JP2009234946A - Combined drug - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound having excellent adiponectin production potentiation. <P>SOLUTION: This combined drug comprises an insulin resistance improving drug and a CB1 receptor antagonist as active ingredients. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to an adiponectin production enhancer comprising a combination of an insulin sensitizer and a cannabinoid (CB) 1 receptor antagonist. Furthermore, the present invention relates to a therapeutic agent or preventive agent for hypoadiponectinemia, syndrome X or metabolic syndrome, which comprises a combination of an insulin sensitizer and a CB1 receptor antagonist, and diabetes caused by hypoadiponectinemia (Including type I diabetes, type II diabetes), diabetic complications (including retinopathy, nephropathy, neurosis, cataract, coronary artery disease), hypertension, obesity or arteriosclerosis .

  Furthermore, the present invention relates to the use of the above-mentioned compound for producing the above-mentioned medicine, or a method for preventing or treating the above-mentioned disease, wherein the above-mentioned medicine is administered to a warm-blooded animal (preferably a human).

  Adiponectin is a protein that is specifically produced and secreted from adipocytes, and is closely involved in energy balance and sugar or lipid metabolism (see Non-Patent Document 1). In fact, patients with cardiovascular disease, diabetes, obesity, etc. have decreased blood adiponectin levels, and among patients with kidney disease, patients with lower blood adiponectin levels than patients with higher blood adiponectin levels It is known that mortality from cardiovascular diseases is high. Therefore, pathological conditions with decreased blood adiponectin levels, so-called hypoadiponectinemia, are closely related to these cardiovascular diseases (arteriosclerosis, hypertension, etc.), lifestyle-related diseases such as diabetes or obesity. This is considered to be one of the root causes (see Non-Patent Document 2 or 3). Therefore, the treatment or prevention of hypoadiponectinemia is also useful for the treatment or prevention of the lifestyle-related diseases caused by hypoadiponectinemia.

  Adiponectin is known to have an action of suppressing adhesion of THP-1 cells to vascular endothelial cells, expression of adhesion molecules, differentiation of vascular smooth muscle cells, foaming of macrophages, and the like. These in vivo phenomena are essential phenomena that occur at an early stage of the onset of arteriosclerosis, and the inhibitory action of these phenomena exhibited by adiponectin is extremely useful in the treatment or prevention of arteriosclerosis. Moreover, it has been shown that increasing the adiponectin concentration in an animal model actually has a therapeutic effect on arteriosclerosis.

  Adiponectin is also closely associated with insulin resistance and diabetes. It is known that insulin resistance increases under hypoadiponectinemia (see Non-patent Documents 2 and 3). In animal models, administration of adiponectin improves insulin resistance and increases sugar production in the liver. It is known to have an effect such as suppression and to exhibit an action of improving sugar metabolism (see Non-Patent Documents 4, 5 or 6). Therefore, increasing the blood adiponectin concentration is useful for the treatment or prevention of diabetes and diabetic complications resulting therefrom.

  Insulin resistance syndrome, a condition with increased insulin resistance, is a major cause of diabetes, as well as a fundamental cause of lifestyle diseases such as cardiovascular diseases (arteriosclerosis, hypertension, etc.) or obesity In the treatment or prevention of the above lifestyle-related diseases, improvement of insulin resistance plays an important role. That is, improvement of insulin resistance is also useful for the treatment or prevention of the above lifestyle-related diseases caused by insulin resistance syndrome. As described above, since adiponectin has an insulin resistance improving action (see Non-Patent Document 4), a drug that enhances the production of adiponectin is useful for the treatment or prevention of insulin resistance syndrome, as well as insulin resistance. It is also useful for treating or preventing diabetes, diabetic complications, cardiovascular diseases (arteriosclerosis, hypertension, etc.) or obesity caused by the syndrome.

  Recently, concepts such as syndrome X (Syndrome X) and metabolic syndrome have been proposed as a pathological condition that increases the risk of coronary artery disease due to a complex association of dyslipidemia, diabetes, and insulin resistance syndrome. Has been. As described above, since adiponectin can contribute to the treatment or prevention of each of the diseases that are factors such as syndrome X and metabolic syndrome, a drug that enhances the production of adiponectin is a treatment such as syndrome X or metabolic syndrome or the like. It is also useful for prevention.

