JPH10298189A - Chromium complex - Google Patents

Abstract

(57) Abstract: A chromium complex represented by the formula (1). Embedded image [R ¹ , R ² and R ³ are the same or different and are each a hydrogen atom,
A lower alkyl group, a hydroxyl group, a benzoyl group, a lower alkoxycarbonyl group, or a 3-lower alkyl-4 (3H) -quinazolinone-2-yl group having a halogen atom on a benzene ring. However, those in which R ¹ , R ² and R ³ are simultaneously a hydrogen atom are excluded. [Effect] It is excellent in blood glucose lowering action and insulin lowering action,
It is useful as a drug such as a hypoglycemic agent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel chromium complex excellent in hypoglycemic action and insulin-lowering action.

[0002]

2. Description of the Related Art Conventionally, various compounds have been known as hypoglycemic agents used for the prevention and treatment of diabetes.
For example, chromium (III) tripicolinate is Nakah
[Bull. Chem. Soc. Jpn., 3
5, 782 (1962)] is a known compound, and X-ray crystal structure analysis was performed by Stearns et al. [Inorg.Chem., 31, 5178 (19)
92)] and Evans et al. Have found an action to promote the uptake of insulin in rat skeletal muscle cultured cells [J. Inorg. Chem., 46 (4), 243 (1992)].

[0003] However, it has been reported that the compound did not have sufficient pharmacological activity in a clinical test by NALee et al. [Diabetes Care, 17, 1449 (1994)]. This is probably because the compound is poorly absorbable.

[0004]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a novel compound having an excellent hypoglycemic effect.

[0005]

Under these circumstances, the present inventors have conducted intensive studies, and as a result, have found that the chromium complex represented by the following general formula (1) has an excellent blood glucose lowering action and insulin lowering action. And completed the present invention.

That is, the present invention provides a compound represented by the general formula (1)

[0007]

Embedded image

Wherein R ¹ , R ² and R ³ are the same or different and each represent a hydrogen atom, a lower alkyl group, a hydroxyl group,
3-lower alkyl-4 having a halogen atom on a benzoyl group, a lower alkoxycarbonyl group or a benzene ring
(3H) -quinazolinone-2-yl group is shown. Where R
Excludes those in which ¹ , R ² and R ³ are simultaneously hydrogen atoms. And a chromium complex represented by the formula:

The present invention also provides a medicine containing the chromium complex (1) as an active ingredient.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The chromium complex of the present invention
This is represented by equation (1). Where R ¹, R^TwoPassing
And R^ThreeOf those represented by, as a lower alkyl group
Is, for example, methyl, ethyl, propyl, isopropyl,
Butyl, isobutyl, tert-butyl, pentyl, hex
Linear or branched lower alkyl groups such as
As the lower alkoxycarbonyl group, for example, methoxy
Carbonyl, ethoxycarbonyl, propoxycarboni
, Butoxycarbonyl, pentyloxycarbonyl,
And a hexyloxycarbonyl group.

Also, 3-lower alkyl-4 (3H) -quinazolinone-2- having a halogen atom on the benzene ring.
Examples of the halogen atom in the yl group include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; 3-lower alkyl-4 (3) having a halogen atom on a benzene ring.
H) -Quinazolinone-2-yl group includes, for example, 7-
Chloro-3-methyl-4 (3H) -quinazolinone-2-
Yl, 7-chloro-3-ethyl-4 (3H) -quinazolinone-2-yl, 7-chloro-3-propyl-4 (3
H) -Quinazolinone-2-yl, 7-chloro-3-butyl-4 (3H) -quinazolinone-2-yl, 7-chloro-3-pentyl-4 (3H) -quinazolinone-2-yl, 7-chloro -3-hexyl-4 (3H) -quinazolinon-2-yl, 7-fluoro-3-methyl-4 (3
H) -quinazolinone-2-yl, 7-bromo-3-methyl-4 (3H) -quinazolinone-2-yl, 7-iodo-3-methyl-4 (3H) -quinazolinone-2-yl,
5-chloro-3-methyl-4 (3H) -quinazolinone-
2-yl, 6-chloro-3-methyl-4 (3H) -quinazolinon-2-yl, 8-chloro-3-methyl-4 (3
H) -quinazolinone-2-yl group and the like.

