JPH0532659A - Diabetic therapeutic agent - Google Patents

Abstract

PURPOSE:To obtain a diabetic therapeutic agent useful for treating diabetes and diabetic complication, having improving action on high blood sugar and nephrosis in diabetic pathology and little side effects, comprising a tetrahydrothiophene derivative as an active ingredient. CONSTITUTION:A diabetic therapeutic agent comprising (3R,4R)-4-(3,4- dimethoxybenzyl)-3-{4-[4-(4-methylpiperazinomethyl)benzoyloxy]-3-metho xybenzyl }tetrahydrothiophen-2-one as an active ingredient. The agent can be pharmaceutically manufactured into tablet, capsule, granule, fine granule, powder, injection or suppository. A daily dose for adult is 10mg-6g calculated as weight of active ingredient daily and administered dividedly several times. The tetrahydrothiophene derivative is obtained by converting actigenin into a thiolactone and acylating.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a therapeutic agent for diabetes which has an effect of improving hyperglycemia and nephrosis in diabetic conditions and is useful for treating diabetes and diabetic complications.

[0002]

BACKGROUND OF THE INVENTION Insulin, which is secreted from β-cells of the islets of Langerhans in the pancreas, mainly acts on the liver and adipose tissue to promote the synthesis of glycogen, enhances the decomposition and consumption of sugar, and increases sugars from amino acids and fats. It shows actions such as suppressing new birth and promoting the production of lipids from sugar.

Insulin deficiency leads to diabetes, which is a disease of metabolic disorders, and long-term metabolic disorders lead to diabetic nephropathy and other diabetic complications. Currently, insulin and oral diabetes drugs are used to treat diabetes, but they are difficult to handle because they have many side effects.

For example, insulin has hypoglycemia and hypokalemia as side effects, and since insulin is a protein, it cannot be administered orally and is effective only by injection, which is difficult to handle. Tolbutamide, a typical oral diabetes drug, has a risk of crossing the placenta and causing hypoglycemia in the newborn.

[0005]

As described above, in the treatment of diabetes, it is the current situation that drug treatment is very difficult due to its side effects, and it is useful for the treatment of diabetes and diabetes which have few side effects and are highly effective. Development of a therapeutic agent for diabetes has been desired.

[0006]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the inventors of the present invention have found that the following general formula I (3R, 4R) -4- (3,4-dimethoxybenzyl) -3- {4- [4- (4-methylpiperazinomethyl) benzoyloxy] -3-methoxybenzyl}
Tetrahydrothiophen-2-one [(3R, 4R)-
4- (3,4-dimethyoxybenzyl) -3
-{4- [4- (4-methylpiperazin
ometyl) benzoyloxy] -3-met
hoxybenzyl} tetrahydrothio
When the pharmacological activity of [phen-2-one] was examined,
They found that they have a hyperglycemic and nephrotic ameliorating action in diabetic conditions, and completed the present invention.

That is, the present invention relates to (3R, 4R) -4-
(3,4-dimethoxybenzyl) -3- {4- [4-
(4-Methylpiperazinomethyl) benzoyloxy]-
3-methoxybenzyl} tetrahydrothiophene-2-
It is a therapeutic agent for diabetes containing ON (hereinafter referred to as the main component of the present invention) as an active ingredient.

The main component of the present invention is obtained by thiolactonating arctigenin and then acylating it. Thiololactonization is carried out by reacting a lactone with a reagent such as potassium thioacetate, sodium sulfide, t-butyl mercaptan, etc. in a suitable solvent such as N, N-dimethylacetamide, N, N-dimethylformamide, alcohol or phosphorous pentasacin. It is achieved by reacting ruffide with dithiolactone and then with singlet oxygen. Acylation is performed according to a conventional method using 4- (4-methylpiperazinomethyl) benzoyl chloride dihydrochloride such as dichloromethane. It is carried out by reacting in the presence of triethylamine in a solvent.

Next, specific examples of the production of the main component of the present invention will be shown.

