JP2577050B2 - Chromanol glycoside - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel chromanol glycoside useful as a medicament having a hypoglycemic effect.

Prior art and object of the present invention (Wherein, R ¹ , R ² , R ⁴ , R ⁵ , U, W, and n have the same meanings as described below) were found to exhibit a hypoglycemic effect.

(Japanese Patent Application Laid-Open Nos. 60-51189, 61-36284 and
No. 62-5980) This time, it has been recognized that the glycoside represented by the following general formula (I) corresponding to the general formula (II) has a marked hypoglycemic effect in genetically hyperglycemic animals. Thus, the present invention has been completed.

Structure of the Invention The present invention has a general formula [In the formula, R ¹ represents a hydrogen atom or an alkyl group.

One of R ² , R ³ , R ⁴ and R ⁵ represents a sugar residue (glycoside group) which may be O-acylated and / or esterified; atom,
Alkyl group, lower alkoxy group, nitro group, optionally substituted amino group, formyl group, carboxy group,
It represents an alkoxycarbonyl group, a carbamoyl group which may have a substituent, a thiocarbamoyl group which may have a substituent, an aliphatic acyl group, an aromatic acyl group or a cyano group.

W is a methylene group, a carbonyl group or a formula (In the formula, V represents a hydrogen atom aliphatic acyl group, an aromatic acyl group, an optionally substituted alkyl group, or a glycosyl group corresponding to the sugar residue.)

U represents a methylene group, W is a carbonyl group or a formula (Wherein V has the same meaning as described above), U may form a double bond with R ¹ , and U may form a double bond with W.

n represents an integer of 1 to 3. ] Or a salt thereof.

In the glycoside represented by the general formula (I), the sugar residue (glycoside group) and the glycosyl group are arabinose, ribose, xylose, glucose, 2-deoxyglucose, galactose, mannose, cellobiose, maltose, and lactose. Such sugars or acyl derivatives thereof, and corresponding moieties of uronic acids such as glucuronic acid and galacturonic acid or acyl derivatives and esters thereof are shown.

When R ¹ , R ² , R ⁵ or V is an alkyl group, the alkyl group includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl,
An alkyl group having 1 to 8 carbon atoms such as isopentyl, hexyl, 1,3-dimethylbutyl, heptyl, octyl, 1-methylheptyl, and 2-ethylhexyl;
When R ³ or R ⁴ is an alkyl group, the alkyl group may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, 1,1- Dimethylbutyl, 1,3-dimethylbutyl, heptyl, octyl, 1-methylheptyl, 2-ethylhexyl, 1,1,
Examples thereof include alkyl groups having 1 to 10 carbon atoms, such as 3,3-tetramethylbutyl and decyl.

When V represents an alkyl group having a substituent, the substituent may be an aryl group which may have a substituent such as a phenyl group, a p-methylphenyl group, an m-chlorophenyl group, and an o-methoxyphenyl group. Alternatively, an alkoxycarbonyl group such as a carboxyl group, an ethoxycarbonyl group, and a t-butoxycarbonyl group can be given.

When R ² , R ³ , R ⁴ and / or R ⁵ is an acyl group, when the hydroxyl group of the sugar moiety is O-acylated and when V represents an acyl group, the acyl group may be an acetyl group. Examples thereof include an aromatic acyl group which may have a substituent such as an aliphatic acyl group, a benzoyl group and a p-methylbenzoyl group, and a heterocyclic acyl group such as a nicotinoyl group.

When R ² , R ³ , R ⁴ and / or R ⁵ are an alkoxy group and when the carboxy group of the sugar moiety is alkylesterified, the alkoxy moiety includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, Mention may be made of s-butoxy, i-butoxy and t-butoxy.

When R ² , R ³ , R ⁴ and / or R ⁵ are an optionally substituted amino group, carbamoyl group or thiocarbamoyl group, the amino group may be amino, methylamino, dimethylamino, Methylethylamino, phenylamino, diphenylamino, 4-methylphenylamino,
Aliphatic amino groups such as benzylamino, aromatic amino groups and aromatic amino groups, alicyclic amino groups such as 1-pyrrolidinyl, piperidino and morpholino, and aliphatic or aromatic acylamino groups such as acetamido and benzamide Can be given.

