JP2003128541A - Sugar transportability-enhancing agent, its use, and new geodin derivative used for the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a sugar transportability-enhancing agent used as an antidiabetic medicine which is administered through medication aids other than injection and scarcely causes adverse effects. SOLUTION: This sugar transportability-enhancing agent contains a geodin derivative expressed by general formula (1) (R is H or a lower alkyl which may be substituted; X is H or a halogen; and Y is a halogen). A compound expressed by the general formula (2) is exemplified as the geodin derivative.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a sugar transport enhancer, a drug for diabetes as a typical use thereof as a medicine, and a novel geodin derivative usable therefor.

[0002]

BACKGROUND OF THE INVENTION Drug treatment for type II diabetes is positioned as a treatment method for patients who do not show sufficient improvement by diet therapy or exercise therapy. An oral hypoglycemic agent having an action of improving peripheral insulin resistance has been developed for drug treatment. Currently, there is a method of strictly controlling blood glucose by using an oral hypoglycemic agent II
It has become the main drug treatment for type 2 diabetes, but it does not secrete enough endogenous insulin to suppress blood sugar elevation I
Oral hypoglycemic agents alone are insufficient for patients with type I diabetes, and insulin therapy is still used as a major means of diabetes drug therapy. In addition, since insulin secretory capacity is abolished in patients with type I diabetes, administration of insulin preparations is the only treatment method.

[0003] However, the implementation of insulin therapy has problems of complicated procedures and education of patients due to the use of injections, and improvement of the administration method is strongly desired from the viewpoint of improving compliance. In recent years, several attempts have been made to develop an insulin administration method using various non-injection preparations that replace this injection preparation, but the absorption efficiency is low, and
It has not been put to practical use due to problems such as unstable absorption.

Under the circumstances as described above, it is required to develop a drug for diabetes which can avoid such injection administration.

[0005]

The problem to be solved by the present invention is to develop and provide a drug for diabetes which can be administered by non-injection, has high drug efficacy and has few side effects.

[0006]

[Means for Solving the Problems] As one of the main pathways of hypoglycemic action of insulin, glucose in blood is taken up into peripheral cells by enhancing glucose transporting ability of peripheral cells, and as a result, in blood The action is to reduce the sugar content of. Therefore, the present inventors consider that an orally administrable drug that lowers blood glucose by enhancing the glucose transporting action of peripheral cells will be a promising therapeutic method for diabetic diseases, and As a result of investigating a substance having a compound (compound having a strong sugar transport enhancing action), a geodin derivative represented by the following general formulas (I) and (II) (including those in the form of a salt) is potent. Based on these findings, it has been found that it has a sugar transport enhancing effect, is effective as a drug for diabetes excellent in non-injection administration such as oral administration, and that the above-mentioned geodin derivative (II) is a novel compound. The present invention has been completed.

That is, the present invention resides in a sugar transport enhancer (also referred to as the “sugar transport enhancer of the present invention”) characterized by containing a geodin derivative represented by the following general formula (I).

In another aspect, the present invention is characterized by containing a eosin derivative represented by the following general formula (I) as a typical pharmaceutical application of the above-mentioned sugar transport enhancer. (Also referred to as the “diabetes drug of the present invention”).

When the derivative represented by the following general formula (I) can be in the form of salt, the geodin derivative may be in the form of salt. When used as a medicine, it is particularly preferable to use a pharmaceutically acceptable salt.

[0010]

[Chemical 4]

In the formula, R represents a hydrogen atom or a lower alkyl group which may have a substituent, X represents a hydrogen atom or a halogen atom, Y represents a halogen atom, and Me represents a methyl group.

Among them, R is hydrogen atom, methyl group, ethyl group, n-propyl group, n-butyl group, benzyl group, 4-
Cyanobenzyl group, 4-nitrobenzyl group, 4-methoxycarbonylbenzyl group, 4-methoxybenzyl group, t
-A butoxycarbonylmethyl group or a carboxymethyl group, X and Y may be the same or different, and each is preferably a chlorine atom, a bromine atom or an iodine atom, and particularly X and Y A derivative in which is a chlorine atom is preferred.

Further, a derivative in which R is any of a benzyl group, a 4-cyanobenzyl group, a 4-nitrobenzyl group and a 4-methoxycarbonylbenzyl group and X and Y are chlorine atoms is more preferable.

The present invention resides, in yet another form, in a eosin derivative characterized by being represented by the following general formula (II) (also referred to as "the novel eosin derivative of the present invention").

Similarly, when the geodin derivative can be in the form of a salt, the geodin derivative can be in the form of a salt.

[0016]

[Chemical 5]

In the formula, R represents a hydrogen atom or a lower alkyl group which may have a substituent, X ¹ and Y ¹ represent a halogen atom, and Me represents a methyl group.

However, when both X ¹ and Y ¹ are chlorine atoms, R is not a hydrogen atom or a methyl group.

