PHARMACEUTICAL COMPOSITION FOR PREVENTION OR TREATMENT OF DIABETES AND METABOLIC DISEASES ASSOCIATED THEREWITH

Abstract

The present invention relates to a pharmaceutical composite composition for prevention or treatment of diabetes mellitus and at least one disease selected from metabolic diseases associated therewith. The pharmaceutical composition according to the present invention exhibits excellent effects of lowering blood glucose levels, body weight, and blood lipid levels. Therefore, the composition can be advantageously used for preventing or treating diabetes mellitus and at least one disease selected from metabolic diseases associated therewith.

Claims

1. A pharmaceutical composition, for preventing or treating diabetes or at least one disease selected from metabolic diseases associated therewith, comprising a compound represented by a following chemical Formula 1, pharmaceutically acceptable salts thereof, optical isomers thereof, hydrates thereof, solvates thereof, or mixtures thereof; and at least one selected from a DPPIV inhibitor, a PPAR agonist, a SGLT2 inhibitor, an insulin secretagogue, a biguanidine drug and an alpha-glucosidase inhibitor: ##STR00004## wherein in above Formula 1, A is an oxadiazole group, a dihydrooxazole group, a thiazole group or a thiadiazole group, in which above A is unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen atom, a C1-C6 straight or branched chain alkyl group, and a C1-C6 straight or branched chain hydroxyalkyl group, in which the alkyl group or the hydroxyalkyl group is each independently unsubstituted or substituted with a halogen atom or a C1-C6 alkoxy group; B is a pyridine group, a pyrimidine group, a pyrazine group or an oxadiazole group, in which above B is unsubstituted or substituted with at least one substituent selected from the group consisting of a halogen atom, a C1-C6 straight or branched chain alkyl group, a C1-C6 straight or branched chain hydroxyalkyl group, a C1-C6 alkoxy group and an oxadiazole group, in which the C1-C6 straight or branched chain alkyl group, the C1-C6 straight or branched chain hydroxyalkyl group, the C1-C6 alkoxy group or the oxadiazole group is each independently unsubstituted or substituted with halogen, a C1-C6 alkyl group or a C1-C6 alkoxy group; and X.sub.1 and X.sub.2 are each independently F, Cl, Br or I.

2. The pharmaceutical composition according to claim 1, wherein above A is ##STR00005## and R.sub.1 to R.sub.3, R.sub.5 and R.sub.6 are each independently at least one substituent selected from the group consisting of a hydrogen atom, a halogen atom, a C1-C6 straight or branched chain alkyl group and a C1-C6 straight or branched chain hydroxyalkyl group, in which the alkyl group or the hydroxyalkyl group is each independently unsubstituted or substituted with a halogen atom or a C1-C6 alkoxy group.

3. The pharmaceutical composition according to claim 1, wherein above B is ##STR00006## and R.sub.7 to R.sub.11 are each independently substituted with at least one substituent selected from the group consisting of a hydrogen atom, a halogen atom, a C1-C6 straight or branched chain alkyl group, a C1-C6 straight or branched chain hydroxyalkyl group, a C1-C6 alkoxy group and an oxadiazole group, in which the alkyl group, the hydroxyalkyl group, the alkoxy group or the oxadiazole group is each independently unsubstituted or substituted with a halogen atom, a C1-C6 alkyl group or a C1-C6 alkoxy group.

4. The pharmaceutical composition according to claim 1, wherein X is F.

5. The pharmaceutical composition according to claim 1, wherein above A is an oxadiazole group substituted with a C1-C6 straight or branched chain alkyl group, above B is a pyrimidine group substituted with a C1-C6 straight or branched chain alkyl group, and X is F.

6. The pharmaceutical composition according to claim 1, wherein the compound represented by above Formula 1 is 3-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin yl)propoxy)-2,6-difluorophenyl)-5-isopropyl-1,2,4-oxadiazole.

7. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition comprises at least one of the DPPIV inhibitor, the PPAR agonist, the SGLT2 inhibitor, the insulin secretagogue, the biguanidine drug and the alpha-glucosidase inhibitor.

8. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition comprises at least one of evogliptin, sitagliptin, elafibranor, dapagliflozin, glimepiride, metformin and voglibose.

