WO2010074271A1 - Therapeutic agent for diabetes - Google Patents

Abstract

Disclosed are a prophylactic or therapeutic agent for diabetes or obesity and a pancreas-protective agent, each of which can exhibit a high therapeutic efficacy and has few adverse side effects. Specifically disclosed is a pharmaceutical preparation for preventing or treating diabetes or obesity, which comprises a combination of (1) a DPP-IV inhibitor, (2) a GPR119 agonist and (3) a biguanide or an α-glucosidase inhibitor.  Also specifically disclosed is a pancreas-protective agent comprising a combination of (1) a DPP-IV inhibitor, (2) a GPR119 agonist and (3) a biguanide or an α-glucosidase inhibitor.

Description

Diabetes treatment

The present invention relates to a novel medicament for preventing or treating diabetes or obesity, a pancreatic protective agent and the like.

(Background of the Invention)
Diabetes is one of the metabolic diseases characterized by high blood glucose levels resulting from abnormal sugar metabolism. This disease is broadly classified into type 1 diabetes, also called insulin dependent diabetes or IDDM, and type 2 diabetes, also called non-insulin dependent diabetes or NIDDM. Diabetes not only causes microvascular complications (eg diabetic retinopathy, diabetic neuropathy, diabetic nephropathy) but also macrovascular disorders (eg arteriosclerosis, cardiovascular disease, myocardial infarction) ) Risk factor. There are various causes of diabetes, such as insulin resistance, insulin secretion deficiency due to pancreatic β-cell dysfunction, etc., and increased gluconeogenesis in the liver, and treatment based on each cause is necessary. Insulin resistance and insulin secretion failure are closely related to obesity, dyslipidemia, hypertension, and the like, and are also the onset factors of complex metabolic diseases called metabolic syndrome.
Insulin preparations, SU agents, α-glucosidase inhibitors, biguanides, insulin sensitivity enhancers, etc. are used as therapeutic agents for diabetes depending on the type of disease and onset factors. There are limited patients who can reduce blood sugar to the level. In addition, since there are many drugs that require attention due to side effects such as hypoglycemia, obesity, and increased cardiovascular risk, new drugs that have both high efficacy and safety are eagerly desired.
In recent years, research on the relationship between gastrointestinal hormone called incretin and diabetes has progressed, and GLP-1 incretin can suppress the increase in blood sugar through insulin secretion stimulating action, pancreatic β-cell protective action, etc. It became clear. Based on this discovery, various GLP-1 derivatives have been developed and sold as pharmaceuticals. Furthermore, the development of drugs that inhibit dipeptidyl peptidase IV (IUBMB enzyme nomenclature EC.3.4.14.5, hereinafter sometimes abbreviated as DPP-IV), a biological enzyme that degrades GLP-1. Some have already been clinically applied.
Recently, it has been reported that GPR119, which is found as a G protein-coupled receptor that is strongly expressed in pancreatic β cells, functions as a blood glucose sensor that promotes insulin secretion depending on the sugar concentration in the blood ( Non-patent document 1). Therefore, GPR119 has attracted attention as a new target molecule for the treatment of diabetes, and several GPR119 agonists have already been found (see Non-Patent Documents 2 to 4 and Patent Documents 1 to 4).
Furthermore, GPR119 is also expressed in the intestinal tract, and the GPR119 agonist promotes GLP-1 secretion, and the GPR119 agonist AR231453 and sitagliptin are combined to give GLP119 agonist blood GLP. The effect of increasing the -1 level is also known (see Patent Document 5 and Non-Patent Document 3).
Patent Document 6 discloses 2-[[6-[(3R) -3-amino-1-piperidinyl] -3,4-dihydro-3-methyl-2,4-dioxo-1 (2H) -pyrimidinyl. ]] Methyl] -benzonitrile or a salt thereof and a biguanide or α-glucosidase inhibitor are disclosed. Patent Document 7 discloses the first part: 2-[[6-[(3R) -3- Amino-1-piperidinyl] -3,4-dihydro-3-methyl-2,4-dioxo-1 (2H) -pyrimidinyl] methyl] -benzonitrile or a salt thereof and substantially containing metformin hydrochloride And the second part: containing metformin hydrochloride and 2-[[6-[(3R) -3-amino-1-piperidinyl] -3,4-dihydro-3-methyl-2,4- Dioxo-1 (2 ) - pyrimidinyl] methyl] - it discloses a benzonitrile or solid preparation containing portion, containing substantially no salts thereof.
International Publication No. 04/065380 Pamphlet International Publication No. 04/076413 Pamphlet International Publication No. 05/007647 Pamphlet International Publication No. 05/007658 Pamphlet International Publication No. 06/076211 Pamphlet International Publication No. 07/033266 Pamphlet International Publication No. 09/011451 Pamphlet Endocrinology, 148 (6), 2601-2609, 2007 Journal of Medicinal Chemistry, 51, 5172-5175, 2008 Endocrinology, 149 (5), 2038-47, 2008 Keystone Symposium 2008, Islet and Beta Cell Biology, Poster Abstract, 102, p. 58

An object of the present invention is to provide a medicament, pancreatic protective agent, etc. for preventing or treating diabetes or obesity that exhibits high therapeutic effects and has few side effects.

The inventor has combined (1) a DPP-IV inhibitor, (2) a GPR119 agonist and (3) a biguanide or α-glucosidase inhibitor (ie, (1) a DPP-IV inhibitor, (2) GPR119 Unexpectedly superior blood GLP-1 by combination of agonist and (3) biguanide, or (1) DPP-IV inhibitor, (2) GPR119 agonist and (3) α-glucosidase inhibitor) It has been found that synergistic effects of concentration increasing action, pancreatic insulin content increasing action and plasma PYY amount increasing action can be obtained, an extremely high diabetes and obesity treatment effect can be expected, and excellent pancreatic protective action can be achieved. It came to complete.

