JP2011001296A - Insulin secretion promoter - Google Patents

Abstract

PROBLEM TO BE SOLVED: To find out a compound which promotes insulin secretion from a pancreas β-cell and to provide a preventing and/or therapeutic agent for a disease resulting from hyperglycemia, for example diabetes.SOLUTION: The insulin secretion promoter makes N,N'-bis[5-(3,4,5-trimethoxyphenyl)-4-pentenyl]homopiperazine or the acid addition salts thereof or these solvates as an active ingredient.

Description

  The present invention relates to a drug that promotes insulin secretion from pancreatic β cells and prevents and / or treats diseases caused by hyperglycemia, such as diabetes.

The pancreas is an endocrine / exocrine gland tissue derived from the endoderm, and is composed of endocrine cells, acinar cells, and duct cells. Pancreatic Langerhans Islet (pancreatic La Islet), which is an endocrine cell, constitutes 1% of the entire pancreas and is mainly classified into four cells. These are α cells that secrete glucagon, β cells that secrete insulin, δ cells that synthesize and secrete somatostatin, and F cells that synthesize and secrete pancreatic polypeptides. Of these, the main physiological function of insulin secreted from β-cells is to lower blood sugar and is the only hormone that exhibits a hypoglycemic action.
Insulin is secreted and released into the portal vein by sensing elevated blood glucose in pancreatic β cells. The released insulin suppresses gluconeogenesis and sugar release in the liver, and promotes glucose uptake in peripheral fat and muscle tissue, thereby maintaining the blood glucose level in the living body.

  Diabetes is a persistent hyperglycemic condition caused by insulin deficiency or by its lack of action. Diabetes mainly causes insulin-dependent diabetes mellitus (IDDM) caused by abnormal pancreatic insulin secretion due to autoimmune diseases, etc., and insulin secretion ability due to pancreatic exhaustion resulting from persistent high insulin state due to insufficient insulin action (insulin resistance) It is divided into two types of non-insulin dependent diabetes mellitus (NIDDM) caused by a decrease. Persistent hyperglycemia due to diabetes causes vascular damage and complications in multiple organs. Typical complications include diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, etc., and problems such as decreased quality of life (QOL), increased medical costs, decreased survival rate, etc. Yes.

Treatment of diabetes includes exercise therapy, diet therapy, and drug therapy. Examples of the drug used for drug therapy include a drug that promotes insulin secretion from pancreatic β cells, a drug that improves insulin resistance, a drug that suppresses sugar absorption, and a drug that promotes the use of sugar. Among them, an insulin secretagogue is expected to increase blood insulin concentration and reduce blood glucose, and is therefore expected to suppress hyperglycemia and improve diabetes. A sulfonylurea preparation (SU drug), Rapid insulin secretion promoters, DPPIV inhibitors (see Non-Patent Document 1), GLP-1 analogs (see Non-Patent Document 2) and the like are actually used in the field of diabetes treatment. However, the most commonly used SU drug in Japan stimulates pancreatic β cells and promotes endogenous insulin secretion (see Non-Patent Document 3), but may exhibit hypoglycemia as a side effect, particularly in the elderly, Care should be taken when using this product if the patient has impaired renal function or if the diet is irregular. Also, side effects such as weight gain have been reported. Furthermore, there may be a primary ineffectiveness in which no effect is seen from the initial administration, or a secondary ineffectiveness in which clinical effects are lost during the administration period (see Non-Patent Document 4), and these side effects are reduced, and the insulin secretion ability Development of an insulin secretagogue that minimizes the burden on pancreatic β cells is desired.

  On the other hand, the following formula (1):

N, N′-bis [5- (3,4,5-trimethoxyphenyl) -4-pentenyl] homopiperazine (hereinafter sometimes referred to as “K-7174”), or An acid addition salt or a solvate thereof is a cerebral protective agent (see Patent Document 1) effective for improving or preventing progression of brain dysfunction, an anti-allergic agent or an anti-inflammatory agent due to cell adhesion inhibitory action and cell infiltration inhibitory action ( Patent Document 2), and therapeutic agents for Sjogren's syndrome, conjunctival disorder, etc. due to apoptosis-inhibiting action (see Patent Document 3), erythropoietin production promoter (see Patent Document 4), preadipocyte differentiation inhibitor (see Patent Document 5) However, it has not been known at all how K-7174 has an effect on insulin secretion from pancreatic β cells.

