WO2017126524A1 - Utilisation d'une association d'agents thérapeutiques anti-diabète - Google Patents

Utilisation d'une association d'agents thérapeutiques anti-diabète Download PDF

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WO2017126524A1
WO2017126524A1 PCT/JP2017/001472 JP2017001472W WO2017126524A1 WO 2017126524 A1 WO2017126524 A1 WO 2017126524A1 JP 2017001472 W JP2017001472 W JP 2017001472W WO 2017126524 A1 WO2017126524 A1 WO 2017126524A1
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inhibitor
pharmaceutically acceptable
acceptable salt
compound
drug
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PCT/JP2017/001472
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Japanese (ja)
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康嗣 松本
佳菜子 高橋
智美 吉富
尚子 生方
貴史 田口
靖彦 中塚
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第一三共株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00

Definitions

  • the present invention is compound (1):
  • it is a pharmaceutical comprising a combination of a pharmaceutically acceptable salt thereof and another therapeutic agent for diabetes.
  • the compound (1) or a pharmaceutically acceptable salt thereof is expected as a novel therapeutic agent for diabetes because it has a hypoglycemic effect and a protective effect on pancreatic ⁇ cells or pancreas (see Patent Document 1). .
  • compound (1) or a pharmaceutically acceptable salt thereof has an excellent lipid metabolism improving action.
  • DPP-4 dipeptidyl peptidase 4 (hereinafter sometimes referred to as “DPP-4”) inhibitor is known as a therapeutic agent for type 2 diabetes (see, for example, Non-Patent Document 1).
  • Biguanide drugs are known as therapeutic agents for type 2 diabetes (for example, see Non-Patent Document 2).
  • SGLT2 Sodium-glucose transporter 2 (hereinafter sometimes referred to as “SGLT2”) inhibitors, sulfonylurea agents, and ⁇ -glucosidase inhibitors are all known as therapeutic agents for type 2 diabetes (for example, (See Patent Documents 3 and 4).
  • An object of the present invention is to provide a medicament for the treatment of diabetes and / or dyslipidemia, which can further reduce blood glucose, improve lipid metabolism, reduce side effects, and the like, or a medicament for protecting pancreatic ⁇ cells. is there.
  • Another object of the present invention is to provide a medicament containing a compound having an excellent effect of improving lipid metabolism.
  • the present invention [1] From the group consisting of compound (1) or a pharmaceutically acceptable salt thereof, a dipeptidyl peptidase 4 inhibitor, a biguanide drug, a sodium glucose transporter 2 inhibitor, a sulfonylurea drug, and an ⁇ -glucosidase inhibitor
  • a medicament comprising a combination with at least one selected drug
  • the dipeptidyl peptidase 4 inhibitor is sitagliptin, teneligliptin,
  • the present invention also provides: (1) Diabetes comprising a combination of compound (1) or a pharmaceutically acceptable salt thereof and at least one drug selected from the group consisting of dipeptidyl peptidase 4 inhibitors and biguanides Therapeutic agent; (2) The therapeutic agent according to (1) above, which is a combination of compound (1) or a pharmaceutically acceptable salt thereof and a dipeptidyl peptidase 4 inhibitor; (3) The therapeutic agent according to (1) above, which is a combination of compound (1) or a pharmaceutically acceptable salt thereof and a biguanide drug; (4) The above (1) or (2), wherein the dipeptidyl peptidase 4 inhibitor is sitagliptin, teneligliptin, linagliptin, alogliptin, saxagliptin, vildagliptin, anagliptin, treragliptin, omalipliptin, or a pharmaceutically acceptable salt thereof.
  • Protective agents for; (28) The protective agent according to (15), wherein the dipeptidyl peptidase 4 inhibitor is sitagliptin phosphate hydrate or teneligliptin hydrobromide hydrate, and the biguanide drug is metformin hydrochloride; (29) comprising administering to a mammal compound (1) or a pharmaceutically acceptable salt thereof and at least one drug selected from the group consisting of a dipeptidyl peptidase 4 inhibitor and a biguanide drug, A method of treating diabetes; (29-1) Compound (1) or a pharmaceutically acceptable salt thereof and at least one drug selected from the group consisting of a dipeptidyl peptidase 4 inhibitor and a biguanide drug are administered simultaneously or separately The method according to (29), wherein (30) The method according to (29) above, wherein the mammal is a human; (31) comprising administering to a mammal compound (1) or a pharmaceutically acceptable salt thereof and at least one drug selected from the group consisting of a dipeptidy
  • the blood glucose level of a patient whose blood glucose level is still high and blood glucose control is insufficient even if each diabetes therapeutic agent is treated alone can be reduced to a normal level.
  • side effects for example, lactic acidosis, pancreatic ⁇ -cell apoptosis promotion, lipid metabolism abnormality, etc.
