhydro-3,4-dideoxy-4-S-phenylthio-β-D-erythro-hexenoenopyranose-2-ulose 1,6-anhydro-3,4- Dideoxy-β-D-glycero-hexo-3-enopyranose-2-ulose 3
To a dry chloroform solution of 0 g and 29.4 ml of thiophenol was added 2.5 ml of triethylamine at 0 ° C.
After stirring the reaction solution at room temperature for 30 minutes, the solvent was distilled off under reduced pressure. The resulting syrupy crude product was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 1).
Purification in 4) yielded 53 g of the desired product.

(2) 1,6-anhydro-3,4-dideoxy-4-methyl-β-D-glycero-hex-3-
Synthesis of enopyranose-2-ulose Dried tetrachloride of 53 g of 1,6-anhydro-3,4-dideoxy-4-S-phenylthio-β-D-hexoenopyranose-2-ulose obtained in (1) above. Carbon solution 50
33 g of N-chlorosuccinimide was added to 0 ml at 0 ° C., and the mixture was stirred at room temperature for 5 hours. The resulting reaction solution was filtered through Celite and the filtrate was added with 5% sodium hydrogen carbonate (500 ml).
It was washed once with. The organic layer was further washed twice with 500 ml of saturated saline and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting syrupy crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9) to obtain 42 g of the desired product.

(3) 1,6-anhydro-3,4-dideoxy-4-methyl-β-D-glycero-hex-3-
Synthesis of enopyranose-2-ulose Copper cuprous iodide at 0 ° C. under an inert atmosphere of nitrogen gas 32.
230 g of methyllithium (diethyl ether solution, 1.5 M) in 800 ml of dry tetrahydrofuran in 9 g.
1 was gradually added, and the mixture was stirred for 15 minutes. The reaction mixture is -78
1,6-anhydro-obtained in the above (2) after cooling to ℃
3,4-Dideoxy-4-phenylthio-β-D-glycero-hexo-3-enopyranose-2-ulose 40
100 ml of a dry tetrahydrofuran solution of g was gradually added. After stirring for 15 minutes, a small amount of ammonium chloride aqueous solution was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. Ethyl acetate (800 ml) was added to the obtained crude product, and saturated saline solution (50) was added.
It was washed twice with 0 ml. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained syrup-like crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to obtain 12 g of the desired product.
Got

(4) 1,6-anhydro-2-bromo-
3,4-dideoxy-4-methyl-β-D-glycero-
Synthesis of Hexo-3-enopyranose-2-ulose 1,6-anhydro-3,4-dideoxy-4-methyl-β-D-glycero-hexo-3-enopyranose-2-obtained in (3) above To 40 ml of a dry carbon tetrachloride solution containing 1 g of ulose, 5 ml of a carbon tetrachloride solution containing 0.74 ml of bromine was added at -20 ° C. The mixture was stirred at 0 ° C for 15 minutes, and 3 ml of triethylamine was added dropwise. After stirring for 10 minutes at room temperature, a small amount of water was added and the mixture was extracted with 200 ml of methylene chloride. It was washed twice with 200 ml of saturated saline, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting syrupy crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to obtain 1.2 g of the desired product. The NMR analysis values of this product are as follows.

¹ H NMR (CDCl ₃ , 400 MH
z): 2.22 (3H, s); 3.76 (1H, d, J
= 7.2 Hz); 3.91 (1H, dd, J = 7.2)
4.4 Hz); 4.96 (1H, d, J = 4.4H)
z); 5.51 (1H, s)

(5) 1,6-anhydro-2-bromo-
3,4-dideoxy-4-methyl-β-D-glycero-
Synthesis of Hexo-3-enopyranose-2-ulose ethylene acetal 1,6-anhydro-3-bromo-obtained in (4) above
3,4-dideoxy-4-methyl-β-D-glycero-
Hexo-3-enopyranose-2-ulose 1.17 g
70 ml of a dry toluene solution containing 3 ml of ethylene glycol and 0.1 g of paratoluenesulfonic acid was heated under reflux for 1 hour. The reaction solution was cooled to room temperature and 70 ml of ethyl acetate was added. The solution was washed twice with 200 ml of saturated saline, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting syrupy crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to obtain 1.25 g of the desired product.
The NMR analysis values of this product are as follows.