Specific Example Operation 1 1 kg of Chinese forsythia fruit was hot extracted with methanol, the extract was concentrated, and the precipitate was collected by filtration, followed by ether,
Partition extraction was performed using 200 ml each of chloroform and butanol in that order. Preparative thin layer chromatography (chloroform: acetone = 5: 1)
The part showing Rf value 0.48 was scraped off and extracted. By recrystallizing the extract with ethyl acetate,
Colorless plate crystals were obtained. This crystal can be found in the literature [Biomedical journals
32 (3), 194-197 (1978)], which is consistent with the physicochemical properties of arctigenin.

Procedure 2 In a 200 ml eggplant-shaped flask, 4.93 g of arctigenin obtained in Procedure 1 and 8.90 g of potassium thioacetate were placed, sufficiently dried, then 35 ml of DMF was added, and the mixture was heated and stirred at 140 ° C. for 1.5 hours. .. Water was added to the reaction solution, followed by extraction with ethyl acetate three times. The organic layer was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, it has the physicochemical properties shown below (3R,
4R) -3- (4-Hydroxy-3-methoxybenzyl) -4- (3,4-dimethoxybenzyl) tetrahydrothiophen-2-one [(3R, 4R) -3- (4-
hydroxy-3-methybenzyl)-
4- (3,4-dimethyl-benzyl) t
ettrahydrothiophene-2-one]
4.49 g was obtained.

Specific rotation (c = 0.124, CHC
l ₃ ); [α] _D = −26.34 ° Infrared absorption spectrum (IR, ν max cm ⁻¹ , K
Br): 3444, 2836, 1694, 1514, 1
452, 1266, 1236, 1156, 1140, 1
122,1028,750 Proton nuclear magnetic resonance spectrum (δ ppm in C
_{DCl 3): 2.52,2.18 (3H,} m), 2.9
1,3.88 (5H, m), 3.79 (3H, s),
3.81 (3H, s), 3.85 (3H, s), 5.5
3 (1H, s), 6.46 (1H, d, J = 1.7H
z), 6.56 (1H, dd, J = 8.3, 1.7H
z), 6.61 (1H, d, J = 2.0 Hz), 6.6
6 (1H, dd, J = 8.1, 2.0Hz), 6.75
(1H, d, J = 8.3 Hz), 6.83 (1H, d,
J = 8.1 Hz) Mass spectrum (EI-MS) m / z (%): 388
(M ⁺ , 44.8), 372 (6.3), 177 (2
0.4), 151 (81.5), 137 (100), 1
22 (8.8), 107 (9.9) high-mass spectrum (EI-MS) m / z (%):
(C ₂₁ H ₂₄ O ₅ S) Calculated value; 388.1344 Measured value; 388.13481

Procedure 3 Obtained in Procedure 2 in a 500 ml eggplant flask (3R, 4
R) -3- (4-hydroxy-3-methoxybenzyl)
-4- (3,4-dimethoxybenzyl) tetrahydrothiophen-2-one 3.23 g, dichloromethane 132
ml and stirred, then, in the presence of 6.6 ml of triethylamine, 6.06 g of 4- (4-methylpiperazinomethyl) benzoyl chloride dihydrochloride was added little by little,
The reaction was carried out at room temperature for 24 hours. The solvent of the reaction solution was evaporated under reduced pressure, the residue was dissolved in 200 ml of ethyl acetate, and washed with sodium hydrogen carbonate (200 ml × 3) and saturated saline. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and flash column chromatography (chloroform: ethyl acetate = 5: 1, chloroform: methanol =
The main component of the present invention having the physicochemical properties shown below was obtained by purification at 10: 1).

