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.

Description

Pharmaceutical composition for the prevention or treatment of diabetes and accompanying metabolic diseases

[0001] The present invention relates to a pharmaceutical composition for preventing or treating diabetes and accompanying metabolic diseases, comprising a GPR119 (G protein coupled receptor 119) ligand and at least one other mechanism drug as active ingredients.

[0002] Diabetes is a chronic, progressive disease characterized by hyperglycemia caused by multifactorial factors. Therefore, using individual medications alone often fails to achieve sufficient diabetes prevention or treatment effects, depending on the specific symptoms. Therefore, despite the fact that more than a dozen different medications with different mechanisms of action are already available, there is a continuing need to develop hypoglycemic agents with diverse mechanisms of action.

[0003] Meanwhile, metabolic disorders accompanying diabetes are a growing concern for diabetic patients. Specifically, obesity and dyslipidemia associated with diabetes are becoming a concern.

[0004] The purpose of the present invention is to provide a pharmaceutical composition that can improve postprandial and fasting blood sugar levels when administered to a subject.

[0005] The purpose of the present invention is to provide a pharmaceutical composition that exhibits the effect of improving blood lipid concentration and reducing body fat when administered to a subject.

[0006] The purpose of the present invention is to provide a pharmaceutical composition that can be usefully used for the prevention or treatment of diabetes or a metabolic disease accompanying diabetes.

[0007] A pharmaceutical composition for preventing or treating at least one disease selected from among diabetes or metabolic diseases accompanying diabetes according to one embodiment of the present invention may include a compound represented by the following chemical formula 1, a pharmaceutically acceptable salt thereof, an optical isomer thereof, a hydrate or solvate thereof, or a mixture thereof; and at least one selected from among a DPPIV inhibitor, a PPAR agonist, an SGLT2 inhibitor, an insulin secretagogue, a biguanide drug, and an alpha-glucosidase inhibitor.

[0008] [Chemical Formula 1]

[0009]

[0010] In the above chemical formula 1, A may be an oxadiazole group, a dihydrooxazole group, a thiazole group, or a thiadiazole group. A may be unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a C1-C6 straight-chain or branched-chain alkyl group, and a C1-C6 straight-chain or branched-chain hydroxyalkyl group. The alkyl group or the hydroxyalkyl group may each independently be unsubstituted or substituted with a halogen atom or a C1-C6 alkoxy group.

[0011] B may be a pyridine group, a pyrimidine group, a pyrazine group, or an oxadiazole group. B may be unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a C1-C6 straight chain or branched chain alkyl group, a C1-C6 straight chain or branched chain hydroxyalkyl group, a C1-C6 alkoxy group, and an oxadiazole group. The C1-C6 straight chain or branched chain alkyl group, the C1-C6 straight chain or branched chain hydroxyalkyl group, the C1-C6 alkoxy group, or the oxadiazole group may each independently be unsubstituted or substituted with a halogen, a C1-C6 alkyl group, or a C1-C6 alkoxy group.

[0012] X1 and X2 can be F, Cl, Br or I. X1 and X2 can be the same or different.

[0013] The above A is , , , or It could be.

[0014] R1 to R3, R5, and R6 may each independently be one or more substituents selected from the group consisting of a hydrogen atom, a halogen atom, a C1-C6 straight-chain or branched-chain alkyl group, and a C1-C6 straight-chain or branched-chain hydroxyalkyl group. The alkyl group or the hydroxyalkyl group may each independently be unsubstituted or substituted with a halogen atom or a C1-C6 alkoxy group.

[0015] The above B is , , , or It could be.

[0016] R7 to R above 11 Each of the above may be independently substituted with one or more substituents selected from the group consisting of a hydrogen atom, a halogen atom, a C1-C6 straight or branched alkyl group, a C1-C6 straight or branched hydroxyalkyl group, a C1-C6 alkoxy group, and an oxadiazole group. Each of the above alkyl group, hydroxyalkyl group, alkoxy group, or oxadiazole group may be independently unsubstituted or substituted with a halogen atom, a C1-C6 alkyl group, or a C1-C6 alkoxy group.

[0017] X can be F.

[0018] In the above chemical formula 1, A may be an oxadiazole group substituted with a C1-C6 straight or branched alkyl group, B may be a pyrimidine group substituted with a C1-C6 straight or branched alkyl group, and X may be F.

[0019] In this embodiment, the term “halogen” means fluorine, chlorine, bromine or iodine.

[0020] In one embodiment, the term "alkyl" means a straight-chain or branched hydrocarbon residue, unless otherwise stated. Examples of C1-C6 alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

[0021] In one embodiment, the term "alkoxy" includes an alkyl-oxygen radical having an alkyl group as defined above, unless otherwise stated. Examples of such C1-C6 alkoxy include methoxy, ethoxy, propoxy, butoxy, pentoxy, and the like.

[0022] In one embodiment, the term "heterocycle" or "heterocyclic" means a 5 to 13 membered heteroaromatic or non-aromatic compound containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S, unless otherwise stated.

[0023] In one embodiment, the compound represented by the above formula 1 may be at least one compound selected from the group consisting of the following compounds.

[0024] 2-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-4,5-dihydrooxazole,

[0025] (R)-2-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-4-methyl-4,5-dihydrooxazole,

[0026] (S)-2-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-4-methyl-4,5-dihydrooxazole,

[0027] (S)-2-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-5-methyl-4,5-dihydrooxazole,

[0028] (R)-2-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-5-methyl-4,5-dihydrooxazole,

[0029] 2-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-5,5-dimethyl-4,5-dihydrooxazole,

[0030] (R)-(2-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-4,5-dihydrooxazol-5-yl)methanol,

[0031] (S)-(2-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-4,5-dihydrooxazol-5-yl)methanol,

[0032] (R)-3-(2-(4-(3-(3,5-difluoro-4-(5-methyl-4,5-dihydrooxazol-2-yl)phenoxy)propyl)piperidin-1-yl)pyrimidin-5-yl)-5-isobutyl-1,2,4-oxadiazole,

[0033] (R)-5-(4-(3-(3,5-difluoro-4-(4-methyl-4,5-dihydrooxazol-2-yl)phenoxy)propyl)piperidin-1-yl)-3-isopropyl-1,2,4-oxadiazole,

[0034] (S)-5-(4-(3-(3,5-difluoro-4-(5-methyl-4,5-dihydrooxazol-2-yl)phenoxy)propyl)piperidin-1-yl)-3-isopropyl-1,2,4-oxadiazole,

[0035] 5-(4-(3-(4-(5,5-dimethyl-4,5-dihydrooxazol-2-yl)-3,5-difluorophenoxy)propyl)piperidin-1-yl)-3-isopropyl-1,2,4-oxadiazole,

[0036] 3-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-5-methyl-1,2,4-oxadiazole,

[0037] 3-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-5-propyl-1,2,4-oxadiazole,

