JP4391122B2 - Diabetes prevention and treatment - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a preventive or therapeutic agent for diabetes.
[0002]
[Prior art]
There are two types of diabetes: type 1 diabetes caused by absolute insulin deficiency caused by destruction of beta cells in the pancreas and type 2 diabetes caused by relative insulin deficiency caused by insulin secretion deficiency and insulin resistance ( Non-patent documents 1 to 3). For the treatment of type 1 diabetes, insulin preparations as injections are used, and for the treatment of type 2 diabetes, oral agents such as biguanides such as metformin hydrochloride and sulfonylureas such as tolbutamide are used. Yes.
[0003]
However, insulin preparations have troublesome use associated with injections, whereas biguanides, which are orally administered, cause lactic acidosis, and sulfonylureas have the side effect of severe hypoglycemia. Yes. Recently, pioglitazone (Pioglitazone; (Patent Document 1)) and thiazolidine-2,4-dione derivatives of rosiglitazone (Rosiglitazone; (Patent Document 2)), which do not have these disadvantages, are caused by insulin resistance. Although it has attracted attention as a treatment for (insulin-resistant diabetes), there are many problems such as reports of side effects such as weight gain and edema (Non-patent Document 4). For this reason, there is currently no satisfactory treatment for diabetes, particularly insulin-resistant diabetes.
[0004]
On the other hand, the compound represented by the general formula (I) has kinase inhibitory activities such as Rho kinase, myosin light chain phosphorylase, protein kinase C, vascular smooth muscle relaxing action, blood flow increasing action, blood pressure reducing action, brain It is already known that it is a substance that exhibits cardioprotective action and the like and is effective in vasodilators (especially angina treatment agents), hypertension treatment agents, brain, cardioprotective agents, arteriosclerosis treatment agents, etc. (For example, (patent documents 3 to 11) (non-patent documents 5 to 8)).
[Patent Document 1]
European Patent No. 193256 [Patent Document 2]
US Patent No. 5,0029533 [Patent Document 3]
Japanese Patent Laid-Open No. 61-152658 [Patent Document 4]
JP-A-61-227581 [Patent Document 5]
JP-A-2-256617 [Patent Document 6]
JP-A-4-264030 [Patent Document 7]
JP-A-6-056668 [Patent Document 8]
JP-A-6-080569 [Patent Document 9]
Japanese Patent Laid-Open No. 7-80854 [Patent Document 10]
WO98 / 06433
[Patent Document 11]
WO00 / 03746
[Non-Patent Document 1]
Nippon Rinsho 60, Suppl 7, 28-35, 2002
[Non-Patent Document 2]
Diabetes 49: 2178-2189,2000
[Non-Patent Document 3]
The Journal of Biological Chemistry 276: 49331-49336,2001
[Non-Patent Document 4]
J. Med. Chem., 35, 2617-2626, 1992
[Non-Patent Document 5]
Br. J. Pharmacol., 98, 1091, 1989
[Non-Patent Document 6]
J. Pharmacol. Exp. Ther., 259, 738, 1991
[Non-Patent Document 7]
Circulation, 96, 4357, 1997
[Non-Patent Document 8]
Cardiovasc. Res., 43, 1029, 1999
[0005]
[Problems to be solved by the invention]
Conventionally, provision of a medicine for preventing or treating diabetes has been desired.
[0006]
[Means for Solving the Problems]
As a result of intensive studies on the compound represented by the general formula (I), the present inventors have found that the compound has the above-mentioned vascular smooth muscle relaxing action, blood flow increasing action, blood pressure reducing action, brain, cardioprotective action, etc. The present invention has been completed by finding a preventive and therapeutic effect for diabetes that is totally unexpected from the conventionally known action.
[0007]
That is, the present invention provides the following general formula (I)
[0008]
[Chemical formula 2]
[0009]
(Wherein R1 represents a hydrogen atom or a hydroxyl group), which is a prophylactic or therapeutic agent for diabetes containing a compound represented by an active ingredient. Furthermore, the present invention provides a compound of the general formula (I) wherein the diabetes is insulin resistant diabetes.
[0010]
[Chemical 3]
[0011]
(Wherein R1 represents a hydrogen atom or a hydroxyl group), which is a prophylactic or therapeutic agent for diabetes containing a compound represented by an active ingredient.
[0012]
The compound represented by the general formula (I) of the present invention is effective for type 1 and type 2 diabetes, but is particularly effective for insulin-resistant diabetes.