That is, the present invention
[1] A drug for the prevention or treatment of diabetes or obesity (hereinafter referred to as “the combination of a (1) DPP-IV inhibitor, (2) a GPR119 agonist and (3) a biguanide or α-glucosidase inhibitor” It is also referred to as “the preventive or therapeutic agent of the present invention”
[2] Pancreatic protective agent (hereinafter also referred to as “pancreatic protective agent of the present invention”) comprising a combination of (1) DPP-IV inhibitor, (2) GPR119 agonist and (3) biguanide or α-glucosidase inhibitor. In addition, “the preventive or therapeutic agent of the present invention” and “the pancreatic protective agent of the present invention” are collectively referred to as “the combination agent of the present invention”).
[3] The pharmaceutical or agent according to [1] or [2] above, wherein the DPP-IV inhibitor is alogliptin or a salt thereof,
[4] The pharmaceutical or agent according to [1] or [2] above, wherein the biguanide is metformin or a salt thereof,
[5] The pharmaceutical or agent according to [1] or [2] above, wherein the α-glucosidase inhibitor is voglibose,
[6] A method for preventing or treating diabetes or obesity, comprising administering (1) a DPP-IV inhibitor, (2) a GPR119 agonist, and (3) a biguanide or α-glucosidase inhibitor in combination.
[7] The method according to [6] above, wherein the DPP-IV inhibitor is alogliptin or a salt thereof,
[8] The method according to [6] above, wherein the biguanide is metformin or a salt thereof.
[9] The method described in [6] above, wherein the α-glucosidase inhibitor is voglibose.
[10] Use of (1) a DPP-IV inhibitor, (2) a GPR119 agonist and (3) a biguanide or α-glucosidase inhibitor for the manufacture of a medicament for the prevention or treatment of diabetes or obesity,
[11] The use according to [10] above, wherein the DPP-IV inhibitor is alogliptin or a salt thereof,
[12] The use according to [10] above, wherein the biguanide is metformin or a salt thereof.
[13] The use according to [10] above, wherein the α-glucosidase inhibitor is voglibose.
[14] (1) alogliptin or a salt thereof, (2) a GPR119 agonist and (3) a drug for preventing or treating diabetes or obesity, comprising a combination of metformin or a salt thereof,
[15] (1) Alogliptin or a salt thereof, (2) a GPR119 agonist and (3) a medicament for the prevention or treatment of diabetes or obesity,
[16] A GLP-1 increasing agent comprising a combination of (1) a DPP-IV inhibitor, (2) a GPR119 agonist and (3) a biguanide or α-glucosidase inhibitor,
[17] A PYY increasing agent comprising a combination of (1) a DPP-IV inhibitor, (2) a GPR119 agonist, and (3) a biguanide or α-glucosidase inhibitor,
[18] A method for increasing blood GLP-1 content comprising administering (1) a DPP-IV inhibitor, (2) a GPR119 agonist and (3) a biguanide or α-glucosidase inhibitor in combination.
[19] A method of increasing plasma PYY content comprising administering a combination of (1) a DPP-IV inhibitor, (2) a GPR119 agonist and (3) a biguanide or α-glucosidase inhibitor,
[20] Use of (1) a DPP-IV inhibitor, (2) a GPR119 agonist and (3) a biguanide or α-glucosidase inhibitor for the manufacture of a medicament for increasing blood GLP-1 content,
[21] Use of (1) a DPP-IV inhibitor, (2) a GPR119 agonist and (3) a biguanide or α-glucosidase inhibitor for the manufacture of a medicament for increasing plasma PYY content,
[22] As a combined medicine for simultaneous, divided or sequential use in the prevention or treatment of diabetes or obesity, (1) a DPP-IV inhibitor, (2) a GPR119 agonist and (3) a biguanide or a medicament containing an α-glucosidase inhibitor,
[23] The medicament according to [22] above, characterized by (1) a DPP-IV inhibitor, (2) a GPR119 agonist and (3) a biguanide or α-glucosidase inhibitor formulated into one composition,
[24] (1) DPP-IV inhibitor, (2) GPR119 formulated in the same composition as a combined medicine for simultaneous, divided or sequential use in the prevention or treatment of diabetes or obesity The pharmaceutical according to [22] above, characterized by an agonist and (3) a biguanide or α-glucosidase inhibitor formulated separately;
[25] (1) a DPP-IV inhibitor and (3) a biguanide formulated in the same composition as a combined medicine for simultaneous, divided or sequential use in the prevention or treatment of diabetes or obesity Or an α-glucosidase inhibitor and (2) a GPR119 agonist formulated separately (2), the medicament according to [22] above,
[26] The present invention relates to a DPP-IV inhibitor or the like for simultaneous, divided or sequential use in the prevention or treatment of diabetes or obesity in combination with a GPR119 agonist and a biguanide or α-glucosidase inhibitor.

The combination agent of the present invention has excellent blood GLP-1 increasing action, pancreatic insulin content increasing action and plasma PYY amount increasing action, and is useful for the prevention and treatment of diabetes and obesity.
In addition, the concomitant drug of the present invention has a pancreatic protective effect that suppresses pancreatic exhaustion caused by glycotoxicity, lipotoxicity, oxidative stress or endoplasmic reticulum stress due to diabetes, and is a sugar-dependent function that is an important function of pancreatic β cells The ability to secrete insulin.
Furthermore, the concomitant drug of the present invention can suppress pancreatic β cell death due to diabetes and promote pancreatic β cell neogenesis or replication.
In addition, the concomitant drug of the present invention induces sugar-dependent insulin secretion promotion, but there are side effects (eg, vascular complications, hypoglycemia) possessed by insulin preparations, and insulin secretory hypoglycemic agents that act on sulfonylurea receptors. Has no side effects (eg, pancreatic exhaustion, hypoglycemia). Therefore, the concomitant drug of the present invention can be safely administered over a long period to a patient suffering from diabetes or the like.

(Detailed description of the invention)
As used herein, a DPP-IV inhibitor means a compound that binds to DPP-IV and inhibits its activity. In the present invention, the compound may be either peptidic or non-peptidic, but is preferably a non-peptidic compound.
In the present invention, the DPP-IV inhibitor may have different forms before and after administration to the living body as long as the inhibitory activity is retained. That is, the DPP-IV inhibitor may be an “active metabolite” having DPP-IV inhibitory activity after becoming a structural change body after undergoing metabolism in vivo. Furthermore, in the present invention, the DPP-IV inhibitor may be a “prodrug” that is converted into an active form by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo.
Examples of the DPP-IV inhibitor used in the present invention include alogliptin or a salt thereof (preferably benzoate), sitagliptin or a salt thereof, vildagliptin or a salt thereof, saxagliptin or a salt thereof, melogliptin or a salt thereof, dutogliptin or a salt thereof Salt, linagliptin or a salt thereof, TS-021 or a salt thereof, T-6666 or a salt thereof, SK-0403 or a salt thereof, PT-630 or a salt thereof, ABT-279 or a salt thereof, KRP-104 or a salt thereof, R -1579 or a salt thereof, PF-734200 or a salt thereof, BMS-686117 or a salt thereof, DSP-7238 or a salt thereof, 2-[[6-[(3R) -3-amino-1-piperidinyl] -3,4 -Dihydro-3-methyl-2,4-dioxo-1 (2H) -pyrimidinyl] methyl] -4-fluorobenzoni And tolyl or a salt thereof. Among them, alogliptin or a salt thereof (preferably benzoate), 2-[[6-[(3R) -3-amino-1-piperidinyl] -3,4-dihydro-3-methyl-2,4- Dioxo-1 (2H) -pyrimidinyl] methyl] -4-fluorobenzonitrile or a salt thereof is preferred.
As used herein, a GPR119 agonist means a compound that activates GPR119 by binding to GPR119 and induces an intracellular response mediated by GPR119. In the present invention, the compound may be either peptidic or non-peptidic, and may be an endogenous ligand of GPR119, but is preferably a non-peptidic compound.
Examples of GPR119 agonists used in the present invention include AR231453, MBX-2982, PSN821, PSN-632408, PSN119-1, PSN119-1M, GSK252A, PSN375963, PSN632408, APD597, MBX-2982, AS1535907, AS1907417, etc. Can be mentioned.
Examples of biguanides used in the present invention include metformin, phenformin, buformin, or salts thereof (eg, hydrochloride, fumarate, succinate). Of these, metformin or a salt thereof (preferably hydrochloride) is preferable.
Examples of the α-glucosidase inhibitor used in the present invention include voglibose, acarbose, miglitol, emiglitate and the like. Of these, voglibose is preferable.

