WO2019108046A1 - Nouvelle utilisation de dérivé d'acide 3-(4- (benzyloxy)phényl)hex-4-inoïque - Google Patents

Nouvelle utilisation de dérivé d'acide 3-(4- (benzyloxy)phényl)hex-4-inoïque Download PDF

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WO2019108046A1
WO2019108046A1 PCT/KR2018/015201 KR2018015201W WO2019108046A1 WO 2019108046 A1 WO2019108046 A1 WO 2019108046A1 KR 2018015201 W KR2018015201 W KR 2018015201W WO 2019108046 A1 WO2019108046 A1 WO 2019108046A1
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pancreatic beta
diabetes
pharmaceutical composition
beta cells
insulin
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PCT/KR2018/015201
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English (en)
Korean (ko)
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김대훈
김춘화
이선희
양고은
강승준
최효선
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현대약품 주식회사
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Priority to KR1020197035780A priority Critical patent/KR102090079B1/ko
Priority to SG11202004891PA priority patent/SG11202004891PA/en
Publication of WO2019108046A1 publication Critical patent/WO2019108046A1/fr
Priority to ZA2020/03028A priority patent/ZA202003028B/en

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/02—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 2
    • C07D317/06—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 2 condensed with carbocyclic rings or ring systems

Definitions

  • the present invention relates to novel uses of 3- (4- (benzyloxy) phenyl) hex-4-enoic acid derivatives. Specifically, the present invention relates to a method for the treatment of pancreatic beta cells of 3- (4- (benzyloxy) phenyl) hex-4-enoic acid derivative and a method for the treatment of type II diabetes in patients whose blood glucose levels are not normally regulated by an insulin secretagogue .
  • Sulfonylurea used in the type II diabetes is bind to the ATP sensitive K + channel and SUR-1 receptors of the pancreatic beta-cell plasma membrane, by depolarizing the cell membrane to increase the Ca + 2 influx and, due to the increase in intracellular Ca 2+ cytoplasm Promotes insulin secretion.
  • insulin secretagogues such as sulfonylureas
  • Sulphonylurea secretes insulin regardless of blood glucose level, and thus is damaged by hyperexcitation of beta cells, and excitotoxic reactions cause apoptosis of beta cells .
  • a decrease in the amount of beta cells leads to a decrease in insulin secretion, leading to a glucose control disorder in the blood.
  • FFAR1 free fatty acid receptor 1
  • GPR40 G-protein coupled receptor
  • GSIS glucose-stimulated insulin secretion
  • Applicants have studied activators for GPR40 in this regard and have found that 3- (4- (benzyloxy) phenyl) hex-4-enoic acid derivatives, their pharmaceutically acceptable salts or optical isomers thereof, And increased the intracellular calcium concentration and showed an excellent blood glucose lowering effect (Patent Document 1: 10-2014-0126248 A).
  • the present invention provides the use of 3- (4- (benzyloxy) phenyl) hex-4-enoic acid derivatives for the treatment of pancreatic beta cells and for the treatment of type II diabetes in patients whose blood glucose levels are not normally regulated by insulin secretagogues .
  • the 3- (4- (benzyloxy) phenyl) hex-4-enoic acid derivative according to the present invention means a compound of the following formula 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof.
  • the compound of Chemical Formula 1 is named as (3S) -3- (4- (3- (1,4-dioxaspiro [4,5] dec-7-en-8-yl) benzyloxy) phenyl) It is Ino Iksan.
  • the compound of formula (I) of the present invention can be used in the form of a pharmaceutically acceptable salt.
  • a base can be used to make a pharmaceutically acceptable metal salt.
  • the alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt.
  • the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).
  • a pharmaceutically acceptable salt can be prepared using an amino acid having an amino group attached to an organic acid.
  • the amino acid salt include natural amino acids such as glycine, alanine, phenylalanine, valine, lysine and glutamic acid And most preferably L-lysine. ≪ Desc / Clms Page number 2 >
  • the compound according to the present invention includes not only the compound of Formula 1 above and pharmaceutically acceptable salts thereof, but also solvates, optical isomers and hydrates thereof which can be prepared therefrom.
  • the inventors of the present invention first confirmed through in vitro experiments that the compound of Chemical Formula 1 has excellent activity against human GPR40 and is an excellent drug for insulin secretion by glucose stimulation (Example 1 ).