Melting point: 58 to 59 ° C. Specific rotation (c = 0.128, CHCl ₃ ); [α] _D = −
4.68 ° infrared absorption spectrum (IR, ν max cm ^-1 , K
Br): 1784, 1740, 1694, 1610, 1
512, 1418, 1282, 1156, 1030, 8
14,748 Proton nuclear magnetic resonance spectrum (δ ppm in C
_{DCl 3): 2.30 (3H,} s), 2.60,3.6
0 (12H, m), 3.60 (2H, s), 3.74
(3H, s), 3.82 (3H, s), 3.85 (3
H, s), 6.52 (1H, d, J = 2.0 Hz),
6.58 (1H, dd, J = 8.5, 2.0Hz),
6.79 (3H, m), 7.06 (1H, d, J = 8.
5Hz), 7.47 (2H, d, J = 8.3Hz),
8.14 (2H, d, J = 8.3 Hz) Mass spectrum (EI-MS) m / z (%): 604
(M ⁺ , 100), 502 (16), 388 (16),
217 (93), 188 (15), 158 (65), 1
46 (40), 137 (29), 118 (43), 99
(52) High-mass spectrum (EI-MS) m / z (%):
(C ₃₄ H ₄₀ O ₆ N ₂ S) Calculated value; 604.2607 Measured value; 604.26066

Next, it will be described that the main component of the present invention has an effect of improving hyperglycemia and nephrosis in diabetic condition by showing experimental examples.

Experimental Example 1 Six-week-old male Wistar rats were used in the experiment. Diabetes is streptozotocin (50mg
/ Kg) was injected into the tail vein, the main component of the present invention was suspended in purified water, and intraperitoneally administered for 7 days from 1 day after streptozotocin administration. Blood was collected on day 4 and day 8 after streptozotocin administration to measure blood glucose concentration. Blood glucose levels were measured in the same manner by using untreated rats as untreated groups and diabetic rats not administered with the main component of the present invention as control groups. The results are shown in Table 1.

[0017]

Experimental Example 2 Six-week-old male Wistar rats were used in the experiment. Diabetes was induced by injecting streptozotocin (50 mg / kg) into the tail vein, and the main component of the present invention was suspended in purified water and intraperitoneally administered from 1 day after the administration of streptozotocin for 7 days. Rats were bred in a urine collection cage, and urinary albumin excretion was measured daily. The urinary albumin excretion was measured daily with the untreated group as the untreated group and the diabetic rat as the control group to which the main component of the present invention was not administered. The results are shown in Table 2.

[0019]

Experimental Example 3 Male ddy mice were used in the experiment. The main component of the present invention was intraperitoneally administered up to 300 mg / kg and observed for 72 hours, but no death case was observed.

From the above results, the main component of the present invention has an effect of improving hyperglycemia and nephrosis in diabetic condition,
It was found to be safe.

Next, the dose and formulation of the main component of the present invention will be described.

The main component of the present invention can be administered to animals and humans as it is or together with a conventional pharmaceutical carrier. The dosage form is not particularly limited and may be appropriately selected and used as needed, and examples thereof include oral agents such as tablets, capsules, granules, fine granules and powders, parenteral agents such as injections and suppositories. Be done.

In order to exert the desired effect as an oral preparation, it varies depending on the age, body weight and degree of disease of the patient, but usually 10 mg to 6 g as the weight of the main component of the present invention is administered to an adult several times a day. It seems appropriate to take them separately.

Oral preparations include, for example, starch, lactose, sucrose,
Mannitol, carboxymethyl cellulose, corn starch, inorganic salts and the like are used according to a conventional method.

In addition to the above-mentioned excipients, a binder, a disintegrating agent, a surfactant, a lubricant, a fluidity promoter, a flavoring agent, a coloring agent, a flavoring agent, etc., may be appropriately used in this type of formulation. You can
Specific examples of each are as shown below.

[Binder] Starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch,
Methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, ethyl cellulose, polyvinylpyrrolidone, macrogol.

[Disintegrant] Starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, low-substituted hydroxypropyl cellulose.

[Surfactant] sodium lauryl sulfate,
Soy lecithin, sucrose fatty acid ester, polysorbate 80.

[Lubricant] Talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol.

[Fluidity promoter] Light anhydrous silicic acid, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

The main component of the present invention can also be administered as a suspension, emulsion, syrup or elixir, and these various dosage forms contain a flavoring agent and a coloring agent. Good.