[0038] 3-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-5-isopropyl-1,2,4-oxadiazole,

[0039] 5-(tert-butyl)-3-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-1,2,4-oxadiazole,

[0040] (3-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-1,2,4-oxadiazol-5-yl)methanol,

[0041] 2-(3-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-1,2,4-oxadiazol-5-yl)ethan-1-ol,

[0042] (S)-1-(3-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol,

[0043] (R)-1-(3-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-1,2,4-oxadiazol-5-yl)propan-2-ol,

[0044] (S)-1-(3-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-1,2,4-oxadiazol-5-yl)propan-2-ol,

[0045] 2-(3-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-1,2,4-oxadiazol-5-yl)-2-methylpropan-1-ol,

[0046] 3-(2,6-difluoro-4-(3-(1-(5-propylpyrimidin-2-yl)piperidin-4-yl)propoxy)phenyl)-5-isopropyl-1,2,4-oxadiazole,

[0047] 3-(2,6-difluoro-4-(3-(1-(5-pentylpyrimidin-2-yl)piperidin-4-yl)propoxy)phenyl)-5-isopropyl-1,2,4-oxadiazole,

[0048] 3-(2,6-difluoro-4-(3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)propoxy)phenyl)-5-isopropyl-1,2,4-oxadiazole,

[0049] 3-(2,6-difluoro-4-(3-(1-(5-methoxypyrimidin-2-yl)piperidin-4-yl)propoxy)phenyl)-5-isopropyl-1,2,4-oxadiazole,

[0050] 3-(2,6-difluoro-4-(3-(1-(5-isopropoxypyrimidin-2-yl)piperidin-4-yl)propoxy)phenyl)-5-isopropyl-1,2,4-oxadiazole,

[0051] 3-(4-(3-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-5-isopropyl-1,2,4-oxadiazole,

[0052] 3-(4-(3-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-5-isopropyl-1,2,4-oxadiazole,

[0053] 3-(2,6-difluoro-4-(3-(1-(5-(5-isobutyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4-yl)propoxy)phenyl)-5-methyl-1,2,4-oxadiazole,

[0054] 3-(2,6-difluoro-4-(3-(1-(5-(5-isobutyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4-yl)propoxy)phenyl)-5-ethyl-1,2,4-oxadiazole,

[0055] 3-(2,6-difluoro-4-(3-(1-(5-(5-isobutyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4-yl)propoxy)phenyl)-5-isopropyl-1,2,4-oxadiazole,

[0056] 5-(sec-butyl)-3-(2,6-difluoro-4-(3-(1-(5-(5-isobutyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4-yl)propoxy)phenyl)-1,2,4-oxadiazole,

[0057] 3-(2,6-difluoro-4-(3-(1-(5-(5-isobutyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4-yl)propoxy)phenyl)-5-(methoxymethyl)-1,2,4-oxadiazole,

[0058] (S)-1-(3-(2,6-difluoro-4-(3-(1-(5-(5-isobutyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4-yl)propoxy)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol,

[0059] 2-(3-(2,6-difluoro-4-(3-(1-(5-(5-isobutyl-1,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4-yl)propoxy)phenyl)-1,2,4-oxadiazol-5-yl)-2-methylpropan-1-ol,

[0060] 3-(4-(3-(1-(5-chloropyrazin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-5-isopropyl-1,2,4-oxadiazole,

[0061] 3-(2,6-difluoro-4-(3-(1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)propoxy)phenyl)-5-isopropyl-1,2,4-oxadiazole,

[0062] 3-(2,6-difluoro-4-(3-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)propoxy)phenyl)-5-methyl-1,2,4-oxadiazole,

[0063] 3-(2,6-difluoro-4-(3-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)propoxy)phenyl)-5-isopropyl-1,2,4-oxadiazole,

[0064] (3-(2,6-difluoro-4-(3-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)propoxy)phenyl)-1,2,4-oxadiazol-5-yl)methanol,

[0065] 2-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-5-methyl-1,3,4-oxadiazole,

[0066] 2-Ethyl-5-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-1,3,4-oxadiazole,

[0067] 2-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-5-isopropyl-1,3,4-oxadiazole,

[0068] 5-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-N-isopropyl-1,3,4-oxadiazol-2-amine,

[0069] 2-(2,6-difluoro-4-(3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)propoxy)phenyl)-5-methyl-1,3,4-oxadiazole,

[0070] 2-(2,6-difluoro-4-(3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)propoxy)phenyl)-5-ethyl-1,3,4-oxadiazole,

[0071] 2-(2,6-difluoro-4-(3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)propoxy)phenyl)-5-isopropyl-1,3,4-oxadiazole,

[0072] 2-(4-(3-(1-(5-chloropyrazin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-5-methyl-1,3,4-oxadiazole,

[0073] 2-(4-(3-(1-(5-chloropyrazin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-5-ethyl-1,3,4-oxadiazole,

[0074] 2-(4-(3-(1-(5-chloropyrazin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-5-isopropyl-1,3,4-oxadiazole,

[0075] 5-(4-(3-(3,5-difluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy)propyl)piperidin-1-yl)-3-propyl-1,2,4-oxadiazole,

[0076] 5-(4-(3-(3,5-difluoro-4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenoxy)propyl)piperidin-1-yl)-3-propyl-1,2,4-oxadiazole,

[0077] 5-(4-(3-(3,5-difluoro-4-(5-isopropyl-1,3,4-oxadiazol-2-yl)phenoxy)propyl)piperidin-1-yl)-3-propyl-1,2,4-oxadiazole,

[0078] 5-(4-(3-(3,5-difluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy)propyl)piperidin-1-yl)-3-isopropyl-1,2,4-oxadiazole,

[0079] 5-(4-(3-(4-(5-ethyl-1,3,4-oxadiazol-2-yl)-3,5-difluorophenoxy)propyl)piperidin-1-yl)-3-isopropyl-1,2,4-oxadiazole,

[0080] 5-(4-(3-(3,5-difluoro-4-(5-isopropyl-1,3,4-oxadiazol-2-yl)phenoxy)propyl)piperidin-1-yl)-3-isopropyl-1,2,4-oxadiazole,

[0081] 5-(4-(3-(3,5-difluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy)propyl)piperidin-1-yl)-3-(2,2,2-trifluoroethyl)-1,2,4-oxadiazole,

[0082] 3-(4-(3-(3,5-difluoro-4-(5-isopropyl-1,3,4-oxadiazol-2-yl)phenoxy)propyl)piperidin-1-yl)-5-isopropyl-1,2,4-oxadiazole,

[0083] 2-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-5-isopropyl-1,3,4-thiadiazole,

[0084] 2-(2,6-difluoro-4-(3-(1-(5-propylpyrimidin-2-yl)piperidin-4-yl)propoxy)phenyl)-5-isopropyl-1,3,4-thiadiazole,

[0085] 2-(2,6-difluoro-4-(3-(1-(5-pentylpyrimidin-2-yl)piperidin-4-yl)propoxy)phenyl)-5-isopropyl-1,3,4-thiadiazole,

[0086] 2-(2,6-difluoro-4-(3-(1-(5-fluoropyrimidin-2-yl)piperidin-4-yl)propoxy)phenyl)-5-isopropyl-1,3,4-thiadiazole,

[0087] 2-(2,6-difluoro-4-(3-(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)propoxy)phenyl)-5-isopropyl-1,3,4-thiadiazole,

[0088] 2-(2,6-difluoro-4-(3-(1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)propoxy)phenyl)-5-isopropyl-1,3,4-thiadiazole, and

[0089] 4-Ethyl-2-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)thiazole.