  • oral glucose tolerance test (OGTT) and glucose-stimulated insulin secretion (GSIS) tests were performed on GK (Goto-Kakizaki) rats, a type II diabetes model with secondary failure and pancreatic beta cell apoptosis (Examples 2 and 3).
  • the compound of the formula (1) maintains excellent blood glucose control ability and insulin secretion controlling ability even after prolonged repeated administration through protection of pancreatic beta cells in GK rats in which the pancreas is already damaged, while the second failure is frequently caused in the treatment of diabetes It has been confirmed that the compound of formula (I) has a pancreatic beta cell protective effect by confirming that the beta-cell function (decrease in insulin secretion ability) of the glutamylidene sulfonylurea drug is decreased. From the result of immunohistochemical staining of rat pancreatic tissue This effect was confirmed again (Example 4).
  • TAK-875 (Patent Document 2: WO2008-001931) of Takeda Co., Ltd., which is known as GPR40 activator, exhibited the same effect on the pancreatic beta cell protection of the compound of Chemical Formula 1, and TAK-875 was used as a positive control, The secretion control ability was evaluated (Example 6). As a result, although the compound of formula (1) was administered at a low dose, the ability to regulate insulin secretion was superior to that of the same GPR40 activator, TAK-875. This result indicates that the GPR40 activator does not prevent the damage of the pancreatic beta cells by repeated administration, that is, the second failure, and that the insulin secretory regulatory abnormality is caused by the damage of pancreatic beta cells.
  • the pancreatic beta cell protective ability of the compound of formula 1 of the invention means that it is an unexpected beneficial effect that only the compounds of the present invention exhibit.
  • the present inventors Based on the previous experimental results on GK rats in which the pancreas has already been damaged, the present inventors have found that the effect of the compound of formula 1 on the protection of the pancreatic beta cells of an additive pancreatic beta cell of a patient already taking a diabetes therapeutic agent causing secondary failure such as glimepiride And to restore the function of pancreatic beta cells.
  • pancreatic beta cells after repeated administration of drugs to Wistar DIO (diet-induced obesity) rats was evaluated (Example 7 and Example 8).
  • the pancreatic beta cells after 4 weeks of repeated administration of glimepiride, it was confirmed that even in the test group which was further repeatedly administered by changing the test drug with the compound, the pancreatic beta cells could be protected from further damage and the pancreatic beta cells could regain insulin secretion regulation ability.
  • pancreatic beta cell protective functions of the compound of formula (I) prevent the damage of the pancreatic beta cells, that is, the secondary failure, which is a side effect of the type II diabetic patients taking the long-term diabetes drug for insulin secretion stimulation, . Therefore, when the compound of formula (I) is used as a first-line treatment for type II diabetes, it can provide sustained and excellent blood-glucose lowering effect and insulin secretion-controlling ability without damaging the pancreatic beta cells.
  • pancreatic beta cells when already administered to patients with type II diabetes caused by secondary failure by taking a therapeutic agent for type II diabetes, it not only prevents further damage of pancreatic beta cells but also restores insulin secretory function of pancreatic beta cells, And can be particularly useful for the treatment of type II diabetes in patients whose blood sugar is not normally regulated.
  • the present invention provides a pharmaceutical composition for protecting pancreatic beta cells, comprising the compound of Chemical Formula 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient, a compound of Chemical Formula 1 for the preparation of a pharmaceutical composition for protecting pancreatic beta cells, The use of an optical isomer thereof or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a compound of formula 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof, for the treatment of pancreatic beta cells .
  • the present invention provides a pharmaceutical composition for the protection of pancreatic beta cells in a patient suffering from type II diabetes, comprising a compound of formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a patient with type II diabetes includes all those suffering from damage to the pancreatic beta cells or who are at risk of damage to the pancreatic beta cells.
  • the pharmaceutical composition for protecting pancreatic beta cells according to the present invention may be administered alone or in combination with other drugs for the treatment of type II diabetes. That is, the pharmaceutical composition for protecting pancreatic beta cells according to the present invention can be used as a single therapeutic agent, but can also be used in combination with other kinds of therapeutic agents for type II diabetes. There are no particular limitations on the types of drugs that can be administered jointly, and any of the drugs used as known type II diabetes therapeutic agents may be all examples.
