JPS6326760B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the formula [A→→Me←←A] ⁺⁺ B ^-- (where A→→ is , Me means a metal selected from the group consisting of cobalt, copper and manganese, and B ^-- means a pharmacologically acceptable anion). The present invention relates to a metal complex salt, a method for producing the same, and a therapeutic agent for arteriosclerosis containing the complex salt as a main component. The above-mentioned compound according to the present invention is a new compound which has not been described in the literature, and in which metal salts such as copper acetate, copper chloride, copper sulfate, manganese chloride, manganese sulfate, cobalt sulfate, cobalt chloride are added to α-tocopheryl nicotinate in the presence of a solvent. In this case, α-tocopheryl nicotinate as a starting material can be easily obtained by the method described in Japanese Patent Publication No. 39-24968. Anion B ^-- includes various types such as hydrochloric acid,
It can be a residue of hydrobromic acid, acetic acid, lactic acid, citric acid, tartaric acid, succinic acid, p-toluenesulfonic acid, sulfuric acid, nitric acid, and the like. Although α-tocophryl nicotinate is known as an excellent cholesterol synthesis inhibitor, it is unstable due to its low melting point of 35 to 40°C, and therefore has the drawback of complicating operations during formulation. have. The present inventors discovered α-tocopheryl nicotinate during their research on purification and stabilization of α-tocopheryl nicotinate.
We succeeded in forming metal complex salts from purified pure tocopheryl nicotinate, and discovered that the copper, cobalt and manganese salts had better pharmacological effects than α-tocopheryl nicotinate itself, The present invention has now been completed. While α-tocophryl nicotinate is an oily substance at a rather high temperature, the present invention has a high melting point of 150°C or higher. Therefore, the temperature conditions during formulation operations are gentler, and complicated formulation innovations are not required. It also has excellent stability. The production of lipid peroxides, especially in vivo, is observed in association with aging and diseases such as arteriosclerosis, and its harmful effects on living organisms have attracted the attention of clinicians. The compound exhibits a strong inhibitory effect on the production of lipid peroxide, and is therefore useful as a therapeutic agent for various diseases related to lipid peroxide, such as arteriosclerosis. When formulating the complex salt according to the present invention, there are no particular restrictions on the dosage form; tablets, granules, fine granules, capsules, etc. can be used for oral administration, and injections can be used for parenteral administration. and external preparations such as external cream preparations. Formulation in these cases can be carried out using conventional methods, and the dosage for administration to humans depends on the symptoms, dosage form, etc., but in general, in the case of oral preparations, the dosage for adults is 10%.
- About 1000 mg/day, preferably about 100-500 mg/day, preferably divided into about 3 doses. Next, the present invention will be explained in more detail with reference to production examples, pharmacological test examples, and formulation examples. Production example 1 [(α-tocopheryl nicotinate) ₂ −Cu]Cl ₂
Complex salt 680 mg (5.1 mmol) of copper chloride in 50 ml of methanol
5.35 g of α-tocopheryl nicotinate in solution
(10 mmol) in 50 ml of ethanol was added dropwise at room temperature with stirring, and the mixture was heated in a water bath for 2 to 3 hours. After cooling, remove the precipitate and recrystallize it from methanol.
Further, the mother liquor is concentrated to obtain secondary crystals. Yield 5.33g
(Yield 88.5%). This crystal is a light blue columnar crystal with a melting point of ~183
It was warm at ℃. Elemental analysis C ₇₀ H ₁₀₆ Cl ₂ CuN ₂ O ₆ (1206.085) Calculation C69.71, H8.86, N2.32, Cl5.88, Cu5.27 Actual measurement C70.01, H9.09, N2.24, Cl5. 77 Cu5.20 (atomic absorption) IR spectrum KBr, cm ^-1 : ν _CH3CH2 3000~2800 ν _CO 1735 ν _-O- 2 of 1280, 1240, 1100 NMR spectrum (CDCl ₃ ) δ: Cu ⁺⁺ normal Pyridine ring protons disappear due to magnetism Comparison with the raw material α-tocopheryl nicotinate 2.6 bt → wide multiplet 2.12, 2.04 and 2.00 S x 3 → 2 lost Other aliphatic protons → present but wide Production example 2 [(α-tocopheryl nicotinate) ₂ -Cu]
(CH ₃ COO ^- ) _dicomplex salt α-tocopheryl nicotinate 2.68 g (5 mmol) in a solution of 30 ml of ethanol under heating.