9. The pharmaceutical composition of claim according to claim 1, wherein the pharmaceutical composition comprises at least one of the DPPIV inhibitor, the PPAR agonist, the SGLT2 inhibitor, the insulin secretagogue, the biguanidine drug and the alpha-glucosidase inhibitor.

10. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition comprises at least one of evogliptin, sitagliptin, elafibranor, dapagliflozin, glimepiride, metformin and voglibose.

11. The pharmaceutical composition according to claim 1, wherein the metabolic disease is at least one of obesity and dyslipidemia.

12. Use of a pharmaceutical composition, comprising the compound represented by Formula 1 according to claim 1, pharmaceutically acceptable salts thereof, optical isomers thereof, hydrates thereof, solvates thereof, or mixtures thereof; and at least one selected from a DPPIV inhibitor, a PPAR agonist, a SGLT2 inhibitor, an insulin secretagogue, a biguanidine drug and an alpha-glucosidase inhibitor, for preventing or treating diabetes or at least one disease selected from metabolic diseases associated therewith.

13. Use of a pharmaceutical composition, comprising a compound represented by Formula 1 according to claim 1, pharmaceutically acceptable salts thereof, optical isomers thereof, hydrates thereof, solvates thereof, or mixtures thereof; and at least one selected from a DPPIV inhibitor, a PPAR agonist, a SGLT2 inhibitor, an insulin secretagogue, a biguanidine drug and an alpha-glucosidase inhibitor, in the manufacture of a pharmaceutical preparation for preventing or treating diabetes or at least one disease selected from metabolic diseases associated therewith.

14. A method for preventing or treating diabetes or at least one disease selected from metabolic diseases associated therewith comprising administering a therapeutically effective amount of a pharmaceutical composition including a compound represented by Formula 1 according to claim 1, pharmaceutically acceptable salts thereof, optical isomers thereof, hydrates thereof, solvates thereof, or mixtures thereof; and at least one selected from a DPPIV inhibitor, a PPAR agonist, a SGLT2 inhibitor, an insulin secretagogue, a biguanidine drug and an alpha-glucosidase inhibitor, into a subject in need of treatment.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0144] FIG. 1 is a graph of showing an effect of a drug(s) on increasing a peak blood concentration of active GLP-1 in five minutes after glucose loading and reducing postprandial blood glucose level for two hours after glucose loading when single oral administration of the drug(s) is given to normal mice.

[0145] FIG. 2 is a graph of showing an efficacy of a drug(s) on postprandial blood glucose for two hours after glucose loading when single oral administration of the drug(s) is given to normal mice.

[0146] FIG. 3 is a graph of showing an efficacy of co-administration of drugs on non-fasting and fasting blood glucose levels when the drugs are co-administered to HF/STZ diabetic mice for ten weeks.

[0147] FIG. 4 is a graph of showing an efficacy of co-administration of drugs on plasma triglyceride concentrations when the drugs are co-administered to HF/STZ diabetic mice for ten weeks.

[0148] FIG. 5 is a graph of showing an efficacy of a drug(s) on postprandial blood glucose levels for two hours after glucose loading when single oral administration of the drug(s) is given to normal mice.

[0149] FIG. 6 is a graph of showing nonfasting blood glucose levels when each of the drugs is administered alone and co-administered to DIO mice for 12 weeks.

[0150] FIG. 7 is a graph of showing levels of plasma concentration of total GLP-1 when each of drugs is administered alone and co-administered to HF mice for three weeks.

[0151] FIG. 8 is a graph of showing fasting blood glucose levels when each of the drugs is administered alone and co-administered to HF mice for three weeks.

[0152] FIG. 9 is a graph of showing levels of change in body weight loss rate over time and change in body composition improvement when each of the drugs is administered alone and co-administered to HF mice for three weeks.

[0153] FIG. 10 is a graph showing an efficacy of drug administration alone and in combination on postprandial blood glucose levels for two hours after sucrose loading when single oral administration of the drug(s) is given to normal mice.

MODE FOR INVENTION

[0154] The features and advantages of the present invention as well as methods for achieving them will be apparent with reference to exemplary embodiments described in detail hereinafter. However, the present invention is not limited to the exemplary embodiments disclosed hereinafter, but will be implemented in various different forms. Hereinafter, the following exemplary embodiments will be suggested for better understanding of the present invention and are provided only for the purpose of completely illustrating the scope of the present invention to those skilled in the art, and thus the present invention will be defined only by the scope of the claims thereto.