  • Known type II diabetes therapeutic agents include, for example, biguanides such as oral hypoglycemic agents such as metformin, buformin, phenformin or derivatives thereof, Alpha-glucosidase inhibitors such as acarbose and voglibose, sulfonylureas acting as an insulin secretagogue, meglitinides and the like, .
  • the concurrent administration includes both sequential or simultaneous administration.
  • the pancreatic cell-protecting ability was already confirmed in the group treated with type II diabetes mellitus already induced by the second failure, it is expected that the pancreatic beta cell damage caused by the combined treatment with type II diabetes mellitus can be prevented.
  • the present invention provides a pharmaceutical composition for the protection of pancreatic beta cells in a patient suffering from damage to pancreatic beta cells containing the compound of formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient, to provide.
  • the cause or damage of the pancreatic beta cell of the " type II diabetic patient suffering from pancreatic beta cell damage " is not particularly limited. If the insulin level is lower than normal, the blood glucose level can not be controlled even if the blood sugar level is high. This means that the pancreatic beta cells responsible for the insulin secretion do not play a role, so it is judged as a beta cell damage. Therefore, by confirming the function of pancreatic beta cells using a method of confirming insulin secretion (for example, GSIS, ASIS, etc.) or a method of confirming insulin synthesis (for example, a method of insulin content confirmation in the pancreas) Can be verified.
  • a method of confirming insulin secretion for example, GSIS, ASIS, etc.
  • a method of confirming insulin synthesis for example, a method of insulin content confirmation in the pancreas
  • pancreatic beta cells Damage to pancreatic beta cells is accelerated by the progression of type II diabetes, and the use of diabetes medicines to promote the secretion of insulin indiscriminately, regardless of glucose concentration, may be a major cause of pancreatic beta cell damage.
  • insulin secretagogue having an action mechanism for promoting insulin secretion in pancreatic beta cells include sulfonylurea drugs and meglitinide drugs.
  • Representative examples of the sulfonylurea drugs include glimepiride, gliclazide, glibenclamide, glipizide, and the meglitinide drugs include nateglinide nateglinide, repaglinide, and the like.
  • the type II diabetic patient suffering from damage to pancreatic beta cells may be a patient receiving an insulin secretagogue, such as a sulfonylurea drug, and / or a meglitinide drug.
  • an insulin secretagogue such as a sulfonylurea drug, and / or a meglitinide drug.
  • the present invention also relates to a pharmaceutical composition for the treatment of type II diabetes mellitus in a patient whose blood sugar level is not normally regulated as an insulin secretion promoting agent comprising the compound of formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient, Use of a compound of formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a compound of formula (I) for the manufacture of a pharmaceutical composition for the treatment of Type II diabetes mellitus in a patient in whom blood glucose is not normally regulated as a secretagogue , An optical isomer thereof or a pharmaceutically acceptable salt thereof, as an insulin secretagogue to a patient whose blood glucose level is not normally regulated.
  • a patient whose insulin secretagogue is not normally regulated by the insulin secretion promoter may be a patient receiving an insulin secretagogue.
  • patients receiving insulin secretagogues may suffer pancreatic beta cell damage during long-term administration.
  • patients whose insulin secretagogue is not normally regulated by the insulin secretion promoting agent may be patients who have received insulin secretagogue and other hypoglycemic agents.
  • patients with type II diabetes receive the beta-guanidine drug as a first-line option and, if the glycemic control is not adequately controlled by the biguanide drug, either receive an insulin secretagogue, Accelerators and biguanides are often used in combination.
  • Patients who received insulin secretagogue, insulin secretagogue, or beta-guanidine drug, or who received insulin secretagogue were not able to regulate their glucose levels due to damage to pancreatic beta cells .
  • the insulin secretagogue may be a sulfonylurea drug, and / or a meglitinide drug.
  • hypoglycemic agent administered in combination with the insulin secretagogue may be a biguanide drug.
  • compositions according to the invention may be administered alone or in combination with other medicaments for the treatment of type II diabetes. That is, it can be used as a single therapeutic agent according to the present invention, but it can also be used in combination with other kinds of therapeutic agents for type II diabetes.