  From the above, a drug that enhances the production of adiponectin has an action of improving insulin resistance, and is an adiponectin production enhancer, a therapeutic or preventive agent for hypoadiponectinemia, an insulin resistance ameliorating agent, syndrome X or Treatment or prevention of metabolic syndrome, diabetes (including type I diabetes, type II diabetes), diabetic complications (including retinopathy, nephropathy, neurosis, cataract, coronary artery disease), hypertension, obesity or arteriosclerosis Diabetes, diabetic complications (including retinopathy, nephropathy, neurosis, cataract, coronary artery disease), hypertension, obesity resulting from hypoadiponectinemia or insulin resistance syndrome Alternatively, it is useful as a therapeutic or prophylactic agent for arteriosclerosis.

  CB1 receptor antagonists are known to have an effect of suppressing appetite by inhibiting cannabinoid (CB) 1 receptor, and are marketed as anti-obesity drugs in Europe.

Furthermore, a combination of a therapeutic drug for diabetes and a CB1 receptor antagonist has already been disclosed in Patent Document 1 and the like. However, the combination with the specific insulin resistance ameliorating agent of the present invention and the adiponectin production enhancing action are not known.
International Publication No. 2006/119260 Pamphlet Biochemical and Biophysical Research Communications, 1996, Vol.221, p.286-289 The Journal of Clinical Endocrinology & Metabolism, 2001, 86, p. 1930-1935 Diabetes, 2001, 50, p.1126-1133 Nature Medicine, 2001, Vol. 7, p.941-946 Nature Medicine, 2001, Vol. 7, p.947-953 Journal of Clinical Investigation, 2001, 108, p.1875-1881

  The present inventors have provided a therapeutic or preventive agent for hypoadiponectinemia, syndrome X or metabolic syndrome having excellent adiponectin production enhancing action, and diabetes caused by hypoadiponectinemia (particularly type II diabetes), As a result of diligent research aimed at developing therapeutic agents for diabetic complications (including retinopathy, nephropathy, neurosis, cataract, coronary artery disease), hypertension, obesity or arteriosclerosis, specific insulin resistance improvement The inventors have found that the object can be achieved by combining a drug and a CB1 receptor antagonist, thereby completing the present invention.

The present invention
(1) 5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2,4-dione or a pharmaceutically acceptable salt And a CB1 receptor antagonist as an active ingredient, a pharmaceutical for enhancing adiponectin production,
(2) The medicament according to (1) above for treating or preventing hypoadiponectinemia,
(3) The medicament according to (1) above for treating or preventing syndrome X, metabolic syndrome, diabetes, diabetic complications, hypertension, obesity or arteriosclerosis caused by hypoadiponectinemia,
(4) The medicament according to (1) above for treating or preventing type II diabetes caused by hypoadiponectinemia,
(5) 5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2,4-dione or a pharmaceutically acceptable salt Is 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2,4-dione hydrochloride (1 ) To (4),
(6) The CB1 receptor antagonist has the following formula

The pharmaceutical according to any one of (1) to (5) above, which is represented by the formula: taranaban, rimonabant hydrochloride, sulinabane or SLV-319,
(7) CB1 receptor antagonist has the following formula

The pharmaceutical according to any one of (1) to (5) above, which is rimonabant hydrochloride represented by:
(8) 5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2,4 for producing an adiponectin production enhancer Use of dione or a pharmacologically acceptable salt and a CB1 receptor antagonist,
(9) 5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2,4-dione or a pharmaceutically acceptable salt Is 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2,4-dione hydrochloride (8 ) Use,
(10) The CB1 receptor antagonist has the following formula

Represented by the use of (8) or (8) above, which is taranaban, rimonabant hydrochloride, sulinaban or SLV-319,
(11) The CB1 receptor antagonist has the following formula

The use according to (8) or (9) above, which is rimonabant hydrochloride represented by:
(12) 5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2,4-dione or a pharmaceutically acceptable salt And prevention of hypoadiponectinemia, syndrome X, metabolic syndrome, diabetes, diabetic complications, hypertension, obesity or arteriosclerosis by administering a drug containing CB1 receptor antagonist and CB1 receptor antagonist as active ingredients Is the law.