[0090] In one embodiment, the compound represented by the above chemical formula 1 may be 3-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-5-isopropyl-1,2,4-oxadiazole (hereinafter, compound 1).

[0091] In one embodiment, the pharmaceutical composition may include a compound represented by the above chemical formula 1; and at least one of the DPPIV inhibitor, the PPAR agonist, the SGLT2 inhibitor, the insulin secretagogue, the biguanide drug, and the alpha-glucosidase inhibitor.

[0092] The above DPPIV inhibitor may be at least one of sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin, and dutogliptin.

[0093] The above PPAR agonist may be at least one of troglitazone, ciglitazone, rosiglitazone, pioglitazone, englitazone, ilafibrana, saroglitazane, and lobeglitazone.

[0094] The above SGLT2 inhibitor may be at least one of canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luteogliflozin, remogliflozin, sugliflozin, sotagliflozin, and tofogliflozin.

[0095] The above insulin secretagogue may be at least one of glibenclamide, glipizide, gliclazide, glimepiride, tolazamide, tolbutamide, acetohexamide, carbutamide, chlorpropamide, glibornuride, gliquidone, glicentide, glisamide, glisoxepide, gliclopiamide, glycylamide, glypentide, repaglinide, and nateglinide.

[0096] The above biguanide drug may be at least one of metformin, buformin, and phenformin. The above alpha-glucosidase inhibitor may be at least one of acarbose, voglibose, emiglitate, and miglitol.

[0097] In one embodiment, the pharmaceutical composition may include a compound represented by the above chemical formula 1; and at least one of evogliptin, sitagliptin, ilafibrana, dapagliflozin, glimepiride, metformin, and voglibose.

[0098] In one embodiment, the pharmaceutical composition may comprise the compound 1; and at least one of the DPPIV inhibitor, the PPAR agonist, the SGLT2 inhibitor, the insulin secretagogue, the biguanide drug, and the alpha-glucosidase inhibitor.

[0099] In one embodiment, the pharmaceutical composition may comprise compound 1; and at least one of evogliptin, sitagliptin, ilapibranac, dapagliflozin, glimepiride, metformin, and voglibose. In one embodiment, the metabolic disease may be at least one of obesity and dyslipidemia.

[0100] When a pharmaceutical composition is described herein as comprising A and B, the pharmaceutical composition is interpreted to mean a composition comprising A and B; a combination comprising A and B as separate preparations; or a composition comprising the combination. Accordingly, in the present invention, the composition may be used interchangeably with the combination.

[0101] The pharmaceutical composition may contain a compound represented by Chemical Formula 1, a pharmaceutically acceptable salt thereof, an optical isomer thereof, a hydrate or solvate thereof, or a mixture thereof; and at least one selected from a DPPIV inhibitor, a PPAR agonist, an SGLT2 inhibitor, an insulin secretagogue, a biguanide drug, and an alpha-glucosidase inhibitor; each as a separate formulation or may contain all of them in the form of a combination formulation.

[0102] The pharmaceutical composition may be a combination of separate preparations or a complex preparation.

[0103] The pharmaceutical composition may comprise a first compartment containing a first active ingredient and a second compartment containing a second active ingredient.

[0104] The first active ingredient may be a compound represented by Chemical Formula 1, a pharmaceutically acceptable salt thereof, an optical isomer thereof, a hydrate or solvate thereof, or a mixture thereof. The second active ingredient may include at least one selected from a DPPIV inhibitor, a PPAR agonist, an SGLT2 inhibitor, an insulin secretagogue, a biguanide drug, and an alpha-glucosidase inhibitor.

[0105] According to embodiments of the present invention, the first compartment containing the first active ingredient and the second compartment containing the second active ingredient in the pharmaceutical composition may be administered together, and the pharmaceutical composition may be a composition for combined administration. Specifically, the pharmaceutical composition may be a combination in which the two components are formulated as separate unit dosage forms. In this case, the first active ingredient and the second active ingredient may be administered together in separate dosage forms.

[0106] In one embodiment of the present invention, it was revealed that the pharmaceutical composition of one embodiment is effective in treating and preventing diabetes by measuring the concentration of blood active GLP-1 and blood sugar concentration through a single-time glucose tolerance improvement drug efficacy evaluation in a normal mouse model.

[0107] In one embodiment of the present invention, in a mouse model in which hyperglycemia, insulin resistance, or obesity were induced by supplying special feed, it was found that the pharmaceutical composition of one embodiment is effective in treating and preventing diabetes and metabolic diseases accompanying diabetes through blood sugar, neutral fat, and body weight measurements.

[0108] More specifically, when administering a pharmaceutical composition according to one embodiment, it is confirmed that the concentration of GLP-1 in the blood increases, blood sugar decreases, plasma triglyceride concentration decreases, and body weight decreases compared to when co-administering a compound represented by Chemical Formula 1 as a GPR119 agonist, a pharmaceutically acceptable salt thereof, an optical isomer thereof, a hydrate or solvate thereof, or a mixture thereof; or a DPPIV inhibitor, a PPAR agonist, an SGLT2 inhibitor, an insulin secretagogue, a biguanide drug, and an alpha-glucosidase inhibitor.

[0109] In the present invention, non-limiting examples of pharmaceutically acceptable salts of the compound represented by the above chemical formula 1 may include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid; salts with organic carboxylic acids such as acetic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid or malic acid, or sulfonic acids such as methanesulfonic acid or para-toluenesulfonic acid; salts with alkali metals such as sodium, potassium or lithium; or salts with various acids known to be capable of forming other pharmaceutically acceptable salts.

[0110] The pharmaceutical composition for the prevention or treatment of diabetes or at least one disease selected from among accompanying metabolic diseases of one embodiment may be used in the form of a general pharmaceutical formulation. The pharmaceutical formulation may be administered in various oral and parenteral dosage forms, and the dosage form may vary depending on the intended use.

[0111] When formulating the pharmaceutical composition of one embodiment into various oral and parenteral dosage forms, it can be manufactured using commonly used excipients such as fillers, diluents, bulking agents, binders, wetting agents, disintegrants, and surfactants.