  • types of drugs that can be administered jointly, and any of the drugs used as known type II diabetes therapeutic agents may be all examples.
  • Known type II diabetes therapeutic agents include, for example, oral hypoglycemic agents such as, for example, beta-guanidate drugs such as metformin, buformin, penformin or derivatives thereof, or alpha glucosidase such as acarbose, Inhibitors, sulfonylurea drugs acting as an insulin secretagogue, meglitinide drugs and the like.
  • oral hypoglycemic agents such as, for example, beta-guanidate drugs such as metformin, buformin, penformin or derivatives thereof, or alpha glucosidase such as acarbose, Inhibitors, sulfonylurea drugs acting as an insulin secretagogue, meglitinide drugs and the like.
  • the concurrent administration includes both sequential or simultaneous administration.
  • the pharmaceutical composition according to the present invention can be administered in combination with a biguanide drug.
  • the sulfonylurea system By administering the pharmaceutical composition according to the present invention in combination with a biguanide drug instead of a drug, it is possible to treat type II diabetes in a patient in which blood glucose is not normally regulated as an insulin secretagogue.
  • the pharmaceutical composition of the present invention may contain, in addition to the active ingredient, a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carriers are those conventionally used at the time of formulation, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose But are not limited to, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like may be further included.
  • Formulations of the pharmaceutical compositions and pharmaceutically acceptable carriers can be appropriately selected according to techniques known in the art and can be found, for example, in the following references: [Urquhart et al., Lancet, 16: 367, 1980 ]; [Lieberman et al., PHARMACEUTICAL DOSAGE FORMS-DISPERSE SYSTEMS, 2nd ed., Vol.
  • the pharmaceutical composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) depending on the intended method, and the dose may vary depending on the condition and weight of the patient, , The type of drug, the route of administration, and the time, but may be suitably selected by those skilled in the art.
  • the effective amount of the active ingredient of the pharmaceutical composition of the present invention generally means the amount required to achieve the treatment of the disease.
  • the use of the compound of formula (I) is used for the protection of pancreatic beta cells or for the treatment of type II diabetes mellitus in patients whose blood glucose level is not normally regulated by an insulin secretagogue
  • the effective amount of the active ingredient means the amount required to protect pancreatic beta cells or the amount required to regulate blood glucose to a normal range in a type II diabetic patient whose insulin secretion promoter is not normally regulated.
  • Effective dose levels are based on the type of disease, severity, activity of the drug, sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, factors including concurrent drugs and other well- Can be determined accordingly.
  • the pharmaceutical composition according to the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapeutic agents, and can be administered singly or in multiple doses. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.
  • the effective amount of the pharmaceutical composition of the present invention may vary depending on the age, sex, condition, body weight, absorbency of the active ingredient, inactivation rate and excretion rate of the patient, type of disease,
  • the compound of formula (1) may be administered in an amount of 0.001 mg to 200 mg, preferably 0.01 mg to 100 mg, more preferably 0.2 mg to 50 mg per kg of body weight once or several times a day.
  • the dosage may be varied depending on the route of administration, the severity of obesity, sex, weight, age, etc. Therefore, the dosage is not limited to the scope of the present invention by any means.
  • subject refers to a subject in need of treatment for a disease, and more particularly, a human or non-human primate, mouse, dog, cat, Means mammals such as horses and cattle.
  • the 3- (4- (benzyloxy) phenyl) hex-4-enoic acid derivative according to the present invention is useful for the treatment of diabetic neuropathy due to the excitotoxic response of the previously developed diabetic agents, resulting in apoptosis of pancreatic beta cells, It solves the side effects that cause secondary failures that can not be avoided.
  • the 3- (4- (benzyloxy) phenyl) hex-4-enoic acid derivative according to the present invention promotes insulin secretion only when the glucose concentration is increased, thereby protecting the pancreatic beta cells from apoptosis, Of insulin secretion function.
  • the 3- (4- (benzyloxy) phenyl) hex-4-enoic acid derivative according to the present invention not only when administered as a primary selective agent for diabetes, but also as a primary selective agent for diabetes And the other pancreatic beta cells are used to treat patients with damaged pancreatic beta cells. In addition, it regenerates the insulin secretory function of pancreatic beta cells, and is consequently useful for treating type II diabetes in patients whose insulin secretagogue is not normally regulated.