In the present invention, the “cannabinoid (CB) 1 receptor antagonist” is not particularly limited as long as it is a drug that inhibits the CB1 receptor.

N-[(1S, 2S) -3- (4-chlorophenyl) -2- (3-cyanophenyl) -1-methylpropyl]-described in WO2003 / 77847 pamphlet, US Pat. No. 6,972,295, etc. 2-methyl-2-[[5- (trifluoromethyl) pyridin-2-yl] oxy] propanamide (generic name: taranaban), US Patent No. 5,624,941, International Publication No. 2003/040105, etc. 1H-pyrazole-3-carboxamide, 5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methyl-N-piperidinyl hydrochloride (generic name: rimonabant hydrochloride), International Publication No. 2000/170700 (4S)-(−)-3- (4-chlorophenyl) -N-methyl-N ′-[(4-chlorophenyl) sulfonyl] -4-phenyl-4, described in US Pat. No. 6,476,060, etc. 5- (4) described in 5-dihydro-1H-pyrazole-1-carboxamidine (SLV-319), WO 2000/46209, US Pat. No. 6,432,984, US Pat. No. 6,645,985, etc. -Bromophenyl) -1- (2,4-dichlorophenyl) -4-ethyl-N- (piperidin-1-yl) -1H-pyrazole-3-carboxamide (generic name: Srinaban), etc. Rimonabant hydrochloride. These compounds have various isomers when they have an asymmetric carbon atom or an unsaturated bond in the molecule. These isomers and mixtures of these isomers are all represented by a single formula. Accordingly, the present invention includes all mixtures of these isomers in an arbitrary ratio.

In the present invention, the “insulin resistance improving drug” is a general term for drugs that improve insulin resistance and enhance insulin sensitivity.

  5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2,4-dione has the following formula

And can be produced according to the method described in US Pat. No. 5,886,014, pamphlet of International Publication No. 00/71540, and the like. 5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof is Since it has an asymmetric carbon atom in the molecule, optical isomers exist. These isomers and mixtures of these isomers are all represented by a single formula. Accordingly, the present invention includes all optical isomers and mixtures of optical isomers in an arbitrary ratio. 5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof is 5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2,4-dione hydrochloride is preferred.

In the present invention, “a pharmacologically acceptable salt thereof” means a case where a basic group such as an amino group is reacted with an acid, and a case where an acidic group such as a carboxyl group is present. Indicates a salt by reacting with a base to form a salt.

  The salt based on the basic group is preferably a hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfuric acid. Inorganic acid salts such as salts and phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate, aliquots such as benzene sulfonate and p-toluene sulfonate Organic acid salts such as sulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, succinate, maleate; and glycine salt, lysine Mention may be made of amino acid salts such as salts, arginine salts, ornithine salts, glutamates, aspartates. Preferred are hydrohalide salts or inorganic acid salts, and more preferred are hydrochlorides.

  On the other hand, the salt based on an acidic group is preferably an alkali metal salt such as a sodium salt, potassium salt or lithium salt, an alkaline earth metal salt such as a calcium salt or magnesium salt, an aluminum salt or an iron salt. Metal salt; inorganic salt such as ammonium salt, t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, Triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) aminomethane Organic salts such as salt And amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, aspartate.

The pharmaceutical composition of the present invention includes, for example, a therapeutic or preventive agent for hypoadiponectinemia, syndrome X or metabolic syndrome, and diabetes (including type I diabetes and type II diabetes) caused by hypoadiponectinemia, It is effective for the treatment or prevention of diabetic complications (including retinopathy, nephropathy, neurosis, cataract, coronary artery disease), hypertension, obesity or arteriosclerosis.

  In the present invention, one or more CB1 receptor antagonists can be used.

  CB1 receptor antagonist, 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2,4-dione and pharmacology thereof The top acceptable salt can be administered in the form of a combination drug. Moreover, each single agent can also be administered simultaneously. In addition, each single agent can be administered in succession at an appropriate interval. The dosing interval allowed to achieve the effect brought about by the administration of such a drug can be confirmed clinically or by animal experiments.