Among them, a derivative in which R is any one of a benzyl group, a 4-cyanobenzyl group, a 4-nitrobenzyl group and a 4-methoxycarbonylbenzyl group is preferable.

This novel geodin derivative is suitable as an active ingredient of the above-mentioned sugar transport enhancer and diabetes drug.

The above-mentioned drug for diabetes of the present invention is a drug used for the treatment, amelioration, prevention of progression, and / or prevention of diabetes, and has a sugar transport enhancing action, and more specifically, diabetes, diabetic It can be used as a drug for peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy, impaired glucose tolerance and the like.

[0022]

BEST MODE FOR CARRYING OUT THE INVENTION Embodiments of the present invention will be described in detail below.

(Sugar Transport Enhancing Agent of the Present Invention) A substance (composition) containing the geodin derivative represented by the general formula (I) or (II) (including the salt form) as an active ingredient.

In the present invention, the sugar transport enhancing action of the sugar transport enhancer means the action of enhancing the sugar transport ability through the biological membrane, and the sugar transport from the outside to the inside of the biological membrane or from the inside of the biological membrane. Actions on either outward sugar transport can be included in this action. Specifically, for example, the action of insulin, that is, the action of enhancing glucose transport into muscle cells and adipocytes can be mentioned.

The sugar in the sugar transport means a sugar existing in the living body, and particularly includes 5 monosaccharides or 6 monosaccharides. Specifically,
For example, glucose, mannose, arabinose, galactose, fructose and the like can be mentioned, with preference given to glucose.

The active ingredient used in the sugar transport enhancer of the present invention is the geodin derivative contained in the general formula (I) (including its salt form), which will be described in detail below. In addition, the content of the active ingredient described in detail here,
The range also applies to the active ingredients used in the drug for diabetes of the present invention described below.

In the above general formula (I) or (II), R
The lower alkyl group represented by preferably has 1 to 1 carbon atoms.
8 represents a linear, cyclic or branched alkyl group, preferably a methyl group, an ethyl group, an n-propyl group, an n-butyl group and the like, more preferably a methyl group.

The lower alkyl group may have a substituent or may not have a substituent. When it has a substituent, for example, the hydrogen atom of the lower alkyl group is substituted with at least one substituent.
When it has a plurality of substituents, the substituents may be the same or different, and the positions of the substituents are arbitrary and are not particularly limited. Specific examples of the substituent include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, a hydroxyl group, an alkyl group (having 1 to 5 carbon atoms).
Etc.), aryl groups (C6-15, etc.), aralkyl groups (C7-16, etc.), mercapto groups, alkoxy groups (C1-5, etc.), aryloxy groups (C6-1).
5 etc.), alkylthio group (1-5 carbon atoms, etc.), arylthio group (6-15 carbon atoms, etc.), acyl group (1-7 carbon atoms)
Etc.), an acyloxy group (having 1 to 7 carbon atoms), an amino group,
Alkylamino group (C1-5 etc.), amino group protected by amino protecting group, carboxyl group, alkoxycarbonyl group (C2-7 etc.), aminocarbonyl group, nitro group, trifluoromethyl group, cyano Groups and the like. Further, the alkyl group, the aryl group, the aralkyl group, the alkoxy group, the aryloxy group, the alkylthio group, the arylthio group, the acyl group, the acyloxy group, the alkylamino group, the alkoxycarbonyl group and the like, each independently, the halogen atom, Hydroxyl group, mercapto group,
It may have one or more substituents such as an amino group, an amino group protected by an amino protecting group, a carboxyl group, an aminocarbonyl group, a nitro group, a trifluoromethyl group and a cyano group.

As a result, R is a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an n-butyl group, a benzyl group, a 4-cyanobenzyl group, a 4-nitrobenzyl group,
A 4-methoxycarbonylbenzyl group, a 4-methoxybenzyl group, a t-butoxycarbonylmethyl group and a carboxymethyl group are preferable, and a 4-cyanobenzyl group is more preferable.

In the formula (I), X and Y are preferably fluorine atom, chlorine atom, bromine atom and iodine atom, and more preferably chlorine atom.

In the formula (II), X ¹ and Y ¹ are preferably a fluorine atom, a chlorine atom, a bromine atom and an iodine atom,
Of these, chlorine atom is more preferable.

However, in the above formula (II), X ¹ and Y
^When all ¹ are chlorine atoms, R is not a hydrogen atom or a methyl group.

The above-mentioned sugar transport enhancer or the geodin derivative used as an active ingredient of the below-mentioned diabetes drug is a derivative represented by the above-mentioned general formula (I), and in the case of a derivative which can take a salt form, its salt Those in the form of are also included in this derivative. As the salt, a pharmaceutically acceptable salt is preferable, and for example, for a sufficiently acidic geodin derivative (free form), its ammonium salt, alkali metal salt (sodium salt, potassium salt, etc.) is exemplified as preferable salt. ), Alkaline earth metal salts (calcium salts,
Magnesium salts and the like are exemplified as preferable ones. ), And salts of organic bases include, for example, dicyclohexylamine salt, benzathine salt, N-methyl-D-glucan salt, hydrabamin salt, arginine, and amino acid salts such as lysine.