[0112] Solid preparations for oral administration may include tablets, pills, powders, granules, capsules, etc., and these solid preparations may be manufactured by mixing at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc., with the pharmaceutical composition. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.

[0113] In addition, liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups, and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included.

[0114] Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solutions and suspensions can include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases include witepsol, macrogol, Tween 61, cacao butter, laurin, and glycerogelatin.

[0115] In addition, the pharmaceutical composition for preventing or treating at least one disease selected from diabetes or its accompanying metabolic diseases according to the present invention may exhibit an effective amount in the dosage range of about 1 to about 1,000 mg. The dosage or administration amount may be administered in various dosages and methods, such as once a day or divided into several times a day, depending on the subject's body weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and disease severity.

[0116] In the present invention, diabetes may encompass both type 1 and type 2 diabetes. Type 1 diabetes is a disease characterized by the destruction of pancreatic beta cells and absolute insulin deficiency, resulting from the interaction of genetic, environmental, and immunological factors. Type 2 diabetes begins with insulin resistance, a condition in which cells fail to respond appropriately to insulin. It can be caused by excess weight and low activity levels. In type 2 diabetes, insulin deficiency may occur as the disease progresses.

[0117] A pharmaceutical composition of one embodiment may include a compound represented by Chemical Formula 1 or an active ingredient exhibiting a similar function; and at least one selected from an insulin secretagogue, a DPPIV inhibitor, a PPAR agonist, an SGLT2 inhibitor, an insulin secretagogue, a biguanide drug, and an alpha-glucosidase inhibitor.

[0118] The present invention also provides a method for preventing or treating at least one disease selected from among diabetes or metabolic diseases accompanying therewith, comprising administering to a subject in need of treatment a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by Chemical Formula 1, a pharmaceutically acceptable salt thereof, an optical isomer thereof, a hydrate or solvate thereof, or a mixture thereof; and at least one selected from among a DPPIV inhibitor, a PPAR agonist, an SGLT2 inhibitor, an insulin secretagogue, a biguanide drug, and an alpha-glucosidase inhibitor.

[0119] In this specification, the term "metabolic disease accompanying diabetes" means a disease that shares some etiology with diabetes, such as obesity or dyslipidemia, and can easily occur frequently with the onset of diabetes.

[0120] The term "at least one" in this specification is interpreted to mean any combination derived from a plurality of configurations. For example, "at least one of A, B, and C" is interpreted to include "A, B, or C," "two selected from A, B, and C," and all combinations derived from "A, B, and C."

[0121] As used herein, the term "subject in need of treatment" refers to a mammal, including a human, and the term "administration" refers to providing a given substance to the subject by any suitable method. The term "therapeutically effective amount" refers to the amount of an active ingredient or pharmaceutical composition that is deemed by a researcher, veterinarian, physician, or other clinician to induce a biological or medical response in an animal or human, including an amount that induces symptomatic relief of the disease or disorder being treated. It will be apparent to those skilled in the art that the therapeutically effective dosage and frequency of administration of the active ingredient of the present invention will vary depending on the desired effect.

[0122] In one embodiment, the route of administration of the pharmaceutical composition of the present invention may be through any common route as long as it can reach the target tissue.

[0123] The pharmaceutical composition of one embodiment may be administered orally, intraperitoneally, intravenously, intramuscularly, subcutaneously, intradermally, intranasally, intrapulmonary, intrarectally, intracavitarily, intraperitoneally, or intrathecally, but is not limited thereto.

[0124] The pharmaceutical composition of one embodiment may be administered once a day or twice a day at regular intervals.

[0125] The pharmaceutical composition of one embodiment may be used alone or in combination with methods using surgery, hormone therapy, drug therapy, and biological response modifiers for the prevention and treatment of at least one disease selected from diabetes or its accompanying metabolic diseases.

[0126] One embodiment also provides a food composition for preventing or improving at least one disease selected from among diabetes or metabolic diseases accompanying therewith, comprising as an active ingredient a compound represented by the above chemical formula 1, a pharmaceutically acceptable salt thereof, an optical isomer thereof, a hydrate or solvate thereof, or a mixture thereof; and at least one selected from among a DPPIV inhibitor, a PPAR agonist, an SGLT2 inhibitor, an insulin secretagogue, a biguanide drug, and an alpha-glucosidase inhibitor.

[0127] In one embodiment, the term "improvement" means any action by which a disease is improved or beneficially altered by administration of the composition.

[0128] In one embodiment, the term "food" includes meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, vitamin complexes, health functional foods, health foods and health supplements, and includes all foods in the conventional sense.

[0129] The term "functional food" above is synonymous with "food for special health use" (FoSHU). It refers to foods with high medical and therapeutic effects, processed to effectively demonstrate bioregulatory functions in addition to providing nutrition. "Functionality" here refers to regulating nutrients for the structure and function of the human body or achieving beneficial health effects, such as physiological effects.

[0130] The term "health food" refers to foods that have a more active health-maintaining or health-promoting effect than regular foods, while "health supplement food" refers to foods intended for health-enhancing purposes. In some cases, the terms "health functional food," "health food," and "health supplement food" may be used interchangeably.

[0131] The food of the present invention can be manufactured by a method commonly used in the art, and can be manufactured by adding raw materials and ingredients commonly added in the art during the manufacturing process. Specifically, the food may include proteins, carbohydrates, fats, nutrients, seasonings, and flavoring agents, and examples of the carbohydrates include, but are not limited to, glucose, fructose, maltose, sucrose, oligosaccharides, dextrin, cyclodextrin, xylitol, sorbitol, erythrol, saccharin, or synthetic flavoring agents. The food composition of the present invention can be manufactured into various forms of formulations without limitation as long as it is a formulation recognized as a food.

[0132] The present invention also provides a method for preventing or improving at least one disease selected from among diabetes or metabolic diseases accompanying therewith, comprising administering to a subject in need of improvement a food composition comprising, as an active ingredient, a compound represented by the above chemical formula 1, a pharmaceutically acceptable salt thereof, an optical isomer thereof, a hydrate or solvate thereof, or a mixture thereof; and at least one selected from among a DPPIV inhibitor, a PPAR agonist, an SGLT2 inhibitor, an insulin secretagogue, a biguanide drug, and an alpha-glucosidase inhibitor.

[0133] The present invention also provides a feed composition for preventing or improving at least one disease selected from among diabetes or metabolic diseases accompanying therewith, comprising as an active ingredient a compound represented by the above chemical formula 1, a pharmaceutically acceptable salt thereof, an optical isomer thereof, a hydrate or solvate thereof, or a mixture thereof; and at least one selected from among a DPPIV inhibitor, a PPAR agonist, an SGLT2 inhibitor, an insulin secretagogue, a biguanide drug, and an alpha-glucosidase inhibitor.

[0134] The term "feed" in the present invention means any natural or artificial diet, meal, etc., or components of such meal, intended for consumption and digestion by livestock or suitable therefor. The feed may include feed additives or supplementary feed.