The medicament of the present invention can be used in preparations that can be administered orally, such as tablets, capsules, pills, granules, or fine granules, but are preferably tablets.

  The said formulation may contain a pharmaceutically acceptable additive suitably. Such additives include, for example, excipients (eg sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbitol; corn starch, potato starch, pregelatinized starch, dextrin, carboxymethyl starch, carboxymethyl starch sodium Starch derivatives such as: pregelatinized starch; cellulose such as crystalline cellulose, methylcellulose, hydroxypropylcellulose, low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carmellose, carmellose calcium, croscarmellose, croscarmellose sodium Derivatives; gum arabic; dextran; pullulan; light anhydrous silicic acid, calcium silicate, silicic acid hydrate, synthetic aluminum silicate, metasilicic acid aluminate Silicate derivatives such as gnesium; phosphate derivatives such as dicalcium phosphate; chloride derivatives such as sodium chloride; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate; ), Binders (eg, compounds exemplified in the above excipients; gelatin; polyvinylpyrrolidone; macrogol; or mixtures thereof), disintegrants (eg, compounds exemplified in the above excipients; cross-linked polyvinyl Pyrrolidone; or mixtures thereof), lubricants (eg, stearic acid; metal stearates such as calcium stearate and magnesium stearate; metal benzoates such as sodium benzoate; waxes such as bee gum and gay wax) Boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid; sodium sulfate Metal sulfates such as thorium; leucine; metal lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicate derivatives exemplified by the above excipients; starch derivatives exemplified by the above excipients; hydrogen Carnauba wax; sucrose fatty acid esters; or mixtures thereof), stabilizers (eg, benzoic acid; benzoic acid metal salts such as sodium benzoate; paraoxybenzoic acid esters such as methylparaben and propylparaben; chlorobutanol; Alcohols such as benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; acetic anhydride; sorbic acid; or a mixture thereof], fluidizing agents (for example, the above-mentioned shaping) Silicate derivatives exemplified by the agent; Or mixtures thereof), surfactants (eg, polysorbates such as polysorbate 80; polyoxyethylene hydrogenated castor oils such as polyoxyethylene hydrogenated castor oil 60; sorbitan fatty acid esters; sucrose fatty acid esters; poly; Oxyethylene polyoxypropylene glycols; polyoxyethylene fatty acid ethers; stearic acid polyoxyls; or mixtures thereof, preferably polysorbate 80, polyoxyethylene hydrogenated castor oil 60 or mixtures thereof), colorants (eg, Yellow iron sesquioxide, iron sesquioxide, black iron oxide), antioxidants, flavoring agents (for example, commonly used sweeteners, acidulants, flavorings, etc.) or additives that can be used and diluents The type and amount depends on the tablet, capsule or other dosage form drug, Selected from well-known techniques.

  For example, in the case of tablets, the content of the binder is usually 1 to 10 parts by weight (preferably 2 to 5 parts by weight) in the total drug composition, and the content of the disintegrant is usually 1 To 40 parts by weight (preferably 5 to 30 parts by weight), and the lubricant content is usually 0.1 to 10 parts by weight (preferably 0.5 to 3 parts by weight). The content is 0.1 to 10 parts by weight (preferably 0.5 to 5 parts by weight).

  The pharmaceutical composition of the present invention is easily produced by a known method (for example, a kneading method using water, a wet granulation method, etc.) using a pharmaceutically acceptable additive. Examples of such production include, for example, the addition of active ingredients, stabilizers, excipients, binders, disintegrants and other types of auxiliaries as required, and mixing with a high speed agitation granulator. Then, an aqueous solution of a binder is added to the obtained mixture and kneaded to obtain a granulated product. The obtained granulated product is dried using a fluidized bed dryer, and the dried granulated product is forcibly passed through a screen using a crushing granulator and granulating agent. If necessary, other types of auxiliaries and the like may be added and mixed in a V-type mixer, and the resulting mixture may be tableted or filled into capsules to produce tablets or capsules, respectively. it can.

  The obtained tablet can be sugar-coated or coated (preferably, coated) as necessary. For example, by spraying the obtained tablet with a coating solution consisting of hydroxypropylmethylcellulose, talc, titanium oxide, lactose, triacetin or polyethylene glycol, yellow iron or iron dioxide, and water in a pan coating machine. Film coating can be applied.