  • Figure 1A shows the results of measuring the functional activity of Compound A against human GPR40 in vitro.
  • Fig. 1B shows the results of confirming insulin secretion ability (GSIS) by glucose stimulation of Compound A.
  • Figures 2A and 2B show results of oral glucose tolerance test (OGTT) on day 1 of administration
  • Figures 2C and 2D show results of oral glucose tolerance test (OGTT) on day 12 of administration
  • Figures 2A and 2C show the glucose levels
  • Figures 2B and 2D show the glucose AUC reduction levels.
  • FIGS. 3A, 3B and 3C show results of oral glucose tolerance test (OGTT) and blood insulin concentration measurement on the first day of administration
  • FIGS. 3D, 3E and 3F show results of oral glucose tolerance test (OGTT) and blood insulin concentration measurement on the fourth week of administration.
  • Figs. 3A and 3D show glucose levels
  • Figs. 3B and 3E show glucose AUC reduction levels
  • Figs. 3C and 3F show insulin secretion index (SI).
  • FIG. 4A shows the islet morphology immunostained with anti-insulin antibody in GK rats at 12 weeks after repeated administration for 4 weeks
  • FIG. 4B shows the islet morphology obtained by immune-staining with anti-insulin antibody in GK rats at 40 weeks of age after repeated administration for 14 weeks Lt; / RTI >
  • FIG. 5 is a graph showing the ratio of the insulin secretion index (SI) of Test Compound Compound A and the control substance TAK-875 administered group to that of the Vehicle administered group.
  • FIG. 6 shows the results of measuring the ability of insulin secretion regulation in fasting state after repeated drug administration in GK rats.
  • FIG. 7 is a graph showing the level of glucose AUC reduction as a result of oral glucose tolerance test (OGTT) of the 4-week treatment group.
  • FIG. 8 is a graph showing the level of glucose AUC reduction as a result of oral glucose tolerance test (OGTT) of the 8 week treatment group.
  • FIGS 9 and 10 are graphs showing the insulin secretion index (SI) as a result of the insulin secretion ability (GSIS) test of the 4-week treatment group and the 8-week treatment group, respectively.
  • Fig. 11 shows the islet form immunostained with anti-insulin antibody in Wistar rats after repeated administration of the test substance for 4 weeks.
  • Figure 12 shows the islet morphology immunostained with anti-insulin antibody in Wistar rats after repeated administration of the test substance for 10 weeks.
  • test substances used as an example of the compound of formula (1) according to the present invention are as follows.
  • CHO cells stably expressing human GPR40 were cultured overnight at 37 ° C and 5% CO 2 . Cells were then incubated in loading buffer (50 ml Ham'F-12 (containing 1% FBS) + 50 ml Fluo-4 solution (Invitrogen, F10471) for 2 hours at 37 ° C. Compound A was added to the cells at various concentrations, and the increase in intracellular calcium ion concentration was monitored with a Flexstation 3 (Molecular Devices) for 100 seconds.
  • loading buffer 50 ml Ham'F-12 (containing 1% FBS) + 50 ml Fluo-4 solution (Invitrogen, F10471)
  • A a cell to which Compound A was added
  • B a cell to which a vehicle was added
  • Example 1-2 Compound A Glucose Insulin by stimulation Secretory function ( GSIS ) Confirm
  • INS-1 pancreatic cells were placed in a 24-well plate at 5 x 10 cells / well. After 48 hours, the cells 1mM glucose -KRB buffer (118mM NaCl, 4.7mM KCl, 1.2mM KH 2 PO 4, 1.16mM MgCl 2, 10mM HEPES, 2.5mM CaCl 2, 25.5mM NaHCO 3, 0.2% BSA, pH7. 4) and incubated for 2 hours with 1 mM glucose-KRB buffer for starvation. After starvation, the cells were washed twice with 1 mM glucose-KRB buffer and incubated with Compound A at the desired concentration for 1 hour in 3 mM or 16 mM glucose-KRB buffer. The supernatant was collected and purified by centrifugation and the insulin levels were measured using an insulin ELISA kit (Millipore, EZRMI-13K) (* p ⁇ 0.05: Student t-test).