[0013]
Furthermore, long-term hyperglycemia is known to cause diabetic complications such as diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, and diabetic hypertension (JAMA 288, 2579- 2588, 2002). Therefore, the compound represented by the general formula (I) of the present invention which is a preventive or therapeutic agent for diabetes is a diabetic complication such as diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, diabetic hypertension and the like. It is also effective against symptoms.
[0014]
The compound represented by the general formula (I) of the present invention is described in a known method such as Chem. Pharam. Bull., 40, (3) 770-773 (1992), JP-A 61-152658, etc. Can be synthesized according to the methods described. Formula (I)
[0015]
[Formula 4]
[0016]
(However, in the formula, R1 represents a hydrogen atom or a hydroxyl group) In producing a medicament containing as an active ingredient, an acid addition salt or hydrate of the general formula (I) can also be used. . The acid addition salt is preferably a pharmaceutically acceptable non-toxic salt, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, and acetic acid, citric acid, tartaric acid, lactic acid, succinic acid, fumaric acid, Mention may be made of salts of organic acids such as maleic acid and methanesulfonic acid. Examples of hydrates include 1/2 hydrate, monohydrate and trihydrate.
[0017]
In preparing the diabetes preventive / therapeutic agent of the present invention as a preparation suitable for administration, the compound represented by the above general formula (I) and a known pharmaceutically acceptable carrier are mixed. Good. Examples of the carrier include gelatin; sugars such as lactose and glucose; starches such as wheat, rice and corn starch; fatty acids such as stearic acid; fatty acid salts such as calcium stearate and magnesium stearate; talc; vegetable oil; stearic alcohol And alcohol such as benzyl alcohol; gum; polyalkylene glycol and the like.
[0018]
Examples of the liquid carrier generally include water, physiological saline, dextrose or a similar sugar solution, and glycols such as ethylene glycol, propylene glycol, polyethylene glycol, and polypropylene glycol. When preparing capsules, it is usually preferable to prepare capsules using gelatin.
[0019]
In the diabetes preventive and therapeutic agent of the present invention comprising the above carrier and the compound represented by the general formula (I), the lower limit is usually 0.01% by weight or more, preferably 5% by weight or more, and the upper limit is 80% by weight or less. Examples that contain 60% by weight or less of the active ingredient are preferred.
[0020]
Examples of the administration method include oral administration and parenteral administration. Examples of dosage forms suitable for oral administration include tablets, capsules, powders, granules, solutions, elixirs, and the like, and dosage forms suitable for parenteral administration include solutions.
[0021]
When administered parenterally by intramuscular injection, intravenous injection, or subcutaneous injection, a sterile solution to which other solutes such as sodium chloride or glucose are added in order to make the compound represented by the general formula (I) isotonic As administered.
[0022]
When administering by injection, it is also preferable to dissolve in sterile water, lidocaine hydrochloride solution (for intramuscular injection), physiological saline, glucose, intravenous injection solution, electrolyte solution (for intravenous injection) and the like. When dissolved in this way, the lower limit is usually adjusted to contain 0.01% by weight or more, preferably 0.1% by weight or more, and the upper limit is 20% by weight or less, preferably 10% by weight or less. There is. In the case of a solution for oral administration, a preferred example is a suspension or syrup containing 0.01 to 20% by weight of the active ingredient. Examples of the carrier in this case include aqueous excipients such as fragrances, syrups, and pharmaceutical micelles.
[0023]
The dosage of the therapeutic agent for preventing diabetes according to the present invention is the age, health status, body weight, symptom level, type of treatment, frequency of treatment, nature of desired effect, administration route or administration of the recipient. Generally, 0.01-20 mg / kg / day for parenteral administration and 0.02-40 mg / kg / day for oral administration can be mentioned, depending on the plan.
[0024]
The diabetes preventive and therapeutic agent of the present invention can be used in combination with a drug such as a diabetic therapeutic agent or a diabetic complication therapeutic agent (hereinafter abbreviated as a concomitant drug). At this time, the administration timing of the diabetes preventive / therapeutic agent and the concomitant drug of the present invention is not limited, and these may be administered simultaneously to the administration subject or may be administered with a time difference. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. Further, the mixing ratio of the diabetes preventive / therapeutic agent and the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, the concomitant drug may be used at a dose of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.