  • there is an effect such as suppressing the deterioration of diabetes by maintaining the function of pancreatic ⁇ cells.
  • the compound (1) or a pharmaceutically acceptable salt thereof has an excellent lipid metabolism improving action, it is useful as an active ingredient of a therapeutic agent for dyslipidemia. Since the therapeutic agent for dyslipidemia of the present invention also has an excellent insulin secretion promoting action, it is particularly useful for the treatment of patients with diabetes and dyslipidemia.
  • FIG. 1 is a graph showing changes over time in blood glucose levels (average value ⁇ standard error at each time point) when a compound (1) and sitagliptin or metformin were administered in combination to ZDF rats.
  • FIG. 2 is a graph showing changes over time in blood lactic acid levels (average value ⁇ standard error at each time point) when a compound (1) and metformin were administered in combination to ZDF rats.
  • FIG. 3 is a graph showing changes over time in blood glucose levels (average value ⁇ standard error at each time point) when a compound (1) and dapagliflozin were administered in combination to C57BL / 6J mice.
  • FIG. 1 is a graph showing changes over time in blood glucose levels (average value ⁇ standard error at each time point) when a compound (1) and sitagliptin or metformin were administered in combination to ZDF rats.
  • FIG. 2 is a graph showing changes over time in blood lactic acid levels (average value ⁇ standard error at each time point) when a compound (1) and metformin were administered in combination to
  • FIG. 4 is a graph showing changes over time in blood glucose levels (average value ⁇ standard error at each time point) when compound (1) and glimepiride were administered in combination to C57BL / 6J mice.
  • FIG. 5 is a graph showing changes over time in blood glucose levels (average value ⁇ standard error at each time point) when compound (1) and voglibose were administered in combination to C57BL / 6J mice.
  • FIG. 6 shows the ratio (%) of glycohemoglobin to total hemoglobin after 4-week combined administration of compound (1) and sitagliptin or metformin to C57BL / 6J mice administered with small and frequent doses of streptozotocin (mean ⁇ standard) FIG.
  • FIG. 7 is a graph showing changes over time in blood glucose levels (average value ⁇ standard error at each time point) when compound (1) and sitagliptin were administered in combination to SDT fatty rats.
  • FIG. 8 is a graph showing the change over time in blood triglyceride values (average value ⁇ standard error at each time point) when compound (1) and sitagliptin were administered in combination to SDT fatty rats.
  • FIG. 9 is a graph showing the time course of blood insulin levels (average value ⁇ standard error at each time point) when compound (1) and sitagliptin were administered in combination to SDT fatty rats.
  • FIG. 8 is a graph showing the change over time in blood triglyceride values (average value ⁇ standard error at each time point) when compound (1) and sitagliptin were administered in combination to SDT fatty rats.
  • FIG. 9 is a graph showing the time course of blood insulin levels (average value ⁇ standard error at each time point) when compound (1) and sitagliptin were administered in combination to SDT fatty rats
  • FIG. 10 is a graph showing the change over time in blood glucose level (average value ⁇ standard error at each time point) when compound (1) and tenerigliptin were administered in combination to SDT fatty rats.
  • FIG. 11 is a graph showing the change over time in blood triglyceride values (average value ⁇ standard error at each time point) when compound (1) and tenerigliptin were administered in combination to SDT fatty rats.
  • FIG. 12 is a graph showing changes over time in blood insulin values (average value ⁇ standard error at each time point) when compound (1) and tenerigliptin were administered in combination to SDT fatty rats.
  • FIG. 13 is a graph showing the 24-hour weighted average blood glucose level change from the baseline when compound (1) was repeatedly administered to patients with type 2 diabetes for 28 days.
  • FIG. 14 is a graph showing the rate of change from baseline in total cholesterol level, HDL cholesterol level, LDL cholesterol level and triglyceride level when compound (1) is orally administered to a type 2 diabetic patient for 28 days
  • the compound (1) used in the present invention has the following formula:
  • “pharmaceutically acceptable salt” refers to a salt formed by reacting a compound with an acid or a base.
  • the salt include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; hydrochloride, nitrate, perchlorate, sulfate, phosphate, etc.
  • Inorganic acid salts lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate; aryl sulfonates such as benzene sulfonate and p-toluene sulfonate; acetate and malic acid Organic salts such as salts, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate; alkali metal salts such as sodium salt, potassium salt, lithium salt; calcium salt Alkaline earth metal salts such as magnesium salts; metal salts such as aluminum salts and iron salts; inorganic salts such as ammonium salts; t-octylamine salts, benzylamine salts, dibenzines Ruamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglu
  • the compound (1) When the compound (1) is left in the atmosphere, for example, it absorbs moisture and attaches adsorbed water to form a hydrate. Such a hydrate is also included in the salt of the compound.
  • Compound (1) or a pharmaceutically acceptable salt thereof can be produced, for example, by the method described in Patent Document 1.