[0135] The type of the above feed is not particularly limited, and feed commonly used in the relevant technical field can be used. Non-limiting examples of the above feed include plant-based feed such as grains, roots, food processing by-products, algae, fiber, pharmaceutical by-products, oils, starches, meal, or grain by-products; and animal-based feed such as proteins, inorganic substances, oils, minerals, oils, single-cell proteins, zooplankton, or food. These may be used alone or in combination of two or more.

[0136] The present invention also provides the use of a pharmaceutical composition comprising, as an active ingredient, a compound represented by the above chemical formula 1, a pharmaceutically acceptable salt thereof, an optical isomer thereof, a hydrate or solvate thereof, or a mixture thereof; and at least one selected from a DPPIV inhibitor, a PPAR agonist, an SGLT2 inhibitor, an insulin secretagogue, a biguanide drug, and an alpha-glucosidase inhibitor, for the prevention or treatment of at least one disease selected from among diabetes or metabolic diseases accompanying diabetes.

[0137] The present invention also provides the use of a pharmaceutical composition comprising, as an active ingredient, a compound represented by the above chemical formula 1, a pharmaceutically acceptable salt thereof, an optical isomer thereof, a hydrate or solvate thereof, or a mixture thereof; and at least one selected from a DPPIV inhibitor, a PPAR agonist, an SGLT2 inhibitor, an insulin secretagogue, a biguanide drug, and an alpha-glucosidase inhibitor, for manufacturing a pharmaceutical preparation for preventing or treating at least one disease selected from among diabetes or metabolic diseases accompanying diabetes.

[0138] The present invention also provides a method for preventing or treating at least one disease selected from among diabetes or metabolic diseases accompanying therewith, comprising administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition comprising a compound represented by the above chemical formula 1, a pharmaceutically acceptable salt thereof, an optical isomer thereof, a hydrate or solvate thereof, or a mixture thereof; and at least one selected from among a DPPIV inhibitor, a PPAR agonist, an SGLT2 inhibitor, an insulin secretagogue, a biguanide drug, and an alpha-glucosidase inhibitor.

[0139] The present invention also provides a combination of a compound represented by the above chemical formula 1, a pharmaceutically acceptable salt thereof, an optical isomer thereof, a hydrate or solvate thereof, or a mixture thereof; and at least one selected from among a DPPIV inhibitor, a PPAR agonist, an SGLT2 inhibitor, an insulin secretagogue, a biguanide drug, and an alpha-glucosidase inhibitor.

[0140] The present invention also provides a pharmaceutical composition for the prevention or treatment of at least one disease selected from among diabetes or metabolic diseases accompanying therewith, comprising a compound represented by the above chemical formula 1, a pharmaceutically acceptable salt thereof, an optical isomer thereof, a hydrate or solvate thereof, or a mixture thereof, used in combination with at least one selected from among DPPIV inhibitors, PPAR agonists, SGLT2 inhibitors, insulin secretagogues, biguanide drugs, and alpha-glucosidase inhibitors.

[0141] In the above treatment method, food composition, improvement method, feed composition, use and combination, the compound represented by the above chemical formula 1 may be specifically 3-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-5-isopropyl-1,2,4-oxadiazole.

[0142] Matters mentioned in each of the pharmaceutical composition, treatment method, food composition, improvement method, feed composition, use and combination according to the embodiments of the present invention are equally applicable to each embodiment unless they are contradictory.

[0143] When the pharmaceutical composition according to the present invention is administered to a subject, postprandial and fasting blood sugar levels can be improved.

[0144] When the pharmaceutical composition according to the present invention is administered to a subject, it can exhibit the effect of improving blood lipid concentration and reducing body fat.

[0145] Therefore, the pharmaceutical composition according to the present invention can be usefully used for the prevention or treatment of diabetes or metabolic diseases accompanying diabetes.

[0146] Figure 1 is a graph showing the increase in the blood peak concentration of active GLP-1 5 minutes after a single oral administration of a drug to normal mice and the postprandial blood glucose-lowering effect for 2 hours after a glucose load.

[0147] Figure 2 is a graph showing the efficacy of a drug administered orally once to normal mice on postprandial blood glucose levels for 2 hours after a glucose load.

[0148] Figure 3 is a graph showing the efficacy of drugs administered in combination for 10 weeks to HF / STZ diabetic mice on non-fasting and fasting blood glucose levels.

[0149] Figure 4 is a graph showing the effectiveness of drugs co-administered for 10 weeks on the concentration of neutral fat in the plasma of HF / STZ diabetic mice.

[0150] Figure 5 is a graph showing the efficacy of a drug administered orally once to normal mice on postprandial blood glucose levels for 2 hours after a glucose load.

[0151] Figure 6 is a graph showing the non-fasting blood sugar levels when drugs were administered alone or in combination for 12 weeks to DIO mice.

[0152] Figure 7 is a graph showing the total GLP-1 concentration in plasma when drugs were administered alone or in combination for 3 weeks to HF mice.

[0153] Figure 8 is a graph showing the fasting blood sugar levels when drugs were administered alone or in combination to HF mice for 3 weeks.

[0154] Figure 9 is a graph showing the changes in body weight loss rate and body composition improvement over time when drugs were administered alone or in combination to HF mice for 3 weeks.

[0155] Figure 10 is a graph showing the efficacy of single and combined administration on postprandial blood glucose levels for 2 hours after a sucrose load in normal mice after a single administration.

[0156] The advantages and features of the present invention, and the methods for achieving them, will become clearer with reference to the embodiments described in detail below. However, the present invention is not limited to the embodiments disclosed below, but may be implemented in various different forms. These embodiments are provided solely to ensure that the disclosure of the present invention is complete and to fully inform those skilled in the art of the scope of the invention. The present invention is defined solely by the scope of the claims.

[0157] A pharmaceutical composition for preventing or treating at least one disease selected from among diabetes or metabolic diseases accompanying diabetes according to the present invention may include a compound represented by the above-described chemical formula 1, a pharmaceutically acceptable salt thereof, an optical isomer thereof, a hydrate or solvate thereof, or a mixture thereof; and at least one selected from among a DPPIV inhibitor, a PPAR agonist, an SGLT2 inhibitor, an insulin secretagogue, a biguanide drug, and an alpha-glucosidase inhibitor.

[0158] The compound represented by chemical formula 1 is a GPR119 ligand, and GPR119 (G protein-coupled receptor 119) is one of the G protein-coupled receptors (GPCR) belonging to class A.

[0159] GRP119 is activated by GRP119 ligand, which induces intracellular signaling by generating cAMP through Gαs, one of the G protein subtypes.

[0160] GRP119 is highly expressed in pancreatic beta cells and small intestinal L cells. Therefore, by administering the pharmaceutical composition of one embodiment, pancreatic GPR119 is activated, increasing insulin secretion from pancreatic beta cells and reducing postprandial blood glucose levels. Therefore, GPR119 activation can promote blood lipid lowering and weight loss in addition to blood sugar control, and may contribute to the improvement of not only diabetes but also associated metabolic diseases.

