JPS6412246B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel preventive/therapeutic agent for cholelithiasis.

In recent years, the number of patients with cholelithiasis, especially cholesterol-based cholelithiasis, has been increasing in Japan due to changes in dietary habits. However, an effective therapeutic agent for this disease has not yet been provided, and the development of such a therapeutic agent is desired.

The present inventor has previously discovered that ML-236B, monacolin K, and their derivatives have extremely low toxicity and have excellent cholesterol-lowering effects,
As already reported [JP-A-50-155690, The
Journal of Antibiotics, Volume 32, Issue 8 (1979)].

Further, the present inventor searched for the physiological activities of these compounds and found that these compounds have excellent preventive and therapeutic effects on cholelithiasis, thereby completing the present invention.

That is, the present invention provides monacolin K or ML-
The present invention provides a prophylactic/therapeutic agent for cholelithiasis containing 236B or a derivative thereof as an active ingredient.

Monacolin K, ML- which is the active ingredient of the present invention
As mentioned above, 236B is a known compound, and derivatives thereof include carboxylic acids, carboxylic acid esters, metal salts of carboxylic acids, and amino acid salts of the compound as shown below.

Monacolin K carboxylic acid or ML-236B carboxylic acid can be obtained by neutralizing monacolin K carboxylic acid metal salt or ML-236B carboxylic acid metal salt described later.

In the above formula, M represents a metal element, and n represents the valence of the metal element. The metal salt of monacolin K or ML-236B can be obtained by saponifying monacolin K or ML-236B with a weak alkali, respectively. These metal salts include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, and aluminum salts, iron salts, zinc salts, copper salts, nickel salts, and cobalt salts. 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.

In the above formula, A represents an amino acid. The amino acid salt of monacolin K or ML-236B can be obtained, for example, by contacting monacolin K carboxylic acid or ML-236B carboxylic acid with an amino acid. As these amino acid salts, basic amino acid salts such as arginine, lysine, histidine, α,γ-diaminobutyric acid, and ornithine are suitable.

In the above formula, R is an alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, n-hexyl; benzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl,
2-ethylbenzyl, 3-ethylbenzyl, 4-
Ethylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-ethoxybenzyl, 3-ethoxybenzyl, 4-ethoxybenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2- unsubstituted or substituted benzyl groups with alkyl groups, alkoxy groups or halogen atoms, such as bromobenzyl, 3-bromobenzyl, 4-bromobenzyl;
Or phenacyl, 2-methylphenacyl, 3
-Methylphenacyl, 4-methylphenacyl, 2
-ethyl phenacyl, 3-ethyl phenacyl, 4
-ethyl phenacyl, 2-methoxy phenacyl,
Unsubstituted or substituted with an alkyl group, alkoxy group or halogen atom such as 3-methoxyphenacyl, 4-methoxyphenacyl, 2-chlorfenacyl, 3-chlorfenacyl, 4-chlorfenacyl, 2-bromophenacyl, 3-bromophenacyl, 4-bromophenacyl, etc. This shows the phenacyl group. Monacolin K carboxylic acid ester is a new compound, and can be produced, for example, by the following method.

React monacolin K with alcohol. At this time, 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.

A metal salt of monacolin K carboxylic acid is reacted with an alkyl halide. At this time, dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, acetone, etc. are used as the solvent.

Monacolin K carboxylic acid is reacted with alcohol in the same manner as in .

Monacolin K carboxylic acid ester and ML-
Among the 236B carboxylic acid esters, particularly preferred are methyl ester, ethyl ester, isopropyl ester, n-butyl ester, n-hexyl ester, benzyl ester, 4-methylbenzyl ester, 4-methoxybenzyl ester, and 4-chlorobenzyl. Examples include ester, phenacyl ester, 4-methylphenacyl ester, 4-methoxyphenacyl ester, and 4-bromophenacyl ester.

These monacolin K, ML-236B and their derivatives have an acute toxicity (LD ₅₀ ) of 2000 mg/Kg or more when administered orally to mice, and 500 mg/Kg or more when administered intraperitoneally to mice.
It is extremely low at more than mg/Kg. These can be used alone or with appropriate excipients in powders, capsules,
It can be made into tablets, injections, etc. The prophylactic/therapeutic agent of the present invention can be administered orally, intraperitoneally or intravenously, and the dosage is 0.5 to 1000.
mg/Kg/day, especially 1 to 100 mg/Kg/day is preferred. Next, examples of the present invention will be described.

Example 1 Four-week-old male hamsters were divided into two groups (each group had 5
one group (control group) was fed only a gallstone-forming diet (75% glucose, % casein, 2.5% carboxymethyl cellulose, 5% salts, 1.5% vitamins), and the other group (administered group) was fed a gallstone-forming diet. Monacolin K was orally administered at a dose of 10 mg/Kg every day while the animals were housed in the same environment. Three weeks later, the abdomen was opened under anesthesia to observe the state of gallstone formation, and liver bile was collected over 3 hours to measure the amounts of phospholipids, total bile acids, and cholesterol. As a result, in the control group, all five animals had 1/2 of the gallbladder.
In contrast, 4 to 1/2 of the animals in the administered group were found to have only a few gallstones in 4 out of 5 animals, indicating a significant preventive effect against gallstone formation.

On the other hand, the gallstone formation index [(phospholipids + total bile acids)/cholesterol] was 27 in the control group, and 34 in the treated group, which was a marked increase, indicating an improvement in bile composition.

Example 2 According to the method of Example 1, ML-236B was orally administered at 50 mg/Kg daily for 3 weeks instead of monacolin K to the administration group. As a result (the control group was the same as in Example 1), gallstones occupied less than 1/4 of the gallbladder in 5 out of 5 animals in the administration group, and a remarkable effect of preventing gallstone formation was observed. In addition, the gallstone formation index was 33.
improved.

Example 3 According to the method of Example 1, the administration group received 50 mg of ML-236B calcium salt daily instead of monacolin K.
mg/Kg, orally administered for 3 weeks. As a result (the control group was the same as in Example 1), gallstones occupied less than 1/4 of the gallbladder in 4 out of 5 animals in the administration group.
A remarkable effect on preventing gallstone formation was observed. In addition, the gallstone formation index was significantly improved to 33.

Claims (1)

[Claims] 1. A prophylactic/therapeutic agent for cholelithiasis characterized by containing monacolin K or ML-236B or a derivative thereof as an active ingredient.