  • DPP-4 inhibitor used in the present invention examples include, but are not limited to, sitagliptin, teneligliptin, linagliptin, alogliptin, saxagliptin, vildagliptin, anagliptin, treragliptin, omalipliptin, and pharmaceutically acceptable salts thereof.
  • a preferred DPP-4 inhibitor is sitagliptin or tenerigliptin or a pharmaceutically acceptable salt thereof, more preferably sitagliptin phosphate hydrate or tenerigliptin hydrobromide.
  • the biguanide used in the present invention includes, but is not limited to, metformin, phenformin, buformin, and pharmaceutically acceptable salts thereof.
  • a preferred biguanide drug is metformin or a pharmaceutically acceptable salt thereof, more preferably metformin hydrochloride.
  • SGLT2 inhibitors used in the present invention include dapagliflozin, canagliflozin, atigliflozin, sergliflozin, ipragliflozin, luceogliflozin, tofogliflozin, empagliflozin and their pharmaceutically acceptable salts.
  • a preferred SGLT2 inhibitor is dapagliflozin propylene glycol hydrate, canagliflozin hydrate or empagliflozin, more preferably dapagliflozin propylene glycol hydrate.
  • sulfonylurea drug used in the present invention examples include, but are not limited to, glibenclamide, tolbutamide, glimepiride, glipizide, glyxone, glibornuride, glubride, glyoxepide, gliclazide, and pharmaceutically acceptable salts thereof.
  • Preferred sulfonylurea drugs are glibenclamide, glimepiride, glipizide or gliclazide, more preferably glimepiride.
  • ⁇ -glucosidase inhibitor used in the present invention examples include, but are not limited to, acarbose, voglibose, miglitol, and pharmaceutically acceptable salts thereof.
  • a preferred ⁇ -glucosidase inhibitor is voglibose.
  • “selected from the group consisting of compound (1) or a pharmaceutically acceptable salt thereof and a DPP-4 inhibitor, biguanide, SGLT2 inhibitor, sulfonylurea, and ⁇ -glucosidase inhibitor” “Combination with at least one drug” refers to the following embodiment.
  • a preparation containing compound (1) or a pharmaceutically acceptable salt thereof and a preparation containing a DPP-4 inhibitor, biguanide, SGLT2 inhibitor, sulfonylurea and / or ⁇ -glucosidase inhibitor Are administered simultaneously or separately,
  • a mode of administering a preparation containing compound (1) or a pharmaceutically acceptable salt thereof and a DPP-4 inhibitor, biguanide drug, SGLT2 inhibitor, sulfonylurea drug and / or ⁇ -glucosidase inhibitor are administered simultaneously or separately.
  • administered simultaneously means that the preparations are administered at approximately the same time.
  • administered separately refers to administration of a preparation at different times. For example, first, a preparation containing a DPP-4 inhibitor, a preparation containing a biguanide drug, a preparation containing an SGLT2 inhibitor, a preparation containing a sulfonylurea drug, and / or a preparation containing an ⁇ -glucosidase inhibitor And then after a predetermined time, compound (1) or a pharmaceutically acceptable salt thereof is administered, or a formulation containing a DPP-4 inhibitor, a formulation containing a biguanide, SGLT2 A preparation containing an inhibitor, a preparation containing a sulfonylurea drug and / or a preparation containing an ⁇ -glucosidase inhibitor are administered simultaneously, and then, after a predetermined time, compound (1) or a pharmaceutically acceptable salt thereof This refers to administration of the resulting salt, but is not limited thereto.
  • One embodiment of the present invention is an embodiment in which the compound (1) or a pharmaceutically acceptable salt thereof and a DPP-4 inhibitor are used in combination.
  • One embodiment of the present invention is an embodiment in which compound (1) or a pharmaceutically acceptable salt thereof and a biguanide drug are used in combination.
  • One embodiment of the present invention is an embodiment in which the compound (1) or a pharmaceutically acceptable salt thereof, a DPP-4 inhibitor and a biguanide drug are used in combination.
  • One embodiment of the present invention is an embodiment in which the compound (1) or a pharmaceutically acceptable salt thereof and an SGLT2 inhibitor are used in combination.
  • One embodiment of the present invention is an embodiment in which the compound (1) or a pharmaceutically acceptable salt thereof and a sulfonylurea drug are used in combination.
  • One embodiment of the present invention is an embodiment in which the compound (1) or a pharmaceutically acceptable salt thereof and an ⁇ -glucosidase inhibitor are used in combination.
  • One embodiment of the present invention is a combination drug containing Compound (1) or a pharmaceutically acceptable salt thereof and a DPP-4 inhibitor as active ingredients.
  • One embodiment of the present invention is a combination drug containing compound (1) or a pharmaceutically acceptable salt thereof and a biguanide drug as active ingredients.