The same applies to the case of diabetic drugs, but the geodin derivative (including salt form) used as the active ingredient is in any of the isomer forms such as all optical isomers and geometric isomers. But it can be used.

Further, it may be in the form of hydrate, solvate or the like, and may be used not only in the crystalline form but also in the form of amorphous derivative.

The sugar transport enhancer of the present invention is a living body, for example, a mammal, particularly a human, for which an action defined as above is required.
It can be applied to pets. The present invention is typically suitable for pharmaceutical use, particularly as a drug for diabetes, and therefore, for more details, refer to the description of the drug for diabetes of the present invention below.

Regarding the production of the geodin derivative used as the active ingredient of the sugar transport enhancer or the diabetes drug in the present invention, and the novel geodin derivative of the present invention described below, the known substances are based on the prior art, and the novel derivatives are It can be manufactured by applying a known technique.

The pharmacological activity of geodine is described, for example, in a paper (The Journal of Antibiotics,
22, Vol. 442, 1969), but it is different from the pharmacological activity aimed at in the present invention. Furthermore, as a compound similar to Geodin, Sch202596 (Tetrahedron Letters, 3
See Volume 8, page 6111, 1997. ), Antibiotic S
S19508B (see JP-A-60-260570) and D (see JP-A-61-43182), R in the compound according to claim 1
Compounds in which is a methyl group and X is a chlorine atom (see The Journal of Chemical Society, p. 1767, 1958) and the like are known, but both compounds have a sugar transport enhancing activity and a hypoglycemic effect. No activity has been reported.

Further, a specific geodin derivative can be produced based on the following method or by applying the method.

(Production Example of Geodin Derivative) For example, Peni
By culturing the cillium glabrum AJ117540 strain,
(+)-Geodin (derivative III) or (+)-antibiotic SS19508B (derivative IV) is obtained. Also,
The dihydrogeogin (derivative V) produced by the same bacterium was prepared by a known method (Tetrahedron Letters, 41, 465, 200).
See Year 0. (±) -geogin (derivative V
I) can also be synthesized.

The above Penicillium glabrum AJ117540 strain was submitted to the National Institute of Advanced Industrial Science and Technology on July 1, 2001.
It has been deposited on the 3rd and the deposit number is FERM P-18419.

[0042]

[Chemical 6]

[0043]

[Chemical 7]

[0044]

[Chemical 8]

In the general formula (I), the compound (derivative VII) in which R is a lower alkyl group or a substituted lower alkyl group and X and Y are chlorine atoms is (+) or (±) -geoZine. (Derivative VI) can be synthesized by the following method using it as a raw material.

[0046]

[Chemical 9]

In the above formula, R is the above general formula (I).
R has the same meaning as R and represents an optionally substituted lower alkyl group.

More specifically, first, (+)-or (±)-
After dissolving geodin in a suitable solvent, it is reacted with a corresponding alkyl halide in the presence of a base such as potassium carbonate. The geodin derivative represented by the general formula (VII) thus obtained can be isolated and purified by a known isolation and purification means, for example, concentration under reduced pressure, solvent extraction, crystallization, phase transfer, chromatography and the like.

In the above reaction, the reaction reagent used for O-alkylation is a reagent for O-alkylating the phenolic hydroxyl group, for example, methyl iodide, benzyl bromide, 4-cyanobenzyl bromide, 4- Examples thereof include nitrobenzyl bromide, 4-methoxycarbonyl benzyl bromide, 4-methoxybenzyl bromide, t-butyl acetate bromide and the like.

On the other hand, in the above general formula (I), the compound (derivative X) in which X and Y are bromine atom or iodine atom is a sulochrin produced by AJ117540 strain.
n) (Formula VIII) can be used as a starting material and synthesized by the following method.

[0051]

[Chemical 10]

More specifically, first, suloculin is dissolved in a suitable solvent and then reacted with a corresponding halogenating reagent, or if necessary, an oxidizing agent is added to react with the halogenating reagent to give a dihydrogeozin derivative (formula IX). Convert. Compound (I
Conversion from X) to compound (X) can be performed according to the above-mentioned method for synthesizing (±) -geodin. When an oxidizing agent coexists, the compound (IX) generated in the reaction system may be oxidized and converted into the compound (X). The obtained compound represented by the general formula (X) can be isolated and purified by a known isolation and purification means, for example, concentration under reduced pressure, solvent extraction, crystallization, phase transfer, chromatography and the like.

In the above reaction, reagents used for halogenation include chlorine, bromine, benzyltetramethylammonium tribromide, iodine and the like.