¹ H NMR (CDCl ₃ , 400 MH
z): 1.90 (3H, s); 3.72 (1H, dd,
J = 6.4, 3.6 Hz); 3.75 (1H, d, J =
6.4 Hz); 4.02 (1 H, m); 4.15 (1
H, m); 4.28 (2H, m); 4.66 (1H,
d, J = 3.6 Hz); 5.24 (1H, s)

(6) Synthesis of 1,6-anhydro-3,4-dideoxy-3,4-dimethyl-β-D-glycero-hex-3-enopyranose-2-ulose ethylene acetal Inert atmosphere of nitrogen gas 1,6-anhydro-3-bromo-3,4-dideoxy-4-methyl-β-D-glycero-hexo-3-enopyranose-2-ulose ethylene obtained in (5) above at -78 ° C. Acetal 1.
3.6 ml of n-butyllithium (hexane solution, 1.6M) was gradually added to 60 ml of 25 g of a dry tetrahydrofuran solution, and the mixture was stirred for 10 minutes. Methyl iodide (1.48 ml) and HMPA (1.65 ml) in a dry tetrahydrofuran solution (5 ml) were gradually added to the reaction solution. After stirring for 10 minutes, the dry ice bath was removed and stirring was continued for another 15 minutes.
A small amount of saturated aqueous ammonium chloride solution was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The residue is ethyl acetate 20
The mixture was extracted with 0 ml, washed twice with 200 ml of saturated saline, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting syrupy crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to obtain 0.76 g of the desired product. The NMR analysis values of this product are as follows.

¹ H NMR (CDCl ₃ , 400 MH
z): 1.60 (3H, s); 1.73 (3H, s);
3.67 (1H, d, J = 6.0 Hz); 3.70 (1
H, dd, J = 6.0, 3.6 Hz); 3.98-4.
18 (4H, m); 4.48 (1H, d, J = 3.6H
z); 5.18 (1H, s) mp. 131-134 ° C

(7) Synthesis of 1,6-anhydro-3,4-dideoxy-3,4-dimethyl-β-D-glycero-hex-3-enopyranose-2-ulose 1 obtained in the above (6) , 6-Anhydro-3,4-dideoxy-3,4-dimethyl-β-D-glycero-hexo-
3-Enopyranose-2-ulose To 5 ml of a chloroform solution of 1.05 g of ethylene acetal, 5 ml of water and 10 ml of trifluoroacetic acid were added, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was neutralized with 1N sodium hydroxide and extracted with 200 ml of chloroform. Saturated saline 2
The organic layer was washed twice with 00 ml and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting syrupy crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to obtain 0.8 g of the desired product. The NMR analysis values of this product are as follows.

¹ H NMR (CDCl ₃ , 400 MH
z): 1.76 (3H, s); 2.01 (3H, s);
3.66 (1H, d, J = 6.8Hz); 3.87 (1
H, dd, J = 6.8, 4.4 Hz); 4.78 (1
H, d, J = 4.4 Hz); 5.35 (1 H, s)

(8) 1,6-anhydro-3,4-dideoxy-3,4-dimethyl-β-D-threo-hexo-
Synthesis of 3-enopyranose The 1,6-anhydro-3,4-dideoxy-3,4-obtained in (7) above at -20 ° C under an inert atmosphere of nitrogen gas.
0.2 g of lithium aluminum hydride was gradually added to 40 ml of a dry tetrahydrofuran solution containing 0.8 g of dimethyl-β-D-glycero-hexo-3-enopyranose-2-ulose. After stirring for 10 minutes, a small amount of water was added and the resulting precipitate was removed by filtration through Celite. The filtrate was concentrated under reduced pressure, and the obtained syrupy crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to obtain 0.6 g of the desired product. The physical properties of this product are listed below.

¹ H NMR (CDCl ₃ , 400 MH
z): 1.66 (3H, s); 1.69 (3H, s);
1.86 (1H, d, J = 11.6 Hz); 3.72
(1H, dd, J = 6.4, 3.6 Hz); 3.74
(1H, d, J = 6.4 Hz); 4.08 (1H, b
r. d, J = to 11 Hz); 4.41 (1H, d, J =
3.6 Hz); 5.49 (1 H, d, J = 3.6 Hz)
mp. 74-75 ° C

The following compounds were synthesized from the desired product of Synthesis Example 1 (3) in the same manner as in Synthesis Example 1 (8) above. Describe its physical properties. 1,6-Anhydro-3,4-dideoxy-4-methyl-β-D-threo-hex-3-enopyranose (Compound No. 3) ¹ H NMR (CDCl ₃ , 400 MHz): 1.75
(3H, t, J = 1.7 Hz); 3.76 (2H,
m); 4.29 (1H, br.d, J = -10 Hz);
4.44 (1H, d, J = 3.8Hz); 5.32 (1
H, m); 5.49 (1H, dd, J = 2.9, 1.8)
Hz) Synthesis Example 2 1,6-anhydro-3,4-dideoxy-
Synthesis of 4-methyl-β-D-erythro-hexo-3-enopyranose (Compound No. 28)