After dropping a solution of 500 mg (2.504 mmol) of Cu(OAc) ₂ 2 H ₂ O in 50 ml of methanol, it was heated at a temperature of around 100°C for 30 minutes.
Warm for 1 minute and evaporate the solvent under reduced pressure to a volume of 30 ml. After cooling, the precipitate is collected and recrystallized from ethanol to obtain 2.20 g of blue-green disk crystals (yield 70.2%). Melting point 150-153℃ (decomposition). Elemental analysis C ₇₄ H ₁₁₂ CuN ₂ O ₁₀ (1253.257) Calculation C70.92, H9.01, N2.24, Cu5.07 Actual measurement C65.83, H8.29, N1.94, Cu10.2 (atomic absorption) IR Spectrum KBr, cm ^-1 : ν _CH3CH2 3000-2800 ν _CO 1740, 1625 ν _-O- 2 of 1275, 1240, 1105 Production example 3 [(α-tocopheryl nicotinate) ₂ -Co]Cl ₂
A solution of 595 mg (2.5 mmol) of CoCl ₂ 6H ₂ O in 50 ml of methanol was added dropwise to a solution of 2.68 g (5 mmol) of complex salt α-tocopheryl nicotinate in 25 ml of ethanol under heating in a water bath, and then the solution was further heated in a water bath for 30 minutes. The mixture is heated intermittently, and then concentrated under reduced pressure to a volume of about 30 ml.After cooling, the precipitate is collected and recrystallized from ethanol to obtain 2.11 g of blue-purple powder (yield: 70.1%). .Melting point (167℃) (decomposition) Elemental analysis C ₇₀ H ₁₀₆ Cl ₂ CoN ₂ O ₆ (1201.473) Calculation C69.98, H8.89, N2.33, Cl5.90, Co4.91 Measurement C69.38, H8 .64, N2.21, Cl6.37, Co4.3 (atomic absorption) IR spectrum KBr, cm ^-1 : ν _CH3CH2 3000-2800 ν _CO 1738 ν _-O- Production example of 2 of 1285, 1245, 1105 4 [(α-tocopheryl nicotinate) ₂ −Mn]
A solution of 495 mg (2.501 mmol) of MnCl ₂ 4H ₂ O in 30 ml of methanol was added to a solution of 2.68 g (5 mmol) of Cl ₂ complex α-tocopheryl nicotinate in 20 ml of ethanol under heating in a water bath, and then heated in a water bath. Warm for 30 minutes and then concentrate under reduced pressure to a volume of 10 ml. After cooling, the precipitate is collected and recrystallized from methanol to obtain 1.80 g of pale yellow powdery crystals (yield: 60.1%). Melting point ~181°C (decomposition). Elemental analysis C ₇₀ H ₁₀₆ Cl ₂ MnN ₂ O ₆ (1197.473) Calculation C70.21, H8.92, N2.34, Cl5.92 Actual measurement C64.08, H7.78, N2.15, Cl5.61 Pharmacological test Example 1 Inhibitory effect on lipid peroxide production A test was conducted according to the method described in J. Nutr. Sci. Vitaminol, Vol. 25, pp. 127-130 (1979).