(Geodin Derivative of the Present Invention) The present invention also includes the geodin derivative represented by the general formula (II) (new derivative). Here, all the compounds of the derivative (II) are
Since it is included in the compound of the derivative (I), the range of the derivative, particularly R, the form of the salt, etc., is not inconsistent and within the necessary range.
The description of can be applied as it is. That is, the geodin derivative of the present invention includes, among the above-mentioned geodin derivatives (II), a novel derivative having a sugar transport enhancing action and a salt thereof.

As with the geodin derivative represented by the general formula (I), the novel geodin derivative represented by the general formula (II) has a sugar transport-enhancing effect as described above, and a disease mediated by this effect. It is extremely useful as an active ingredient of a drug or an intermediate thereof for the treatment of vaccination and treatment of animals that require such an action. Typically, as a sugar transport enhancer, it can be used as an active ingredient of a drug for treating, ameliorating, preventing the progress, preventing, etc. of diabetes or an intermediate thereof by lowering the blood glucose level by a sugar transport enhancing effect. .

With respect to the production method, the desired geodin derivative can be produced based on the description of the production of the geodin derivative.

(Diabetes drug of the present invention) A drug containing a geodin derivative represented by the above general formula (I) or (II) (including a salt form) as an active ingredient.

Regarding the subject to which the drug of the present invention is administered,
Treatment for diabetic diseases, IDDM, NIDDM,
There is no particular limitation as long as it requires improvement, prevention of progress, prevention, etc., but it is applied to mammals, usually humans (patients).

In particular, it can be used as a drug for diabetes, diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy, impaired glucose tolerance and the like.

Although the present invention is a drug containing the above-mentioned geodin derivative as an active ingredient, other active ingredients (the same pharmacologically active substance as the active ingredient used in the present invention or different pharmacologically active substances) may be used in combination. In addition, it may contain an auxiliary agent useful in the preparation. In the present invention, any drug containing the above-mentioned geodin derivative in an effective amount for exhibiting a sugar transport enhancing effect is included in the drug of the present invention.

Regarding the administration route, oral administration, intravenous administration,
Various administration forms such as transdermal administration are possible.

Regarding the dose, the symptoms of the patient to be administered,
Since it varies depending on the age and the administration method, it is appropriately selected according to such factors. Usually, for example, in the case of oral administration, preferably 0.001 to 1000 mg / kg / day, more preferably 0.005 to 50
About 0 mg / kg / day, more preferably about 0.01 to 100 mg / kg / day may be adopted. On the other hand, in the case of parenteral administration such as injection administration, about 1/2 to 1/10 of the dose in the case of oral administration is adopted.

In addition to the above-mentioned active ingredients, pharmaceutically acceptable excipients, carriers, diluents and other formulation auxiliaries are appropriately mixed as auxiliaries useful in the above formulation, and tablets and capsules are prepared by a conventional method. It can be administered orally or parenterally in the form of an agent, granule, fine granule, powder, pill, syrup, suspension, emulsion, ointment, suppository or injection. In the present invention, a pharmaceutical preparation or a pharmaceutical composition containing the above-mentioned geodin derivative as an active ingredient (active ingredient) and a pharmaceutically acceptable carrier and / or diluent is preferable.

Here, examples of the carrier and diluent include glucose, sucrose, lactose, talc, silica, cellulose, methyl cellulose, starch, gelatin, ethylene glycol, polyethylene glycol, glycerin, ethanol, water and oils and fats.

The drug of the present invention in the above-exemplified pharmaceutical form may be in the form of the above-mentioned components (geozin derivative represented by the general formula (I) or (II) or a salt thereof) in an amount effective for exerting a medicinal effect. It is a matter of course that it should contain.

The drug of the present invention is used as a health food, a medical food, a specified health food, etc. for the purpose of the above-mentioned anti-diabetes including the prevention thereof or for providing a meal to a patient already having such a disease. However, even when used in such health foods, orally ingestible components necessary as health foods etc. with reference to the above-mentioned oral administration preparation,
It can be prepared by adding additives. In that case, it is possible to provide in the form of food (including all things put into the mouth such as chewing gum and toothpaste), nutritional supplement, infusion preparation, etc., which are naturally included in the use of the drug of the present invention. The medical food and the like may be solid or liquid, and its form is not limited.

[0067]

EXAMPLES The present invention will now be described in detail with reference to examples, but the present invention is not limited to these examples.

(Example 1) (+)-geodin and (+)-antibiotic SS
Isolation of 19508B (Step 1) Penicill isolated from soil collected in Okinawa Prefecture
ium glabrum AJ117540 strain (trust number: FERM P-18419)
Mashed potato (20g / L), glucose (5g / L), N
Z-Case (2g / L), yeast extract (2g / L), NaCl (2g / L),
Inoculate an Erlenmeyer flask containing a liquid medium (pH 7.0) containing CaCO ₃ (3 g / L) and shake at 4 ° C for 4 days.
Cultured at 80 rpm). Glucose (20 g /
L), mannitol (20g / L), glycerol (5g / L),
Corn jam meal (20g / L), Ebios (10g / L),
Inoculate an Erlenmeyer flask containing a liquid medium (pH 6.8) of the composition of total amino acid (3g / L) and CaCO ₃ (4g / L), and
The cells were cultured on a rotary shaker (180 rpm) for a day.