[0161] Meanwhile, activation of GPR119 in the small intestine can increase the secretion of glucagon-like peptide-1 (GLP-1) from small intestinal L cells. GLP-1 may exert a local action in the small intestine to suppress postprandial fat influx into the bloodstream.

[0162] Typically, GLP-1 receptor-like actions are modulated by high molecular weight compounds, such as peptide ligands. However, according to one embodiment, the pharmaceutical composition comprises a relatively low molecular weight compound, the GPR119 ligand, thereby enabling GLP-1 receptor-like actions to be achieved with an oral low molecular weight compound.

[0163] In one embodiment, the compound represented by Chemical Formula 1 has a halogen atom substituted at positions 2 and 6 of the phenyl moiety of 4-(3-phenoxypropyl)piperidine. Accordingly, it can react more sensitively with GPR119 than when other GPR119 ligands are administered, and the degree of GPR119 activation can be dramatically increased.

[0164] In one embodiment, the pharmaceutical composition may further comprise, in addition to the compound represented by the above-described chemical formula 1, at least one selected from a DPPIV inhibitor, a PPAR agonist, an SGLT2 inhibitor, an insulin secretagogue, a biguanide drug, and an alpha-glucosidase inhibitor. Therefore, the pharmaceutical composition of one embodiment can effectively control blood sugar by lowering blood sugar through various mechanisms by administering two or more drugs with different mechanisms in combination.

[0165] Currently, hypoglycemic agents used in diabetic patients include dipeptidyl peptidase IV inhibitors (DPPIV inhibitors), insulin sensitizers, sodium glucose co-transporter 2 inhibitors (SGLT2 inhibitors) that promote urinary glucose excretion by inhibiting the sodium-glucose co-transporter 2, insulin secretagogues, biguanides, and alpha-glucosidase inhibitors.

[0166] Dipeptidyl peptidase IV (DPPIV) is an enzyme that inactivates GLP-1 by removing two N-terminal amino acids from blood GLP-1. GLP-1 secreted by GPR119 ligands can be inactivated by the DPPIV enzyme within minutes of entering the bloodstream. Therefore, co-administration of a GPR119 ligand that increases GLP-1 secretion and a DPPIV inhibitor that blocks GLP-1 inactivation can show a direct insulin secretion effect through GPR119 activation in beta cells, while also prolonging the duration of action of active GLP-1 in the blood. Therefore, it may have excellent pharmacological efficacy in improving metabolic diseases. In other words, DPPIV inhibitors can promote insulin secretion by prolonging the biological action of endogenous GLP-1, thereby exhibiting a postprandial blood glucose lowering effect.

[0167] 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.

[0168] Insulin sensitizers are drugs that activate peroxisome proliferator-activated receptors (PPARs). PPAR agonists may include at least one of the following: troglitazone, ciglitazone, rosiglitazone, pioglitazone, englitazone, elafibranor, saroglitazar, and lobeglitazone.

[0169] Sodium glucose co-transporter 2 inhibitors (SGLT2 inhibitors) can promote glucose excretion by inhibiting glucose reabsorption in the kidney in an insulin-independent manner. They may also be accompanied by weight loss through caloric loss due to glucose excretion. SGLT2 inhibitors may include at least one of canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin, sergliflozin, sotagliflozin, and tofogliflozin, for example.

[0170] Insulin secretagogues may include drugs with a sulfonylurea structure and non-sulfonylurea drugs. For example, an insulin secretagogue having a sulfonylurea structure may include at least one of glybenclamide (glyburide), glipizide, gliclazide, glimepiride, tolazamide, tolbutamide, acetohexamide, carbutamide, chlorpropamide, glibornuride, gliquidone, glisentide, glisolamide, glisoxepide, glyclopyamide, glycylamide, and glipentide. The non-sulfonylurea insulin secretagogue may comprise at least one of repaglinide and nateglinide.

[0171] Biguanide drugs can inhibit glucose production in the liver. Biguanide drugs may include at least one of metformin, buformin, and phenformin, for example.

[0172] Alpha-glucosidase inhibitors can delay carbohydrate absorption by inhibiting the enzyme activity that breaks down disaccharides into monosaccharides in the intestine. Alpha-glucosidase inhibitors may include at least one of agarbose, voglibose, emiglitate, and miglitol.

[0173] The pharmaceutical composition of one embodiment comprises a combination of ingredients. Therefore, when administered, the pharmaceutical composition of one embodiment can exhibit not only a hypoglycemic effect, but also a blood lipid-lowering effect and a weight-loss effect, due to two drugs with different mechanisms of action.

[0174] Therefore, it can exhibit superior effects in treating or preventing diabetes and metabolic diseases accompanying diabetes compared to when individual components are administered alone.

[0175] Hereinafter, a pharmaceutical composition according to one embodiment of the present invention will be described in detail with reference to examples and comparative examples.

[0176]

[0177] <Example 1> Confirmation of the efficacy of combined use of GPR119 ligand and DPPIV inhibitor

[0178] Evaluation of single-dose efficacy in normal mice

[0179] Compound 1, sitagliptin or evogliptin as DDPIV inhibitors, were administered alone to ICR 7-week-old male mice fasted for more than 16 hours, or either sitagliptin or evogliptin was administered in combination with compound 1. In both monotherapy and combination therapy, compound 1 was administered orally at 0.3 mg / kg, sitagliptin at 10 mg / kg, and evogliptin at 0.2 mg / kg. At 30 minutes after drug administration, glucose solution was administered orally at 2 g / kg / 10 ml.

[0180] To measure changes in blood concentrations of active GLP-1 according to combination therapy, plasma was separated from a DPPIV inhibitor-pretreated vessel 5 minutes after glucose loading, and blood concentrations of active GLP-1 were quantified using a GLP-1 (Active) ELISA kit (Millipore, Cat. EGLP-35K). To evaluate drug response to postprandial blood glucose, whole blood glucose was collected via the caudal vein at 0, 15, 30, 60, 90, and 120 minutes after blood glucose injection, and measured using an AccuChek Active blood glucose meter from Roche. Time-glucose response curves were obtained, and the area under the time-glucose curve of the control group administered only the solvent was compared with the rate of change in the area under the time-glucose curve in the drug administration group. The results are shown in Figs. 1 and 2.

[0181] As confirmed in Figure 1, when Compound 1 was co-administered with sitagliptin, a DPPIV inhibitor, the concentration of active GLP-1 in the blood significantly increased compared to the monotherapy group. In addition, blood glucose levels after 2 hours of glucose loading were significantly increased in the combination therapy group compared to the monotherapy group.

[0182] As confirmed in Figure 2, when compound 1 was co-administered with evogliptin, another DPPIV inhibitor, a synergistic effect in improving postprandial blood sugar levels was observed.