  • One embodiment of the present invention is a combination drug containing Compound (1) or a pharmaceutically acceptable salt thereof, a DPP-4 inhibitor and a biguanide as active ingredients.
  • One embodiment of the present invention is a combination drug containing compound (1) or a pharmaceutically acceptable salt thereof and an SGLT2 inhibitor as active ingredients.
  • One embodiment of the present invention is a compounding agent containing compound (1) or a pharmaceutically acceptable salt thereof and a sulfonylurea drug as active ingredients.
  • One embodiment of the present invention is a combination drug containing compound (1) or a pharmaceutically acceptable salt thereof and an ⁇ -glucosidase inhibitor as active ingredients.
  • One embodiment of the present invention is an embodiment in which a compound (1) or a pharmaceutically acceptable salt thereof and a combination drug containing a DPP-4 inhibitor as an active ingredient and a biguanide drug are used in combination.
  • One embodiment of the present invention is an embodiment in which a compounding agent containing a compound (1) or a pharmaceutically acceptable salt thereof and a biguanide drug as active ingredients and a DPP-4 inhibitor are used in combination.
  • One embodiment of the present invention is an embodiment in which a combination drug containing a DPP-4 inhibitor and a biguanide drug as active ingredients is combined with compound (1) or a pharmaceutically acceptable salt thereof.
  • diabetes refers to type 1 diabetes or type 2 diabetes.
  • Fasting blood glucose level is 126 mg / dL or more
  • 75 g oral glucose tolerance test (OGTT) 2-hour value Diabetes is diagnosed when is at least 200 mg / dL, (3) at any time the blood glucose level is at least 200 mg / dL, or (4) HbA1c is at least 6.5%.
  • diabetes therapeutic agent refers to a drug that improves blood glucose control in a mammal that has developed diabetes.
  • a glycemic control that needs improvement (insufficient) in humans means a state in which the patient's HbA1c is 6.5% or more.
  • means for improving blood glucose control include promoting insulin secretion.
  • dyslipidemia refers to a condition in which lipids in the blood are excessive or insufficient, and hypercholesterolemia or high LDL cholesterolemia (high LDL-C blood disease) depending on the pathological condition. It is classified as low HDL cholesterolemia (low HDL-C blood) and hypertriglyceridemia (high TG). Hypercholesterolemia is a type of dyslipidemia with a high total cholesterol level in blood (220 mg / dL or higher), and high LDL cholesterolemia is a high level of bad cholesterol (LDL) in blood (140 mg / dL).
  • LDL bad cholesterol
  • dyslipidemia low HDL cholesterolemia is a low amount of good cholesterol (HDL) in the blood (less than 40 mg / dL), type dyslipidemia, hypertriglyceridemia is in the blood It means dyslipidemia of the type with a lot of triglycerides (150mg / dL ⁇ ).
  • the “dyslipidemic agent” refers to a drug that improves lipid metabolism.
  • pancreatic ⁇ -cell protective agent refers to a drug that maintains pancreatic ⁇ -cell function or a drug that suppresses ⁇ -cell function deterioration. Whether pancreatic ⁇ -cell function is maintained or deteriorated is, for example, an increase in blood glucose level or glycated hemoglobin over time due to pancreatic ⁇ -cell damage, a decrease in blood insulin level, insulin secretion It is possible to judge by confirming the decline in performance.
  • the pharmaceutical of the present invention when administered to a mammal (eg, human, horse, cow, pig, etc., preferably human), it can be administered systemically or locally, orally or parenterally.
  • a mammal eg, human, horse, cow, pig, etc., preferably human
  • it can be administered systemically or locally, orally or parenterally.
  • the medicament of the present invention has a hypoglycemic action, a lipid metabolism improving action and a pancreatic ⁇ -cell protecting action, it is preferably used in patients with diabetes and / or dyslipidemia, preferably type 2 diabetes and / or high triglycerides. It can be administered to patients who develop septicemia.
  • the medicament of the present invention is preferably for patients whose total cholesterol in blood is 220 mg / dL or more, more preferably for patients whose total cholesterol in blood is 220 mg / dL or more and HbA1c is 6.5% or more, more preferably It can be administered to patients whose total cholesterol in blood is 220 mg / dL or more and HbA1c is 7.0% or more.
  • the medicament of the present invention is preferably used for patients with LDL in blood of 140 mg / dL or more, more preferably for patients with LDL in blood of 140 mg / dL or more and HbA1c of 6.5% or more, more preferably LDL in blood. Can be administered to patients with 140 mg / dL or more and HbA1c of 7.0% or more.
  • the medicament of the present invention is preferably used in patients whose blood HDL is less than 40 mg / dL, more preferably in patients whose blood HDL is less than 40 mg / dL and HbA1c is 6.5% or more, more preferably in blood. Can be administered to patients whose HDL is less than 40 mg / dL and HbA1c is 7.0% or more.
