JPH0414670B2 - - Google Patents

Description

Detailed Description of the Invention (Industrial Application Field) The present invention relates to a novel α-benzylidene-γ-butyrolactone derivative and a salt thereof.More specifically, the present invention relates to a novel α-benzylidene-γ-butyrolactone derivative and a salt thereof. The present invention relates to α-(3,5-di-tertiary-butyl-2-hydroxybenzylidene)-γ-butyrolactone and its salts.

The compound of the present invention represented by the above formula (1) and its salt have an ultraviolet absorbing effect and are useful as an ultraviolet absorber, and also have a platelet aggregation inhibiting effect and are therefore useful as a platelet aggregation inhibitor.

(Problems to be Solved by the Invention) As a result of measuring the ultraviolet absorption spectrum of α-benzylidene-γ-butyrolactone and its salt represented by the above formula (1), the present inventors found that it has a strong ultraviolet absorption effect. and found that the compound (1) and its salt according to the present invention are useful as ultraviolet absorbers. Further, as a result of extensive testing of the pharmacological effects of the compound represented by formula (1) and its salts according to the present invention, it was found that the compound has an inhibitory effect on platelet aggregation, and the present invention was achieved.

(Means and effects for solving the problems) The novel compound according to the present invention has the formula (1) It is expressed as Compound (1) according to the present invention is a colorless needle crystal which is insoluble in water and soluble in tetrahydrofuran, chloroform and dimethyl sulfoxide, and its properties are as follows.

Melting point 195-197℃ Molecular weight 302.42 Elemental analysis value C H Experimental value 75.28 8.85 Logical value 75.46% 8.67% (C ₁₉ H ₂₆ O ₃ ) Nuclear magnetic resonance spectrum (CDCl ₃ ) δ 1.44 (s, 18H), 2.1-2.8 (m, 2H), 3.76 (m,
1H), 4.2-4.6 (m, 2H), 5.41 (s, 1H), 7.01
(s, 2H) s: singlet, m: multiplet infrared absorption spectrum (KBr) 3590, 2960, 1745, 1435, 1160 cm ^-1 Compound (1) according to the present invention is capable of forming a salt with a base. Any base that can form a salt with compound (1) can be selected. Examples of specific salts include (1) metal salts, sometimes salts with alkali metals, alkaline earth metals, and aluminum; (2)
ammonium salts, (3) amine salts, especially methylamine, ethylamine, diethylamine, triethylamine, pyrrolidine, piperidine, morpholine,
There are salts with hexamethyleneimine, aniline, pyridine, etc.

Compound (1) according to the present invention can be synthesized by the following method.

(1) GA
Howie et al.'s method [J.Med.Chem., 17 ,
840 (1974)]. This method uses the so-called Winteig reaction, and the ylide to be reacted with the benzaldehyde is as follows:
In addition to the above-mentioned compounds, ylides derived from trialkylsulfosphine and triphenylarsine can also be used.

(2) 3.5-di-tert-shari-butyl-2-hydroxybenzaldehyde and γ-butyrolactone
H. Zimmer et al.'s method [J.Org.Chem., 24 ,
28 (1959)] by condensation using a base or acid as a catalyst. Bases that can be used as catalysts include alkali metal alcoholates such as sodium methylate and sodium ethylate; alkali metal hydrides such as sodium hydride and potassium hydride; amines such as piperidine, morpholine, and ethanolamine; sodium hydroxide. , alkali metal hydroxides such as potassium hydroxide; alkali metal amides such as lithium diisopropylamide; and alkali metal salts of organic acids such as sodium acetate and potassium acetate. Furthermore, examples of acids that can be used as catalysts include boron trifluoride, titanium tetrachloride, p-toluenesulfonic acid, and benzenesulfonic acid.

(3) 3.5-Di-tertiary-butyl-2-hydroxybenzaldehyde and α-acetyl-γ-butyrolactone were prepared by the method of S.Tsuboi et al. [Chemistry Letters, 1325
(1978)], it is synthesized by reaction in the presence of a basic catalyst such as potassium carbonate.

Platelet aggregation inhibitory effect: Platelet aggregation inhibitory effect was tested by the method shown below.

(1) Preparation of platelet-rich plasma (PRP solution) Blood from the carotid artery of a Japanese white male rabbit (9 volumes of blood: 1 volume of 3.8% sodium citrate solution)
was collected and centrifuged at 1000 rpm for 10 minutes, and the supernatant was used as the PRP solution.

(2) Preparation of arachidonic acid solution Sodium arachidonic acid was dissolved in physiological saline to prepare a 2 mg/ml solution of arachidonic acid.

(3) Measurement Put 0.94 ml of PRP solution and 0.01 ml of the ethanol solution of the test compound into the cuvette of the platelet aggregometer.
After incubation at 37°C for 1 minute, 0.05 ml of arachidonic acid, a platelet aggregation-inducing agent, was added. Track changes in permeability associated with platelet aggregation,
The ability of the test compound to inhibit platelet aggregation was measured.

As a result, the α-(3,5-jitter according to the present invention)
Shary-butyl-2-hydroxybenzylidene)
-γ-Butyrolactone has a strong platelet aggregation inhibitory effect, and it was found that addition of 1 μg/ml completely inhibits platelet aggregation.

(Example) Next, the present invention will be specifically explained with reference to production examples of the compounds of the present invention, but these Examples are not intended to limit the present invention.

Example 1 Synthesis of 3,5-di-tertiary-butyl-2-hydroxybenaldehyde 10 g of 2,4-di-tertiary-butylphenol
14g of sodium hydroxide in 25ml of ethanol solution
and a small amount of benzyltriethylammonium chloride were added. This mixture was heated to 70 to 80°C, and 9.2 g of chloroform was added dropwise over 30 minutes while stirring. Furthermore, after stirring for 50 minutes at the same temperature, chloroform was distilled off under reduced pressure. The remaining reaction mixture was made acidic by adding dilute sulfuric acid, and extracted with 100 ml of ether. The ether extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 11 g of a brown oil. 8.8 g of the oil was taken and purified by silica gel column chromatography using chloroform as the developing solvent to obtain the desired 3.5-di-tert.
0.82 g of 2-hydroxybenzaldehyde was obtained as light brown crystals. (Yield 7.2%).

Example 2 Synthesis of mixture (1) 0.82 g of 3,5-di-tertiary-2-hydroxybenzaldehyde and 1.21 g of α-triphenylphosphoranylidene-γ-butyrolactone were mixed in 10 ml of dimethyl sulfoxide. The reaction was carried out at ℃ for 5 hours. After cooling the reaction mixture, 100 ml of water was added and extracted with 150 ml of chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. The extract was dried under reduced pressure to obtain 2 g of a brown residue, which was crystallized from methanol to obtain 0.3 g of a crude product. Further, preparative layer chromatography using chloroform as a developing solvent was performed to obtain 0.15 g of the target compound (1) (yield 14%).

Claims (1)

[Claims] 1 formula α-(3,5-dit-tertiary-butyl-2-hydroxybenzylidene)-γ-butyrolactone and its salts.