[0183] Evaluation of the efficacy of 10-week repeated administration in diabetic mice

[0184] ICR 7-week-old male mice were fed a high-fat diet (Research Diets Inc., D12492; 60% kcal fat) for 3 weeks. In the third week, streptozotocin (STZ) was injected intraperitoneally at 80 mg / kg, and after 3 weeks, the mice were divided into groups according to body weight, blood glucose, and blood triglyceride concentrations. Specifically, mice with non-fasting blood glucose levels increased by 1 SD (Standard Deviation) or more and plasma triglycerides increased by 2 SD or more compared to normal mice were selected and divided into groups. The divided group was administered a drug mixture diet containing 100 mg / kg / day of compound 1 and 150 mg / kg / day of sitagliptin. The diet was supplied for 10 weeks. Thereafter, fasting blood glucose, non-fasting blood glucose, and plasma triglyceride concentrations were measured. Fasting and non-fasting blood glucose levels were measured using a Roche AccuChek Active blood glucose meter from blood drawn via the caudal vein. Plasma triglyceride concentrations were measured using an automated blood analyzer (Konelab 20i) from plasma collected after non-fasting autopsy.

[0185] As confirmed in Fig. 3, when compound 1 and sitagliptin were administered in combination and repeatedly for 10 weeks, it was confirmed that the mice showed blood sugar levels similar to those of normal mice in both fasting blood sugar and non-fasting blood sugar compared to HF / STZ (High fat / Streptozotocin) mice that were only fed a high-fat diet without the drug mixture. In other words, the mice showed excellent blood sugar lowering rates in both fasting blood sugar and non-fasting blood sugar.

[0186] As confirmed in Fig. 4, when compound 1 and sitagliptin were co-administered to HF / STZ mice with diabetes and hypertriglyceridemia, an excellent rate of reduction in plasma triglyceride concentration was observed. In particular, as the plasma triglyceride concentration was approximately 200 mg / dl, it was confirmed that when compound 1 and sitagliptin were co-administered, the plasma triglyceride concentration was reduced to a level equivalent to that of normal mice.

[0187] <Example 2> Confirmation of the efficacy of combined use of GPR119 ligand and SGLT2 inhibitor or insulin secretagogue glimepiride

[0188] Compound 1, dapagliflozin as an SGLT2 inhibitor, or glimepiride as an insulin secretagogue were administered alone or in combination with compound 1 to ICR 7-week-old male mice fasted for more than 16 hours. Compound 1 was administered orally at 3 mg / kg, dapagliflozin as an SGLT2 inhibitor, or glimepiride as an insulin secretagogue at 0.3 mg / kg or glimepiride as an insulin secretagogue, either alone or in combination. After oral drug administration of compound 1 at 3 mg / kg, 0.3 mg / kg of dapagliflozin as an SGLT2 inhibitor, or 0.1 mg / kg of glimepiride as an insulin secretagogue, glucose solution was orally administered at 2 g / kg / 10 ml 30 minutes after oral drug administration. To evaluate the drug response to postprandial blood glucose, blood glucose was measured in whole blood collected through the tail vein at 0, 15, 30, 60, 90, and 120 minutes after blood glucose injection using an AccuChek Active blood glucose meter from Roche. A time-blood glucose response curve was obtained, and the rate of change in the area under the time-blood glucose curve in the drug administration group was compared with the area under the curve in the control group administered only the solvent.

[0189] As confirmed in Figure 5, when the two drugs were administered together, the blood sugar lowering effect was significantly increased compared to when administered alone.

[0190] <Example 3> Confirmation of the efficacy of combined use of GPR119 ligand and PPAR agonist

[0191] To induce insulin resistance, 6-week-old male C57BL / 6J mice were fed a special diet containing high fat, high fructose, and high cholesterol (Research Diets Inc., D09100301) for more than 27 weeks. A drug-mixed diet was prepared to administer compound 1 at 100 mg / kg / day and the PPAR agonist elafibranac at 30 mg / kg / day, either alone or in combination, to diet-induced obese (DIO) mice. The prepared drug-mixed diet was fed to the mice for 12 weeks. After 12 weeks of drug administration, non-fasting blood glucose levels in plasma collected after necropsy were measured using an AccuChek Active blood glucose meter from Roche.

[0192] As confirmed in Figure 6, compound 1 alone did not exhibit a significant hypoglycemic effect in severe insulin-resistant mice, while ilafibrana alone exhibited a hypoglycemic effect due to improvement in insulin resistance. However, when the two drugs were used in combination, a significantly superior hypoglycemic effect was observed compared to either drug alone.

[0193] <Example 4> Confirmation of the efficacy of combined use with GPR119 ligand and biguanide drugs.

[0194] Four-week-old male C57BL / 6J mice were fed a high-fat diet (Research Diets Inc., D12492; 60% kcal fat) for 10 weeks to induce insulin resistance. After adapting to drug administration for 2 weeks, the mice were divided into groups based on body weight and body fat. The compound 1 monotherapy group was administered compound 1 at 50 mg / kg twice daily, and the metformin monotherapy group was administered metformin at 150 mg / kg twice daily. The combination therapy group was administered compound 1 at 50 mg / kg orally twice daily with metformin at 150 mg / kg for 3 weeks. Body weight was measured periodically until the 16th day of dosing, and body composition was measured sequentially in the last week using a Minispec LF90II NMR spectrometer (Bruker Optics, Ettlingen, Germany). Fasting blood glucose levels were measured using a Roche AccuChek Active blood glucose meter from whole blood obtained via the caudal vein after a 6-hour fast in the second week of administration. After 3 weeks of administration, non-fasting autopsies were performed, and total GLP-1 concentrations in plasma were quantified using the Total GLP-1 ELISA (7-36 and 9-36) Assay Kit (Alpco, 43-GPTHU-E01).

[0195] As confirmed in Figure 7, no significant increase in GLP-1 secretion was observed in mice administered either compound 1 or metformin alone. However, when the two drugs were administered together, the total blood GLP-1 concentration significantly increased compared to when each drug was administered alone, confirming the synergistic effect of drug combination on GLP-1 secretion.

[0196] As confirmed in Figure 8, when each drug was administered alone, a minimal fasting blood sugar reduction trend was observed, but when the two drugs were administered together, a significant fasting blood sugar lowering effect was observed. In other words, a synergistic increase in drug efficacy was observed with combined administration.

[0197] As confirmed in Figure 9, when compound 1 and metformin were administered alone for two weeks, body weight reductions of -4.0% and -4.4% were observed, respectively. Conversely, when the two drugs were co-administered for two weeks, a -16.3% body weight reduction was observed. In other words, co-administration of the two drugs significantly increased drug responsiveness compared to when each drug was administered alone. From this, the synergistic effect of co-administration of the two drugs in the prevention or treatment of obesity was confirmed.