  • an insulin ELISA kit Millipore, EZRMI
  • GK rats with characteristics of type II diabetes such as hyperglycemia, hypothyroidism, and normal blood lipid concentration were used as non-obese model animals from the 2nd week of life.
  • GK rats are known as type II diabetes models with secondary failure and apoptotic cell death.
  • Male 5-week-old GK rats were purchased and fed to ad libitum until 26 weeks old to induce weight loss of the pancreas.
  • GK rats, Vehicle Glimepiride (10 mg / kg)
  • Compound A administration group (8 rats) using only those individuals whose diabetes induction was confirmed by randomized complete block design according to body weight and blood sugar (1, 3, and 10 mg / kg).
  • Wistar rats 26 week old male were divided into 6 groups as vehicle (WT) Respectively.
  • the solvent used in the vehicle and Compound A was a 0.5% CMC solution, and the group containing glimepiride used 0.25% CMC with a solvent containing 1% PEG and 1% Tween 80.
  • Oral glucose tolerance test (OGTT) was performed after fasting for 16-18 hours at the first day of administration and at the 12th week of the administration. After 60 minutes of administration of the sample, glucose (4 g / kg) was orally administered at a dose of 5 ml / kg. Using a blood glucose meter (G-doctor AGM-4000), 0, 20, 40, 60 and 120 minutes after fasting glucose and glucose administration, blood glucose was measured by puncturing the vein.
  • Figures 2A and 2B show results of oral glucose tolerance test (OGTT) on day 1 of administration
  • Figures 2C and 2D show results of oral glucose tolerance test (OGTT) on day 12 of administration
  • Figures 2A and 2C show the glucose levels
  • Figures 2B and 2D show the glucose AUC reduction levels.
  • GK rats Male 6-week-old rats of GK rats were purchased and reared at 8 weeks of age (young).
  • Glimepiride (10 mg / kg)
  • Compound A (3, 4) groups were administered to 8 rats using only those individuals whose diabetes mellitus was confirmed by the nude method according to body weight and blood sugar. 10 mg / kg).
  • Wistar rats (8-week-old male) were orally administered with vehicle at 5 ml / kg for 4 weeks.
  • the solvent used in the vehicle and Compound A was 0.5% CMC (CarboxyMethyl Celluluse) solution.
  • a solvent containing 1% PEG (polyethylene glycol) and 1% Tween 80 in 0.25% CMC was used.
  • Oral glucose tolerance test (OGTT) and blood insulin concentrations were measured after fasting for 16-18 hours at the 1st and 4th weeks of the administration. After 60 minutes of administration of the sample, glucose (4 g / kg) was orally administered at a dose of 5 ml / kg. Blood glucose was measured by taking blood from the tail vein at 0, 30, 60 and 120 minutes after fasting blood glucose and glucose administration using a blood glucose meter (G-doctor AGM-4000).
  • Figures 3A, 3B and 3C show the results of oral glucose tolerance test (OGTT) on the first day of administration and Figures 3D, 3E and 3F show the results of oral glucose tolerance test (OGTT) on the fourth week of administration.
  • Figures 3A and 3D show the glucose levels
  • Figures 3B and 3E show the glucose AUC reduction levels
  • Figures 3C and 3F show the insulin secretion index (SI).
  • pancreatic beta cells used in Examples 2 and 3 were detached from the pancreatic tissues in each test group and fixed in a 10% neutral formalin solution in a tissue cassette. After the tissue was made transparent in an automatic paraffin infiltration machine, paraffin was infiltrated in a tissue embedding device to make a block, and the block was cut into a thickness of 5 ⁇ with a tissue micro-slicer and attached to the slide. Then, the slide was subjected to anti-insulin antibodies immunostain, Respectively.
  • FIG. 4A is an islet image obtained by immunostaining an anti-insulin antibody in a rat used in Example 3, i.e., GK rats aged 12 weeks after repeated administration for 4 weeks
  • Fig. 4B is an islet image obtained by adding GK rats used in Example 2 After 2 weeks of administration, the mice were immunized with anti-insulin antibody in GK rats at 40 weeks of age.
  • wild-type rat islets retain their morphology, but GK rats exhibit morphological damage as a whole.
  • the relative amount of beta cells in GK rats does not show any significant difference between the 4-week and 14-week repeated doses of each drug. Suggesting that the effect of compound A on blood glucose control is due to the difference in function of beta cells due to beta cell protection rather than on the mass of beta cells.