  • the medicament of the present invention is preferably used for patients whose blood triglyceride is 150 mg / dL or more, more preferably for patients whose blood triglyceride is 150 mg / dL or more and HbA1c is 6.5% or more, and more preferably blood triglycerides.
  • the medicament of the present invention can be administered to a patient who has already been administered another therapeutic agent for diabetes or therapeutic agent for dyslipidemia.
  • the medicament of the present invention may be used in combination with other therapeutic agents for dyslipidemia.
  • therapeutic agents for dyslipidemia include statins, anion exchange resins, small intestinal cholesterol transporter inhibitors, fibrates, nicotinic acid derivatives, probucol, proprotein convertase subtilisin / kexin type 9 (hereinafter referred to as “PCSK9”). And inhibitors) and polyunsaturated fatty acids.
  • statins examples include pravastatin, simvastatin, fluvastatin, atorvastatin, pitavastatin, rosuvastatin and the like.
  • anion exchange resin examples include cholestyramine, colestimide, and the like.
  • small intestinal cholesterol transporter inhibitors examples include ezetimibe.
  • fibrate examples include bezafibrate, fenofibrate, clofibrate, clinofibrate and the like.
  • nicotinic acid derivative examples include tocopherol nicotinic acid ester, niceritrol, nicomol and the like.
  • PCSK9 inhibitors examples include evolocumab and arilocumab.
  • polyunsaturated fatty acid examples include ethyl icosapentate and ethyl omega-3 fatty acid.
  • the medicament of the present invention can be prepared by selecting an appropriate form according to the administration method and preparing various preparations usually used.
  • Oral pharmaceutical forms include tablets, powders, granules, capsules, suspensions, emulsions, syrups and the like.
  • Such forms of pharmaceuticals are commonly used excipients, binders, disintegrants, lubricants, swelling agents, coating agents, plasticizers, stabilizers, preservatives, antioxidants, colorants, suspensions.
  • Agents, emulsifiers, sweeteners, buffers, diluents and the like can be selected as necessary and can be produced according to conventional methods.
  • parenteral pharmaceutical forms include injections, ointments, gels, creams, poultices, patches, sprays, inhalants, sprays, eye drops, nasal drops, suppositories, and the like.
  • forms of pharmaceuticals include stabilizers, preservatives, solubilizers, moisturizers, preservatives, antioxidants, flavoring agents, gelling agents, neutralizing agents, buffering agents, isotonic agents that are commonly used as additives.
  • An agent, a surfactant, a colorant, a buffering agent, a thickening agent, a wetting agent, a filler, an absorption enhancer, a suspending agent, a binder and the like are selected as necessary, and can be produced according to a conventional method.
  • the dose of compound (1) or a pharmaceutically acceptable salt thereof used in the medicament of the present invention varies depending on symptoms, age, body weight, etc., but in the case of oral administration, 1 to several times a day, It is 1-1000 mg, preferably 5-200 mg, more preferably 10-100 mg as a compound (1) per adult. Taking into account side effects such as hypoglycemia, it is also considered to reduce the dose as appropriate.
  • the dose of the DPP-4 inhibitor, biguanide drug, SGLT2 inhibitor, sulfonylurea drug and / or ⁇ -glucosidase inhibitor used in the medicament of the present invention is determined according to the dose described in the package insert of each drug. Good. In consideration of side effects such as hypoglycemia, lactic acidosis caused by biguanide drugs, promotion of pancreatic ⁇ -cell apoptosis caused by sulfonylurea drugs, lipid metabolism abnormalities, etc., the dose should be reduced appropriately.
  • Example 1 Rat Oral Glucose Tolerance Test 6-week-old male ZDF rats were purchased from Japan Charles River Co., Ltd. and fed with FR-2 chow (Funabashi Farm Co., Ltd.) to acclimatize to 9 weeks of age. . The breeding room was switched off at 7 pm and switched on and off at 7 am. Two days before the glucose tolerance test, body weight, blood glucose level, and blood insulin level were measured for selection and grouping of rats. Rats with a blood glucose level of 400-600 mg / dL and a blood insulin level of 4-20 ng / mL were selected and assigned to 6 groups (n 8).
  • test substances (compound (1), sitagliptin hydrochloride or metformin hydrochloride) were orally administered as follows.
  • the test substance was suspended or dissolved in 0.5% methylcellulose and then administered to rats.
  • Vehicle (0.5% methylcellulose) administration group Compound (1) (10 mg / kg) administration group, Sitagliptin (100 mg / kg) administration group, Metformin (300 mg / kg) administration group, Compound (1) (10 mg / kg) + sitagliptin (100 mg / kg) administration group, Compound (1) (10 mg / kg) + metformin (300 mg / kg) administration group.