[0030]

[Chemical 6]

(1) Synthesis of 1,6-anhydro-3,4-dideoxy-2-formyloxy-4-methyl-β-D-erythro-hex-3-enopyranose At 0 ° C. under an inert atmosphere of nitrogen gas. And 1,6-anhydro-3,4-dideoxy-4-methyl-β-D-threo-
To 30 ml of a dry tetrahydrofuran solution containing 0.54 g of hexo-3-enopyranose, 3 g of triphenylphosphine and 0.43 ml of formic acid, 1.8 ml of diethylazodicarboxylate was gradually added. After stirring at room temperature for 30 minutes, a small amount of water was added and the reaction solution was concentrated under reduced pressure. The obtained syrupy crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 6) to obtain 0.28 g of the desired product. The NMR analysis values of this product are as follows. ¹ H NMR (CDCl ₃ , 400 MHz): 1.83
(3H, s); 3.68 (1H, d, J = 6.4H
z); 3.72 (1H, dd, J = 6.4, 4.4H
z); 4.55 (1H, d, J = 4.4 Hz); 4.8
6 (1H, m); 5.45 (1H, m); 5.53 (1
H, br. s); 8.06 (1H, s)

(2) 1,6-anhydro-3,4-dideoxy-4-methyl-β-D-erythro-hex-3-
Synthesis of enopyranose 1,6-anhydro-3,4-dideoxy-2-formyloxy-4-methyl-β-D-obtained in the above (1)
To 10 ml of a dry methanol solution of 0.275 g of threo-hex-3-enopyranose was added 0.1 ml of sodium methoxide (28% in methanol) at room temperature. 15
After stirring for a minute, a small amount of 20% citric acid aqueous solution was added, and the generated precipitate was removed by filtration through Celite. The filtrate was concentrated under reduced pressure, and the obtained syrupy crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 3) to obtain 0.192 g of the desired product.
The physical properties of this product are listed below.

¹ H NMR (CDCl ₃ , 400 MH
z): 1.65 (1H, d, J = 10.8Hz);
78 (3H, t, J = 1.6Hz); 3.62 (1H,
m); 3.64 (1H, d, J = 6.8Hz); 3.6
9 (1H, dd, J = 6.8, 4.0 Hz), 4.46
(1H, d, J = 4.0 Hz); 5.47 (1H, d
q, J = 5, 6, 1.6 Hz); 5.49 (1H, t,
J = 1.6 Hz) mp. 88-89.5 ° C Synthesis Example 3 1,6-anhydro-3,4-dideoxy-
Synthesis of 3,4-dimethyl-2- (2-furancarbonyloxy) -β-D-threo-hex-3-enopyranose (Compound No. 20)

[0034]

[Chemical 7]

1,6-anhydro-obtained in Synthesis Example 1
To a solution of 0.25 g of 3,4-dideoxy-3,4-dimethyl-β-D-threo-hex-3-enopyranose in dry pyridine at 0 ° C. was added 2-furoyl chloride 0.32 ml.
Was gradually added. After removing the ice bath and stirring at room temperature for 15 minutes, a small amount of water was added, and subsequently 100 ml of ethyl acetate was added. The reaction mixture was diluted with 100 ml of saturated saline to 2 ml.
After washing twice and drying the organic layer with anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure. The obtained syrup-like crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to obtain 0.375 g of the desired product.
Got The physical properties of this product are listed below.

¹ H NMR (CDCl ₃ , 400 MH
z): 1.61 (3H, s); 1.75 (3H, s);
3.78 (1H, dd, J = 6.8, 4.4Hz);
3.94 (1H, d, J = 6.8 Hz); 4.46 (1
H, d, J = 4.4 Hz); 5.62 (1H, br.
s); 5.73 (1H, d, J = 3.2Hz); 6.5
1 (1H, dd, J = 3.6, 2.4 Hz); 7.25
(1H, d, J = 3.6 Hz); 7.59 (1H, d,
J = 2.4 Hz) mp. 116-118 ° C