[0155] A pharmaceutical composition for preventing or treating of diabetes or at least one disease selected from metabolic diseases associated therewith according to the present invention may include a compound represented by Formula 1 described above, pharmaceutically acceptable salts thereof, optical isomers thereof, hydrates thereof, solvates thereof or mixtures thereof; and at least one selected from a DPPIV inhibitor, a PPAR agonist, a SGLT2 inhibitor, an insulin secretagogue, a biguanidine drug and an alpha-glucosidase inhibitor.

[0156] The compound represented by Formula 1 may be a GPR119 ligand, and G protein-coupled receptor 119 (GPR119) may be one of G protein-coupled receptors (GPCRs) belonging to class A.

[0157] GRP119 may be activated by the GRP119 ligand to generate cAMP through Gαs among G protein subtypes, thereby inducing intracellular signaling.

[0158] GRP119 may have a high expression level in pancreatic beta cells and L cells of small intestines. Thus, when GPR119 of the pancreas is activated by administering the pharmaceutical composition of one embodiment, insulin secretion from pancreatic beta cells may increase, thereby reducing postprandial blood glucose. Thus, when GPR119 is activated, an effect of reducing blood lipids and body weights may be achieved in addition to glycemic control, thus contributing to alleviation of diabetes as well as metabolic diseases associated therewith.

[0159] Meanwhile, when GPR119 of small intestines is activated, the secretion of glucagon-like peptide-1 (GLP-1) from the small intestine L-cells may be increased. GLP-1 may exhibit a local action of inhibiting an influx of postprandial fat into bloodstream in small intestines.

[0160] In general, a GLP-1 receptor-like action may be modulated by high molecular compounds such as peptide ligands. However, since the pharmaceutical composition according to one embodiment includes the GPR119 ligand, which is a relatively low molecular compound, a GLP-1 receptor-like action may be implemented by an oral low molecular compound.

[0161] In the compound represented by Formula 1 in one embodiment, a halogen element may be substituted at positions 2 and 6 of a phenyl moiety of 4-(3-phenoxypropyl)piperidine. Accordingly, it may react more sensitively with GPR119 and a degree of GPR119 activation may be sharply higher than when other GPR119 ligands are administered.

[0162] The pharmaceutical composition of one embodiment may further include at least one selected from a DPPIV inhibitor, a PPAR agonist, a SGLT2 inhibitor, an insulin secretagogue, a biguanidine drug and an alpha-glucosidase inhibitor, in addition to the compound represented by Formula 1 described above. Thus, the pharmaceutical composition of one embodiment may be administered at least two drugs having different mechanisms, so as to reduce blood glucose through various mechanisms, thereby effectively controlling blood glucose.

[0163] Hypoglycemic agents currently applied to diabetic patients may include dipeptidyl peptidase IV (DPPIV) inhibitor, insulin sensitizer, sodium glucose co-transporter 2 (SGLT2) inhibitor for promoting urinary glucose excretion through a mechanism of inhibiting sodium-glucose co-transporter 2, insulin secretagogue, biguanidine drug (Biguanide), alpha-glucosidase inhibitor, etc.

[0164] Dipeptidyl peptidase IV (DPPIV) may be an enzyme which inactivates GLP-1 by removing two amino acids from an N-terminus of GLP-1 in the blood. GLP-1, of which secretion is induced by GPR119 ligand, may be inactivated by DPPIV enzyme within minutes after translocation into blood. Thus, when the GPR119 ligand increasing GLP-1 secretion and the DPPIV inhibitor blocking GLP-1 inactivation are used in combination, a duration of action of active GLP-1 in the blood may be extended along with a direct insulin secretion effect according to GPR119 activation of beta cells. Thus, a medicinal efficacy for alleviating metabolic diseases may be excellent. In other words, the DPPIV inhibitor may promote insulin secretion by prolonging a biological action of endogenous GLP-1, and thus may exhibit a postprandial hypoglycemic effect.

[0165] The DPPIV inhibitor may include, for example, at least one of sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin and dutogliptin.

[0166] An insulin sensitizer may be a drug for activating a peroxisome proliferator-activated receptor (PPAR). The PPAR agonist may include, for example, at least one of troglitazone, ciglitazone, rosiglitazone, pioglitazone, englitazone, elafibranor, saroglitazar and lobeglitazone.

