JPS6253494B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to ML-236C carboxylic acid esters and carboxylic acid metal salts. ML-236C itself is a known compound.
-136886), has the following structural formula. When this compound forms a carboxylic acid ester or carboxylic acid metal salt, the lactone ring therein opens to form a compound having the structural formula of formula (). The present invention is represented by the formula ()
The target is ML-236C carboxylic acid ester or carboxylic acid metal salt (hereinafter referred to as ML-236C derivative). In the above formula, R represents an alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, n-hexyl; a benzyl group; or 1/n·M, M is a metal element, and n is the metal element. Indicates the valence of Metal salts of ML-236C include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, aluminum salts, iron salts, zinc salts, copper salts, nickel salts, and cobalt salts. However, among these, alkali metal salts, alkaline earth metal salts and aluminum salts are preferred, and sodium salts, calcium salts and aluminum salts are most preferred. The ML-236C derivative represented by the above formula () is a new compound, and among these, the ML-236C carboxylic acid metal salt can be obtained by saponifying ML-236C with a weak alkali. Further, ML-236C carboxylic acid ester can be produced, for example, by the following method. React ML-236C with alcohol. In this case, as a catalyst, an inorganic acid such as hydrochloric acid or sulfuric acid, or boron fluoride, or an acidic ion exchange resin is used, and as a solvent, the same alcohol or one that does not participate in the reaction, such as benzene, chloroform, or ether, is used. ML-236C carboxylic acid metal salt is reacted with alkyl halide. At this time, dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, acetone, etc. are used as the solvent. ML-236C carboxylic acid is reacted with alcohol in the same manner as in . (ML-236C carboxylic acid can be obtained by neutralizing a metal salt of ML-236C carboxylic acid.) Hereinafter, based on an example, the general formula () is represented by
The method for producing the ML-236C derivative will be explained in more detail. Example 1 ML-236C methyl ester ML-236C (2.9 g, 0.01 mol) was dissolved in dry methanol (70 ml) and Amberlite IR-120
(8.0g) and boil under reflux for 3 hours. After the reaction is completed, the resin is separated and the solvent is distilled off to obtain an oil. This oil was subjected to flash chromatography on silica gel (100 g), developed with a solvent system of benzene-ethyl acetate (3:1), separated and purified,
ML-236C methyl ester (1.6 g) is obtained. This product was crystallized from n-hexane-ether to obtain ML-236C methyl ester (0.8 g) as white needle-like crystals. Elemental analysis values Actual value C; 70.91, H; 9.47 Theoretical value C; 70.77, H; 9.38 Mass analysis value M ⁺ 322 (C ₁₉ H ₃₀ O ₄ ) Melting point 58-59°C Ultraviolet absorption spectrum: λethanol _naX 231, 238 , 246mμ Infrared absorption spectrum: Nuclear magnetic resonance spectrum shown in Figure 1: (60MHz, CDCl ₃ )
5.93 (double line H), 5.76 (double, double line H),
5.48 (multiplet H), 4.23 (multiplet H), 3.88 (multiplet H), 3.68 (singlet 3H), 3.37 (multiplet H), 2.45 (doublet 2H), 2.2~1.0 (17H), 0.87
(Double line 3H) Example 2 ML-236C ethyl ester ML-236C (2.9 g, 0.01 mol) was treated in the same manner as in Example 1 using dry ethanol, and the obtained ML-236C ethyl ester Ester (1.3
g) is crystallized from n-hexane-ether;
ML-236C ethyl ester (0.6
g) was obtained. Elemental analysis values Actual value C; 70.27, H; 9.60 Theoretical value C; 71.39, H; 9.59 Mass analysis value M ⁺ 336 (C ₂₀ H ₃₂ O ₄ ) Melting point 66.5-67.5°C Ultraviolet absorption spectrum: λethanol _naX 231, 238 , 246mμ Infrared absorption spectrum: Nuclear magnetic resonance spectrum shown in Figure 2: (60MHz, CDCl ₃ )
5.83 (double line H), 5.64 (double, double line H),
5.37 (Multiplet H), 4.05 (Quadruplet 2H), 3.68 (Multiplet H), 3.21 (Multiplet H), 2.37 (Doublet
2H), 2.2~1.0 (17H), 1.21 (triple line 3H),