The following compounds were synthesized according to the case of Synthesis Example 3 above, and the physical properties thereof are described below. 1,6-anhydro-3,4-dideoxy-2- (2-
Furancarbonyloxy) -4-methyl-β-D-threo-hex-3-enopyranose (Compound No. 8) ¹ H NMR (CDCl ₃ , 400 MHz): 1.81
(3H, t, J = 1.7 Hz); 3.82 (1H, dd
d, J = 6.5, 4.4, 0.7 Hz); 3.97 (1
H, d, J = 6.5 Hz); 4.50 (1H, d, J =
4.4 Hz); 5.35 (1 H, m); 5.66 (1
H, br. s); 5.74 (1H, t, J = 2.4H
z); 6.50 (1H, dd, J = 3.3, 1.8H
z); 7.25 (1H, dd, J = 3.3, 0.9H
z); 7.58 (1H, dd, J = 1.8, 0.9H
z) mp. 68-70 ° C

1,6-anhydro-3,4-dideoxy-2- (2-furancarbonyloxy) -4-methyl-
β-D-erythro-hexo-3-enopyranose (Compound No. 33) ¹ H NMR (CDCl ₃ , 400 MHz): 1.84
(3H, t, J = 1.6Hz); 3.70 (1H, d,
J = 6.4 Hz); 3.74 (1H, dd, J = 6.
4,4.4 Hz), 4.57 (1H, d, J = 4.4H)
z); 4.96 (1H, dq, J = 5.6, 1.6H
z); 5.52 (1H, dq, J = 5.6, 1.6H
z); 5.63 (1H, m); 6.50 (1H, dd,
J = 4.0, 2.0 Hz); 7.24 (1H, d, J =
4.0 Hz); 7.58 (br.s) mp. 80-82 ° C

When a lower alkyllithium such as ethyllithium or propyllithium is used in place of methyllithium in Synthesis Example 1 (3) above, a derivative in which R ² has a lower alkyl group other than methyl can be obtained. To obtain a derivative in which R ¹ has a lower alkyl group other than methyl, a lower alkyl iodide such as ethyl iodide or propyl iodide may be used in place of methyl iodide in Synthesis Example 1 (6). The general formula (I-
The conversion of the compound of 1) to the compound of general formula (I-3) can be carried out according to the above-mentioned Synthesis Example 2. In particular, if the compound No. 19 obtained in Synthesis Example 1 is used in place of the starting material of Synthesis Example 2, compound No. 44 can be obtained. To obtain a derivative in which X is an acyl group, a compound in which X is a hydrogen atom may be reacted with a carboxylic acid or a carboxylic acid chloride as in Synthesis Example 3 above. R ³ is a hydrogen atom or an acyl group, and R ⁴ is —OH.
In order to obtain a derivative which is a group or an acyloxy group, the compound obtained in the above (3) or the compound obtained in the above (7) in Synthesis Example 1 is treated with an acid anhydride at −20 ° C.
Reacted with 0.05-0.5 equivalents of sulfuric acid at a temperature of 15 ° C, then optionally in water or alcohol at 10 ° C-30
React with 0.05-0.3 equivalents of sodium hydroxide at a temperature of ° C. Further, by subsequently reacting with carboxylic acid or chloride of carboxylic acid, the selection of the acyl group as R ^{3 and} the acyloxy group as R ⁴ becomes free.
After these reactions, the reaction may be carried out according to Synthesis Example 1 (8) and Synthesis Example 3.

The enopyranose derivative represented by the general formula (I) or a salt thereof has an α-glucosidase inhibitory activity. The α-glucosidase inhibitor can be used as a cancer metastasis inhibitor, a viral disease, diabetes, hyperlipidemia, inflammatory disease, autoimmune disease, rejection reaction and allergic disease therapeutic agent. The general formula (I)
When using the enopyranose derivative or its salt as an active ingredient of a medicine, it cannot be unconditionally specified due to differences in administration conditions such as patient age, body weight, nature and degree of illness, administration route, etc. Usually, it is about 50 mg to 5000 mg per day for an adult and is orally or parenterally administered. The drug can be administered by oral, intravenous, intramuscular, intraarticular, intratissue, cutaneous, mucosal or other methods. Dosage forms include powders, powders, fine granules, granules, tablets, dragees, capsules, injections, nasal drops, suspensions, drops, ointments, syrups, sublingual tablets, suppositories. Agents, sustained-release preparations and the like. These can be produced by an ordinary method using an ordinary pharmaceutically acceptable pharmaceutical carrier as in the case of ordinary pharmaceuticals.

[0041]

EXAMPLES Representative examples of enopyranose or a salt thereof, which is the active ingredient of the present invention, are shown in Tables 1 and 2.