[0167] Drug sodium glucose co-transporter 2 (SGLT2) inhibitor may promote glucose excretion by inhibiting glucose reabsorption in the kidneys in an insulin-independent manner. In addition, it may be accompanied by weight loss through calorie loss due to glucose excretion. The SGLT2 inhibitor may include, for example, at least one of canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin, sergliflozin, sotagliflozin and tofogliflozin.

[0168] The insulin secretagogue may include a drug of sulfonylureas and non-sulfonylureas. For example, the insulin secretagogue of sulfonylureas may include at least one of glibenclamide (glyburide), glipizide, gliclazide, glimepiride, tolazamide, tolbutamide, acetohexamide, carbutamide, chlorpropamide, glibornuride, gliquidone, glisentide, glisolamide, glisoxepide, glyclopyamide, glycylamide and glipentide. The insulin secretagogue of a non-sulfonylurea structure may include at least one of repaglinide and nateglinide.

[0169] The biguanidine drug may inhibit gluconeogenesis in the liver. The biguanidine drug may include, for example, at least one of metformin, buformin and phenformin.

[0170] The alpha-glucosidase inhibitor may exhibit an action of delaying absorption of carbohydrates by inhibiting an enzyme activity that breaks down disaccharides into monosaccharides in intestines. The alpha-glucosidase inhibitor may include, for example, at least one of acarbose, voglibose, emiglitate and miglitol.

[0171] The pharmaceutical composition of one embodiment may include a complex of ingredients. Thus, when administering the pharmaceutical composition of one embodiment, not only a hypoglycemic effect but also an effect of reducing blood lipids and body weights may be achieved by two drugs having different mechanisms of action from each other.

[0172] Thus, it may exhibit an excellent effect of treating or preventing diabetes and metabolic diseases associated therewith compared to the case of administering individual ingredients alone.

[0173] Hereinafter, the pharmaceutical composition according to one embodiment of the present invention will be described in detail with reference to Examples and Comparative Examples.

<Example 1> Confirmation of Combination Efficacy of GPR119 Ligand and DPPIV Inhibitor

[0174] Evaluation of Efficacy of Single Dose Administration in Normal Mice

[0175] Seven-weeks old ICR male mice fasted for at least 16 hours were administered with each of compound 1, sitagliptin or evogliptin as a DDPIV inhibitor alone, or administered with compound 1 in combination with one of sitagliptin and evogliptin. In both administration alone and co-administration, the mice were orally administered compound 1 at 0.3 mg/kg, sitagliptin at 10 mg/kg, and evogliptin at 0.2 mg/kg. At a time point of 30 minutes after drug administration, a glucose solution was orally loaded at 2 g/kg/10 ml.

[0176] To measure a change in plasma concentrations of active GLP-1 according to the combination, plasma at five minutes after glucose loading was separated using a container pretreated with the DPPIV inhibitor, and the plasma concentrations of active GLP-1 was quantified by using a GLP-1 (Active) ELISA kit (Millipore, Cat. EGLP-35K). To evaluate a drug response to postprandial blood glucose levels, blood glucose levels in whole blood collected from tail vein at a time point of 0, 15, 30, 60, 90, and 120 minutes after glucose challenge were measured using a Roche's AccuChek Active glucose meter. A time-blood glucose level response curve was obtained. In terms of a rate of change, a comparison was made between an area under time-blood glucose level curve in a control group administered with solvent only and an area under the time-blood glucose level curve in a drug administration group. The results thereof are shown in FIG. 1 and FIG. 2.

[0177] As confirmed in FIG. 1, when compound 1 and sitagliptin as a DPPIV inhibitor, were administered in combination, the blood concentration of active GLP-1 was significantly increased compared to the group administered compound 1 or sitagliptin alone. In addition, the blood glucose level for two hours after glucose loading was also significantly increased in the co-administration group compared to the group administered compound 1 or sitagliptin alone.

[0178] As confirmed in FIG. 2, a synergistic effect of alleviating postprandial blood glucose level was also exhibited when compound 1 and evogliptin as another DPPIV inhibitor.