The “(1) DPP-IV inhibitor, (2) GPR119 agonist and (3) biguanide combination” of the present invention is preferably
[1] (1) Alogliptin, sitagliptin, vildagliptin, saxagliptin, 2-[[6-[(3R) -3-amino-1-piperidinyl] -3,4-dihydro-3-methyl-2,4-dioxo- 1 (2H) -pyrimidinyl] methyl] -4-fluorobenzonitrile, or a salt thereof (preferably alogliptin, 2-[[6-[(3R) -3-amino-1-piperidinyl] -3,4- Dihydro-3-methyl-2,4-dioxo-1 (2H) -pyrimidinyl] methyl] -4-fluorobenzonitrile, or a salt thereof), (2) a combination of a GPR119 agonist and (3) a biguanide;
[2] A combination of (1) a DPP-IV inhibitor, (2) a GPR119 agonist and (3) metformin, phenformin, buformin or a salt thereof (preferably metformin or a salt thereof);
[3] (1) Alogliptin, sitagliptin, vildagliptin, saxagliptin, 2-[[6-[(3R) -3-amino-1-piperidinyl] -3,4-dihydro-3-methyl-2,4-dioxo- 1 (2H) -pyrimidinyl] methyl] -4-fluorobenzonitrile, or a salt thereof (preferably alogliptin, 2-[[6-[(3R) -3-amino-1-piperidinyl] -3,4- Dihydro-3-methyl-2,4-dioxo-1 (2H) -pyrimidinyl] methyl] -4-fluorobenzonitrile, or salts thereof), (2) GPR119 agonist and (3) metformin, phenformin, buformin Or a combination thereof;
[4] (1) Alogliptin, 2-[[6-[(3R) -3-amino-1-piperidinyl] -3,4-dihydro-3-methyl-2,4-dioxo-1 (2H) -pyrimidinyl ] Methyl] -4-fluorobenzonitrile, or a salt thereof (preferably alogliptin or a salt thereof (preferably benzoate)), (2) a GPR119 agonist and (3) a combination of metformin or a salt thereof;
[5] (1) Alogliptin or a salt thereof (preferably benzoate), (2) GPR119 agonist and (3) a combination of metformin or a salt thereof;
Etc.

The “(1) DPP-IV inhibitor, (2) GPR119 agonist and (3) α-glucosidase inhibitor combination” of the present invention is preferably
[1] (1) Alogliptin, sitagliptin, vildagliptin, saxagliptin, 2-[[6-[(3R) -3-amino-1-piperidinyl] -3,4-dihydro-3-methyl-2,4-dioxo- 1 (2H) -pyrimidinyl] methyl] -4-fluorobenzonitrile, or a salt thereof (preferably alogliptin, 2-[[6-[(3R) -3-amino-1-piperidinyl] -3,4- Dihydro-3-methyl-2,4-dioxo-1 (2H) -pyrimidinyl] methyl] -4-fluorobenzonitrile, or a salt thereof), (2) a GPR119 agonist and (3) an α-glucosidase inhibitor combination;
[2] A combination of (1) a DPP-IV inhibitor, (2) a GPR119 agonist and (3) voglibose, acarbose, miglitol, or emiglitate (preferably voglibose);
[3] (1) Alogliptin, sitagliptin, vildagliptin, saxagliptin, 2-[[6-[(3R) -3-amino-1-piperidinyl] -3,4-dihydro-3-methyl-2,4-dioxo- 1 (2H) -pyrimidinyl] methyl] -4-fluorobenzonitrile, or a salt thereof (preferably alogliptin, 2-[[6-[(3R) -3-amino-1-piperidinyl] -3,4- Dihydro-3-methyl-2,4-dioxo-1 (2H) -pyrimidinyl] methyl] -4-fluorobenzonitrile, or salts thereof), (2) GPR119 agonist and (3) voglibose, acarbose, miglitol, Or a combination of emigrates;
[4] (1) Alogliptin, 2-[[6-[(3R) -3-amino-1-piperidinyl] -3,4-dihydro-3-methyl-2,4-dioxo-1 (2H) -pyrimidinyl ] Methyl] -4-fluorobenzonitrile, or a salt thereof, (2) a combination of GPR119 agonist and (3) voglibose;
[5] (1) Combination of alogliptin or a salt thereof (preferably benzoate), (2) GPR119 agonist and (3) voglibose;
Etc.

The present invention preferably comprises:
[A1] (1) Alogliptin or a salt thereof (preferably benzoate), (2) a GPR119 agonist and (3) a drug for the prevention or treatment of diabetes or obesity, which is a combination of metformin or a salt thereof ;
[A2] (1) Alogliptin or a salt thereof (preferably benzoate), (2) a GPR119 agonist, and (3) a drug for the prevention or treatment of diabetes or obesity;
[B1] (1) Alogliptin or a salt thereof (preferably benzoate), (2) a GPR119 agonist and (3) a pancreatic protective agent comprising a combination of metformin or a salt thereof;
[B2] (1) Alogliptin or a salt thereof (preferably benzoate), (2) a GPR119 agonist, and (3) a pancreatic protective agent comprising voglibose;
[C1] Prevention or treatment of diabetes or obesity comprising administering (1) alogliptin or a salt thereof (preferably benzoate), (2) a GPR119 agonist and (3) metformin or a salt thereof in combination Method;
[C2] A method for preventing or treating diabetes or obesity comprising administering (1) alogliptin or a salt thereof (preferably benzoate), (2) a GPR119 agonist, and (3) voglibose;
[D1] (1) Alogliptin or a salt thereof (preferably benzoate), (2) a GPR119 agonist and (3) metformin or a compound thereof for the manufacture of a medicament for the prevention or treatment of diabetes or obesity Use of salt;
[D2] Use of (1) alogliptin or a salt thereof (preferably benzoate), (2) a GPR119 agonist and (3) voglibose for the manufacture of a medicament for the prevention or treatment of diabetes or obesity ;
Etc.

DPP-IV inhibitors, GPR119 agonists, biguanides and α-glucosidase inhibitors may form salts. The salt is preferably a pharmacologically acceptable salt, for example, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like.
Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
Preferable examples of the salt with organic acid include acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzoic acid, toluenesulfonic acid salt and the like. And the salt.
Preferable examples of the salt with basic amino acid include a salt with arginine and the like.
Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.

The concomitant drug of the present invention is obtained by combining (1) a DPP-IV inhibitor, (2) a GPR119 agonist and (3) a biguanide or α-glucosidase inhibitor as active ingredients. These active ingredients may be formulated separately or simultaneously with a pharmacologically acceptable carrier.
Here, as the pharmacologically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations , Solubilizing agents, suspending agents, isotonic agents, buffers, soothing agents and the like. If necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.