Specific compounds of the chromanol glycoside (I) of the present invention include, for example, the following compounds, but the present invention is not limited thereto.

 Abbreviations in the table are shown below.

Me = methyl group Et = ethyl group Pr = propyl group iPr = isopropyl group Bu = butyl group sBu = s-butyl group tBu = t-butyl group Pn = pentyl group Hx = hexyl group DMB = 1,3-dimethylbutyl group Hp = Heptyl group Oc = octyl group TMB = 1,1,3,3-tetramethylbutyl group Ph = phenyl group Ac = acetyl group glu = β-D-glucose residue (β-D-Glucopyra-no
syloxy-) gal = β-D-galactose residue (β-D-Glacto-pyr
anosyloxy-) cel = cellobiose residue (4-O-β-D-Glucopy-ra)
nosyl-β-D-glucopyranosyloxy-) man = D-mannose residue (α-D-Mannopyran-osylo)
xy-) mal = maltose residue (4-O-α-D-Glucopy-rano
syl-β-D-glucopyranosyloxy-) lac = lactose residue (4-O-β-D-Galacto-pyra
nosyl-β-D-glucopyranosyloxy-) glu-u = β-D-glucuronic acid residue (β-D-Glucopy
ranuronosyloxy-) gal-u = calacturonic acid residue (β-D-Galacto-pyra)
nuronosyloxy-) In the compound (I) of the present invention, more preferably, R ¹ , R ² and R ⁵ are the same or different and each is an alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, propyl, butyl and isobutyl. Yes; R ³ is a residue of uronic acid such as glucuronic acid or a residue represented by an ester derivative thereof, particularly a residue represented by a glucuronic acid residue or a methyl ester derivative thereof; R ⁴ is methyl, ethyl, 1 carbon atom such as propyl, butyl, t-butyl
W is a methylene or carbonyl group, especially a methylene group; U is a methylene group;
And n is 1.

The target compound represented by the above general formula (I) of the present invention can be converted into a pharmacologically acceptable non-toxic salt according to a conventional method. As such a salt, for example, lithium, sodium, potassium or the like can be used. Alkali metal salts; alkaline earth metal salts such as calcium and barium: aluminum salts; and basic amino acid salts such as lysine and arginine. When the salt indicates, for example, a salt of an alkali metal, it may be in the form of its monosalt or disalt.

In the compound (I), when U is a methylene group, the carbon atom at the 2-position of the chroman ring and the carbon atom at the 5-position of the thiazolidine ring are asymmetric carbon atoms, and isomers based on these are also included in the present invention. Included in the compound. In the compound (I), when U and R ¹ constitute a double bond, the carbon atom at the 5-position of the thiazolidine ring is an asymmetric carbon atom, and isomers based on the asymmetric carbon atom are also included in the compounds of the present invention. You.

Sugar residues (for glycoside groups, the 2,2
The 3,4,5 and 6 positions are all asymmetric carbon atoms, but the respective isomers based on them are also included in the compounds of the present invention.

Furthermore, as for the thiazolidine moiety of the compound (I), the following tautomers can be considered, and these are represented by a single general formula (I).

The chromanol glycoside having the general formula (I) of the present invention has the general formula: [In the formula (III), R ¹ , U and n have the same meanings as described above;
² ', R ^3', one of R ⁴ 'and R ^5' represents a hydroxyl group and the other the same meanings as described above, W 'is a methylene group, a carbonyl group, or a group of the formula (Wherein V ′ represents a hydrogen atom, an aliphatic acyl group, an aromatic acyl group or an alkyl group which may have a substituent). And a general formula Gly-X (IV) (in the formula (IV), Gly represents the O-acylated and esterified glycosyl group, and X represents a halogen atom or an acyloxy group.) And a known phenol glycoside synthesis method, for example, JP-A-61-3059.
It is produced by reacting in accordance with the reaction conditions described in the specification of JP-A No.4. In compound (IV), preferred substituents X and O-acyl groups are lower aliphatic acyloxy groups such as acetoxy groups, and preferred ester groups are lower alkyl esters such as methyl esters. Specific examples of compound (IV) include β-D-mannopyranose penta-O-acetate, β-D-maltopyranose octa-O-acetate, and β-D-lactopyranose described in the patent publication. Octa-O-acetate, α- or β-D-glucopyranose penta-O-acetate or J. Am. Chem. So
c., 77 , 3310 (1955), 1,2,3,4-tetra-O-
Methyl acetyl-β-D-glucopyranuronate can be mentioned, and the methyl uronate is preferably used.