0.86 (double line 3H) Example 3 ML-236Cn-butyl ester ML-236C (2.9 g, 0.01 mol) was treated in the same manner as in Example 1 using dry n-butanol. ML-236Cn-butyl ester (0.8gr) was crystallized from n-hexane-ether to give ML-236Cn-butyl ester (0.4g) as white needles. Elemental analysis values Actual value C; 72.32, H; 9.84 Theoretical value C; 72.49, H; 9.96 Mass analysis value M ⁺ 336 (C ₂₂ H ₃₆ O ₄ ) Melting point 65.5-66°C Ultraviolet absorption spectrum: λethanol _naX 231, 238 , 246 mμ. 0.67 ml) and stirred at room temperature for 2 hours and 30 minutes. The reaction solution is concentrated under reduced pressure, the concentrate is dissolved in ethyl acetate, the ethyl acetate layer is washed with water, dried, and the solvent is distilled off. The obtained oil was purified by silica gel flash chromatography (benzene:ethyl acetate 1:1 v/v%) to obtain an oil (0.8 g, yield 40%). This oil was crystallized from n-hexane-ether to form white needles of ML-236C benzyl ester (0.3
g) was obtained. Elemental analysis values Actual value C; 74.84, H; 8.52 Theoretical value C; 75.34, H; 8.60 Mass analysis value M ⁺ 398 (C ₂₅ H ₃₄ O ₄ ) Melting point 68-69°C Infrared absorption spectrum: Nuclei shown in Figure 4 Magnetic resonance spectrum: (60MHz, _CDCl3 )
7.40 (Singlet 5H), 5.96 (Double H), 5.77 (Double, Doublet H), 5.53 (Multiplet H), 5.17 (Singlet 2H), 4.31 (Broad Multiplet H), 3.77 (wide singlet), 2.51 (double 2H), 2.5~1.0
(17H), 0.85 (double line 3H) Example 5 ML-236C sodium salt ML-236C (6.0g, 0.02mol) in 0.1NNaOH
(200 ml) and heated at 80-90°C for 1 hour. After cooling, the reaction solution is separated, washed with ether to remove unreacted ML-236C, and the aqueous layer is freeze-dried.
White hygroscopic powder ML-236C sodium salt (7.3
g) was obtained. Infrared absorption spectrum: Example shown in Figure 5 6 ML-236C calcium salt In a 200 ml beaker, ML-236C (1.5 g,
Dissolve 0.005 mol) in a mixed solvent of methanol (15 ml) and methylene chloride (25 ml), and add water (15 ml) and slaked lime (5.6 g, 0.0075 mol) to this. Place the reaction solution in an ultrasonic cleaner for 30 minutes at room temperature. Raw material ML-236C using thin layer chromatography
When the disappearance of the lime is confirmed, the reaction solution is filtered to remove excess slaked lime. The aqueous layer is extracted with methylene chloride, and the methylene chloride solution is filtered, washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off to obtain an anhydrous oil. N-hexane was added to this oil, it was pulverized by ultrasonication, filtered, and the precipitate was dried to form a white powder (1.3gr, yield:
81%). Elemental analysis values Actual value C; 64.63, H; 8.39 Theoretical value C; 66.02, H; 8.31 Melting point > 200℃ (decomposition point) Infrared absorption spectrum: shown in Figure 6 The ML-236C derivative represented by formula () is ML −
Like 236C, it inhibits hepatic cholesterol synthesis. However, its action is stronger than ML-236C. Therefore, ML−
236C derivatives can be used medicinally as hyperlipidemia therapeutics and arteriosclerosis preventive agents. Next, the cholesterol synthesis inhibitory effect of the ML-236C derivative will be shown. Cholesterol synthesis inhibitory effect: ML-236C derivatives are 3-hydroxy-3-
Methylglutaryl coenzyme A reductase (3-hydroxy-3-methylglutaryl-Co
It was found that the enzyme specifically inhibits A-areductase. Table 1 shows the cholesterol synthesis inhibitory effects of these compounds [measured by the method described in Journal of Biological Chemistry (J. Biol. Chem.) Vol. 234, p. 2835 (1959)]. 【table】

[Brief explanation of the drawing]

Figure 1 is the infrared absorption spectrum of ML-236C methyl ester, Figure 2 is the infrared absorption spectrum of ML-236C ethyl ester, and Figure 3 is ML-236C ethyl ester.
Infrared absorption spectrum of 236C n-butyl ester, Figure 4 is infrared absorption spectrum of ML-236C benzyl ester, Figure 5 is infrared absorption spectrum of ML-236C sodium salt, Figure 6 is
The infrared absorption spectrum of ML-236C calcium salt is shown.

Claims (1)

[Claims] 1 formula (In the formula, R is an alkyl group; a benzyl group; or
1/n·M, where M is a metal element and n is the valence of the metal element. ) ML-236C derivative.