[0025]
As therapeutic agents for diabetes, insulin preparations, insulin sensitizers (eg, pioglitazone hydrochloride, rosiglitazone or its maleate, KRP-297 (Bioorganic Medicinal Chemistry Letters, 9, 533-538, 1999), AZ- 242 (Structure, 9, 699-706, 2001), BMS-298585, TAK-559 (Chem. Pharm. Bull., 51, 138-151,2003), etc.), α-glucosidase inhibitors (eg, voglibose, acarbose) Etc.), biguanides (eg, metformin, etc.), insulin secretagogues (sulfonylurea (eg, glibenclamide, tolazamide, etc.) nateglinide, mitiglinide, etc.), dipeptidyl peptidase IV inhibitors (eg, NVP-DPP-278, PT- 100), β3 agonist (
Examples, SB-226552, AJ-9677, BMS-196085, AZ-40140, etc.), amylin agonists (eg, pramlintide, etc.), phosphotyrosine phosphatase inhibitors (eg, vanadic acid, etc.), gluconeogenesis inhibitors (eg, glycogen phosphorylase) Inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists, etc.), SGLUT (sodium-glucose cotransporter) inhibitors (eg, T-1095, KGT-1251 etc.) and the like.
[0026]
As therapeutic agents for diabetic complications, aldose reductase inhibitors (eg, epalrestat etc.), neurotrophic factors (eg, NGF, BDNF etc.), neurotrophic factor production / secretion promoters, PKC inhibitors (eg, LY- 333531), AGE inhibitors (eg, ALT946, etc.), active oxygen scavengers (eg, thioctic acid, etc.), and cerebral vasodilators (eg, thiaprid, mexiletine, etc.).
[0027]
The concomitant drug is preferably an insulin preparation, an insulin resistance improving agent, an α-glucosidase inhibitor, a biguanide agent, an insulin secretagogue (preferably a sulfonylurea agent) and the like.
[0028]
【Example】
Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited thereto.
[0029]
[Example 1]
Oral glucose tolerance test Zucker rats are known to exhibit insulin resistance (Diabete. Metab. 21, 106-111, 1995). Therefore, 10-week-old male Zucker rats were divided into 4 groups, and the test solution (R1 in the general formula (I) was a hydrogen atom) was abdominal cavity at a rate of 0, 3, 10, 20 mg / kg / day for 4 weeks. The experiment was started after internal administration.
[0030]
Blood glucose (mg / dl) was measured before glucose (2 g / kg) was orally administered (0 min) and after administration at 30 min, 60 min and 120 min.
[0031]
The results are shown in Table 1.
[0032]
[Table 1]
[0033]
As a result, administration of the general formula (I) (wherein R1 is a hydrogen atom) caused a decrease in blood glucose level, and strongly showed an improvement effect on diabetes, particularly an improvement effect on insulin resistance diabetes.
[0034]
[Example 2]
Insulin tolerance test Male Zucker rats aged 10 weeks are divided into 4 groups, and the test solution (general formula (I) where R1 is a hydrogen atom) is administered at a rate of 0, 3, 10, 20 mg / kg / day for 4 weeks. The experiment was started after intraperitoneal administration.
[0035]
Blood was collected at 15 min, 30 min, 60 min, and 120 min before intraperitoneal administration of insulin (2.0 U / kg) (0 min), and blood glucose (mg / dl) was measured before administration. The blood glucose level was calculated as 100%.
[0036]
The results are shown in Table 2.
[0037]
[Table 2]
[0038]
As a result, administration of the general formula (I) (wherein R1 is a hydrogen atom) caused a decrease in blood glucose level, and strongly showed an improvement effect on diabetes, particularly an improvement effect on insulin resistance diabetes.
[0039]
Furthermore, by using a model animal for diabetes other than insulin resistance (Diabete. Metab. 21, 106-111, 1995), etc., the effect on diabetes other than insulin resistance diabetes can also be confirmed.
[0040]
Example 3
Formulation example (sterile injection)
The components in Table 3 below were dissolved in distilled water for injection, and then distilled water for injection was added to the required final weight, and 2 ml of this solution was sealed in an ampoule and sterilized by heating.
[0041]
[Table 3]
[0042]
Example 4
Formulation example (tablet)
Tablets containing the components shown in Table 4 below were prepared by a conventional method.
[0043]
[Table 4]
[0044]
【The invention's effect】
According to the present invention, a preventive and therapeutic agent for diabetes can be provided.

Claims (2)

The following general formula (I)
A prophylactic or therapeutic agent for diabetes comprising a compound represented by the formula ( wherein R1 represents a hydrogen atom ) or an acid addition salt or a hydrate thereof as an active ingredient.   The preventive or therapeutic agent according to claim 1, wherein the diabetes is insulin resistant diabetes.