In carrying out this reaction, it is preferable to use an organic acid such as paratoluenesulfonic acid as a catalyst, and to promote the de-HX (X has the same meaning as described above) reaction. The reaction is preferably carried out under reduced pressure, and the reaction is usually carried out under a pressure of several mmHg to several tens mmHg. The reaction temperature is not particularly limited, but is usually 50 to 100 ° C.
Heating is preferred. The reaction time varies depending on the reaction temperature, but is usually from 10 minutes to 10 hours. When a solvent is used in this reaction, aromatic hydrocarbons such as toluene and xylene, and nitro compounds such as nitrobenzene are exemplified, and nitrobenzene is preferred. The molar ratio of compound (III) to compound (IV) is not particularly limited, but 1 mol to 10 mol, preferably 2 mol to 4 mol of chromanol compound (III) per 1 mol of compound (IV). It is.

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be isolated by silica gel column chromatography.

If desired, hydrolysis of the acyloxy bond of the sugar moiety and the ester bond of the uronic acid moiety can be carried out. Examples of the solvent include lower alcohols such as hydrated or anhydrous methanol and ethanol, and hydrated methanol is suitable. As the base, 4 to 10 equivalents, preferably 5 to 6 equivalents of sodium hydroxide and potassium hydroxide are used. And alkali hydroxides such as

The reaction temperature is not particularly limited, but is usually preferably -10 ° C to 40 ° C. The reaction time varies depending on the reaction temperature and the type of solvent, but is usually from 10 minutes to 10 hours.

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. Usually, the basic reaction mixture is neutralized with a weakly acidic substance, for example, carbon dioxide, and the resulting crude product can be purified by a conventional method, for example, silica gel column chromatography. it can.

Effect of the Invention The chromanol glycoside having the above general formula (I) of the present invention has shown significant efficacy in an antidiabetic pharmacological test using genetically hyperglycemic animals.

The compound having the general formula (I) and a pharmaceutically acceptable salt thereof are useful as antidiabetic agents for treating diabetes and their complications. Examples of the administration form include oral administration methods such as tablets, capsules, granules, powders, and syrups, and parenteral administration methods such as injections such as subcutaneous injections and intravenous injections, eye drops and suppositories. The dose varies depending on the administration method, symptoms, age and the like. For example, in the case of oral administration, it is 30 mg to 3 g per day for an adult, which can be administered in two or three divided doses.

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

Example 1 2,3,4-tri-O-acetyl-1-O- [2- {4-
(2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl} -2,5,7,8-tetramethylchroman-6
-Yl] -β-D-glucopyranuronic acid methyl 3- {4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl} -2,4-thiazolidinedione 31.0 g 9.8 g of methyl 1,2,3,4-tetra-O-acetyl-β-D-glucopyranuronate, 1.0 g of p-toluenesulfonic acid monohydrate and nitrobenzene
87 ml of the mixture was heated and stirred at 85 ° C. for 4 hours under a reduced pressure of 20 mmHg. Then, it was subjected to silica gel column chromatography of 1.2, and benzene, benzene: ethyl acetate = 100:
Elution was from 1 to 3: 1. From the 4: 1 eluate, 4.6 g (23% yield) of the target product in the form of a caramel was obtained.