JP-A-3-2144 Japanese Patent Laid-Open No. 9-143075 WO02 / 20477 pamphlet WO04 / 02493 pamphlet JP 2009-051796 A

J Clin Endocrinol Metab. 2004 May 89; (5): 2078-84. Regul Pept. 2004 Feb 15; 117 (2): 77-88 The Lancet. 1985 Aug 31; 2 (8453): 474-5 The Lancet. 1998 Sep 12; 352 (9131): 837-53.

  An object of the present invention is to find a compound that promotes insulin secretion from pancreatic β cells, and to provide a drug for preventing or treating a disease caused by hyperglycemia, such as diabetes.

  As a part of research to find a compound having insulin secretion promoting activity, the present inventors have searched for a compound that promotes insulin secretion using a hamster pancreatic β cell line HIT-T15 cell. N, N′-bis [5- (3,4,5-trimethoxyphenyl) -4-pentenyl] homopiperazine (K-7174) has an action of promoting insulin secretion from pancreatic β cells. As a result, the present invention has been completed.

  That is, the present invention uses N, N′-bis [5- (3,4,5-trimethoxyphenyl) -4-pentenyl] homopiperazine, an acid addition salt thereof, or a solvate thereof as an active ingredient. An insulin secretion promoter is provided.

  Further, the present invention comprises N, N′-bis [5- (3,4,5-trimethoxyphenyl) -4-pentenyl] homopiperazine, an acid addition salt thereof, or a solvate thereof as an active ingredient. A hypoglycemic agent is provided.

  Further, the present invention comprises N, N′-bis [5- (3,4,5-trimethoxyphenyl) -4-pentenyl] homopiperazine, an acid addition salt thereof, or a solvate thereof as an active ingredient. The present invention provides a preventive and / or therapeutic agent for diabetes.

  Furthermore, the present invention administers an effective amount of N, N′-bis [5- (3,4,5-trimethoxyphenyl) -4-pentenyl] homopiperazine, or an acid addition salt thereof, or a solvate thereof. It is intended to provide a method for promoting insulin secretion.

  The present invention also administers an effective amount of N, N′-bis [5- (3,4,5-trimethoxyphenyl) -4-pentenyl] homopiperazine, an acid addition salt thereof, or a solvate thereof. The present invention provides a method for lowering blood glucose, characterized by:

  The present invention also administers an effective amount of N, N′-bis [5- (3,4,5-trimethoxyphenyl) -4-pentenyl] homopiperazine, an acid addition salt thereof, or a solvate thereof. Therefore, the present invention provides a method for preventing and / or treating diabetes.

  Furthermore, the present invention provides N, N′-bis [5- (3,4,5-trimethoxyphenyl) -4-pentenyl] homopiperazine, or an acid addition salt thereof, for producing an insulin secretagogue. The use of these solvates is provided.

  In addition, the present invention provides N, N′-bis [5- (3,4,5-trimethoxyphenyl) -4-pentenyl] homopiperazine, or an acid addition salt thereof, for producing a hypoglycemic agent, or these The use of a solvate of

  The present invention also provides N, N′-bis [5- (3,4,5-trimethoxyphenyl) -4-pentenyl] homopiperazine, or a method for producing an agent for preventing and / or treating diabetes. The use of acid addition salts or their solvates is provided.

  N, N′-bis [5- (3,4,5-trimethoxyphenyl) -4-pentenyl] homopiperazine, or an acid addition salt thereof, or a solvate thereof of the present invention is produced from pancreatic β cells to insulin. It is a low molecular weight compound that can be administered orally and has an action of strongly promoting secretion, and is useful as a preventive and / or therapeutic agent for diseases caused by hyperglycemia in mammals including humans, such as diabetes.

It is a figure which shows the insulin secretion promotion effect when K-7174 is added to HIT-T15 cell.

  N, N′-bis [5- (3,4,5-trimethoxyphenyl) -4-pentenyl] homopiperazine (K-7174) used in the present invention is, for example, disclosed in JP-A-3-2144 and JP-A-Hei. It can be produced according to the method described in Japanese Patent No. 9-143075.