[0042]

[Table 1]

[0043]

[Table 2]

[0044]

[Table 3]

[0045]

[Table 4]

Test Example 1 [α-Glucosidase Inhibitory Activity] α-glucosidase is allowed to act with 4-nitrophenyl-α-D-glucopyranoside as a substrate, and 4-nitrophenol liberated by hydrolysis is quantified by a colorimetric method. It was measured by That is, 0.01 ml of a 40 mU / ml α-glucosidase solution (dissolved in 10 mM phosphate buffer, pH 7.2) and 0.01 ml of a sample-containing solution (dissolved in 10 mM phosphate buffer, pH 7.2) were mixed. rear,
1.5 mg / ml substrate solution (10 mM phosphate buffer,
(dissolved in pH 7.2) 0.08 ml was added to start the reaction. After reacting at 37 ° C. for 60 minutes, 1M sodium carbonate 0.1.
The reaction was stopped by adding 1 ml, and the absorbance at 405 nm was measured. The absorbance (A) of the reaction solution containing the sample and the absorbance (B) of the reaction solution not containing the sample were measured, and the inhibition rate was calculated as (B-
The concentration (IC ₅₀ ) at which α-glucosidase activity was inhibited by 50% was calculated by calculating A) / B × 100. The test results are shown in Table 3. The α-glucosidase used was derived from Saccharomyces sp. The results in Table 3 show that the active ingredient compounds in the present invention have α-glucosidase inhibitory activity.

[0047]

[Table 5]

[Toxicity] DBA1 / J mouse, 6 weeks old,
The active ingredient compound (50 mg / kg) of the present invention was orally administered once a day for 4 weeks every day for 4 weeks, and the change in body weight and the number of deaths were examined. As a result, there was no marked change in body weight or death in any of the administered compounds.

Test Example 2 [Lung Metastasis Inhibition Test of Tumor] By cloning B16F10 mouse melanoma (distributed by Chiba University, Faculty of Medicine), clone B16F10 / L5 showing high metastatic property to lung was established ( Cli
n. Exp / Metastasis 10, 267-2
72, 1992), and an experimental lung metastasis test was performed using this cell line. First, 8 × 10 ⁴ melanoma cells were made to have a diameter of 1 in 10 ml of DME medium containing 10% fetal bovine serum.
The culture was performed using a 0 cm tissue culture dish (5% carbon dioxide gas in an incubator, 37 ° C.). After 3 days, the active ingredient compound was added and the cells were further cultured for 18 hours. As a control, the same amount (6 μl) of dimethyl sulfoxide used as a solubilizer of the active ingredient compound was added, and the same operation as the test drug was performed. Then, the cells were washed once with MEM medium, and the melanoma cells in the dish-attached state were pipetted in 5 ml of MEM medium to obtain a cell suspension. Subsequently, the cells were collected by centrifugation and the number of cells was adjusted to 5 × 10 ⁵ cells / ml. 0.2 ml (1 × 10 ⁵ ) of the melanoma cell suspension thus prepared was added to C57BL / 6NCrj.
It was administered through the tail vein of a mouse (female, 6 weeks old). Administration 17
After a day, the lung was removed and the number of metastatic nodules on the lung surface was counted. Table 4 shows that the compound of the present invention suppressed the experimental lung metastasis of B16 melanoma. The statistically significant difference test was performed by Student's t-test.

[0050]

[Table 6]

[0051]

INDUSTRIAL APPLICABILITY According to the present invention, a new type of α-, which has a different chemical structure from known α-glucosidase inhibitors
Glucosidase inhibitors are provided.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 31/35 ADP ADY AED C07D 493/08 B C12N 9/99 // C07D 493/20 (C07D 493) / 08 309: 00 317: 00)

Claims (4)

[Claims] 1. A compound represented by the general formula (I): (In the formula, R ¹ and R ² are each independently a hydrogen atom or a lower alkyl group, R ³ is a hydrogen atom or an acyl group, R ⁴ is an —OH group or an acyloxy group, and R ³ and R ^{4 are} May form a single bond together, and X is a hydrogen atom or an acyl group), and the α-glucosidase inhibitor is contained as an active ingredient. 2. The active ingredient is represented by general formula (I-1) or (I-
3) [Chemical 2] (In the formula, R ¹ and R ² are each independently a hydrogen atom or a lower alkyl group, R ³ and R ⁴ are taken together to form a single bond, and X is a hydrogen atom or an acyl group). The enopyranose derivative or a salt thereof according to claim 1.
Α-Glucosidase inhibitor of. 3. The α-glucosidase inhibitor according to claim 2, wherein R ¹ is a hydrogen atom or a lower alkyl group, R ² is a lower alkyl group, and X is a hydrogen atom or an acyl group. 4. The α-glucosidase inhibitor according to claim 1, wherein the α-glucosidase inhibitor is a cancer metastasis inhibitor.