As the chromium complex of the present invention, in formula (1), R ¹ is a hydrogen atom, a lower alkyl group, a hydroxyl group, a benzoyl group or a 3-lower alkyl-4 (3H) having a halogen atom on a benzene ring. ) -Quinazolinone-2-yl group, wherein R ² is a hydrogen atom or a 3-lower alkyl-4 having a halogen atom on a benzene ring.
A (3H) -quinazolinone-2-yl group, wherein R ³ is a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or a 3-lower alkyl-4 (3H) -quinazolinone-2- having a halogen atom on a benzene ring; Preferred is an yl group, and preferred is one in which ^{two of} R ¹ , R ² and R ³ are hydrogen atoms.

A compound of the formula (1) wherein R ¹ is a hydroxyl group and R ² and R ³ are hydrogen atoms;
R ² is 3-lower alkyl -4 having a halogen atom on the benzene ring (3H) - R ¹ in quinazolinone-2-yl group
And R ³ is a hydrogen atom; R ³ is a lower alkoxycarbonyl group or a 3-lower alkyl-4 (3H) -quinazolinone-2- having a halogen atom on a benzene ring.
Compounds in which R ¹ and R ² are hydrogen atoms in the yl group are preferred, and chromium (III) tris (5-ethoxycarbonylpicolinate) is particularly preferred.

The chromium complex (1) of the present invention has cis and trans geometrical isomers, and the present invention naturally includes both. The chromium complex (1) of the present invention has an optical isomer having a chromium atom as an asymmetric center, and the present invention naturally includes both a racemic form and an optically active form. The optical isomers can be separated by a conventional resolution method, for example, a method using an optical resolution column. Further, the chromium complex (1) of the present invention includes both solvates such as anhydrides and hydrates.

The chromium complex (1) of the present invention can be produced, for example, according to the method described in JP-A-8-291190. That is, a trivalent chromium compound and the following compound (2)

[0016]

Embedded image

(Wherein R ¹ , R ² and R ³ have the same meanings as described above) in water at a temperature of about 40 to 90 ° C. to give the chromium complex (1) of the present invention. Obtainable. As the chromium compound used here,
Examples thereof include chromium (III) chloride, chromium (III) fluoride, chromium (III) sulfate, and chromium (III) acetate. These can be used regardless of whether they are anhydrous salts or hydrated salts. it can. The amount of the compound (2) to be used is at least three times the molar amount of the trivalent chromium compound, and in particular, 3 to
It is preferably four-fold, and the pH of the reaction solution is preferably 4.2 or less.

The reaction is usually completed in 10 minutes to 20 hours,
Since the target compound precipitates in the reaction solution, it can be isolated by filtration, washing and drying. Furthermore,
The obtained chromium complex (1) can be purified by usual purification means, for example, adsorption chromatography, recrystallization and the like.

Incidentally, among the above starting compounds (2),
Compound (2a) in which one of R ¹ , R ² and R ³ is a 3-lower alkyl-4 (3H) -quinazolinone-2-yl group having a halogen atom on a benzene ring and the remainder is a hydrogen atom, For example, it can be produced according to the method shown in the following reaction scheme.

[0020]

Embedded image

[Wherein R ⁴ and R ⁵ represent a lower alkyl group, and X represents a halogen atom. ]

That is, the compound (3) is reacted with the acid halide (4) to obtain a compound (5), which is converted into a compound (6) by a cyclization reaction, and then hydrolyzed to obtain a compound (5). (2a) can be obtained.