Preferable examples of the excipient include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light Anhydrous silicic acid, synthetic aluminum silicate, magnesium magnesium metasilicate, etc. are mentioned.
Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
Preferred examples of the binder include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxy Examples thereof include propylmethylcellulose and polyvinylpyrrolidone.
Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, low substituted hydroxypropyl cellulose and the like.
Preferable examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like.
Preferable examples of solubilizers include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. Etc.
Suitable examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, polyvinyl Examples include hydrophilic polymers such as pyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, polyoxyethylene hydrogenated castor oil, and the like.
Preferable examples of the isotonizing agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like.
Preferable examples of the buffer include buffer solutions such as phosphate, acetate, carbonate, citrate and the like.
Preferable examples of the soothing agent include benzyl alcohol.
Preferable examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Preferable examples of the antioxidant include sulfite and ascorbate.
Preferred examples of the colorant include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, edible blue Nos. 1 and 2, etc.), water-insoluble lake dyes (Eg, aluminum salts of the above-mentioned water-soluble edible tar dyes), natural dyes (eg, β-carotene, chlorophyll, bengara, yellow ferric oxide) and the like.
Preferable examples of the sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.

The three active ingredients of the present invention (1) DPP-IV inhibitor, (2) GPR119 agonist or (3) α-glucosidase inhibitor are known per se as methods for producing pharmaceutical formulations (eg, Japanese Pharmacy) According to the method described in the above), alone or mixed with a pharmacologically acceptable carrier, for example, tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), Pills, powders, granules, capsules (including soft capsules and microcapsules), troches, syrups, solutions, emulsions, suspensions, controlled-release preparations (eg, immediate-release preparations, sustained-release preparations) , Sustained-release microcapsules), aerosols, films (eg, orally disintegrating films, oral mucosal film), injections (eg, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections) Agent), As drops, transdermal preparations, ointments, lotions, patches, suppositories (eg, rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, etc. , Orally or parenterally (eg, intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, instillation, intracerebral, rectal, intravaginal, intraperitoneal, intratumoral, proximal to tumor, etc. And direct administration to the lesion). Among these preparations, an oral preparation excellent in convenience or compliance is preferable.
The total content of active ingredients (DPP-IV inhibitor, GPR119 agonist and biguanide or α-glucosidase inhibitor) in the concomitant drug of the present invention varies depending on the type of active ingredient, the size of the preparation, etc. 90% by weight, preferably 5 to 80% by weight.

In the concomitant drug of the present invention, the mixing ratio of the DPP-IV inhibitor, GPR119 agonist and biguanide or α-glucosidase inhibitor is appropriately selected depending on the administration subject, administration route, target disease, dosage form, drug combination, etc. be able to. For example, (1) GPR119 agonist is usually used in an amount of about 0.005 to 200 parts by weight, preferably about 0.01 to 100 parts by weight, and biguanide is usually used in an amount of 1 to 200 parts by weight with respect to 1 part by weight of the DPP-IV inhibitor. (2) GPR119 agonist is usually about 0.005 to 200 parts by weight, preferably 0.01 to 100 parts by weight per 1 part by weight of the DPP-IV inhibitor. The α-glucosidase inhibitor may be used in an amount of usually about 0.001 to 1 part by weight, preferably about 0.005 to 0.2 part by weight.
The administration form of the concomitant drug of the present invention is not particularly limited, as long as the DPP-IV inhibitor, GPR119 agonist and biguanide or α-glucosidase inhibitor are combined at the time of administration. Examples of such administration forms include 1) administration of a single preparation obtained by simultaneously formulating a DPP-IV inhibitor, a GPR119 agonist and a biguanide or α-glucosidase inhibitor, 2) a DPP-IV inhibitor Co-administration of three formulations obtained by separately formulating a GPR119 agonist and a biguanide or α-glucosidase inhibitor by the same route of administration; 3) a DPP-IV inhibitor, a GPR119 agonist and a biguanide or α-glucosidase Administration of three types of preparations obtained by separately formulating inhibitors at different time intervals in the same administration route, 4) Formulating DPP-IV inhibitor, GPR119 agonist and biguanide or α-glucosidase inhibitor separately Co-administration of three different preparations obtained by different routes of administration, 5) DPP-IV inhibitors Administration of GPR119 agonist and biguanide or α-glucosidase inhibitor separately formulated at different time courses by different administration routes (DPP-IV inhibitor, GPR119 agonist, biguanide or α- Administration in order of glucosidase inhibitor, DPP-IV inhibitor, biguanide or α-glucosidase inhibitor, administration in order of GPR119 agonist, GPR119 agonist, DPP-IV inhibitor, biguanide or α-glucosidase inhibitor Administration in order, administration in order of GPR119 agonist, biguanide or α-glucosidase inhibitor, DPP-IV inhibitor, administration in order of biguanide or α-glucosidase inhibitor, GPR119 agonist, DPP-IV inhibitor , Biguanide or α-glucosidase Harm agents, DPP-IV inhibitors, administration in the order of GPR119 agonist), and the like.

The concomitant drug of the present invention has low toxicity and is safe, and is administered orally or parenterally to mammals (eg, human, mouse, rat, rabbit, dog, cat, cow, horse, pig, monkey). can do.
The dose of the concomitant drug of the present invention may be in accordance with the dose of the active ingredient DPP-IV inhibitor, GPR119 agonist and biguanide or α-glucosidase inhibitor, and the administration subject, administration route, target disease, agent It can be appropriately selected depending on the shape, combination of drugs, and the like. For example, dosages of DPP-IV inhibitors, GPR119 agonists, biguanides and α-glucosidase inhibitors described below can be mentioned. This amount can also be administered in 2 to 3 divided doses per day.
In addition, the dose of the DPP-IV inhibitor, GPR119 agonist and biguanide or α-glucosidase inhibitor can be appropriately selected based on the clinically used dose.
The dose of the DPP-IV inhibitor is usually 0.01 to 500 mg / day, preferably 0.1 to 100 mg / day, for example, per adult patient (body weight 60 kg). This amount can also be administered in 2 to 3 divided doses per day.
In particular, when the DPP-IV inhibitor is alogliptin (preferably benzoate), the effective amount of alogliptin is usually 1 to 100 mg / day, preferably 6.25 to 50 mg per adult patient (body weight 60 kg). / Day, more preferably 6.25, 12.5, 25 mg / day, etc.
The dose of the GPR119 agonist is usually 0.01 to 1000 mg / day, preferably 0.1 to 500 mg / day, more preferably 1 to 20 mg / day per adult patient (body weight 60 kg), for example. This amount can also be administered in 2 to 3 divided doses per day.
The dosage of biguanide is usually 125 to 2550 mg / day, preferably 250 to 2550 mg / day per adult patient (body weight 60 kg).
In particular, when the biguanide is metformin hydrochloride, the effective amount of metformin is usually 125 to 2550 mg / day, preferably 500, 750, 1000, 1500 mg / day, etc. per adult patient (body weight 60 kg). This amount can also be administered in 2 to 3 divided doses per day.
The dose of the α-glucosidase inhibitor is usually 0.01 to 10 mg / day, preferably 0.1 to 5 mg / day, more preferably 0.1 to 2 mg / day per adult patient (body weight 60 kg), for example. Day.
In particular, when the α-glucosidase inhibitor is voglibose, the effective amount of voglibose is usually 0.01 to 10 mg / day, preferably 0.6, 0.9 mg / day per adult patient (body weight 60 kg). Etc. This amount can also be administered in 2 to 3 divided doses per day.