(Step 2) The culture solution (10 L) thus obtained was centrifuged to separate the cells and the supernatant. The cells were extracted with acetone (3.5 L) at room temperature. Acetone extract is filtered to remove bacterial cell residues, and
Concentrated to 600 mL water suspension. Methanol (400m
L) was added to make a 40% aqueous methanol solution, and the mixture was extracted with chloroform (600 mL x 3). The chloroform transfer fraction was passed through a Diaion HP-20 column, washed with a 50% aqueous methanol solution, and then eluted with methanol. The methanol elution fraction was passed through a silica gel column and eluted with a chloroform / methanol (99: 1) solution containing 1% formic acid. The active fraction was passed through a Sephadex LH-20 column, and eluted and purified with a chloroform / methanol (1: 1) solution. The active fraction was collected by HPLC using ODS (water containing 0.1% formic acid-acetonitrile).
And silica gel preparative TLC (chloroform containing 1% formic acid-
(+)-Geodine (formula II
I) (27 mg) and (+)-antibiotic SS19508
B (derivative IV; 15 mg) was obtained.

Example 2 Dihydrogeodin (derivative V; 150 mg) was obtained by the silica gel column chromatography in Example 1.

Example 3 A chloroform broth (3 L) of the AJ117540 strain separately cultured under the same conditions as in Example 1 was obtained according to the method of Example 1 and subjected to silica gel column chromatography [chloroform containing 1% formic acid]. / Methanol (95:
5)], washing with methanol, and purification by HPLC fractionation using ODS (water-acetonitrile containing 0.1% formic acid) to obtain slocculin (derivative VIII; 52 mg).

(Example 4) Synthesis of (±) -geoZine from dihydrogeoZine DihydrogeoZine (135 mg) in chloroform / methanol (1: 1) solution (4 mL) Was added to 2,3-dichloro-5,6-. Dicyano-
p-Benzoquinone (DDQ; 80 mg) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluted with chloroform containing 1% formic acid) to obtain (±) -geodin (derivative VI; 95 mg) (yield 71%).

Example 5 Methyl 5,7-dichloro-4,6'-dimethoxy-6-methyl-3,4'-
Synthesis of dioxospiro [benzofuran-2 (3H), 1 '-[2,5] cyclohexadiene] -2'-carboxylate (±) -Geozine (4.5 mg) in dimethylformamide (D
MF) solution (0.2 mL) was added with potassium carbonate (2 mg) and methyl iodide (0.03 mL), and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel preparative thin layer chromatography (chloroform) to obtain a eosin derivative (derivative VIIa; 3 mg).

Yield 64%; FAB MS m / z 413 (M + H) ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ ) d: 2.59 (3H, s), 3.70 (3
H, s), 3.74 (3H, s), 4.12 (3H, s), 5.81 (1H, d,
J = 1.5Hz), 7.13 (1H, d, J = 1.5Hz).

[Chemical 11]

Example 6 Methyl 4-benzyloxy-3,5-dichloro-6′-methoxy-6
-Methyl-3,4'-dioxospiro [benzofuran-2 (3H),
Synthesis of 1 '-[2,5] cyclohexadiene] -2'-carboxylate According to the same method as in Example 4, using (±) -geodine and benzyl bromide as raw materials, the geosine derivative (derivative VII
b) was synthesized.

Yield 92%; FAB MS m / z 489 (M + H) ⁺ ; ¹ H NMR d: 2.58 (3H, s), 3.68 (3H, s), 3.74 (3H,
s), 5.29 (1H, d, J = 11.1Hz), 5.38 (1H, d, J = 11.1H)
z), 5.82 (1H, d, J = 1.8Hz), 7.15 (1H, d, J = 1.8H
z), 7.34-7.40 (3H, m), 7.53 (2H, brd, J = 7.2Hz).

[0077]

[Chemical 12]

Example 7 Methyl 5,7-dichloro-6′-methoxy-6-methyl-4- (4-nitrobenzyloxy) -3,4′-dioxospiro [benzofuran-2 (3H), 1 ′ Synthesis of-[2,5] cyclohexadiene] -2'-carboxylate According to the same method as in Example 4, (±) -geodin and 4-
A geozin derivative (derivative VIIc) was synthesized using benzyl nitrobromide as a raw material.