  • FIG. 1 and Table 1 show the results of changes in blood glucose level and the area under the curve of blood glucose level (Area Under Curve, hereinafter referred to as “AUC”) from before glucose administration (0 min) to 180 minutes (3 h) after glucose administration.
  • AUC Blood glucose level
  • FIG. 2 and Table 2 show the results of lactic acid level AUC with the changes in blood lactic acid levels in the vehicle, compound (1), metformin and compound (1) + metformin administration groups, respectively.
  • Example 2 Mouse oral glucose tolerance test Male C57BL / 6J mice aged 7 to 8 weeks old were purchased from Charles River Japan Co., Ltd. and supplied with FR-2 solid feed (Funabashi Farm Co., Ltd.), 10 weeks old. Accustomed to. The breeding room was switched off at 7 pm and switched on and off at 7 am. Fasted overnight from the day before the glucose tolerance test, the test substance (compound (1), dapagliflozin or glimepiride was orally administered as follows. The test substance was suspended or dissolved in 0.5% methylcellulose and then administered to mice. .
  • glucose was orally administered to all mice at a dose of 3 g / kg.
  • Blood was collected from the tail vein before compound administration (-30 minutes), before glucose administration (0 min), and 30, 60 and 120 minutes after administration, and blood glucose levels were measured.
  • the results of blood glucose level transition in mouse oral glucose tolerance test 1, blood glucose level AUC from -30 minutes to 120 minutes, and blood glucose level at 30 minutes after glucose administration are shown in FIG. 3, Table 3 and Table 4, respectively.
  • FIG. 4, Table 5 and Table 6 show the results of blood glucose level transition in the load test 2, blood glucose level AUC from -30 minutes to 120 minutes, and blood glucose level at 30 minutes after glucose administration, respectively.
  • Glimepiride (10,100mg / kg) is saturated with a drug effect at a dose of 10mg / kg, and is significantly higher than that of a single agent in combination with compound (1) at that dose (P ⁇ 0.05) after glucose load A decrease in blood glucose level at 30 minutes (corresponding to blood glucose level Tmax in the Vehicle group) was observed, confirming the significance of combined use of compound (1) and glimepiride related to blood glucose level control.
  • mice (Example 3) Mouse oral starch tolerance test Eight-week-old male C57BL / 6J mice were purchased from Japan Charles River Co., Ltd. and fed with FR-2 solid feed (Funabashi Farm Co., Ltd.) to acclimatize to the age of 10 weeks. I let you. The breeding room was switched off at 7 pm and switched on and off at 7 am.
  • the test substance (compound (1), voglibose) was orally administered as follows from the day before the starch load test, and the test substance was suspended or dissolved in 0.5% methylcellulose and then administered to mice.
  • Test substance and starch were administered to all mice simultaneously. Starch 2 g / kg was orally administered. Blood was collected from the tail vein before compound administration (0 min) and 30, 60, 120 and 180 minutes after administration, and blood glucose levels were measured. The results of blood glucose level transition and blood glucose level AUC in the mouse oral starch tolerance test are shown in FIG. 5 and Table 7, respectively.
  • pancreatic ⁇ cells Protection test of pancreatic ⁇ cells Referring to Junko Ogawa, et al., Life Sciences Vol. 65, No. 12 pp.1287-1296 (1999), the protective action of pancreatic ⁇ cells of the present invention was demonstrated. confirmed. Seven-week-old male C57BL / 6J mice were purchased from Nihon Charles River Co., Ltd. and fed with FR-2 solid feed (Funabashi Farm Co., Ltd.) for 3 days. The breeding room was switched off at 7 pm and switched on and off at 7 am. 60 animals were received, body weight was measured on the third day from the arrival date, and 56 animals were selected excluding individuals with a body weight of less than 22.0 g. There were 8 animals per group, and 4 animals were raised per cage.
  • Streptozotocin (Wako Pure Chemical Industries, Ltd.) is dissolved in 0.1M citrate buffer (pH 4.5) to a concentration of 4 mg / mL from the 6th day after arrival. A dose of / kg was administered intraperitoneally once daily at a volume of 10 mL / kg for 5 consecutive days. Streptozotocin was prepared at the time of use. After completion of the first administration of streptozotocin, feeding of the test substance-added feed (mixed feed) shown below was started, and the vehicle group was fed with FR-2 powdered feed.
  • test substance compound (1), sitagliptin and metformin was administered at a high dose (0.1%, equivalent to about 100 mg / kg) at a high dose so that the respective drug effects were saturated as follows. (Funabashi Farm Co., Ltd.) was used.
  • the ratio (%) of glycohemoglobin to the total blood hemoglobin was measured using liquid chromatography (HLC-723G8, Tosoh Corporation) 4 weeks after the start of administration of the diet. The measurement results are shown in FIG. 6 and Table 8, respectively.