The combination agent of the present invention has an excellent effect of increasing blood GLP-1 and pancreatic insulin content by combining a DPP-IV inhibitor, a GPR119 agonist and a biguanide or α-glucosidase inhibitor, and as a result It exhibits a synergistic hypoglycemic effect. Here, “synergistic hypoglycemic effect of DPP-IV inhibitor, GPR119 agonist and biguanide or α-glucosidase inhibitor” means “hyperglycemic effect of DPP-IV inhibitor alone”, “GPR119 agonist alone Means a hypoglycemic effect superior to the sum of “hypoglycemic effect of biguanide alone” or “hyperglycemic effect of α-glucosidase alone”.
The combination agent of the present invention has excellent blood GLP-1 increasing action, pancreatic insulin content increasing action, plasma PYY amount increasing action and pancreatic protective action.
In the present specification, “increase in GLP-1 in blood” means blood in GLP-1 that retains incretin activity (eg, GLP-1 (7-36) amide and GLP-1 (7-37)). Means that the concentration increases. The blood GLP-1 increasing action can be evaluated by measuring the blood GLP-1 level in the administration subject according to a method known per se, and an increase in the measured value means an increase in each action. GLP-1 may be measured by any method as long as GLP-1 can be measured. Specifically, radioimmunoassay or enzyme immunoassay using one type of anti-GLP-1 antibody; or two types having different epitopes And an enzyme immunoassay using the anti-GLP-1 antibody.
In the present specification, “pancreatic insulin content” means the insulin content in the pancreas. The “pancreatic insulin content” is determined by measuring insulin extracted from a pancreatic tissue of a test animal according to a method known per se according to a method known per se. The method for measuring insulin may be any method as long as insulin can be measured. Specifically, radioimmunoassay or enzyme immunoassay using one type of anti-insulin antibody; or two types of anti-insulin antibodies having different epitopes are used. An enzyme immunoassay or the like is used.
The “pancreatic insulin content” can also be evaluated using pancreatic insulin mRNA or pancreatic β cell mass as an index.
Here, the amount of pancreatic insulin mRNA and pancreatic β cells can be measured using a method known per se. For example, the method of tissue staining using an insulin antibody is generally used to measure the amount of pancreatic β cells. For in situ hybridization for detecting insulin mRNA, or for proteins that are selectively expressed in pancreatic β cells. For example, a method of labeling an endogenous or exogenous substance that binds with high specificity and measuring the labeling activity after administering the label to a test animal may be used. The endogenous or exogenous substance can be labeled with, for example, a radioisotope, a luminescent substance (low molecular compound or protein such as luciferase or GFP), a fluorescent substance, or the like.
Furthermore, the “pancreatic insulin content” can also be evaluated by a known method used for estimating the amount of residual pancreatic β cells. Examples of the method include a method of measuring active insulin or C-peptide in blood by performing a glucagon tolerance test. Alternatively, a glucose tolerance test can be performed instead of the glucagon tolerance test to measure active insulin or C-peptide in the blood. In addition, active insulin or C-peptide in the blood can be measured without performing a glucagon tolerance test.
In the present specification, “increase in the amount of plasma PYY” means that the concentration of PYY in the plasma, which shows an antifeedant activity, increases via the PYY receptor. The effect of increasing the amount of plasma PYY can be evaluated by measuring the plasma PYY value in the administration subject according to a method known per se, and an increase in the measured value means an increase in each effect. The PYY may be measured by any method as long as PYY can be measured. Specifically, a radioimmunoassay or enzyme immunoassay using one type of anti-PYY antibody; or two types of anti-PYY antibodies having different epitopes are used. An enzyme immunoassay or the like is used.
In the present specification, the “pancreatic protective action” means an action of suppressing pancreatic exhaustion caused by glycotoxicity, lipotoxicity, oxidative stress or endoplasmic reticulum stress due to diabetes. The “pancreatic protective effect” can be evaluated by measuring the “pancreatic insulin content” and the amount of pancreatic β cells described above.

Examples of the concomitant drug of the present invention include diabetes [eg, type 1 diabetes, type 2 diabetes, type 1.5 diabetes (LADA (Lentic Autoimmune Diabetes in Ads)), gestational diabetes, insulin secretion deficiency type diabetes, obesity type diabetes, glucose tolerance Dysfunction (IGT (Impaired Glucose Tolerance)), IFG (Impaired Fasting Glucose), IFG (Impaired Fasting Glycaemia)], diabetic complications [eg, neuropathy, nephropathy, retinopathy, cataract, macrovascular disorder, , Osteopenia, diabetic hyperosmotic coma, infection (eg respiratory infection, urinary tract infection, digestive organ infection, skin soft tissue infection, lower limb infection), diabetic gangrene, dry mouth Disease, hearing loss, cerebrovascular disorder, peripheral blood circulation disorder] It can be used for prevention and treatment of Moreover, the concomitant drug of the present invention can suppress the progression from diabetes to diabetic complications (preferably diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, arteriosclerosis).
In mammals whose blood glucose level is higher than the normal level, pancreatic insulin content is reduced due to hyperglycemia itself. Therefore, the concomitant drug of the present invention is used for mammals whose blood glucose level is higher than the normal level. Can be used for normalization of blood glucose level. Furthermore, the concomitant drug of the present invention is useful for mammals whose blood glucose level is higher than the normal level and whose pancreatic (β cell) function is reduced and insulin secretion is incomplete.
Moreover, the concomitant drug of the present invention can increase the amount of pancreatic insulin mRNA. In addition, the concomitant drug of the present invention suppresses pancreatic exhaustion caused by glycotoxicity, lipotoxicity, glycolipotoxicity, oxidative stress or endoplasmic reticulum stress due to diabetes, and is a sugar-dependent insulin that is an important function of pancreatic β cells. Can retain secretory capacity. Furthermore, the concomitant drug of the present invention can suppress pancreatic β cell death due to diabetes, and can promote the formation or replication of pancreatic β cells. Furthermore, the concomitant drug of the present invention can promote the enlargement of pancreatic β cells.

The concomitant drug of the present invention is used in combination with other drugs (hereinafter abbreviated as concomitant drugs) as long as it does not adversely affect the active ingredient DPP-IV inhibitor, GPR119 agonist and biguanide or α-glucosidase inhibitor. Can be used.
Here, "concomitant drugs" include antidiabetic drugs, diabetic complication drugs, antiobesity drugs, hypertension drugs, hyperlipidemia drugs, diuretics, antiarteriosclerotic drugs, antithrombotic drugs, arthritis drugs , Anti-anxiety drugs, antidepressants, neuropsychiatric drugs, sleep inducers and the like.
The administration time of the concomitant drug and the concomitant drug of the present invention is not limited, and these may be administered simultaneously to the administration subject or may be administered with a time difference. Furthermore, the concomitant drug and the concomitant drug of the present invention may be administered as four or more types of preparations containing the respective active ingredients, or may be administered as a single preparation containing both active ingredients.
The dose of the concomitant drug can be appropriately selected on the basis of the clinically used dose. The mixing ratio of the concomitant drug and the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight with respect to 1 part by weight of the active ingredient in the combination agent of the present invention.