  Moreover, after mixing with the high-speed agitation granulator and adding the aqueous solution of the binder and kneading, the kneaded product is granulated with an extrusion granulator, and then with a fence dryer. Granules can be produced by forcing the dried granules to pass through a screen using a crushing and granulating machine.

  The amount of the active ingredient compound contained in the pharmaceutical preparation is not particularly limited and is appropriately selected within a wide range, but is usually 1 to 70% by weight, preferably 1 to 30% by weight in the total composition. Is appropriate.

  The dose and dose ratio of each drug used in the present invention can vary greatly depending on various conditions such as the activity of individual substances, patient symptoms, age, body weight and the like.

  The amount of the CB1 receptor antagonist contained in the pharmaceutical preparation is not particularly limited and is appropriately selected within a wide range, but is usually 1 to 70% by weight, preferably 1 to 40% by weight in the total composition. It is appropriate to do.

  The dosage varies depending on symptoms, age, body weight, dosage form, etc., but is usually 0.001 mg (preferably 0.01 mg, more preferably 0.1 mg) as the lower limit for adults, and 2000 mg as the upper limit. (Preferably 200 mg, more preferably 100 mg) can be administered. As rimonabant hydrochloride, it can be normally administered to an adult in a range of 5 mg to 20 mg per day, and preferably 5 mg, 10 mg or 20 mg.

  5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2,4-dione or its pharmacology contained in the above pharmaceutical preparation The amount of the salt allowed above is not particularly limited and is appropriately selected within a wide range. Usually, it is appropriate that the amount is 1 to 70% by weight, preferably 1 to 30% by weight in the total composition.

  The dose varies depending on symptoms, age, body weight, dosage form, etc., but can usually be administered to adults in the range of 0.5 mg to 2.0 mg daily, preferably 0.5 mg, 1.0 mg 1.5 mg or 2.0 mg.

  In the present invention, a CB1 receptor antagonist and 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2,4-dione Or the pharmacologically acceptable salt thereof is divided into the above-mentioned dosage once or divided into several times a day, and is administered separately at the same time or at different times.

  According to the present invention, an insulin sensitizer 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2, By using 4-dione or a pharmacologically acceptable salt thereof in combination with a CB1 receptor antagonist, it exerts an excellent enhancing effect on the production of adiponectin and is a therapeutic agent for hypoadiponectinemia, syndrome X or metabolic syndrome Diabetes (including type I diabetes, type II diabetes), diabetic complications (including retinopathy, nephropathy, neurosis, cataract, coronary artery disease), hypertension due to prophylactic agents and hypoadiponectinemia Thus, obesity or arteriosclerosis can be effectively prevented and treated.

  EXAMPLES Next, although an Example etc. are given and this invention is demonstrated further in detail, this invention is not limited to these.

  5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2,4-dione hydrochloride, an insulin sensitizer (Compound A) can be produced according to the method described in US Pat. No. 5,886,014, International Publication No. 00/71540, etc.

  Rimonabant hydrochloride (compound B) can be produced according to the methods described in US Pat. No. 5,624,941, International Publication No. 2003/040105, etc.

<Test Example 1>
Adiponectin production enhancing action by combined use of Compound A and Compound B 11 weeks old female ZDF rats (ZDF / Crl-Lepr ^fa , Charles River Japan, Inc.) who developed diabetes (blood glucose level 400 mg / dL or higher) The control group, the compound A administration group, the compound B administration group and the combination group were assigned so that the values and body weights were uniform among the groups (6 cases in each group).

  In all groups, feed (FR-2, Funabashi Farm Co., Ltd.) can be freely consumed, 0.5% carboxymethylcellulose solution (0.5% CMC) is used in the control group, 0.2 mg / kg of compound A is administered in the compound A administration group, compound Compound B 1 mg / kg was administered to the B administration group, and Compound A 0.2 mg / kg and Compound B 1 mg / kg were administered to the combination group. Compound A and Compound B were each suspended in 0.5% CMC. Forcible oral administration was performed once a day for 7 days, and plasma adiponectin concentrations were compared. Plasma was separated from blood collected from the tail vein of each individual, and plasma adiponectin concentration was measured using a radioimmunoassay kit (Mouse Adiponectin RIA Kit, Linco Research, Inc.). Radioactivity was measured using a gamma counter, and the plasma adiponectin concentration was calculated from the measured radioactivity (unit of measurement: μg / mL). The results are shown in FIG.