  • Examples 1 to 4 can be summarized as follows.
  • Compound A was highly active in in vitro and increased glucose-stimulated insulin secretion (GSIS) in INS-1 pancreatic beta cells.
  • GSIS glucose-stimulated insulin secretion
  • Compound A and glimepiride administration in young GK rats improved glycemic control and insulin secretion, whereas chronic administration of glimepiride resulted in loss of glycemic control efficacy, while compound A did not.
  • glimepiride treated group had lower blood glucose control and insulin secretion at oral glucose tolerance test (OGTT) than compound A treated group.
  • OGTT oral glucose tolerance test
  • Compound A administration group maintained blood glucose control ability, but not glimepiride administration group.
  • mice Seven-week-old male Sprague Dawley (SD) rats were obtained and subjected to a glucose-stimulated insulin secretion (GSIS) test using only healthy individuals after a week of purifying period.
  • Vehicle (0.5% CMC) or test substance Compound A, control substance TAK-875 were orally administered at a dose of 10 mg / kg each after 12 to 16 hour fasting.
  • Glucose (2 g / kg) was administered intraperitoneally 60 minutes after vehicle or test substance administration. After 20 minutes, the whole blood was collected through a capillary tube and the plasma was separated and measured using a Morinaga Ultra Sensitive Mouse / Rat Insulin ELISA Kit (MIoBS).
  • MIoBS Morinaga Ultra Sensitive Mouse / Rat Insulin ELISA Kit
  • the insulin secretion index (SI) was obtained from the following formula.
  • SI Secretion Index
  • FIG. 5 is a graph showing the ratio of the insulin secretion index of Test Compound Compound A and the control substance TAK-875 administered group to that of the vehicle-treated group.
  • the insulin secretion potency of Compound A in the glucose-stimulated insulin secretion (GSIS) test using SD rats was superior to that of the control substance TAK-875.
  • MIoBS Morinaga Ultra Sensitive Mouse / Rat Insulin ELISA Kit
  • FIG. 6 shows the results of measuring the ability of insulin secretion regulation in fasting state after repeated drug administration in GK rats.
  • Many diabetic therapeutic agents exhibit insulinotropic dysregulation which, when repeatedly administered, secretes insulin excessively regardless of glucose concentration.
  • the compound A was administered at a low dose, the ability to regulate insulin secretion was superior to that of the same GPR40 activator TAK-875. Since the abnormality of insulinotropic regulation is caused by the damage of pancreatic beta cells, Compound A can be judged as having excellent ability to protect pancreatic beta cells.
  • the animals were housed in Wistar DIO (diet-induced obesity) rats, 4 weeks old, and high fat diet (Research diets, D12492) According to body weight and blood sugar, the groups were divided by the nude method according to Table 1 below.
  • the 4 week treatment group was divided into 4 normal groups (Wistar rat, Lean), no treatment group (Wistar DIO rat, Vehicle), Glimepiride (10 mg / kg) Week.
  • the solvent used in the vehicle and Compound A was a 0.5% CMC solution, and the group containing glimepiride used 0.25% CMC with a solvent containing 1% PEG and 1% Tween 80.
  • GSIS glucose-stimulated insulin secretion
  • FIG. 7 is a graph showing the level of glucose AUC reduction as a result of oral glucose tolerance test (OGTT) of the 4-week treatment group.
  • FIG 8 is a graph showing the glucose AUC reduction level as a result of oral glucose tolerance test (OGTT) in the 8 week treatment group.
  • FIGS 9 and 10 are graphs showing the insulin secretion index (SI) as a result of the glucose-stimulated insulin secretion (GSIS) test in the 4-week treatment group and the 8-week treatment group, respectively.
  • SI insulin secretion index
  • GSIS glucose-stimulated insulin secretion
  • Rats belonging to the 4 week treatment group tested in Example 4 were sacrificed after completion of the test and the pancreatic tissue was removed from each test group. Were placed in a tissue cassette and fixed in 10% neutral formalin solution. After the tissue was transparentized by an automatic paraffin infiltration machine, paraffin was infiltrated into a tissue embolization device to make a block, and the block was cut into a thickness of 5 ⁇ m with a tissue microsperting machine and attached to the slide. Then, an anti-insulin antibodies immunostain was performed, . Slides were scanned with .Z1 [Carl Zeiss, Germany]. The results were shown in 2.5x using ZEN Imaging Software.