Yield 37%; ESI MS m / z 532 (MH) ^- ; ¹ H NMR (300 MHz, CDCl ₃ ) d: 260 (3H, s), 3.69 (3
H, s), 3.76 (3H, s), 5.39 (1H, d, J = 12.0Hz), 5.
47 (1H, d, J = 12.0Hz), 5.83 (1H, d, J = 1.5Hz), 7.1
4 (1H, d, J = 1.5Hz), 7.72 (2H, d, J = 8.4Hz), 8.23
(2H, d, J = 8.4Hz).

[0080]

[Chemical 13]

Example 8 Methyl 5,7-dichloro-4- (4-cyanobenzyloxy)-
Synthesis of 6'-methoxy-6-methyl-3,4'-dioxospiro [benzofuran-2 (3H), 1 '-[2,5] cyclohexadiene] -2'-carboxylate Following the same method as in Example 4 , (±) -geozin and 4-
A geozin derivative (derivative VIId) was synthesized using benzyl cyanobromide as a raw material.

Yield 52%; ESI MS m / z 512 (MH) ⁻ ; ¹ H NMR (300 MHz, CDCl ₃ ) d: 2.60 (3H, s), 3.69 (3
H, s), 3.75 (3H, s), 5.33 (1H, d, J = 11.7Hz), 5.
41 (1H, d, J = 11.7Hz), 5.82 (1H, d, J = 1.2Hz), 7.1
4 (1H, d, J = 1.2Hz), 7.66 (4H, s).

[0083]

[Chemical 14]

Example 9 Methyl 5,7-dichloro-4- (4-methoxycarbonylbenzyloxy) -6′-methoxy-6-methyl-3,4′-dioxospiro [benzofuran-2 (3H), 1 Synthesis of '-[2,5] cyclohexadiene] -2'-carboxylate By following the same procedure as in Example 4, (±) -geoZine and 4-
A geozin derivative (derivative VIIe) was synthesized using benzyl methoxycarbonyl bromide as a raw material.

Yield 61%; FAB MS m / z 547 (M + H) ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ ) d: 2.58 (3H, s), 3.68 (3
H, s), 3.75 (3H, s), 3.91 (3H, s), 5.35 (1H, d,
J = 11.4Hz), 5.45 (1H, d, J = 11.4Hz), 5.81 (1H, d,
J = 1.2Hz), 7.14 (1H, d, J = 1.2Hz), 7.60 (2H, d, J
= 8.1Hz), 8.03 (2H, d, J = 8.1Hz).

[0086]

[Chemical 15]

Example 10 Methyl 5,7-dichloro-4- (4-methoxybenzyloxy)
Synthesis of -6'-methoxy-6-methyl-3,4'-dioxospiro [benzofuran-2 (3H), 1 '-[2,5] cyclohexadiene] -2'-carboxylate 4-methoxybenzyl alcohol (0.05 Acetyl bromide (0.1 mL) was added to (mL), and the mixture was stirred at room temperature for 1 hour, and then excess reagent was distilled off under reduced pressure to give 4-methoxybenzyl bromide. By using this 4-methoxybenzyl bromide and (±) -geozin as the starting materials and following the same method as in Example 4, a eosin derivative (derivative VIIf) was synthesized.

Yield 27%; FAB MS m / z 519 (M + H) ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ ) d: 2.58 (3H, s), 3.68 (3
H, s), 3.74 (3H, s), 3.81 (3H, s), 5.22 (1H, d,
J = 10.5Hz), 5.30 (1H, d, J = 10.5Hz), 5.82 (1H, d,
J = 1.5Hz), 6.88 (2H, d, J = 8.7Hz), 7.15 (1H, d, J
= 1.2Hz), 7.45 (2H, d, J = 8.7Hz).

[0089]

[Chemical 16]

Example 11 Methyl 4- (tert-butoxycarbonylmethyl) -3,5-dichloro-6′-methoxy-6-methyl-3,4′-dioxospiro [benzofuran-2 (3H), 1 ′ -[2,5] Cyclohexadiene] -2 '
-Synthesis of Carboxylate According to the same method as in Example 4, (±) -geodine and t-butyl bromide acetate were used as raw materials to synthesize a geodin derivative (derivative VIIg).

Yield 91%; ESI MS m / z 530 (M + NH ₄ ) ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ ) d: 1.44 (9H, s), 2.59 (3
H, s), 3.67 (3H, s), 3.72 (3H, s), 4.95 (1H, d,
J = 15.9Hz), 5.02 (1H, d, J = 15.9Hz), 5.79 (1H, d,
J = 2.1Hz), 7.12 (1H, d, J = 2.1Hz).

[0092]

[Chemical 17]

Example 12 Methyl 4- (carboxymethyl) -5,7-dichloro-6'-methoxy-6-methyl-3,4'-dioxospiro [benzofuran-2
(3H), 1 '-[2,5] Cyclohexadiene] -2'-carboxylate synthetic compound VIIg (5mg) in dichloromethane solution (0.5mL) trifluoroacetic acid (0.1mL) was added and stirred for 1 hour The solvent was distilled off under reduced pressure to synthesize a geodin derivative (derivative VIIh; 4.5 mg).