Examples of the “diabetic therapeutic agent” include insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations genetically engineered using Escherichia coli and yeast; insulin zinc; protamine insulin zinc; insulin Fragment or derivative (eg, INS-1), oral insulin preparation), insulin resistance improving agent (eg, pioglitazone or a salt thereof (preferably hydrochloride), rosiglitazone or a salt thereof (preferably maleate) , Metaglidasen, AMG-131, Balaglitazone, MBX-2044, Riboglitazone, Aleglitazar, Chiglitazar, Lobeglitazone, PLX-204, PN-2034 , GFT-505, THR-0921, WO2007 / 013694, WO2007 / 018314, WO2008 / 093639 or WO2008 / 0997 94 compounds), insulin secretagogues (eg, sulfonylureas (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybazole), repaglinide, nateglinide, mitiglinide Or calcium salt hydrate thereof), β3 agonist (eg, N-5984), GPR40 agonist (eg, WO2004 / 041266, WO2004 / 106276, WO2005 / 063729, WO2005 / 063725, WO2005 / 087710, WO2005 / 095338, WO2007 / 013689 Or a compound described in WO2008 / 001931), a GLP-1 receptor agonist (eg, GLP-1, GLP-1 MR agent, Liraglutide, Exenatide, AVE-0010, BIM-51077, Aib (8, 35) ) hGLP-1 (7,37) NH ₂ , CJC-1131, Albiglutide), amylin agonist (eg, pramlintide), phosphotyrosine phosphatase inhibitor ( Eg, sodium vanadate), gluconeogenesis inhibitor (eg, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, glucagon antagonist, FBPase inhibitor), SGLT2 (sodium-glucose cotransporter 2) inhibitor (eg, Depagliflozin) , AVE2268, TS-033, YM543, TA-7284, Remogliflozin, ASP1941), SGLT1 inhibitor, 11β-hydroxysteroid dehydrogenase inhibitor (eg, BVT-3498, INCB-13739), adiponectin or agonist, IKK inhibitor (Eg, AS-2868), leptin resistance improver, somatostatin receptor agonist, glucokinase activator (eg, Piragliatin, AZD1656, AZD6370, TTP-355, WO2006 / 112549, WO2007 / 028135, WO2008 / 047821, WO2008 / 050821, WO2008 / 136428 or WO2008 / 156757), GIP (Glucose-dependent insulinotropic peptide), FGF21, FGF analog and the like.

Examples of the “diabetic complication therapeutic agent” include aldose reductase inhibitors (eg, tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat (AS-3201), ridressat), neurotrophic factor and its increase drug (Eg, NGF, NT-3, BDNF, neurotrophin production / secretion promoter described in WO01 / 14372 (eg, 4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5- [3- (2-methylphenoxy) propyl] oxazole), compounds described in WO2004 / 039365), PKC inhibitors (eg, ruboxistaurin mesylate), AGE inhibitors (eg, ALT946, N-phenol) Nasyl thiazolium bromide (ALT766), EXO-226, pyridoline (Pyridorin), pyridoxamine), GABA receptor agonist (eg, gabapentin, pregabalin), serotonin noradrenaline Uptake inhibitors (eg, duloxetine), sodium channel inhibitors (eg, lacosamide), active oxygen scavengers (eg, thioctic acid), cerebral vasodilators (eg, thiaprid, mexiletine), somatostatin receptor agonists (eg, BIM23190), apoptosis signal regulating kinase-1 (ASK-1) inhibitor and the like.

Examples of the “anti-obesity agents” include monoamine uptake inhibitors (eg, phentermine, sibutramine, mazindol, floxetine, and tesofensin), serotonin 2C receptor agonists (eg, lorcaserin), serotonin 6 receptor antagonist, histamine H3 receptor Body, GABA modulator (eg, topiramate), neuropeptide Y antagonist (eg, Berneperit), cannabinoid receptor antagonist (eg, rimonabant, taranaban), ghrelin antagonist, ghrelin receptor antagonist, ghrelin acylase Inhibitor, opioid receptor antagonist (eg, GSK-1521498), orexin receptor antagonist, melanocortin 4 receptor agonist, 11β-hydroxysteroid dehydrogenase inhibitor (eg, AZD-4017), pancreatic lipase inhibitor (eg, , Orlistat, cetilistat), β3 agonists (eg, N-5984 ), Diacylglycerol acyltransferase 1 (DGAT1) inhibitor, acetyl CoA carboxylase (ACC) inhibitor, stearate CoA desaturase inhibitor, microsomal triglyceride transfer protein inhibitor (eg, R-256918), Na-glucose cotransporter Carrier inhibitors (eg, JNJ-28431754, remogliflozin), NFκ inhibitors (eg, HE-3286), PPAR agonists (eg, GFT-505, DRF-11605), phosphotyrosine phosphatase inhibitors (eg, sodium vanadate, Trodaschemin) (Trodusquemin)), GPR119 agonist (eg, PSN-821), glucokinase activator (eg, AZD-1656), leptin, leptin derivative (eg, metreleptin), CNTF (ciliary neurotrophic factor), BDNF (Brain-derived neurotrophic factor), cholecystokinin agonist, glucagon-like peptide-1 (GLP-1) preparation (eg, extracted from bovine and porcine pancreas) Animal GLP-1 preparations; human GLP-1 preparations genetically engineered using E. coli and yeast; fragments or derivatives of GLP-1 (eg, exenatide, liraglutide)), amylin preparations (eg, pramlintide, AC- 2307), neuropeptide Y agonists (eg, PYY3-36, derivatives of PYY3-36, obineptide, TM-30339, TM-30335), oxyntomodulin preparations: FGF21 preparations (eg, extracted from bovine, porcine pancreas) Animal FGF21 preparations; human FGF21 preparations genetically engineered using Escherichia coli and yeast; FGF21 fragments or derivatives)), antifeedants (eg, P-57) and the like.

Examples of the “hypertensive drug” include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril, etc.), angiotensin II antagonists (eg, candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan , Irbesartan, tasosartan, olmesartan, olmesartan, medoxomil, azilsartan, azilsartan, medoxomil, etc.), calcium antagonists (eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine, amlodipine, sinyldipine, etc.), β-blockers (eg, metoprolol, teprolol) Propranolol, carvedilol, pindolol, etc.), clonidine and the like. Examples of diuretics include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine, etc.), thiazide preparations (eg, etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, penfluolide. Thiazide, poly-5 thiazide, meticlotiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide, etc.) ), Azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and the like.

Examples of the “hyperlipidemic agent” include HMG-CoA reductase inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin, or salts thereof (eg, sodium salt, calcium salt)) Squalene synthase inhibitors (eg, compounds described in pamphlet of WO97 / 10224, for example, N-[[(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl) -7-chloro- 5- (2,3-dimethoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid), fibrate compounds (Eg, bezafibrate, clofibrate, simfibrate, clinofibrate), anion exchange resin (eg, cholestyramine), probucol, nicotinic acid drugs (eg, nicomol, niseritro) (Niceritrol), niaspan), ethyl icosapentate, plant sterol (eg, soysterol, gamma-oryzanol), cholesterol absorption inhibitor (eg, zetia), CETP inhibitor (eg, Examples thereof include dalcetrapib, anacetrapib, and omega-3 fatty acid preparations (eg, omega-3-acid ethylesters 90).