[0198] Referring to the body composition analysis results conducted after the completion of the 3-week treatment in Figure 9, compound 1 did not show a body fat reduction effect when administered alone for 2 weeks. Metformin, when administered alone for 2 weeks, showed minimal body fat reduction. However, when the two drugs were administered together, a body fat reduction rate of approximately 30% was observed. In other words, when the two drugs were administered together, it was confirmed that the effect of lowering blood sugar levels as well as reducing body fat was observed. From this, the synergistic effect of the combined administration of the two drugs in the prevention or treatment of obesity was confirmed.

[0199] <Example 5> Confirmation of the efficacy of combined use with GPR119 ligand and α-Glucosidase inhibitor drugs.

[0200] Compound 1 was administered orally at 3 mg / kg and the alpha-glucosidase inhibitor voglibose at 0.02 mg / kg to ICR 8-week-old male mice fasted for more than 16 hours. After oral drug administration alone or in combination, sucrose solution was orally administered at 2 g / kg / 10 ml 30 minutes later. To evaluate the drug response to postprandial blood glucose, blood glucose in whole blood collected through the tail vein was measured at 0, 15, 30, 60, 90, and 120 minutes after blood glucose injection using an AccuChek Active blood glucose meter from Roche. Time-glucose response curves were obtained, and the rate of change in the area under the time-glucose curve in the drug-administered group was compared with that of the control group administered only the solvent.

[0201] As confirmed in Fig. 10, when voglibose was administered alone, no blood sugar lowering effect was observed, but when it was administered in combination with compound 1, a synergistic effect was observed that increased the blood sugar lowering effect compared to when compound 1 was administered alone.

Claims

1. A compound represented by the following chemical formula 1, a pharmaceutically acceptable salt thereof, an optical isomer thereof, a hydrate or solvate thereof, or a mixture thereof; and A pharmaceutical composition for the prevention or treatment of diabetes or at least one disease selected from among metabolic diseases accompanying diabetes, comprising at least one selected from among DPPIV inhibitors, PPAR agonists, SGLT2 inhibitors, insulin secretagogues, biguanide drugs and alpha-glucosidase inhibitors: [Chemical Formula 1] In the above chemical formula 1, A is an oxadiazole group, a dihydrooxazole group, a thiazole group or a thiadiazole group, wherein A is unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a C1-C6 straight-chain or branched-chain alkyl group and a C1-C6 straight-chain or branched-chain hydroxyalkyl group, and wherein 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, wherein B is unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a C1-C6 linear or branched alkyl group, a C1-C6 linear or branched hydroxyalkyl group, a C1-C6 alkoxy group and an oxadiazole group, and wherein the C1-C6 linear or branched alkyl group, the C1-C6 linear or branched hydroxyalkyl group, the C1-C6 alkoxy group or the oxadiazole group are each independently unsubstituted or substituted with a halogen, a C1-C6 alkyl group or a C1-C6 alkoxy group, X 1 and X 2 are each independently F, Cl, Br or I.

2. In paragraph 1, The above A is , , , or And, R 1 Inland R 3 , R 5 , and R 6 A pharmaceutical composition wherein each of said at least one substituent is independently selected from the group consisting of a hydrogen atom, a halogen atom, a C1-C6 straight-chain or branched-chain alkyl group, and a C1-C6 straight-chain or branched-chain hydroxyalkyl group, wherein said alkyl group or said hydroxyalkyl group is each independently unsubstituted or substituted with a halogen atom or a C1-C6 alkoxy group.

3. In paragraph 1, The above B , , , or And, R 7 Inland R 11 A pharmaceutical composition wherein each of the compounds of formula (I) is independently substituted with at least one substituent selected from the group consisting of a hydrogen atom, a halogen atom, a C1-C6 linear or branched alkyl group, a C1-C6 linear or branched hydroxyalkyl group, a C1-C6 alkoxy group, and an oxadiazole group, wherein each of the alkyl group, the hydroxyalkyl group, the alkoxy group, or the oxadiazole group is independently unsubstituted or substituted with a halogen atom, a C1-C6 alkyl group, or a C1-C6 alkoxy group.

4. In paragraph 1, A pharmaceutical composition wherein X is F.

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

6. In paragraph 1, A pharmaceutical composition wherein the compound represented by the chemical formula 1 is 3-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-5-isopropyl-1,2,4-oxadiazole.

7. In paragraph 6, The pharmaceutical composition comprises at least one of the DPPIV inhibitor, the PPAR agonist, the SGLT2 inhibitor, the insulin secretagogue, the biguanide, and the alpha-glucosidase inhibitor drugs.

8. In paragraph 6, The pharmaceutical composition comprises at least one of evogliptin, sitagliptin, ilafibrana, dapagliflozin, glimepiride, metformin and voglibose.

9. In paragraph 1, The pharmaceutical composition comprises at least one of the DPPIV inhibitor, the PPAR agonist, the SGLT2 inhibitor, the insulin secretagogue, the biguanide drug, and the alpha-glucosidase inhibitor.

10. In paragraph 9, The pharmaceutical composition comprises at least one of evogliptin, sitagliptin, ilafibrana, dapagliflozin, glimepiride, metformin and voglibose.

11. In paragraph 1, A pharmaceutical composition wherein the metabolic disease is at least one of obesity and dyslipidemia.

12. A compound represented by the chemical formula 1 according to claim 1 for the prevention or treatment of at least one disease selected from diabetes or metabolic diseases accompanying said diabetes, a pharmaceutically acceptable salt thereof, an optical isomer thereof, a hydrate or solvate thereof, or a mixture thereof; and Use of a pharmaceutical composition comprising at least one selected from the group consisting of a DPPIV inhibitor, a PPAR agonist, an SGLT2 inhibitor, an insulin secretagogue, a biguanide drug and an alpha-glucosidase inhibitor.

13. A compound represented by the chemical formula 1 according to claim 1 for producing a pharmaceutical preparation for preventing or treating at least one disease selected from diabetes or metabolic diseases accompanying said diabetes, a pharmaceutically acceptable salt thereof, an optical isomer thereof, a hydrate or solvate thereof, or a mixture thereof; and Use of a pharmaceutical composition comprising at least one selected from the group consisting of a DPPIV inhibitor, a PPAR agonist, an SGLT2 inhibitor, an insulin secretagogue, a biguanide drug and an alpha-glucosidase inhibitor.

14. A compound represented by the chemical formula 1 according to paragraph 1, a pharmaceutically acceptable salt thereof, an optical isomer thereof, a hydrate or solvate thereof, or a mixture thereof; and A method for preventing or treating at least one disease selected from diabetes or a metabolic disease accompanying therewith, comprising the step of administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutical composition comprising at least one selected from a DPPIV inhibitor, a PPAR agonist, an SGLT2 inhibitor, an insulin secretagogue, a biguanide drug and an alpha-glucosidase inhibitor.

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