Yield 100%; ESI MS m / z 455 (MH) ^- ; ¹ H NMR (300 MHz, CDCl ₃ ) d: 2.62 (3H, s), 3.70 (3
H, s), 3.75 (3H, s), 4.89 (2H, br), 5.83 (1H,
s), 7.14 (1H, d, J = 1.2Hz).

[0095]

[Chemical 18]

Example 13 Methyl 5,7-dibromo-4-hydroxy-6′-methoxy-6-methyl-3,4′-dioxospiro [benzofuran-2 (3H), 1 ′-[2,
Synthesis of 5] cyclohexadiene] -2'-carboxylate (formula Xa) (Step 1) Sulocrine (40 mg) was dissolved in a dichloromethane / methanol mixture (1 mL), and then calcium carbonate (25 mg) and benzyltetramethylammonium tribromide ( 95m
g) was added, and the mixture was stirred at room temperature for 30 minutes. After adding dichloromethane to the reaction solution, the organic layer was washed with 5% hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. The residue was purified by silica gel preparative TLC (chloroform / methanol containing 1% formic acid) to obtain compound IXa (37 mg).

Yield 63%; ESI MS m / z 487 (MH) ^- ; ¹ H NMR (300MHz, CDCl ₃ / DMSO-d ₆ (3: 1)) d 2.52 (3H, s),
3.61 (3H, s), 3.63 (3H, s), 6.57 (d, J = 1.5Hz), 6.93 (1
H, d, J = 1.5Hz).

[0098]

[Chemical 19]

(Step 2) Compound IXa (30 mg) was dissolved in THF / methanol (1: 1) (1.5 mL), DDQ (15 mg) was added, and the mixture was stirred at room temperature for 2 hours.
Stir for hours. After adding water to the reaction solution, it was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. The residue was purified by silica gel preparative TLC (chloroform / methanol containing 1% formic acid) to synthesize a geodin derivative (derivative Xa; 16 mg).

Yield 54%; ESI MS m / z 485 (MH) ^- ; ¹ H NMR (300MHz, CDCl ₃ ) d 2.69 (3H, s), 3.70 (3H, s),
3.74 (3H, s), 5.83 (d, J = 1.5Hz), 7.15 (1H, d, J = 1.5H
z).

[0101]

[Chemical 20]

Example 14 Methyl 5,7-diiodo-4-hydroxy-6′-methoxy-6-methyl-3,4′-dioxospiro [benzofuran-2 (3H), 1 ′-[2,
5] Cyclohexadiene] -2'-carboxylate synthesis In a DMF solution (1 mL) of sloculin (20 mg), iodine (16 mg)
And potassium iodide (11mg) and sodium acetate (5m
g) was added, and the mixture was stirred at room temperature for 14 hours. After adding ethyl acetate to the reaction mixture, the mixture was washed with 5% sodium hydrogen sulfite.
The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel preparative thin layer chromatography (chloroform / methanol) to obtain a eosin derivative (derivative Xb; 4 mg).

Yield 11%; ESI MS m / z 581 (MH) ^- ; ¹ H NMR (300MHz, DMSO-d ₆ ) d 2.79 (3H, s), 3.64 (3H,
s), 3.69 (3H, s), 6.02 (d, J = 1.5Hz), 7.01 (1H, d, J = 1.
5Hz).

[0104]

[Chemical 21]

(Example 15) Evaluation of sugar transport activity 1. Acquisition of rat adipocytes Six male Wistar rats (body weight 150-200 g) were laparotomized after decapitation and bleeding, and a total of 6 g of paratesticular adipose tissue was extracted. this
6 mL KRH (Krebs Ringer Hepes: composition, sodium chloride 130 mM, potassium chloride 4.7 mM, potassium dihydrogen phosphate 1.2 mM, magnesium sulfate 1.2 mM, calcium chloride 1 mM, Hepes 25 mM containing 5% BSA (bovine serum albumin) , PH
= 7.6), shredded into 2 mm squares, added with 24 mg of collagenase (type I) and digested for about 40 minutes to obtain about 6 ml of isolated adipocytes. After removing collagenase by buffer exchange, 2% BSA / KRH solution was added and resuspended to obtain 45 ml of adipocyte suspension.

2. Evaluation of Sugar Transport Activity The sugar transport activity of the active ingredient, the eosin derivative, used in the present invention was evaluated with reference to the method described in the literature (Annual Review of Biochemistry, 55, 1059, 1986). . That is, the above adipocyte suspension was dispensed into polystyrene test tubes by 200 μL each, and the test substance (10
Dilute the mg / mL dimethyl sulfoxide solution with KRH. 100 μL of the above solution was added, and the mixture was shaken and then incubated at 37 ° C for 30 minutes.