Examples of the “diuretic” include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine), thiazide preparations (eg, etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, penflutide, Polythiazide, meticlotiazide), anti-aldosterone formulation (eg, eplerenone, spironolactone, triamterene), carbonic anhydrase inhibitor (eg, acetazolamide), chlorobenzenesulfonamide-based formulation (eg, chlorthalidone, mefluside, indapamide), azosemide, isosorbide, Examples include ethacrynic acid, piretanide, bumetanide, furosemide and the like.

Examples of the “anti-atherosclerotic agent” include acylcoenzyme A cholesterol acyltransferase (ACAT) inhibitors (eg, K-604), LpPLA2 inhibitors (eg, dalapradiv, rilapradib etc.), FLAP inhibitors (eg, AM103, AM803 etc.), 5LO inhibitors (eg, VIA-2291 etc.), sPLA2 inhibitors (eg, A-002), apoAI mimetic peptides (eg, D4F etc.), HDL preparations (eg, CSL-111 etc.), etc. Can be mentioned.
Examples of the “antithrombotic agent” include heparin (eg, heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarin (eg, warfarin potassium), antithrombin drug (eg, argatroban) (aragatroban), dabigatran), FXa inhibitors (eg, rivaroxaban, apixaban, edoxaban, YM150, WO02 / 06234, WO2004 / 048363, WO2005 / 030740, WO2005 / 058823 or WO2005 / 113504 compounds), thrombolytic drugs (eg, urokinase, tisokinase, alteplase, nateplase, monteplase, pamitepase (pamiteplase)), platelet aggregation inhibitors (eg Ticlopidine hydrochloride, clopidogrel, prasugrel, E5 555, SHC530348, cilostazol, ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride) and the like.

Examples of the “arthritis therapeutic agent” include ibuprofen and the like.
Examples of the “anti-anxiety agents” include alprazolam, etizolam, oxazolam, tandospirone, cloxazolam, clothiazepam, dichlorinated potassium chlorazepate, chlordiazepoxide, diazepam, fludiazepam, flutazolam, flutopazepam, prazepam, brozepampampamzem, , Ethyl loflazepate, lorazepam and the like.
Examples of the “antidepressant” include tricyclic antidepressants (eg, imipramine, trimipramine, clomipramine, amitriptyline, nortriptyline, amoxapine, lofepramine, dosrepin, desipramine), tetracyclic antidepressants (eg, maprotiline, Mianserin, seriprine), selective serotonin uptake inhibitors (eg, fluoxetine, fluvoxamine, paroxetine, sertraline, escitalopram), serotonin and noradrenaline uptake inhibitors (eg, milnacipran, duloxetine, venlafaxine), trazodone, mirtazapine , Moclobecdo and the like.
Examples of the “psycho-neurological agent” include typical antipsychotic drugs (eg, clocapramine, chlorpromazine, phenobarbital, sultopride, thioprid, thioridazine, fluropamide, mosapramine, moperon, oxypertin, carpipramine, spiperone, sulpiride, zotepine, timiperone, Nemonapride, haloperidol, pimozide, prochlorperazine, propericazine, bromperidol, perphenazine, fluphenazine maleate, mizoribine, levomepromazine), atypical antipsychotics (eg, perospirone, olanzapine, quetiapine, risperidone, clozapine, Aripiprazole, ziprasidone, blonanserin, lurasidone) and the like.
Examples of the “sleep inducer” include, for example, ramelteon, GABA hypnotics (eg, brotizolam, estazolam, flurazepam, nitrazepam, triazolam, flunitrazepam, lormetazepam, rilmazaphone, quazepam, zopiclone, eszopicone, zolpidem, Non-GABA hypnotics (eg, eprivaserin, purvanserin, diphenhydramine, trazodone, doxepin) and the like.

The present invention further relates to “a therapeutic agent for diabetes and obesity comprising (1) a DPP-IV inhibitor, (2) a GPR119 agonist and (3) a biguanide or α-glucosidase inhibitor”.
“(1) DPP-IV inhibitors, (2) GPR119 agonists and (3) diabetes and obesity therapeutics containing biguanides or α-glucosidase inhibitors” are DPP-IV inhibitors, GPR119 agonists and Using a biguanide or an α-glucosidase inhibitor, it can be produced in the same manner as the combination agent of the present invention. “(1) a DPP-IV inhibitor, (2) a GPR119 agonist and (3) a therapeutic agent for diabetes and obesity containing a biguanide or α-glucosidase inhibitor” has an excellent effect of increasing blood GLP-1; It has an effect of increasing pancreatic insulin content and increasing the amount of plasma PYY, and can be used for patients requiring prevention and treatment of diabetes and obesity and pancreatic protection as well as the combination agent of the present invention.
Further, “(1) DPP-IV inhibitor, (2) GPR119 agonist and (3) a therapeutic agent for diabetes and obesity containing biguanide or α-glucosidase inhibitor” is used in combination with the above combination drug You can also.

The present invention will be described in more detail with reference to the following reference examples and experimental examples, but these are not intended to limit the present invention, and may be changed without departing from the scope of the present invention. Since alogliptin and metformin used in Reference Examples and Experimental Examples are benzoate and hydrochloride, respectively, the dosage was converted to free form.

Reference example 1
The effect of GLP119 secretion promotion by combined use with GPR119 agonist and DPP-IV inhibitor in female Wistar fatty rats (WF rats) was examined.
First, 25 15-week-old WF rats were divided into 5 groups of A to E, and blood was collected for measurement of blood GLP-1 level before drug administration. Thereafter, 0.5% MC (methylcellulose) was orally administered to group A (control group), and GSK252A (4-({7- [2-fluoro-4- ( Methylsulfonyl) phenyl] -6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-4-yl} oxy) piperidine-1-carboxylate 1-methylethyl, hereinafter referred to as “Compound A”) Is administered orally at 10 mg / kg, Compound A is orally administered at 30 mg / kg, Group A is orally administered with 0.3 mg / kg of alogliptin known as a DPP-IV inhibitor, and Compound E is administered at Group E. A and alogliptin were orally administered at 10 mg / kg and 0.3 mg / kg, respectively. 60 minutes after compound administration, each individual was loaded with 1 g / kg of glucose by oral administration, blood was collected 10 minutes, 30 minutes, and 60 minutes after the load, and the amount of GLP-1 in the blood was measured with anti-GLP-1 antibody. The enzyme immunoassay used (Glucagon-Like Peptide-1 (Active) ELISA Kit [EGLP-35K]; MILLIPORE) was examined. The results are shown in Table 1.