  In FIG. 1, the combined administration of Compound A and Compound B showed a significant increase in plasma adiponectin compared to the single agent. Therefore, it is particularly excellent to administer a combination of 5- [4- (6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione and a CB1 receptor antagonist. Adiponectin production enhancer, adiponectin production enhancer, hypoadiponectinemia therapeutic or preventive agent, insulin resistance ameliorating agent, and diabetes caused by hypoadiponectinemia or insulin resistance syndrome (particularly II Type diabetes), diabetic complications (including retinopathy, nephropathy, neurosis, cataract, coronary artery disease), hypertension, obesity, or arteriosclerosis.

<Formulation example>
(1) Capsule Compound A 1 mg
Rimonabant hydrochloride 10 mg
Lactose 110 mg
Corn starch 57 mg
Magnesium stearate 2 mg
180 mg total
Capsules can be produced by thoroughly mixing the powders of the components shown above and filling the capsules.
(2) Tablet Compound A 1 mg
Rimonabant hydrochloride 10 mg
Lactose 86 mg
Corn starch 42 mg
Microcrystalline cellulose 6 mg
Hydroxypropylcellulose 4 mg
Magnesium stearate 1 mg
150 mg total
The powder of each component shown above is mixed well and compressed into tablets each weighing 150 mg. If necessary, these tablets may be coated with sugar or film.
(3) Granules Compound A 1 mg
Rimonabant hydrochloride 10 mg
Lactose 710 mg
Corn starch 210 mg
Microcrystalline cellulose 39 mg
Hydroxypropylcellulose 30 mg
1000 mg total
After thoroughly mixing the powders of each component shown above, adding an aqueous solution of a binder and kneading the mixture into granules, the dried granules are screened using a crushing and granulating machine. A granule can be produced by forcibly passing through.

It is the figure which showed the plasma adiponectin density | concentration in combined use of a rimonabant hydrochloride (compound A) and an insulin sensitizer (compound B). (Test Example 1)

Claims (12)

  5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2,4-dione or pharmacologically acceptable salt and CB1 receptor A medicament for enhancing adiponectin production, comprising a body antagonist as an active ingredient.   The medicament according to claim 1, for treating or preventing hypoadiponectinemia.   The medicament according to claim 1, for treating or preventing syndrome X, metabolic syndrome, diabetes, diabetic complications, hypertension, obesity or arteriosclerosis caused by hypoadiponectinemia.   The medicament according to claim 1, for treating or preventing type II diabetes caused by hypoadiponectinemia.   5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2,4-dione or a pharmacologically acceptable salt is 5 The compound according to claim 1, which is-{4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2,4-dione hydrochloride. The pharmaceutical described. The CB1 receptor antagonist has the following formula

The medicament according to any one of claims 1 to 5, which is taranavan, rimonabant hydrochloride, sulinabane or SLV-319 represented by the formula: The CB1 receptor antagonist has the following formula

The medicament according to any one of claims 1 to 5, which is rimonabant hydrochloride represented by the formula:   5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2,4-dione for producing an adiponectin production enhancer Use of a pharmacologically acceptable salt and a CB1 receptor antagonist.   5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2,4-dione or a pharmacologically acceptable salt is 5 9. The method according to claim 8, which is-{4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2,4-dione hydrochloride. use. The CB1 receptor antagonist has the following formula

The use according to claim 8 or 9, which is represented by the formula: taranaban, rimonabant hydrochloride, sulinaban or SLV-319. The CB1 receptor antagonist has the following formula

The use according to claim 8 or 9, which is rimonabant hydrochloride represented by:   5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2,4-dione or pharmacologically acceptable salt and CB1 receptor A method for treating or preventing hypoadiponectinemia, syndrome X, metabolic syndrome, diabetes, diabetic complications, hypertension, obesity or arteriosclerosis by administering a drug containing a body antagonist as an active ingredient.