That is, the liver is removed from a 150 g male Wistar rat that has been fasted for about 12 hours, used to prepare a liver homogenate, and further centrifuged to obtain a liver microsome fraction. In the presence of Fe ions and APD, this liver microsome exhibits an NADPH-dependent lipid peroxidation reaction and produces cologne dialdehyde, which is positive for thiobarbituric acid reaction. The inhibitory effect of the test substance on lipid peroxide production was determined by measuring the amount of colondialdehyde using a thiobarbituric acid reaction. That is,
Inhibition rate by each test sample at 1mM concentration and concentration of test sample that inhibits lipid peroxide production by 50% (ID ₅₀ )
After investigating this, the following results were obtained.

[Table] From the above results, the compounds according to the present invention are a starting material and have extremely strong effects compared to α-tocopheryl nicotinate, a known lipid peroxide production inhibiting compound. It is found to be useful as a therapeutic agent for various diseases associated with oxidized lipid production, particularly arteriosclerosis. Pharmacology test example 2 Acute toxicity Wistar rats (both male and female, 6 weeks old, body weight
(around 180g) and ICR mice (male and female, both 5 weeks old)
Weight: 24-30 g)) Each group consisted of 5 animals, and the complex salt prepared in Production Example 1 was dissolved in physiological saline and administered orally.
Administration was performed subcutaneously, intramuscularly, or intravenously. After administration of the above complex salt, general symptoms were observed for 7 days, body weight was measured, and Litchfield
The results of calculating the LD ₅₀ value using the Wilcoxon method were as shown in the table below.

[Table] The same results as above were obtained for the complex salts of Production Examples 2 to 4. In addition, when the complex salt prepared in Production Example 1 was orally administered to rats at a dose of 5 g/Kg, no deaths or abnormalities in behavior were observed. Formulation Example 1 (Tablet) The following ingredients were mixed and tablets were manufactured by a conventional method. Complex salt according to Production Example 1 100 (mg) Crystalline cellulose 20 Lactose 41 Corn starch 30 Hydroxypropyl cellulose 6 Magnesium stearate 3 200 mg per tablet Formulation example 2 (Capsules) The following ingredients are blended and capsules are prepared by a conventional method. was manufactured. Complex salt according to Production Example 2 200 (mg) Crystalline Cellulose 50 Silicic Anhydride 2 Magnesium Stearate 3 255 mg per capsule Formulation Example 3 (Granules) The following ingredients were blended and granules were produced by a conventional method. Complex salt according to Production Example 3 300 (mg) Lactose 323 Corn starch 150 Polyvinylpyrrolidone 25 Silicic anhydride 2 800 mg per package Formulation Example 4 (Tablet) The following ingredients were blended and tablets were produced by a conventional method. Complex salt according to Production Example 4 100 (mg) Crystalline cellulose 20 Lactose 41 Corn starch 30 Hydroxypropyl cellulose 6 Magnesium stearate 3 200 mg per tablet

Claims (1)

[Claims] 1 Formula [A→→Me←←A] ⁺⁺ B ^-- (In the formula, A→→ is , Me means a metal selected from the group consisting of cobalt, copper and manganese, and B ^-- means a pharmacologically acceptable anion) Metal complex salt. 2. Metal complex salt according to claim 1, characterized in that Me means manganese. 3. The formula [A→→ Me←←A] ⁺⁺ B ^-- (A→→ in the formula is , Me means a metal selected from the group consisting of cobalt, copper and manganese, and B ^-- means a pharmacologically acceptable anion) Method for producing metal complex salts. 4 Formula [A→→Me←←A] ^-- B ^-- (In the formula, A→→ is , Me means a metal selected from the group consisting of cobalt, copper and manganese, and B ^-- means a pharmacologically acceptable anion) A therapeutic agent for arteriosclerosis characterized by containing a metal complex salt as its main ingredient. 5. The artery according to claim 4, characterized in that the main component is "α-tocopheryl cotinate-Mn" Cl ₂ complex salt, where Me means manganese and B means chlorine. Sclerosis treatment.