Experimental example 1
The GLP-1 secretion-promoting effect of a combination of a GPR119 agonist, a DPP-IV inhibitor and a biguanide in male Wistar fatty rats (WF rats, Takeda Labix) was examined.
First, 42 23-week-old WF rats fasted overnight were divided into 7 groups of A to G, and 6 blood samples were collected to obtain plasma samples before drug administration (−60 minutes). Thereafter, 0.5% MC (methylcellulose) was orally administered to group A (control group), compound A was orally administered to group B at 10 mg / kg, and alogliptin was orally administered to group C at 1 mg / kg. , M formformin, known as a biguanide, is orally administered to group D, compound A and alogliptin are orally administered to group E at 10 mg / kg and 1 mg / kg, respectively, and metformin and alogliptin are administered to group F, respectively. 50 mg / kg and 1 mg / kg were orally administered, and Group A was orally administered with Compound A, metformin and alogliptin 10 mg / kg, 50 mg / kg and 1 mg / kg, respectively. 60 minutes after compound administration, each individual was loaded with 1 g / kg of glucose by oral administration, and blood was collected before the load (0 minutes) and 10 minutes after the load. Measure plasma GLP-1 levels before drug administration (-60 minutes), before glucose load (0 minutes), and 10 minutes after glucose load. The enzyme immunoassay using an anti-GLP-1 antibody (Glucagon-Like Peptide-1 (Active) ELISA Kit [EGLP-35K]; MILLIPORE) was examined. The results are shown in Table 2.

Also, the combined effect of the triple combination was examined by two-way analysis of variance between the A, B, F, and G groups and the A, D, E, and G groups. The results are shown in Table 3.

As shown in Table 3, the combined use of compound A, metformin and alogliptin produced a synergistic GLP-1 secretion enhancing action.

Experimental example 2
The effect of GLP-1 secretion promotion by the combined use of GPR119 agonist, DPP-IV inhibitor and α-glucosidase inhibitor in male N-STZ rats (Takeda Rabix) was examined.
First, 42 19-week-old N-STZ rats fasted overnight were divided into 7 groups of A to G. Thereafter, 0.5% MC (methylcellulose) was orally administered to group A (control group), compound A was orally administered to group B at 10 mg / kg, and alogliptin was orally administered to group C at 0.3 mg / kg orally. In Group D, voglibose known as an α-glucosidase inhibitor is orally administered at 0.03 mg / kg, and in Group E, Compound A and alogliptin are orally administered at 10 mg / kg and 0.3 mg / kg, respectively. In group F, voglibose and alogliptin were orally administered at 0.03 mg / kg and 0.3 mg / kg, respectively, and in group G, compound A, voglibose and alogliptin were respectively 10 mg / kg, 0.03 mg / kg and 0.3 mg. Per kg / kg. Sixty minutes after compound administration, each individual was loaded with 2.5 g / kg of sucrose by oral administration, and blood was collected before loading (0 minutes), 10 minutes, 30 minutes, and 60 minutes after loading. The amount of plasma GLP-1 before sucrose loading (0 minutes), 10 minutes, 30 minutes, and 60 minutes after sucrose loading was measured, and the amount of plasma GLP-1 increase from before sucrose loading (0 minutes) to 60 minutes after sucrose loading Was examined by an enzyme immunoassay (Glucagon-Like Peptide-1 (Active) ELISA Kit [EGLP-35K]; MILLIPORE) using an anti-GLP-1 antibody. The results are shown in Table 4.

Also, the combined effect of the triple combination was examined by two-way analysis of variance between the A, B, F, and G groups and the A, D, E, and G groups. The results are shown in Table 5.

As shown in Table 5, the combined use of compound A, voglibose, and alogliptin produced a synergistic GLP-1 secretion enhancing action.

Experimental example 3
The effect of increasing the plasma PYY amount by the combined use of GPR119 agonist, DPP-IV inhibitor and α-glucosidase inhibitor in male N-STZ rats (Takeda Rabix) was examined.
First, 42 19-week-old N-STZ rats fasted overnight were divided into 7 groups of A to G. Thereafter, 0.5% MC (methylcellulose) was orally administered to group A (control group), compound A was orally administered to group B at 10 mg / kg, and alogliptin was orally administered to group C at 0.3 mg / kg orally. In Group D, voglibose known as an α-glucosidase inhibitor is orally administered at 0.03 mg / kg, and in Group E, Compound A and alogliptin are orally administered at 10 mg / kg and 0.3 mg / kg, respectively. In group F, voglibose and alogliptin were orally administered at 0.03 mg / kg and 0.3 mg / kg, respectively, and in group G, compound A, voglibose and alogliptin were respectively 10 mg / kg, 0.03 mg / kg and 0.3 mg. Per kg / kg. 60 minutes after compound administration, 2.5 g / kg sucrose was orally administered to each individual, blood was collected for 180 minutes after the load, and the amount of PYY in plasma was determined using a radioimmunoassay (RAT / MOUSE PYY RIA KIT [RMPYY-68HK]; MILLIPORE). The results are shown in Table 6.

The combination agent of the present invention has an excellent blood GLP-1 increasing action, pancreatic insulin content increasing action and plasma PYY amount increasing action, and is useful for the treatment of diabetes or obesity.

This application is based on Japanese Patent Application No. 2008-335141 filed in Japan, the contents of which are incorporated in full herein.

Claims (15)

1. (1) A pharmaceutical agent for preventing or treating diabetes or obesity, comprising a combination of a DPP-IV inhibitor, (2) a GPR119 agonist and (3) a biguanide or α-glucosidase inhibitor.
2. (1) A pancreatic protective agent comprising a combination of a DPP-IV inhibitor, (2) a GPR119 agonist, and (3) a biguanide or α-glucosidase inhibitor.
3. The medicament or agent according to claim 1 or 2, wherein the DPP-IV inhibitor is alogliptin or a salt thereof.
4. The pharmaceutical or agent according to claim 1 or 2, wherein the biguanide is metformin or a salt thereof.
5. The medicament or agent according to claim 1 or 2, wherein the α-glucosidase inhibitor is voglibose.
6. (1) A method for preventing or treating diabetes or obesity, comprising administering a combination of (1) a DPP-IV inhibitor, (2) a GPR119 agonist, and (3) a biguanide or α-glucosidase inhibitor.
7. The method according to claim 6, wherein the DPP-IV inhibitor is alogliptin or a salt thereof.
8. The method according to claim 6, wherein the biguanide is metformin or a salt thereof.
9. The method according to claim 6, wherein the α-glucosidase inhibitor is voglibose.
10. Use of (1) DPP-IV inhibitor, (2) GPR119 agonist and (3) biguanide or α-glucosidase inhibitor for the manufacture of a medicament for the prevention or treatment of diabetes or obesity.
11. The use according to claim 10, wherein the DPP-IV inhibitor is alogliptin or a salt thereof.
12. The use according to claim 10, wherein the biguanide is metformin or a salt thereof.
13. The use according to claim 10, wherein the α-glucosidase inhibitor is voglibose.
14. (1) A pharmaceutical agent for preventing or treating diabetes or obesity, comprising a combination of alogliptin or a salt thereof, (2) a GPR119 agonist and (3) metformin or a salt thereof.
15. (1) A pharmaceutical agent for preventing or treating diabetes or obesity, comprising alogliptin or a salt thereof, (2) a GPR119 agonist and (3) voglibose.