  • Streptozotocin is a compound that damages pancreatic ⁇ -cell function, and disrupts the body's blood glucose control by impairing the basic secretion of insulin, which is the main function of pancreatic ⁇ -cells, and additional secretion after meals.
  • HbA1c (%) is used in humans and glycated hemoglobin (%) relative to total blood hemoglobin is used in mice as a biochemical marker that reflects blood glucose level control in the living body. Therefore, in this example, the protective action of compound (1), sitagliptin or metformin against pancreatic ⁇ -cell injury induced by streptozotocin was evaluated by measuring the glycohemoglobin value.
  • the compound (1), sitagliptin or metformin-administered group showed a low level of glycated hemoglobin (%) relative to total blood hemoglobin 4 weeks after streptozotocin administration.
  • the protective effect was confirmed.
  • the glycohemoglobin value in the compound (1) administration group was lower than that in the sitagliptin or metformin administration group, suggesting that the compound (1) has a stronger pancreatic ⁇ -cell protective effect than sitagliptin or metformin.
  • the glycohemoglobin level is lower than that of the single agent, and the glycohemoglobin level (%) of the combination group of sitagliptin and compound (1) is the sitagliptin single administration group.
  • Example 5 Rat Oral Lipid + Glucose Tolerance Test 6-week-old male SDT fatty rats (SDT.Cg-Leprfa / JttJcl ⁇ Leprfa / Leprfa>) were purchased from Japan Marie Co., Ltd. Company Funabashi Farm). The breeding room was switched off at 7 pm and switched on and off at 7 am. Animals were weighed on the 7th and 15th days after arrival on the 0th day. On the 15th day, plasma glucose level (PG), plasma triglyceride level (TG), and plasma insulin level (Ins) were measured.
  • PG plasma glucose level
  • TG plasma triglyceride level
  • Ins plasma insulin level
  • mice satisfying the conditions of 400 g, Ins value of 10-22 ng / mL, PG value of 530-720 mg / dL and TG value of 600-1100 mg / dL were selected. Using these measured values, grouping was performed, and groups were divided into 8 groups of 6 animals. Sitagliptin and teneligliptin were used as DPP-4 inhibitors and used for lipid + glucose tolerance tests at 8 weeks and 12 weeks of age, respectively. Animals were housed in 2 / cage and fasted overnight the day before the oral lipid + glucose tolerance test. On the day of the lipid + glucose tolerance test, the body weight of rats (8, 12 weeks of age) was measured and the dosage was calculated.
  • the glucose load was 1 g / kg
  • the lipid load was 0.4 g / kg
  • a 50% (w / v) glucose solution and 20% Intralipos infusion were diluted at a ratio of 1: 1.
  • the test substance and lipid + glucose mixed solution were orally administered in a volume of 4 mL / kg.
  • Plasma glucose level is glucose CII-Test Wako (Wako Pure Chemical Industries, Ltd.), triglyceride level is triglyceride E-Test Wako (Wako Pure Chemical Industries, Ltd.), and insulin is Morinaga ultrasensitive rat insulin measurement kit ( Measured using Morinaga Bioscience Institute).
  • the blood glucose level AUC of the combination group of compound (1) 100 mg / kg and sitagliptin 10 mg / kg is significantly lower (P ⁇ 0.05) than the blood glucose level AUC of sitagliptin 10 mg / kg single agent group This confirmed the significance of concomitant use in relation to blood glucose control.
  • the triglyceride value AUC average value of the compound (1) (10,100 mg / kg) single agent administration group was lower than the triglyceride value AUC average value of the vehicle administration group.
  • the triglyceride value AUC in the sitagliptin 10 mg / kg single agent group showed a tendency to be higher than the triglyceride value AUC in the vehicle group, and it was estimated that there was no lowering effect.
  • compound (1) 100 mg / kg was used in combination with sitagliptin 10 mg / kg, the triglyceride level AUC was the same as that of compound (1) 100 mg / kg alone.
  • the insulin value AUC of the compound (1) (10,100 mg / kg) single agent administration group was significantly higher (P ⁇ 0.05) than the insulin value AUC of the vehicle administration group.
  • Insulin level AUC in the sitagliptin (10,100 mg / kg) single-dose group is higher than that in the vehicle-dose group, but is insufficient to lower or control blood glucose level AUC (P> 0.2 (Table 9)).
  • Compound (1) unlike sitagliptin, can promote insulin secretion depending on lipid + glucose, that is, nutrients absorbed in the body even in diabetic conditions complicated with lipid metabolism abnormalities such as SDT fatty rats used in this experiment. confirmed.
  • the insulin value AUC of the combination group of compound (1) 100 mg / kg and sitagliptin 10 mg / kg was significantly higher (P ⁇ 0.05) than the insulin value AUC of the sitagliptin 10 mg / kg single agent group From these results, the significance of combined use related to insulin secretion control was confirmed.