In order to exert the desired effect as a parenteral agent, it depends on the age, body weight and degree of disease of the patient.
Usually, the weight of the main component of the present invention is 5 to 200 per day in adults.
Intravenous injection up to mg, intravenous drip, subcutaneous injection, and intramuscular injection seem to be appropriate.

This parenteral preparation is manufactured by a conventional method, and is generally used as a diluent in distilled water for injection, physiological saline, glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol. Etc. can be used. Further, if necessary, a bactericidal agent, a preservative, and a stabilizer may be added. Further, from the viewpoint of stability, this parenteral preparation can be frozen after filling in a vial or the like, water is removed by a usual freeze-drying technique, and a liquid preparation can be re-prepared from the freeze-dried product immediately before use. Further, if necessary, a tonicity agent, a stabilizer, a preservative, a soothing agent and the like may be added appropriately.

Other parenteral agents include external preparations, coating agents such as ointments, and suppositories for rectal administration.
It is manufactured according to a conventional method.

Next, the present invention will be described in more detail with reference to formulation examples, but the present invention is not limited thereto.

Formulation Example 1

According to the above formulation, the ingredients (1) to (4) were uniformly mixed and compression-molded with a tableting machine to give tablets (200 mg each). The main ingredient 2 of the present invention obtained in the specific example
It contains 0 mg, and 5 to 15 tablets for adults are to be taken in several divided doses.

Formulation Example 2

According to the above formulation, a part of and was uniformly mixed, compression-molded, crushed, and the remaining amount of and was added and mixed, and the mixture was compression-molded with a tableting machine to give one tablet.
A 00 mg tablet was obtained. This tablet contains 20 mg of the main ingredient of the present invention obtained in the specific example, and 5 to 15 tablets for adults are to be taken in several divided doses per day.

Formulation Example 3

According to the above formulation, and were uniformly mixed, and the mixture was kneaded by an ordinary method, granulated by an extrusion granulator, dried and crushed, and then mixed, and compressed by a tableting machine. It was molded to obtain a tablet of 200 mg each. This tablet contains 20 mg of the main ingredient of the present invention obtained in the specific example, and 5 to 15 tablets for adults are to be taken in several divided doses per day.

Formulation Example 4

According to the above formulation, the components (1) to (4) are uniformly mixed, compression-molded by a compression molding machine, and then crushed by a crusher,
Sieve to obtain granules. 1 g of this granule contains 100 mg of the main component of the present invention obtained in the specific example, and 1 to 3 g of an adult is taken in several divided doses per day.

Formulation Example 5

According to the above recipe, the ingredients (1) to (4) were uniformly mixed and kneaded. After granulating with an extrusion granulator, it was dried and sieved to obtain granules. 1 g of this granule contains 100 mg of the main component of the present invention obtained in the specific example,
Take 1 to 3 g of an adult daily in several divided doses.

Formulation Example 6

According to the above-mentioned formulation, 1 to 3 were mixed uniformly, and 200 mg was filled in a No. 2 capsule. One capsule of this capsule contains 20 main ingredients of the present invention obtained in the specific example.
The dosage is 5 to 15 capsules for adults, divided into several times a day.

Formulation Example 7

According to the above-mentioned formulation, was dissolved in and, and a solution of and was added thereto and emulsified to obtain an injection.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Kunio Hosaka 3586 Yoshihara, Ami-cho, Inashiki-gun, Ibaraki Tsumura Co., Ltd.

Claims (1)

Claims: (3R, 4R) -4- (3,4-dimethoxybenzyl) -3- {4- [4- (4-methylpiperazinomethyl) benzoyloxy] -3 -Methoxybenzyl} tetrahydrothiophen-2-one [(3R, 4
R) -4- (3,4-dimethyloxybenzy
l) -3- {4- [4- (4-methylpiper
azinomethyl) benzoyloxy] -3
-Methoxybenzyl} tetrahydro
Thiophene-2-one] as an active ingredient.