The reaction between the compound (3) and the acid halide (4) can be carried out in an inert solvent in the presence of a deoxidizing agent. As the inert solvent, benzene, toluene, xylene, aromatic hydrocarbons or aliphatic hydrocarbons such as petroleum ether, ethers such as diethyl ether, ketones such as acetone, ethyl methyl ketone, acetophenone, dichloromethane, chloroform , Carbon tetrachloride, halogenated hydrocarbons such as 1,2-dichloroethane, N, N-dimethylformamide (DMF), and the like. As the deoxidizing agent, amines such as triethylamine, N, N-diethylaniline, N-methylmorpholine, pyridine, and 4-dimethylaminopyridine can be suitably used.

The amount of the acid halide (4) used is
The amount is preferably from equimolar amount to a small excess with respect to compound (3), and the amount of the deoxidizing agent is preferably from equimolar amount to excess amount with respect to compound (3). The reaction is generally performed at 0 ° C.
It can be carried out under a temperature condition of about to room temperature, for about 0.5 to 50 hours.

Next, the cyclization reaction of the compound (5) can be carried out by reacting the compound (5) with a halogenated trialkylsilane in an inert solvent in the presence of a base. Here, as the inert solvent, for example, benzene,
Aromatic or aliphatic hydrocarbons such as toluene, xylene, petroleum ether, ethers such as diethyl ether, dichloromethane, chloroform, carbon tetrachloride, 1,
Halogenated hydrocarbons such as 2-dichloroethane can be used. As the base, for example, tertiary amines such as triethylamine, N, N-diethylalinin, N-methylmorpholine, pyridine and 4-dimethylaminopyridine can be preferably used. Examples of the halogenated trialkylsilane include chlorotrimethylsilane, chlorotriethylsilane, chloroethyldimethylsilane, chlorodimethylpropylsilane, chlorobutyldimethylsilane, chlorotripropylsilane, tributylchlorosilane, and chloroethylmethylpropylsilane. Trialkylsilanes can be suitably used.

The amounts of the halogenated trialkylsilane and base are not particularly limited, but are generally 1 to excess equivalent, preferably 3 to 20 equivalents, relative to compound (5). Usually at 0-100 ° C,
It is completed in about 0.5 to 20 hours.

Next, the compound (6) obtained may be hydrolyzed with an alkali in an inert solvent such as methanol, ethanol, dioxane, tetrahydrofuran (THF) or dichloromethane, for example. Thereby, the compound (2a) can be obtained.
As the alkali used here, for example, an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, or the like is suitably used, and the reaction can be performed at a temperature of 0 ° C. to room temperature in 10 minutes to 5 hours. .

The chromium complex (1) of the present invention thus obtained has an excellent hypoglycemic action and insulin-lowering action, and is used as a medicament such as a hypoglycemic agent and an insulin-lowering agent for the treatment and prevention of diabetes. Useful. Accordingly, it is possible to provide a pharmaceutical composition, a hypoglycemic agent composition, and an insulin-lowering agent composition comprising an effective amount of the compound of the present invention and a pharmaceutically acceptable carrier.

When the compound of the present invention is used as a medicine,
A pharmaceutical composition can be prepared according to a usual method using an appropriate pharmaceutical carrier. As the carrier, various types commonly used for ordinary drugs, for example, excipients, binders, disintegrants,
Lubricants, coloring agents, flavoring agents, flavoring agents, surfactants and the like can be used.

The dosage unit form of the medicament according to the present invention is not particularly limited and can be appropriately selected depending on the purpose of treatment. Specifically, parenteral preparations such as injections and suppositories, tablets, coated tablets, powders and granules Oral preparations such as preparations, capsules, solutions, pills, suspensions, emulsions and the like can be mentioned. The above various drugs are formulated by a formulation method generally known in this field.