R _f value by silica gel thin layer chromatography (developing solvent; benzene: ethyl acetate = 4: 1) = 0.19 NMR spectrum (500 MHz, δppm, CDCl ₃ ): 1.404 (3H, s.), 1.89 (1H, m. ), 2.1 (1H, m.), 2.016 (3H, s.), 2.049 (3H, s.), 2.059 (3H, br.), 2.137 (3H, br.), 2.173 (3H, br.), 2.600 (2H, m.), 3.106 (1H, dd., J = 14.0 and 9.2Hz), 3.441 (1H, dd, J = 14.3 and 4.0 Hz), 3.849 (1H, d., J = 9.8Hz), 3.875 (1H, d., J = 9.2Hz), 4.494 (1H, dd., J = 9.5 and 3.9Hz), 4.750 (1H, d., J = 7.6Hz), 5.236 (1H, dd., J = 9.8 and 8.8Hz), 5.371 (1H, dd., J = 9.6 and 8.8 Hz), 5.344 (1H, dd., J = 9.7 and 7.7 Hz) 6.868 (2H, d., J = 8.5 Hz), 7.126 (2H, d., J = 8.6 Hz), 7.982 ( 1H, br.).

FAB mass spectrum (m / e): 780 ( M + + Na), 757
(M ⁺ ).

Example 2 1-O- [2- {4- (2,4-dioxothiazolidine-
5-ylmethyl) phenoxymethyl {-2,5,7,8-tetramethylchroman-6-yl] -β-D-glucopyranuronic acid (hereinafter abbreviated as glucuronide) The methyl uronate 3.9 obtained in Example 1 g to methanol
The mixture was dissolved in 150 ml, and 26.3 g of a 2.4% by weight aqueous sodium hydroxide solution was added dropwise while stirring under ice cooling. Then, after stirring at room temperature for 1 hour, carbon dioxide gas was blown. Methanol was distilled off under reduced pressure, and 50 ml of silica gel and 150 ml of benzene were added to the obtained residue. Benzene and water were distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. The ethyl acetate: acetic acid = 5: 1 eluate was concentrated under reduced pressure,
The obtained residue was dissolved in ethyl acetate, washed with water, and then dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure to obtain a pale yellow caramel product. Purified water was added to this to make a jelly-like solid. This was ultracentrifuged and then dried under reduced pressure over phosphorus pentoxide to obtain 1.85 g (Y = 55.7%) of the desired glucuronide hemihydrate in the form of a pale yellow powder.

Confirmation of product i) Glucuronide obtained in Example 2 and 5- [4-
(6-Hydroxy-2,5,7,8-tetramethylchroman-
Glucuronide, which is a metabolite of 2-ylmethoxy) benzyl} -2,4-thiazolidinedione in the body, is HP
LC retention times were completely consistent.

ii) When the glucuronide obtained in Example 2 was treated with β-glucuronidase derived from E-Coli, 5-
[4- (6-Hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl} -2,4-thiazolidinedione was provided.

(72) Inventor Kunihiro Sasahara 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. Inside (72) Inventor Daigo No. 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Stock In-house (72) Inventor Takeshi Kinoshita 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Harumitsu Kuwano 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd.

Claims (1)

(57) [Claims] (1) General formula [In the formula, R ¹ represents a hydrogen atom or an alkyl group. One of R ² , R ³ , R ⁴ and R ⁵ is O-acylated and / or
Or a sugar residue (glycoside group) which may be esterified, and the other groups are the same or different and are a hydrogen atom, an alkyl group, a lower alkoxy group, a nitro group, or an amino group which may have a substituent Represents a formyl group, a carboxy group, an alkoxycarbonyl group, a carbamoyl group which may have a substituent, a thiocarbamoyl group which may have a substituent, an aliphatic acyl group, an aromatic acyl group or a cyano group. . W is a methylene group, a carbonyl group or a formula (In the formula, V represents a hydrogen atom, an aliphatic acyl group, an aromatic acyl group, an alkyl group which may have a substituent, or a glycosyl group corresponding to the sugar residue.) U represents a methylene group, W is a carbonyl group or a formula (Wherein V has the same meaning as described above), U may form a double bond with R ¹ , and U may form a double bond with W. n represents an integer of 1 to 3. ] Or a salt thereof.