  • the blood glucose level AUC in the compound (1) (10, ⁇ 100 mg / kg) and tenerigliptin (100 mg / kg) monotherapy group was significantly lower (P ⁇ 0.05) than the blood glucose level AUC in the vehicle administration group .
  • Tenerigliptin 10 mg / kg alone showed partial and non-significant suppression of blood glucose AUC.
  • the blood glucose level was significantly lower (P ⁇ 0.05) compared with the blood glucose level AUC in the tenerigliptin 10 mg / kg monotherapy group when compound (1) 100 mg / kg was used in combination with tenerigliptin 10 mg / kg. The significance of the combination related to the control was confirmed.
  • the triglyceride value AUC of the compound (1) (10,100 mg / kg) single agent administration group was significantly lower (P ⁇ 0.05) than the triglyceride value AUC of the vehicle administration group.
  • Control of triglyceride levels when compound (1) 100 mg / kg is combined with 10 mg / kg of tenerigliptin is significantly lower (P ⁇ 0.05) than the triglyceride value AUC of the 10 mg / kg monotherapy group of tenerigliptin The combined significance related to was confirmed.
  • the insulin value AUC of the compound (1) (10,100 mg / kg) single agent administration group was significantly higher (P ⁇ 0.05) than the insulin value AUC of the vehicle administration group.
  • Tenerigliptin was 10 mg / kg alone and the insulin level AU could not be increased compared to the vehicle administration group. Even if teneregliptin is 100 mg / kg, the increase in insulin AUC remains low (1.7 ⁇ 1.2 ng / h / mL) compared with the value in the vehicle group (-0.3 ⁇ 0.5 ng / h / mL), which is significant.
  • the action could not be confirmed (P> 0.2), and the blood glucose level AUC and triglyceride AUC were also lowered and controlled compared to the compound (1).
  • Compound (1) unlike tenerigliptin, promotes insulin secretion depending on lipid + glucose, that is, nutrients absorbed in the body, even in diabetic conditions complicated with lipid metabolism such as the SDT fatty rat used in this experiment. It was confirmed that blood glucose level AUC and triglyceride AUC can be significantly decreased (P ⁇ 0.05 (Tables 12 and 13)), respectively.
  • Tenerigliptin 10 mg / kg combined with compound (1) 100 mg / kg is significantly (P ⁇ 0.05) higher than the tenuregliptin 10 mg / kg single-agent group insulin level AUC, and tenerigliptin 100 mg / kg When combined with 100 mg / kg of compound (1) kg in kg, it is significantly higher (P ⁇ ⁇ 0.05) compared to the insulin level AUC in the 100 mg / kg monotherapy group of tenerigliptin, and sitagliptin as shown in Table 11
  • the combined use of DPP-4 inhibitors including tenerigliptin and compound (1) related to insulin secretion control was confirmed.
  • Example 6 Japanese Type 2 Diabetes subject Phase II study in Japanese subjects
  • 24 hours from baseline when Compound (1) 10 mg and 75 mg were orally administered repeatedly for 28 days Effectiveness and safety were examined in a double-blind parallel group comparison study using the weighted average blood glucose level as an index and placebo as a control.
  • the 24-hour weighted mean blood glucose change from baseline on day 28 of administration was compared to placebo.
  • fasting blood glucose level, 2 hour postprandial blood glucose level, changes in lipid profile and safety were examined.
  • FIG. 13 shows the results of the 24-hour weighted average blood glucose level change from baseline in the placebo, compound (1) 10 mg and compound (1) 75 mg mg administration groups.
  • the 24-hour weighted mean blood glucose level was statistically significantly reduced compared to the placebo group.
  • the compound (1) 10 mg group showed a decrease of -13.32 mg / dL (P ⁇ 0.01)
  • the compound (1) 75 mg group showed a decrease of -18.9 mg / dL (P ⁇ 0.001), confirming the dose dependency.
  • the fasting blood glucose level and the 2-hour postprandial blood glucose level were statistically significantly decreased as compared with the placebo group.
  • FIG. 14 and Table 15 show the results of the rate of change from baseline in the total cholesterol level, HDL cholesterol level, LDL cholesterol level, and triglyceride level for the placebo, Compound (1) 10 mg and Compound (1) 75 mg groups.

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Abstract

La présente invention concerne un médicament médicinal permettant, par exemple, de réduire encore la glycémie, d'améliorer le métabolisme lipidique, et de réduire les effets secondaires. Le médicament médicinal est obtenu par l'association : d'un composé (1) ou d'un sel pharmaceutiquement acceptable de celui-ci ; et d'au moins un médicament sélectionné dans le groupe constitué par un inhibiteur de dipeptidylpeptidase 4, un médicament de type biguanide, un inhibiteur des transporteurs 2 du sodium-glucose, un médicament de type sulfonylurée, et un inhibiteur d'α-glucosidase.
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