  In the present invention, an acid addition salt or solvate of K-7174 can also be used. Acid addition salts and solvates can be prepared by conventional methods.

  The acid forming the acid addition salt of the present invention is not particularly limited as long as it is pharmaceutically acceptable, but examples thereof include inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid; And organic acids such as lactic acid, succinic acid, tartaric acid, malic acid, maleic acid, citric acid, fumaric acid, methanesulfonic acid and p-toluenesulfonic acid.

  Examples of the solvate of the present invention include hydrates, alcohol solvates (for example, ethanol solvates) and the like.

  As shown in Examples described later, K-7174 showed an effect of significantly promoting insulin secretion in the hamster pancreatic β cell line HIT-T15 cells. Therefore, K-7174, or an acid addition salt thereof, or a solvate thereof is useful as a hypoglycemic agent and as a prophylactic and / or therapeutic agent for diseases caused by hyperglycemia in mammals including humans, such as diabetes. is there. Here, as diabetes, non-insulin dependent diabetes mellitus (NIDDM) is mentioned in more detail.

  The medicament of the present invention can be used alone or in combination with other pharmaceutically acceptable solubilizers, excipients, binders, diluents, etc., tablets, capsules, granules, powders, lotions, ointments. The dosage form may be an agent, an injection, a suppository, or the like. These preparations can be produced by known methods. For example, in the case of a preparation for oral administration, solubilizers such as gum tragacanth, gum arabic, sucrose ester, lecithin, olive oil, soybean oil, PEG400; excipients such as starch, mannitol, lactose; sodium carboxymethylcellulose, hydroxy Binders such as propylcellulose; disintegrating agents such as crystalline cellulose and carboxymethylcellulose calcium; lubricants such as talc and magnesium stearate; fluidity improvers such as light anhydrous silicic acid; diluents such as corn starch, etc. It can be manufactured by prescribing.

  The medicament of the present invention is administered by oral administration or parenteral administration. The dose of the medicament of the present invention varies depending on the patient's body weight, age, sex, symptom, etc., but in the case of an ordinary adult, it is usually 0.01 to 1000 mg, preferably 0.1 to 100 mg per day as K-7174. It is preferable to administer in 3 divided doses.

  EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, this invention is not limited at all by these Examples.

Example 1 Insulin Secretion Promoting Action Hamster pancreatic β cell line HIT-T15 cells are passaged using Ham's F-12K medium containing penicillin (100 units / mL), streptomycin (100 μg / mL) and 10% fetal bovine serum. Subcultured. An appropriate amount of cells was seeded in a 24-well culture plate, cultured at 37 ° C. for 48 hours, and then washed with a KRBH buffer containing 0.1% albumin. Subsequently, it left still at 37 degreeC with the same buffer for 1 hour. To this, glucose was added to a final concentration of 2 mM, and K-7174 dissolved in DMSO at a concentration 1000 times the concentration shown in FIG. Added under conditions. After addition of K-7174, the mixture was allowed to stand at 37 ° C. for 1 hour, and then the supernatant was collected and the insulin concentration was measured with Levis Insulin Kit Mouse T (Shiba Goat Co., Ltd.). A control to which only DMSO was added was used.

FIG. 1 shows the insulin secretion promoting effect of K-7174 in HIT-T15 cells. Each point is shown as mean ± standard error, and Dunnett's multiple comparison test was used for statistical processing and comparison with the control was performed.
As can be seen from FIG. 1, when K-7174 was added to a concentration of 0.03 to 1.0 μM, insulin secretion increased significantly, and a concentration-dependent insulin secretion promoting action was confirmed.

Claims (3)

  An insulin secretion promoter comprising N, N'-bis [5- (3,4,5-trimethoxyphenyl) -4-pentenyl] homopiperazine, an acid addition salt thereof, or a solvate thereof as an active ingredient.   A hypoglycemic agent comprising N, N′-bis [5- (3,4,5-trimethoxyphenyl) -4-pentenyl] homopiperazine, an acid addition salt thereof, or a solvate thereof as an active ingredient.   N, N′-bis [5- (3,4,5-trimethoxyphenyl) -4-pentenyl] homopiperazine, or an acid addition salt thereof or a hydrate thereof, is used as an active ingredient to prevent diabetes and / or Or a therapeutic agent.

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