JPS5811960B2 - Cyclobranol succinic acid ester alkali metal salt - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The invention relates to novel compounds of cyclobranol succinic ester aluminum metal salts.

Cyclobranol, which exists in trace amounts in plants, and cyclobranol ferulic acid ester or acetate, which specifically exists in rice bran oil, are each a type of plant steroid with physiological activity in animals, and both have long-lasting effects. It has pharmacological effects that stabilize the autonomic nervous system by acting on the hypothalamus and other areas of the brain.

However, the above-mentioned plant steroids are fat-soluble substances and are hardly soluble in water; on the contrary, they are water-repellent and are not miscible with water at all.

Therefore, when the above-mentioned plant steroids are orally administered, they have the disadvantage that they are extremely difficult to drink, and when preparing an injection solution, a considerable amount of surfactant must be used in combination.

By the way, Japanese Patent Publication No. 40-25515 teaches an example of manufacturing an injection containing a plant steroid.
According to this, approximately 10% of surfactant is required to prepare an injection solution with a steroid content of 1%.

Of course, if a suitable solubilizing agent is used, the amount of surfactant used can be reduced to some extent, but the ratio of steroid to surfactant cannot be lowered to less than 1:5.

The non-inventor has the above-mentioned pharmacological action, and has low solubility.
As a result of repeated research aimed at developing a new cyclobranol derivative with particularly improved dispersibility in water, an alkali metal salt of cyclobranol succinate ester represented by the following structural formula was discovered at the request of the inventor. (We have discovered that there is a compound that meets this requirement.

The novel compound according to the invention is a cyclobranol succinic acid ester alkali metal salt represented by the above structural formula, and its molecular formula is C35H5504Na or C3
In 5H6,04, the molecular weight of the Na salt is 562.8 and the molecular weight of the K salt is 578.9.

This novel compound can be produced, for example, by the following method.

That is, cyclobranol derived from rice bran oil and an excess amount of succinic anhydride were mixed in an organic solvent at a concentration of 90 to 100%.
The reaction is carried out for 3-4 hours at a temperature of °C.

In this case, pyridine, triethylamine, etc. can be used as the organic solvent.

After the reaction is completed, the produced cyclobranol succinic ester is separated from unreacted components by appropriate means.

Next, dissolve the above succinic ester in methanol containing a small amount of ethyl ether, add an equivalent amount of sodium hydroxide or potassium hydroxide also dissolved in methanol to form an alkali metal salt of the succinic ester, and distill the methanol. leave

Thereafter, the obtained alkali metal salt is recrystallized with acetone to obtain the target alkali metal salt of cyclobranol succinate.

Yield is usually 80-90g per 100g of cyclobranol
It is.

Next, Table 1 shows the physical properties of the new compound according to the present invention.

In the table, A, B, C, D, and E each represent the following compounds, and the melting point and solubility are based on Japanese Pharmacopoeia-9.

A Nidiclobranol As a natural product, in addition to being present in extremely small amounts in rice bran oil, 2
It is derived from 4-methylenecycloartanol and is the starting material for the new compounds of the present invention.

B Nidiclobranol ferulic acid ester In addition to being present in trace amounts in rice bran oil, it is derived from 24-methylenecycloartanol ferulic acid ester in the form of an ester.

Although it is not known as a natural product, it is known as a derivative of cyclobranol.

D = cycloprano-, succinic acid ester E dichlorobranol succinic acid ester alkaline earth gold (Note 1) sinking pointer.

(Does not show a clear melting point) (Note 2) Forms a suspension at any ratio.

In order to evaluate the absorbability of the new compound according to the present invention,
Absorption and excretion experiments were conducted by orally administering each of the above compounds A, B, C, and E to rats.

According to No. 216, the concentrations of all compounds in blood, bile, and urine were below the detection sensitivity of ordinary gas chromatography.

Incidentally, the detection sensitivity of normal gas chromatography is as follows.