[0179] Evaluation of Efficacy of Ten-Weeks Multiple Dose Administration in Diabetic Mice

[0180] Seven-weeks old ICR male mice were supplied with a high fat diet (Research Diets Inc., D12492; 60% kcal fat) for three weeks. The mice were divided into groups according to body weight, blood glucose and blood triglyceride concentration at a time point of three weeks after intraperitoneally injecting streptozotocin (STZ) at 80 mg/kg at the third week. Specifically, grouping was performed by selecting individuals of which nonfasting blood glucose level was increased 1SD (standard deviation) or higher and a plasma triglyceride level was increased 2SD or higher compared to normal mice. A drug-diet admixture, in which 100 mg/kg/day of compound 1 and 150 mg/kg/day of sitagliptin were mixed, was given to the selected group. The admixture was supplied for ten weeks. After that, fasting blood glucose levels, nonfasting blood glucose levels and plasma triglyceride concentrations were measured. Fasting and nonfasting blood glucose were measured from blood collected from tail vein using a Roche's AccuChek Active glucose meter. The plasma triglyceride concentration was measured from plasma collected after nonfasting autopsy using an automatic hematology analyzer (Konelab 20i).

[0181] As confirmed in FIG. 3, when compound 1 and sitagliptin were co-administered for ten weeks, it was confirmed that a level of both fasting and nonfasting blood glucose is similar to that of normal mice compared to high fat/streptozotocin (HF/STZ) mice administered with high fat diet only without mixing drugs. In other words, an excellent hypoglycemic rate was exhibited in both fasting and nonfasting blood glucose levels.

[0182] As confirmed in FIG. 4, an excellent rate of lowering plasma triglyceride concentration was exhibited in HF/STZ mice with diabetes and hypertriglyceridemia when co-administered with compound 1 and sitagliptin. In particular, when the mice were co-administered with compound 1 and sitagliptin, it is confirmed that the plasma triglyceride concentration is decreased to a level equivalent to that of normal mice, as the plasma triglyceride concentration is about early 200 S (mg/dl).

<Example 2> Confirmation of Combination Efficacy of GPR119 Ligand and SGLT2 Inhibitor or Insulin Secretagogue Glimepiride

[0183] Seven-weeks old ICR male mice fasted for at least 16 hours were administered with each of compound 1, dapagliflozin as an SGLT inhibitor, or glimepiride as an insulin secretagogue alone, or administered with compound 1 in combination with one of dapagliflozin and glimepiride. Glucose solution was orally loaded at 2 g/kg/10 ml at a time point of 30 minutes after orally administering each of compound 1 at 3 mg/kg, dapagliflozin at 0.3 mg/kg as a SGLT2 inhibitor, or glimepiride at 0.1 mg/kg as an insulin secretagogue alone or in combination. To evaluate a drug response to postprandial blood glucose level, a blood glucose in whole blood collected from tail vein at a time point of 0, 15, 30, 60, 90, and 120 minutes after glucose challenge in the blood was measured with a Roche's AccuChek Active glucose meter. A time-blood glucose level response curve was obtained. In terms of a rate of change, a comparison was made between an area under the time-blood glucose level curve in a control group administered with solvent only and an area under the time-blood glucose level curve in a drug administration group.

[0184] As confirmed in FIG. 5, a hypoglycemic efficacy was increased more significantly when co-administered with the two drugs than when administered alone.

<Example 3> Confirmation of Combination Efficacy of GPR119 Ligand and PPAR Agonist

[0185] To induce insulin resistance, six-weeks old male C57BL/6J mice were supplied with a special diet of high fat, high fructose and high cholesterol (Research Diets Inc., D09100301) for at least 27 weeks. A drug-diet admixture was prepared so that diet-induced obese (DIO) and insulin resistant mice could be administered with each of compound 1 at 100 mg/kg/day and elafibranor at 30 mg/kg/day as a PPAR agonist alone or in combination. The prepared drug-diet admixture was supplied to mice for 12 weeks. Nonfasting blood glucose level was measured from plasma collected after autopsy at a time point of 12 weeks after drug administration using a Roche's AccuChek Active glucose meter.

[0186] As confirmed in FIG. 6, compound 1 alone did not exhibit a significant hypoglycemic effect in severe insulin resistant mice, and elafibranor alone exhibited a hypoglycemic effect according to the alleviation of insulin resistance. However, when the two drugs were used in combination, it was confirmed that a significantly excellent hypoglycemic effect is exhibited compared to each drug alone.