  • the rats belonging to the 8 week treatment group tested in Example 6 were further administered with the sample under the same conditions for 2 weeks, and immunostaining was performed by the same method after the completion of the administration for 10 weeks in total.
  • Fig. 11 shows the islet form immunostained with anti-insulin antibody in Wistar rats after repeated administration of the test substance for 4 weeks.
  • the islet cells of wild-type Wistar rats (Lean) maintain their shape, but DIO rats show some morphological damage.
  • Glimepiride-treated groups show overall morphological damage, suggesting secondary failure.
  • Compound A administration group showed no significant difference even after 4 weeks of administration.
  • Figure 12 shows the islet morphology immunostained with anti-insulin antibody in Wistar rats after repeated administration of the test substance for 10 weeks.
  • the compound A administration group did not change morphologically even after 10 weeks of administration.
  • glimepiride administration group (glymepyrid 10 week group) showed more morphological damage whereas compound A administration group (Glimepiride 10 mg / kg pre-treatment (4 w) + Compound A, 1 mg / kg (6 w)) The degree of damage was suppressed.

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Abstract

La présente invention concerne l'utilisation d'un dérivé d'acide 3-(4-(benzyloxy)phényl)hex-4-inoïque pour protéger des cellules bêta pancréatiques. Un dérivé d'acide 3-(4-(benzyloxy)phényl)hex-4-inoïque selon la présente invention résout un effet secondaire dans lequel des agents développés conventionnellement pour traiter le diabète induisent l'apoptose de cellules bêta pancréatiques par l'intermédiaire de réactions excitotoxiques, de façon à causer une défaillance secondaire dans laquelle une fonction de sécrétion d'insuline n'est pas contrôlée. Un dérivé d'acide 3-(4-(benzyloxy)phényl)hex-4-inoïque selon la présente invention stimule la sécrétion d'insuline uniquement lorsque la concentration de glucose est augmentée, de façon à protéger les cellules bêta pancréatiques contre l'apoptose et restaurer la fonction de sécrétion d'insuline des cellules bêta pancréatiques. Par conséquent, selon la présente invention, le dérivé d'acide 3-(4-(benzyloxy)phényl)hex-4-inoïque : présente un excellent effet de protection des cellules bêta pancréatiques, lorsqu'il est administré en tant qu'agent sélectif primaire pour le diabète et également lorsqu'il est administré à un patient ayant des cellules bêta pancréatiques endommagées par l'utilisation d'autres médicaments, qui sont des agents de sélection primaires pour le diabète et provoquent une défaillance secondaire ; et restaure la fonction de sécrétion d'insuline des cellules bêta pancréatiques, de façon à être utile pour traiter le diabète de type II chez un patient dont la glycémie n'est pas régulée de façon normale en utilisant un agent stimulant la sécrétion d'insuline.
PCT/KR2018/015201 2017-12-01 2018-12-03 Nouvelle utilisation de dérivé d'acide 3-(4- (benzyloxy)phényl)hex-4-inoïque WO2019108046A1 (fr)

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SG11202004891PA SG11202004891PA (en) 2017-12-01 2018-12-03 Novel use of 3-(4-(benzyloxy)phenyl)hex-4-inoic acid derivative
ZA2020/03028A ZA202003028B (en) 2017-12-01 2020-05-22 Novel use of 3-(4-(benzyloxy)phenyl)hex-4-inoic acid derivative

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CN116509830A (zh) * 2023-06-16 2023-08-01 桂林医学院 甲基阿魏酸在制备胰岛素促泌剂与合成剂中的应用

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KR102270026B1 (ko) * 2020-01-31 2021-06-28 현대약품 주식회사 (3s)-3-(4-(3-(1,4-다이옥사스파이로[4,5]데스-7-엔-8-일)벤질옥시)페닐)헥스-4-이노익산의 품질 평가 방법

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CN116509830A (zh) * 2023-06-16 2023-08-01 桂林医学院 甲基阿魏酸在制备胰岛素促泌剂与合成剂中的应用

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