In the preparation of oral solid preparations such as tablets, powders and granules, carriers such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silica, Methylcellulose, glycerin, sodium alginate, gum arabic excipient, simple syrup, glucose solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethylcellulose, shellac, methylcellulose, ethylcellulose, hydroxypropylcellulose, water , Ethanol, potassium phosphate and other binders, dried starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid Disintegrators such as steals, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearic acid, cocoa butter, hydrogenated oil, etc., and absorption promoters such as quaternary ammonium bases and sodium lauryl sulfate , Humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, and lubricants such as purified talc, stearates, boric acid powder, polyethylene glycol and the like. Further, the tablet can be a tablet coated with a usual coating, if necessary, for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, a multilayer tablet, or the like.

In the case of molding into a pill form, as a carrier, for example, binding of lactose, excipients such as lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, etc., carabi gum powder, tragacanth powder, gelatin, ethanol, etc. Agent,
Disintegrators such as laminaran and agar can be used.

Capsules are prepared by mixing with the above various carriers and filling into hard gelatin capsules, soft capsules and the like.

In molding into a suppository, carriers include, for example, polyethylene glycol, cocoa butter, lanolin, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, Witepsol (registered trademark Dynamite Nobel) and the like. And an appropriate absorption enhancer.

In the case of forming an injection, carriers such as water, ethyl alcohol, macrogol,
Diluents such as propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, sodium citrate, sodium acetate, pH adjusters and buffers such as sodium phosphate, sodium pyrosulfite, Stabilizers such as ethylenediaminetetraacetic acid, thioglycolic acid, and thiolactic acid can be used. In this case, a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution may be included in the pharmaceutical preparation, and ordinary dissolution aids, soothing agents, local anesthetics, etc. may be added. May be. By adding these carriers, injections for subcutaneous, intramuscular, and intravenous injections can be produced by a conventional method.

Liquid preparations include aqueous or oily suspensions, solutions,
Syrups and elixirs may be prepared according to a conventional method using ordinary additives.

The amount of the compound of the present invention to be contained in the above-mentioned preparations varies depending on the dosage form, administration route, administration schedule and the like and cannot be determined unconditionally, and is appropriately selected from a wide range. The content is preferably about 70% by weight.

The method of administration of the above preparation is not particularly limited, and may be enteral administration, oral administration, rectal administration, buccal administration depending on the form of the preparation, the age of the patient, gender and other conditions, the degree of symptoms of the patient, and the like. The administration method such as transdermal administration is appropriately determined. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally, and suppositories are administered rectally. In the case of an injection, it is administered intravenously either alone or as a mixture with a normal replenisher such as glucose or amino acid, and if necessary, it is administered alone, intraarterially, intramuscularly, intradermally, subcutaneously or intraperitoneally.

The dosage of the active ingredient of the preparation of the present invention depends on the usage,
It is appropriately selected according to the patient's age, sex, disease state, kind of the compound of the present invention to be administered, other conditions, and the like, and is usually about 0.5 to 20 mg / kg / day, preferably 1 to 20 mg / kg / day.
It is preferable that the amount be in the range of about 10 to 10 mg / kg / day. These preparations of the present invention can be administered once or twice or four times a day.

[0040]

Industrial Applicability The chromium complex (1) of the present invention has excellent hypoglycemic action and insulin-lowering action, is useful as a medicament such as a hypoglycemic agent and an insulin-lowering agent, and is suitably used for the prevention and treatment of diabetes. be able to.

[0041]

Next, the present invention will be further described with reference to examples, but the present invention is not limited to these examples.

Reference Example 1 Production of 5- [7-chloro-3-methyl-4 (3H) -quinazolinon-2-yl] picolinic acid: 18.1 g of 6-methoxycarbonylnicotinic acid was added to 10
The suspension was suspended in 0 ml of dichloromethane and 20 ml of N, N-dimethylformamide, and 11.9 g of thionyl chloride was added thereto, followed by refluxing for 1 hour. After the reaction, the mixture was cooled with ice. Next, 2- (N
-Methylcarbamoyl) -5-chloroaniline 18.5
g was dissolved in 200 ml of pyridine, and the above ice-cooled reaction solution was slowly added dropwise at room temperature, followed by stirring at room temperature. After 30 minutes, 100 ml of pyridine was added, and the mixture was further stirred for 1.5 hours. The reaction mixture was poured into ice water, the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to give methyl 5- [N- [5-chloro-2- (N-methylcarbamoyl) phenyl] carbamoyl] picolinate. 8 g were obtained.