The sugar transport activity was evaluated by measuring the amount of 2- [ ¹⁴ C (U)]-deoxy-D-glucose incorporated into adipocytes per unit time. That is, 2- [ ¹⁴ C (U)]-deoxy-D-glucose was added to the adipocyte suspension after the pre-culture (final concentration 0.5 μCi / sample), and after 5 minutes, cytochalasin B was added.
Sugar transport was stopped by adding (final concentration 10 μM). Dinonyl phthalate is layered and then centrifuged to separate the fat cells from the buffer,
The amount of [ ¹⁴ C (U)]-deoxy-D-glucose was measured with a liquid scintillation counter to quantify the amount of incorporated sugar. In this evaluation system, insulin (100 nM), which has a sugar transport enhancing action, showed a 7-fold enhancing action as compared with the drug-free control group.

The table below shows the results of evaluating the sugar transport activity of the compound of the present invention at a concentration of 30 μg / mL. The sugar transport activity in Table 1 shows the ratio to the sugar transport enhancing action with respect to 1 when the drug was not added.

[0109]

[Table 1]

As a result of the above evaluation, it can be seen that the geodin derivative used in the present invention exhibits a sugar transport enhancing action. In particular,
(+) Or (±) -geogin and geodin derivatives (VI
It can be seen that Id) and the like have more excellent effects.

[0111]

As is clear from the above results, the geodin derivatives (including those in the form of salts) used in the present invention have a sugar transport-enhancing effect and are particularly useful as a drug for diabetes. It is useful for treating diabetes. That is, it lowers blood glucose by enhancing action of glucose transport, and is a drug for diabetes, diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy, glucose intolerance, etc. It is useful as a therapeutic drug.

Thus, according to the present invention, a sugar transport enhancer,
In particular, a drug for diabetes can be provided, and therefore the present invention is industrially very useful in the field of medicine. Furthermore, it is possible to provide a novel geodin derivative which can be used as an active ingredient of such a drug or an intermediate thereof.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 27/02 A61P 27/02 C07D 307/94 C07D 307/94 (72) Inventor Takao Ikegami Kawasaki City, Kanagawa Prefecture 1-1 Ajinomoto Co., Ltd., Kawasaki-ku, Ajinomoto Co., Inc. (72) Inventor Yama-saki ▼ Akiyo 1-1 Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa Ajinomoto Co., Inc. F-term (reference) 4C037 WA02 4C086 AA01 AA02 BA05 MA01 NA14 ZA20 ZA33 ZA36 ZA81 ZC35

Claims (9)

[Claims] 1. A sugar transport enhancer comprising a geodin derivative represented by the following general formula (I). When the geodin derivative can take a salt form, the geodin derivative may take a salt form. [Chemical 1] In the formula, R represents a hydrogen atom or a lower alkyl group which may have a substituent, X represents a hydrogen atom or a halogen atom, Y represents a halogen atom, and Me represents a methyl group. 2. A drug for diabetes, which comprises a geodin derivative represented by the following general formula (I). When the geodin derivative can take a salt form, the geodin derivative may take a salt form. [Chemical 2] In the formula, R represents a hydrogen atom or a lower alkyl group which may have a substituent, X represents a hydrogen atom or a halogen atom, Y represents a halogen atom, and Me represents a methyl group. 3. The drug for diabetes according to claim 2, wherein X and Y in the formula (I) are halogen atoms. 4. In the formula (I), R is a hydrogen atom, methyl group, ethyl group, n-propyl group, n-butyl group, benzyl group, 4-cyanobenzyl group, 4-nitrobenzyl group, 4- The diabetes drug according to claim 2 or 3, which is any one of a methoxycarbonylbenzyl group, a 4-methoxybenzyl group, a t-butoxycarbonylmethyl group and a carboxymethyl group. 5. In the formula (I), R is a benzyl group,
4-cyanobenzyl group, 4-nitrobenzyl group and 4-
The drug for diabetes according to any one of claims 2 to 4, which is any one of methoxycarbonylbenzyl groups and X and Y are chlorine atoms. 6. The drug for diabetes according to claim 2, which is used for diabetes, diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy or impaired glucose tolerance. 7. A geodin derivative represented by the following general formula (II). When the geodin derivative can take a salt form, the geodin derivative may take a salt form. [Chemical 3] In the formula, R is a hydrogen atom or a lower alkyl group which may have a substituent, X ¹ and Y ¹ are halogen atoms, and Me is
Represents a methyl group, respectively. However, when both X ¹ and Y ¹ are chlorine atoms, R is not a hydrogen atom or a methyl group. 8. In the formula (II), R is a benzyl group,
The eosin derivative according to claim 7, which is one of a 4-cyanobenzyl group, a 4-nitrobenzyl group, a 4-methoxycarbonylbenzyl group, a 4-methoxybenzyl group, a t-butoxycarbonylmethyl group and a carboxymethyl group. 9. The geodin derivative according to claim 7, which has a sugar transport enhancing effect.