Blood (serum): 1 μg/ml Bile: 5 μg/ml Urine: 1 μg/me Based on this experimental fact, the alkali metal salt of cyclobranol succinate of the present invention can be compared with compounds A-C, which are known as plant steroids with pharmacological effects. It can be seen that the absorbency is comparable to that of

Next, the efficacy analysis of the new compound according to the present invention was also conducted.

Control drug: Chlorpromazine Test drug 2 Compounds A, B, C and E above Animals used: Rabbit Administration route: Oral Results: Chlorpromazine 10 mg/Kg and Compound E
30*47 could be considered to have approximately the same potency as Compound A.

In cases B and C, even after administering 300 mg/Kg, it was still not possible to obtain the same amplitude as when administering 10 mg/Kg of Lillepromacin.

Although the above results are somewhat inferior to those of the cyclobranol succinate ester promacine of the present invention, the known related compounds cyclobranol (compound A), its ferulic acid ester (compound B), and its acetate ester (compound Compared to C), this shows extremely good efficacy.

Chlorpromazine has many side effects such as blood disorders, liver disorders, extrapyramidal system disorders, and decreased blood pressure, but the new compound of the present invention, like general plant steroids, has almost no toxicity or side effects. Together with this, the compound is judged to have extremely high usefulness as a pharmaceutical.

Example I A. Preparative Preparation of Cyclobranol The currently commercially available oryzanols include campesterin ferulate, β-sitosterin ferulate, cycloartenol ferulate, and 24-methylenecycloartanol ferulate. The mixture contains almost no cyclobranol ferulic acid ester.

However, cyclobranol can be derived from 24-methylenecycloartanol ferulic acid ester in oryzanol.

To 1 kg of oryzanol, 2 parts of acetic anhydride, 9 parts, and 4 parts of pyridine, 9 parts were added, and the mixture was reacted at 110 DEG C. for 4 hours to acetylate oryzanol. After that, 10 kg of water was added and the mixture was left overnight.

Thereafter, 15 kg of benzene was added to the mixture to form a benzene phase in which the acetylated product was dissolved and an aqueous phase in which acetic acid and pyridine were dissolved. After separating these phases, the benzene phase was thoroughly washed with water.

Then, benzene was distilled off from the benzene phase, and methanol 1
By crystallizing the acetylated product of oryzanol from 0~, filtering it and drying it, the acetylated product of oryzanol 9
I got 61.

Next, this acetylated product was repeatedly recrystallized with a mixed solvent of chloroform, ethyl acetate, and ethanol (1:1:1 volume) to obtain 110 g of an acetylated product of 24-methylenecycloartanol ferulic acid ester by ship.

60 g of this was dissolved in benzene at 300 mA, 18 g of commercially available activated clay was added, and the water was distilled off as an azeotropic mixture by heating.

The amount of distillate was 10,100O.

The residue was then heated for 6 hours while refluxing benzene, the activated clay was removed by filtration, and then the benzene was distilled off.

According to gas chromatography, the above procedure yields 2
It was observed that 66.1% of the acetylated product of 4-methylene cycloartanol ferulate ester was transferred to the acetylated product of cyclobranol ferulate ester.

The acetylated product of cyclobranol ferulic acid ester thus obtained was mixed with ethanol 600 containing 1% KOH.
Deacetylation was carried out by adding 1 rLl and heating under reflux for 2 hours, and then neutralized with acetic acid, followed by benzene 500
After adding m1 and washing with water, benzene was distilled off.

Next, the obtained product was repeatedly recrystallized with a mixed solvent of chloroform, ethyl acetate, and ethanol (1:1:1 volume) to separate the cyclobranol ferulic acid ester from the remaining 24-methylenecycloartanol ferulic acid ester. Then, the cyclobranol ferulic acid ester was collected in a flask, 10,100 O of ethanol containing 10% KOH was added, and a reflux condenser was attached for saponification and decomposition at the boiling point for 6 hours.

Thereafter, 500 ml of benzene was added thereto, and after washing with water, the benzene was distilled off, and the residue was crystallized with methanol, then filtered and dried.