27.82 g of the crystals obtained above were suspended in 200 ml of dichloromethane and 97.14 g of triethylamine, 38.24 g of chlorotrimethylsilane were added dropwise at room temperature, and the mixture was heated to reflux. After 30 minutes, 200 ml of dichloromethane was added, and the mixture was further refluxed for 3.5 hours. The reaction solution was poured into ice-cooled 1N hydrochloric acid, 34 g of anhydrous potassium carbonate was added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from dichloromethane-diethyl ether to give methyl 5- [7-chloro-3.
Thus, 18.9 g of colorless crystals of -methyl-4 (3H) -quinazolinone-2-yl] picolinate were obtained.

Subsequently, 18.1 g of the crystals obtained above was dissolved in 300 ml of dichloromethane and 150 ml of ethanol, 28 ml of a 2N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hour. 19 ml of 3N hydrochloric acid was added to the reaction mixture,
Extracted with dichloromethane. After the organic layer was washed with saturated saline, 300 ml of diethyl ether was added. The precipitated crystals were collected by filtration and washed with diethyl ether to obtain 13.3 g of the target compound as colorless crystals.

Reference Example 2 In the same manner as in Reference Example 1, 4- [7-chloro-3-methyl-4 (3H) -quinazolinone-2-yl] picolinic acid was produced.

Example 1 Preparation of chromium (III) tris (3-hydroxypicolinate): 4.17 g of 3-hydroxypicolinic acid and 2.66 g of chromium (III) chloride hexahydrate are suspended in 25 ml of water. And stirred at 80 ° C. for 5 hours. After completion of the reaction, the reaction solution was allowed to cool, the resulting crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain 1.67 g of crystals of the target compound. Structure of the obtained compound, fast atom bombardment mass spectrum (FAB-M
S), Elemental analysis results and infrared absorption spectrum (IR)
Is shown in Table 1. In addition, as a result of X-ray crystal structure analysis, it was confirmed that the obtained compound was in a trans form.

Examples 2 to 7 In the same manner as in Example 1, the compounds shown in Table 1 were produced. Table 1 also shows the structure and physical properties of the obtained compound.

[0048]

[Table 1]

Test Example 1 Five-week-old 6-week-old male Wistar rats (test group)
Dexamethasone (Decadron S Injection; Manyu Pharmaceutical) 0.5 mg / kg was intraperitoneally administered 4 times a day for 4 days. Immediately after the administration, the test compound was dissolved in a 5% gum arabic solution, and Oral administration. Day 4 of dexamethasone administration
After hours, decapitated blood was collected and centrifuged (3000 rpm, 4 ° C,
After 15 minutes), the amounts of glucose and insulin in the obtained serum were measured using glucose cII Test Wako (manufactured by Wako Pure Chemical Industries) and Insulin Test Wako (manufactured by Wako Pure Chemical Industries), respectively. Rats were fed ad libitum and fasted 24 hours prior to blood collection. As a control group, a group to which a 5% gum arabic solution was administered instead of the test compound and a group to which only free feeding was performed as a normal group were provided. The blood glucose and insulin reduction rates were determined from the values (average value) of each group by the following formula. Table 2 shows the results.

[0050]

(Equation 1)

[0051]

[Table 2]

From the results shown in Table 2, the compound (1) of the present invention was
Chromium (III) tripicolinate, a known compound, did not show either effect of lowering blood glucose or at least one of lowering blood insulin.