<Example 4> Confirmation of Combination Efficacy of GPR119 Ligand and Biguanidine Drug

[0187] Four-weeks old C57BL/6J male mice were supplied with a high fat diet (Research Diets Inc., D12492; 60% kcal fat) for ten weeks so as to induce insulin resistance. After acclimatization to drug administration for two weeks, the mice were assigned into each group based on body weight and body fat. Compound 1 was administered alone at 50 mg/kg twice a day to a compound 1 monotherapy group, and metformin was administered alone at 150 mg/kg twice a day to a metformin monotherapy group. The co-administration group was orally co-administered with compound 1 at 50 mg/kg and metformin at 150 mg/kg twice a day for three weeks. A body weight was measured over time until a time point of administration on day 16, and a body composition was sequentially measured by using a Minispec LF90II NMR spectrometer (Bruker Optics, Ettlingen, Germany) in the last week. Fasting blood glucose was measured from whole blood collected from a tail vein after fasting for six hours at the second week of administration using a Roche's AccuChek Active glucose meter. After administration for three weeks, a nonfasting autopsy was performed and a plasma concentration of total GLP-1 was quantified using the Total GLP-1 ELISA (7-36 and 9-36) Assay Kit (Alpco, 43-GPTHU-E01).

[0188] As confirmed in FIG. 7, a significant increase in GLP-1 secretion was not identified in mice administered with compound 1 or metformin alone. However, when co-administered with the two drugs, it was confirmed that a blood concentration of total GLP-1 is significantly increased compared to the administration of each drug alone, thus achieving a synergistic effect of increasing GLP-1 secretion according to the drugs combination.

[0189] As confirmed in FIG. 8, when the mice were administered with each drug alone, there was a slight tendency to decrease fasting blood glucose levels. However, when the mice were co-administered with the two drugs, a significant fasting hypoglycemic effect was exhibited. In other words, there was a synergistic increase in medicinal efficacy according to the co-administration.

[0190] As confirmed in FIG. 9, when the mice were administered with each of compound 1 and metformin alone for two weeks, there was a weight loss of −4.0% and −4.4%, respectively. In contrast, when the mice were co-administered with both drugs for two weeks, there was a weight loss of −16.3%. In other words, when the mice were co-administered with both drugs, it is confirmed that reactivity to the drugs is significantly increased compared to when administered with each drug alone. From this, it was confirmed that co-administration of both drugs has a synergistic effect on the prevention or treatment of obesity.

[0191] Referring to the results of body composition analysis performed after the end of administration for three weeks in FIG. 9, there was no effect of reducing body fat when the mice were administered with compound 1 alone for two weeks. When the mice were administered with metformin alone for two weeks, there was an insignificant effect of reducing body fat. When the mice were co-administered with both drugs, however, it was confirmed that there is a rate of decrease in body fat of about 30%. In other words, when the mice were co-administered with both drugs, it was confirmed that there are not only a hypoglycemic effect but also a body fat reduction effect. From this, it was confirmed that co-administration of both drugs has a synergistic effect on the prevention or treatment of obesity.

<Example 5> Confirmation of Combination Efficacy of GPR119 Ligand and α-Glucosidase Inhibitor

[0192] Eight-weeks old ICR male mice fasted for at least 16 hours were orally administered with each of compound 1 at 3 mg/kg and voglibose at 0.02 mg/kg as an alpha-glucosidase inhibitor alone or in combination. At a time point of 30 minutes later, sucrose solution was orally loaded at 2 g/kg/10 ml. To evaluate a drug response to postprandial blood glucose levels, a blood glucose in whole blood collected from tail vein at a time point of 0, 15, 30, 60, 90, and 120 minutes after glucose injection in the blood was measured with a Roche's AccuChek Active glucose meter. A time-blood glucose level response curve was obtained. In terms of a rate of change, a comparison was made between an area under the time-blood glucose level curve in a control group administered with solvent only and an area under the time-blood glucose level curve in a drug administration group.

[0193] As confirmed in FIG. 10, when the mice were administered with voglibose alone, there was no hypoglycemic effect. However, when the mice were co-administered with compound 1 and voglibose, there was a synergistic effect of increasing a hypoglycemic efficacy more than when administered with compound 1 alone.