The yield was 11.3p. This substance has a melting point of 158°C, shows a triterpene coloration in Lieberman reaction, and in gas chromatography, a single peak is obtained at a retention time ratio of 2.54 when the retention time of cholesterol is 1.00. Ta.

The acetate of this substance also had a melting point of 166°C.

According to "Oil Chemistry" Volume 18 (1969) No. 2 and "Oil Chemistry Handbook", the above facts support that the substance in question is cyclobranol.

Figure 1 shows the infrared absorption spectrum of this material (10
m9/ 1000m9KBr NaCl prism used)
.

B. Synthesis of cyclobranol succinic acid ester sodium salt 5 g of cyclobranol obtained in the above preparative example and 12.5.9 g of commercially available succinic anhydride were mixed with 100 ml of trimethylamine (
The esterification reaction was carried out with stirring at 95-98°C on a water bath for 5 hours, and then 100 ml of cold water was added and left to cool while stirring for 5 hours to remove excess succinic anhydride. was converted into.

Next, 150 ml of ethyl ether was mixed with this, the mixture was washed twice with 200 ml of cold water, and then a 200 ml buffer solution adjusted to pH 4f with citric acid-disodium phosphate was added.
Repeat the washing operation with ml of water twice, and then wash with 100ml of pure water.
The ethyl ether phase containing the esterified product was separated by washing once with No. 1.

Thereafter, the ethyl ether phase was dehydrated, and the ethyl ether was distilled off and dried.

Next, this dried product was dissolved in 15 ml of benzene, and this solution was passed through a column packed with 100 I silica gel to adsorb the succinic ester, and then 400 ml of benzene was passed through to elute unreacted components.

Next, 300 ml of ethyl acetate was passed through the column to elute the succinic ester, and the ethyl acetate was distilled off from the eluate to obtain cyclobranol succinic ester.

Yield is 4.1. Figure 2 shows the infrared absorption spectrum of this succinic acid ester (10mg/100mpK
Br.

(using NaCl prism).

Next, 4.0 g of cyclobranol succinic acid ester was dissolved in 10 ml of ethyl ether, 100 ml of methanol was added thereto, and while stirring, a methanol solution containing 1% NaOH was gradually added to adjust the pH of the solution to 7. 5, the remaining liquid was evaporated to dryness under vacuum.

After adding 30 ml of acetone to this dry solid and heating it, it was left to cool overnight, then it was filtered, and the filter cake was washed with 1 ml of acetone.
After washing at zero swelling, the product was dried under vacuum to obtain a white cyclobranol succinate sodium salt.

The yield was 4.1g, which was 64.3% of the theoretical yield.
corresponds to

Figure 3 shows the infrared absorption spectrum of the cyclobranol succinate sodium salt obtained here (10ml
? / 1000m9 KB using rNaCl prism)
.

Example 2 In the synthesis example of cyclobranol succinate sodium salt shown in Section B of Example 1, the method was exactly the same as Example 1 except that trimethylamine used as the esterification reaction solvent was replaced with pyridine. First, cyclobranol succinate was obtained.

Yield is 4.4g. Next, the above succinic acid ester was dissolved in 10 ml of ethyl ether, 100 mA of methanol was added thereto, and while stirring, methanol containing 1% KOH was gradually added to adjust the pH of the solution to 7.5. The liquid was evaporated to dryness under vacuum.

Add 30 ml of acetone to this dry solid, warm it, let it stand overnight, then filter, and filter the resulting filter cake with 10 ml of acetone.
After washing with m1 and drying under vacuum, white potassium succinate salt was obtained.

The yield was 7.35 g, 56% of the theoretical yield.

[Brief explanation of the drawing]

Figure 1 shows the infrared absorption spectrum of cyclobranol, which is the starting material for the compound of the invention. Figure 2 shows the infrared absorption spectrum of cyclobranol succinate, which is the intermediate for the compound of the present invention. The figures show infrared absorption spectra of cyclobranol succinate sodium salt, which is an example of an uninvented compound.

Claims (1)

[Claims] 1 Cyclobranol succinic acid ester alkali metal salt represented by the following structural formula