Example 8 (Preparation of Tablet) Using the compound obtained in Example 1 as an active ingredient, a tablet for oral administration containing 5 mg per tablet (1000 mg)
Tablets) were prepared according to the following formulation:

[0054]

[Table 3] (Formulation) Compound obtained in Example 1 5 g Lactose (Japanese Pharmacopoeia product) 50 g Corn starch (Japanese Pharmacopoeia product) 25 g Microcrystalline cellulose (Japanese Pharmacopoeia product) 25 g Methylcellulose (Japanese Pharmacopoeia product) 1.5 g Magnesium stearate (Japanese Pharmacopoeia) 1g

That is, according to the above formula, the compound obtained in Example 1, lactose, corn starch and crystalline cellulose were thoroughly mixed, the mixture was granulated with a 5% aqueous solution of methylcellulose, carefully dried through a 200-mesh sieve, and dried. The granules thus obtained were passed through a 200-mesh sieve, mixed with magnesium stearate, and pressed into tablets to obtain target tablets.

Example 9 (Preparation of capsules) Using the compound obtained in Example 5 as an active ingredient, two hard gelatin capsules (1000 pieces) for oral administration containing 10 mg per capsule were prepared as follows. Was prepared according to the following formula.

[0057]

[Table 4] (Formulation) Compound obtained in Example 5 10 g Lactose (Japanese Pharmacopoeia) 80 g Starch (Japanese Pharmacopoeia) 30 g talc (Japan Pharmacopoeia) 5 g Magnesium stearate (Japanese Pharmacopoeia) 1 g

That is, according to the above formula, each component was finely powdered, sufficiently stirred so as to form a uniform mixture, and then filled in a capsule for oral administration having a desired size to obtain a desired capsule.

Claims (10)

[Claims] 1. A compound of the general formula (1) [Wherein R ¹ , R ² and R ³ are the same or different and each is a hydrogen atom, a lower alkyl group, a hydroxyl group, a benzoyl group, a lower alkoxycarbonyl group or a 3-lower alkyl-4 having a halogen atom on a benzene ring. (3H) -quinazolinone-2-yl group is shown. However, those in which R ¹ , R ² and R ³ are simultaneously a hydrogen atom are excluded. ] The chromium complex represented by these. 2. In the general formula (1), R ¹ is a hydrogen atom, a lower alkyl group, a hydroxyl group, a benzoyl group or a 3-lower alkyl-4 (3H) -quinazolinone-2- having a halogen atom on a benzene ring. An yl group, R
² is a hydrogen atom or a 3-lower alkyl-4 (3H) -quinazolinone-2-yl group having a halogen atom on a benzene ring, and R ³ is a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or a benzene ring. The chromium complex according to claim 1, which is a 3-lower alkyl-4 (3H) -quinazolinone-2-yl group having a halogen atom. 3. The chromium complex according to claim ¹ , wherein in the general formula (1), two substituents among R ¹ , R ² and R ³ are hydrogen atoms. 4. In the general formula (1), R¹Is hydroxy
R in the sil group^TwoAnd R ^ThreeWherein R is a hydrogen atom, R^TwoBut
3-lower alkyl having a halogen atom on a benzene ring
-4 (3H) -quinazolinone-2-yl group with R¹And R
^ThreeWherein R is a hydrogen atom, and R^ThreeIs lower alkoxy
Has a halogen atom on the carbonyl group or benzene ring
3-lower alkyl-4 (3H) -quinazolinone-2-i
R¹And R^TwoIs a compound selected from the group consisting of
The chromium complex according to claim 3. 5. The chromium complex according to claim 4, which is chromium (III) tris (5-ethoxycarbonylpicolinate). 6. A medicine comprising the chromium complex according to claim 1 as an active ingredient. 7. A hypoglycemic agent comprising the chromium complex according to claim 1 as an active ingredient. 8. A pharmaceutical composition comprising the chromium complex according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier. 9. A hypoglycemic agent composition comprising the chromium complex according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier. 10. An insulin-lowering agent composition comprising the chromium complex according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier.