JPH0967263A - Inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme a reductase activity - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new inhibitor, comprising an essence of a plant belonging to the genus Ligustrum of the family Oleaceae, useful for treating lipid dysbolism and having high safety. SOLUTION: This inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase activities comprises an essence of a plant belonging to the genus Ligustrum of the family Oleaceae. Ligustrum purpurascens, Ligustrum pedunculare, etc., are preferably used as the plant. An essence obtained by extracting a leaf part thereof with warm water, then adsorbing the resultant extract on a specific adsorbent, eluting the adsorbed extract with ethanol and further concentrating the eluate under a reduced pressure is preferred as the essence thereof. The inhibitor is preferably perorally administered; however, in the case of peroral administration, the daily dose thereof for an adult is preferably 5-500mg administered in several divided portions. When the essence is used as a parenteral injection, the dose thereof is preferably 1-100mg. When the inhibitor is blended in a food composition, the content thereof is preferably 0.1-1wt.%.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a 3-hydroxy-3-methylglutaryl coenzyme A reductase activity inhibitor useful for abnormal lipid metabolism.

[0002]

2. Description of the Related Art 3-Hydroxy-3-methylglutaryl coenzyme A reductase is an important enzyme involved in lipid metabolism, and if the activity of this enzyme is enhanced, various lipid metabolism disorders such as hyperlipidemia may occur. cause. here,
Regarding hyperlipidemia, hyperlipidemia is caused by the enhancement of lipid metabolizing enzymes. Examples of such lipid metabolizing enzymes include cholesterol acyltransferase and 3-hydroxy-3-methylgluta. A plurality of rilcoenzyme A reductases and the like are known, and it is necessary to suppress or inhibit the activity of the enhancing enzyme among these for the treatment of dyslipidemia. That is, in the treatment of dyslipidemia, it is necessary to suppress or inhibit the specific lipid-metabolizing enzyme that is the cause.

Among these, as a 3-hydroxy-3-methylglutaryl coenzyme A reductase activity inhibitor, compactin, dalvastatin, fluindostatin, mevinolin, monacolin, etc. were developed, but they were referred to as headache and myelopathy. Adverse reactions may appear, and there is no problem in using these drugs for the treatment or prevention of dyslipidemia caused by the increased 3-hydroxy-3-methylglutaryl coenzyme A reductase activity that requires continuous administration. It didn't mean that. That is, a new substance having an activity of inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase activity has been desired.

On the other hand, the plants of the genus Iridaceae of the family Oleaceae are
In Sichuan and Yunnan provinces of China, its leaves are consumed in large quantities as tea every day. Further, it was known that the extract had an action of adjusting the balance of lipids in blood, but it was not known at all that it had an action of inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. It was

[0005]

SUMMARY OF THE INVENTION The present invention has been made in view of such circumstances, and provides a new substance having a 3-hydroxy-3-methylglutaryl coenzyme A reductase activity inhibitory action. Is an issue.

[0006]

[Means for Solving the Problems] In view of the above situation, 3-
A new substance having an inhibitory activity on hydroxy-3-methylglutaryl coenzyme A reductase activity was sought, and various materials were intensively screened with an inhibitory effect on 3-hydroxy-3-methylglutaryl coenzyme A reductase activity as an index. The inventors have found that the essence of plants belonging to the genus Ibotan has such a function and completed the invention. The present invention will be described in detail below.

(1) 3-Hydroxy-3-methylglutaryl coenzyme A reductase activity inhibitor of the present invention The 3-hydroxy-3-methylglutaryl coenzyme A reductase activity inhibitor of the present invention is a plant of the genus Iridaceae of the family Oleaceae. It consists of the essence of. Suitable examples of plants of the genus Ibotanaceae include Yunnan bitchocha (ligustrum purpurasensu) and Sichuan bitchoencha (ligustrum pedon clare), which are commercially available at Chinese herbal medicine stores and the like and are easily available. . Here, the essence is the whole or a part of the plant itself, the whole or a part of the plant is dried, crushed, a processed product that is shredded, the whole or a part of the plant or a solvent-extracted product thereof, It is a generic term for those obtained by collecting only volatile components by steam distillation or the like, and those obtained by fractionating and purifying them by column chromatography or liquid-liquid extraction using silica gel, ODS, ion exchange resin or the like as a carrier. As for the extraction method, for example, a polar solvent may be added to a plant or a processed product thereof in an amount of 1 to 10 times, and immersed at room temperature for several days, and at a temperature near the boiling point for several hours. If necessary, insoluble matter may be removed by filtration or the solvent may be removed by concentration under reduced pressure. The solvent is not particularly limited, but water, ethanol or methanol, 1,3-
Alcohols such as butanediol, ketones such as acetone and methyl ethyl ketone, ethers such as diethyl ether and tetrahydrofuran, halogenated hydrocarbons such as methylene chloride and chloroform, esters such as ethyl acetate and methyl formate, nitriles such as acetonitrile. Suitable examples are the classes. Only one kind of these solvents may be used, or two or more kinds thereof may be mixed and used. Among these essences, the most preferable one is one in which the leaf portion is extracted with warm water, adsorbed on DIAION HP-20 (manufactured by Mitsubishi Kasei), eluted with ethanol, and concentrated under reduced pressure. The part to be used is not particularly limited, but the leaf part is preferable. The thus-obtained essence has an excellent 3-hydroxy-3-methylglutaryl coenzyme A reductase activity inhibitory action, and is safe because the source plant has been cultivated in large amounts for beverages as tea for many years. It is also very useful for the treatment and prevention of dyslipidemia caused by the enhancement of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. The dose of this product is 1 adult per day for oral administration.
It is suitable to administer 5 to 500 mg per person in several divided doses. When used as an injection, 1-100mg
Is appropriate. Other administration routes may be similar to these.

(2) Food composition of the present invention The food composition of the present invention contains the above-mentioned 3-hydroxy-3-methylglutaryl coenzyme A reductase activity inhibitor, and 3-hydroxy-3. -Methylglutaryl coenzyme A for preventing or ameliorating diseases caused by enhanced reductase activity. The type of food is not particularly limited as long as it is a nutrient that can be supplemented by the daily oral route. Specifically, for example, gummy,
Examples thereof include sweets such as candy and cookies, beverages such as juice, carbonated drinks and tea, staple foods such as bread and pancakes, scones, tacos and spaghetti, and side dishes such as pickles, pickles and boiled vegetables. The preferable content of the 3-hydroxy-3-methylglutaryl coenzyme A reductase activity inhibitor of the present invention in these food compositions is 0.01% to 10% by weight. More preferably 0.1
~ 1% by weight. However, when used as tea, dried leaves or processed products thereof may be used as they are. In addition to the 3-hydroxy-3-methylglutaryl coenzyme A reductase activity inhibitor of the present invention, the food composition of the present invention can contain any component commonly used in food compositions. Examples of such optional components include excipients, extenders, binders, coating agents, sugar coating agents, stabilizers, colorants, lubricants, pH adjusters, solubilizers, dispersants,
Examples thereof include thickeners, isotonic agents, preservatives and the like. 3-of the present invention
The food composition of the present invention can be prepared by processing a hydroxy-3-methylglutaryl coenzyme A reductase activity inhibitor and such an optional component by a usual food production method. When the food composition of the present invention is administered to a person who has already developed a disease caused by the enhancement of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the symptom can be improved, and even if it does not occur, clinical examination The onset can be prevented by administering it to people whose data such as values indicate the risk of onset.

(3) Pharmaceutical Composition of the Present Invention The pharmaceutical composition of the present invention is characterized by containing the above-mentioned 3-hydroxy-3-methylglutaryl coenzyme A reductase activity inhibitor. The types of pharmaceutical compositions include
Although not particularly limited, for example, oral administration agents such as granules, powders, tablets, sugar coatings, solutions, elixirs, injections such as ampoules and vials, rectal administration agents such as suppositories,
Examples thereof include ointments, creams, and transdermal preparations such as patches. The pharmaceutical composition of the present invention is the above 3-hydroxy-3-
In addition to the methylglutaryl coenzyme A reductase activity inhibitor, it may contain optional components usually used in pharmaceutical compositions. As such optional ingredients, as optional ingredients, excipients, fillers, binders, coating agents, sugar coating agents,
Examples thereof include stabilizers, disintegrants, colorants, lubricants, pH adjusters, solubilizers, dispersants, thickeners and isotonic agents. Further, it is possible to contain a drug involved in lipid regulation such as a cholesterol acyltransferase activity inhibitor or a drug for cardiovascular system. The administration route of the present invention can be used without particular limitation as long as it is medically used, but the most preferable one is oral administration in view of the necessity of continuity of administration. When the pharmaceutical composition of the present invention is administered to a person who has developed a disease caused by the enhancement of 3-hydroxy-3-methylglutaryl coenzyme A reductase, this disease can be treated. Moreover, the onset can be prevented by administration to a person at risk of onset.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION Embodiments of the present invention will be described below with reference to examples. In addition, HMGCOA-1 and 2 were produced according to the below-mentioned Example.

Example 1 Candy A candy was prepared according to the following formulation. That is,
The component A was heated and melted at 150 ° C., cooled to 120 ° C., the component B was added, the mixture was stirred, and a uniform product was molded and cooled to obtain a candy. A sugar 59 parts by weight starch syrup 30 parts by weight B citric acid 1 part by weight HMGCOA-1 10 parts by weight

Example 2 Candy A candy was prepared according to the following formulation. That is,
The component A was heated and melted at 150 ° C., cooled to 120 ° C., the component B was added, the mixture was stirred, and a uniform product was molded and cooled to obtain a candy. A sugar 59 parts by weight starch syrup 30 parts by weight B citric acid 1 part by weight HMGCOA-2 10 parts by weight

(Example 3) Gummy A component is heated and dissolved at 110 ° C., B component separately swelled and dissolved is added, and further C component is poured and stirred, poured into a mold and left for one day and night, and then removed from the mold to remove the gummy. Obtained. A sugar 40 parts by weight starch syrup 40 parts by weight B gelatin 8 parts by weight water 5 parts by weight C citric acid 2 parts by weight HMGCOA-3 5 parts by weight

(Example 4) Gummy A component is heated and dissolved at 110 ° C., B component separately swelled and dissolved is added, and further C component is poured and stirred, poured into a mold and left for one day and night, and then removed from the mold to remove the gummy. Obtained. A sugar 40 parts by weight starch syrup 40 parts by weight B gelatin 8 parts by weight water 5 parts by weight C citric acid 2 parts by weight HMGCOA-4 5 parts by weight

Example 5 Bread Bread was prepared according to the following formulation. In other words, after weighing all the prescription ingredients, kneading them well, and carrying out primary fermentation at 40 ° C for 1 hour, a bench time of 15 minutes was taken and molded at 40 ° C.
Second fermentation was performed for 45 minutes, and baking was performed for 25 minutes while steaming in an oven at 230 ° C to obtain bread. Strong flour 500 parts by weight Dry yeast 10 parts by weight Melted butter 50 parts by weight Salt 8 parts by weight Sugar 15 parts by weight 38 ° C lukewarm water 320 parts by weight HMGCOA-1 10 parts by weight HMGCOA-2 10 parts by weight

Example 6 Granules Granules were prepared according to the following formulation. That is, the prescription ingredients were weighed, part A was put into a glad granulator, mixed at low speed, and granulated while spraying part B at high speed. This was blow-dried at 40 ° C. for 48 hours and sieved to obtain a granule. A crystalline cellulose 40 parts by weight lactose 40 parts by weight aluminum stearate 2 parts by weight hydroxypropylmethyl cellulose 8 parts by weight HMGCOA-1 10 parts by weight B 50% ethanol aqueous solution 20 parts by weight

(Example 7) Granules Granules were prepared according to the following formulation. That is, the prescription ingredients were weighed, part A was put into a glad granulator, mixed at low speed, and granulated while spraying part B at high speed. This was blow-dried at 40 ° C. for 48 hours and sieved to obtain a granule. A crystalline cellulose 40 parts by weight lactose 40 parts by weight aluminum stearate 2 parts by weight hydroxypropylmethylcellulose 8 parts by weight HMGCOA-2 10 parts by weight B 50% ethanol aqueous solution 20 parts by weight

Example 8 Granules Granules were prepared according to the following formulation. That is, the prescription ingredients were weighed, part A was put into a glad granulator, mixed at low speed, and granulated while spraying part B at high speed. This was blow-dried at 40 ° C. for 48 hours and sieved to obtain a granule. A crystalline cellulose 40 parts by weight lactose 40 parts by weight aluminum stearate 2 parts by weight hydroxypropylmethylcellulose 8 parts by weight HMGCOA-3 5 parts by weight HMGCOA-4 5 parts by weight B 50% ethanol aqueous solution 20 parts by weight

Example 9 Granules Granules were prepared according to the following formulation. That is, the prescription ingredients were weighed, part A was put into a glad granulator, mixed at low speed, and granulated while spraying part B at high speed. This was blow-dried at 40 ° C. for 48 hours and sieved to obtain a granule. A Crystalline cellulose 40 parts by weight Lactose 40 parts by weight Aluminum stearate 2 parts by weight Hydroxypropyl methylcellulose 8 parts by weight HMGCOA-1 5 parts by weight Mevalotin 5 parts by weight B 50% Ethanol aqueous solution 20 parts by weight

[0020]

【Example】

Example 1 Production Example 1 l of boiling water was added to 100 g of Sichuan Kitchingcha (dried leaves) to prepare 3
Extracted while heating for hours. After cooling, insoluble matter was removed by filtration, freeze-dried, and 3-hydroxy-3-methylglutaryl coenzyme A reductase activity inhibitor 1 (HM
25 g of GCOA-1) was obtained. This was dispersed in 500 ml of water, and passed through a column filled with Diaion HP-20 (manufactured by Mitsubishi Kasei), and deionized water, 20% ethanol aqueous solution, and ethanol (3 l each) were fractionated. The ethanol fraction was concentrated to obtain 13.1 g of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity inhibitor 2 (HMGCOA-2).

Example 2 Production Example To 100 g of Yunnan bitcho tea (dried leaves), 1 liter of boiling water was added to give 3
Extracted while heating for hours. After cooling, insoluble matter was removed by filtration and freeze-dried to give 3-hydroxy-3-methylglutaryl coenzyme A reductase activity inhibitor 3 (HM
33 g of GCOA-3) was obtained. This was dispersed in 500 ml of water, and passed through a column filled with Diaion HP-20 (manufactured by Mitsubishi Kasei), and deionized water, 20% ethanol aqueous solution, and ethanol (3 l each) were fractionated. The ethanol fraction was concentrated to obtain 21.8 g of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity inhibitor 4 (HMGCOA-4).

Example 3 3-Hydroxy-3-methylglutaryl coenzyme A
Measurement of reductase activity inhibitory action Regarding HMGCOA-1 to 4 prepared in Example 1 3-
The hydroxy-3-methylglutaryl coenzyme A reductase activity inhibitory effect was measured. In other words, DL [3- ¹⁴
C] 3-hydroxy-3-methylglutaryl coenzyme A 2.5 μl, 10 mM NADPH aqueous solution 5 μl,
5 μl of 100 mM dithiothreitol aqueous solution, 100
5 μl of mM EDTA / 2Na aqueous solution, 10 μl of 500 mM potassium dihydrogen phosphate buffer (pH 7.4),
7.5 μl of water, aqueous solution of the specimen with a concentration of 50 mg / ml 5
After adding μl to the culture tube and incubating at 37 ° C. for 3 minutes, 10 μl of rat liver microsomes was further added and incubated for 15 minutes, and 2N hydrochloric acid was added and incubated for 15 minutes.
μl was charged and developed with benzene: acetone = 1: 1, the lactone body of mevalonic acid was cut off, the radiation dose was measured with a liquid scintillator, and the value obtained by subtracting the radioactivity of the sample from the radioactivity of the control was divided by the radioactivity of the control. Then, the product was multiplied by 100 to obtain the inhibition rate of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity.
As a control, water was used instead of the aqueous solution of the sample. The results are shown in Table 1. From this, it is understood that the 3-hydroxy-3-methylglutaryl coenzyme A reductase activity inhibitor of the present invention is excellent in 3-hydroxy-3-methylglutaryl coenzyme A reductase activity inhibitory action.

[0023]

[Table 1]

[0024]

According to the present invention, 3-hydroxy-3-
A new substance having a methylglutaryl coenzyme A reductase activity inhibitory action can be provided.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A23L 1/30 A23L 1/30 B C12N 9/99 C12N 9/99 (72) Inventor Yoshio Kitada 560 Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Pola Chemical Industry Co., Ltd. Totsuka Laboratory

Claims (6)

[Claims] 1. A 3-hydroxy-3-methylglutaryl coenzyme A reductase activity inhibitor consisting of the essence of a plant of the genus Ibotanaceae of the family Oleaceae. 2. The 3-hydroxy-3-methylglutaryl coenzyme A reductase according to claim 1, wherein the plant of the genus Ibotanaceae is Yunnan Kitchingcha (ligustrum purpurense) or Sichuan Kitchingcha (ligustrum pedonclare). Activity inhibitor. 3. The 3-hydroxy-3-methylglutaryl coenzyme A reductase activity inhibitor according to claim 1, wherein the essence is a polar solvent extract. 4. The essence is obtained by extracting a leaf portion with hot water, adsorbing the leaf portion onto DIAION HP-20 (manufactured by Mitsubishi Kasei) and eluting with ethanol, and concentrating under reduced pressure. Or 3-hydroxy-3-.
Methylglutaryl coenzyme A reductase activity inhibitor. 5. The method according to any one of claims 1 to 4,
Hydroxy-3-methylglutaryl coenzyme A reductase activity inhibitor was blended, 3-hydroxy-3-
A food composition for preventing or ameliorating a disease caused by enhanced activity of methylglutaryl coenzyme A reductase. 6. The method according to any one of claims 1 to 4,
A pharmaceutical composition for preventing or treating a disease caused by enhanced 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, which comprises a hydroxy-3-methylglutaryl coenzyme A reductase activity inhibitor.