FR2518546A1 - DIHYDRO- AND TETRAHYDROMONACOLINES, THEIR PREPARATION METHOD AND THEIR THERAPEUTIC APPLICATION - Google Patents

Abstract

THE INVENTION CONCERNS NEW PHYSIOLOGICALLY ACTIVE SUBSTANCES, DIHYDRO- AND TETRAHYDROMONACOLINS L, REPRESENTED BY THE FOLLOWING GENERAL FORMULA: (CF DRAWING IN BOPI) IN WHICH X IS -CHCH- OR -CH-CH-, AND THEIR DERIVATIVES, ACTION (HYPOCHOLESTEROLEMIANTE), A PROCESS FOR THE PREPARATION OF THESE SUBSTANCES, AS WELL AS A COMPOSITION FOR THE TREATMENT OF HYPERLIPEMIA CONTAINING THESE SUBSTANCES AS AN ACTIVE INGREDIENT.

Description

The invention relates to new physio-

  logically active with hypocholesterolemic action.

  More specifically, the invention relates to new substances

  physiologically active compounds, dihydro and tetrahydromonacol

  Nes L represented by the following general formula (I): HO o (I)

CH 3

  X CH 3 wherein X is -CH = CH or -CH 2 -CH 2, having a cholesterol-lowering activity and their metal salts as well as their alkyl esters, represented by the following general formula (II), HO OOY b H (II) )

CH 3

X CH 3

  where Y is l M (where M is a metallic element and n n is an atomic valency of the metal element), or a group

  lower alkyl having from 1 to 6 carbon atoms, X has the same

  meaning me as above; a process for their preparation

  and a composition for treating hyperlipemia

  containing these substances as an active ingredient.

  Hyperlipemia, particularly hypercholesterolemia, is recognized as one of the important factors

  such as myocardial infarction and atherosclerosis

  The Applicant has therefore conducted research to find new physiologically active substances having a cholesterol-lowering activity, from microbial products. As a result, the Applicant has succeeded in obtaining

  an active substance, dihydromonacoline L, from the middle

  place of cultivation of a strain of mushrooms.

  It has been found in an experiment on rats that

  the present substance is effective as a hypochlorous agent

  In addition, the substances were found to be

  new substances, as confirmed by a review of the pro-

  physicochemical properties of said substance.

  Dihydromonacoline L corresponds to the general formula

  above (I), where X is -CH = CH and is represented by

  the following formula (III).

  HO (III) The Applicant has further found in the context of research that tetrahydromonacoline L represented by the following formula (IV) (IV) CH corresponds to the general formula (I) above in which

  X is -CH 2 -CH 2, has a similar effect and that metal salts are

  and alkyl esters of dihydro and tetrahydro-

  L monacolines are also excellent new

  these physiologically active having a hypocholes-

  such as dihydromonacoline L.

  The object of the invention is to provide new subsi-

  physiologically active substances with hypo-

  cholesterol-lowering agents and a process for the preparation of these substances. Another object of the invention is to provide an agent

  treatment of hyperlipemia, containing a new

  physiologically active substance with a hypo-

  cholesterol-lowering agent, as an active ingredient.

  Other objects and advantages of the invention will become apparent

  upon reading the description below.

In the accompanying drawings:

  FIG. 1 represents an absorption spectrum below

  red (K Br) of dihydromonacoline L, and Figs 2 and 3 represent the NMR spectrum

  (CDC 13) and the spectrum of mass analysis of dihydromona-

coline L, respectively.

  The dihydromonacoline L provided by the invention and

  presented by the following formula (III)

HO O

2 O (III) CH 3 CH 3

  can be obtained by a culture of microorganisms, a

  mushrooms, in particular microorganisms

  belonging to the genus Monascus, and separation from the cultivated medium. The microorganisms used in the invention are the strains producing dihydromonacoline L, belonging to the

  kind Monascus and the strain that is considered by the Application-

  particularly effective, is, for example,

  nascus ruber no. 1005, which she isolated from

  produced in Thailand, the said strain being

  placed under the admission number FERM-P 4822 at Fermentation Re-

  Research Institute, Ministry of International Trade and Industry, Japan, and ATCC accession number 20657 to the American Type Culture Collec-

tion, US.

  Needless to say, not only are there

  but also mutant strains of microorganisms

  belonging to the genus Monascus other than that indicated

  above can be used if they are capable of

to obtain dihydromonacoline L.

  The bacteriological properties of the microorganism

  of the dihydromonacoline L are: I Development

  Development on a medium of potato-glu

  cose agar at 25 ° C is rapid and the diameter of the colony

  dyes 5 to 6 cm 10 days after inoculation The colony is

  flat and a relatively thin base layer of hyphae is

  veloppe The development of aerial hyphae is weak; the

  aerial hyphae are white and most of them have a

  Woolly Pect Many Creistothecia are formed on the base layer of the hyphae and turn reddish-brown at maturity. The surfaces and back of the colony are brown to reddish-brown. The development on Sabouraud agar medium at 25 ° C is very fast and the colony diameter reaches 6 to 6.5 cm 10 days after inoculation. The surface of the colony is very flat and the hyphae of base and the Aerial hyphae grow better than on a potato medium glucose-agar The number of cleistothecia counted is very low The surface of the colony is yellow-reddish

  has a reddish brown and the reverse is brown-red to dark brown.

  The development on oatmeal-C agar is slow and the diameter of the colony reaches 1.5 to 2 cm 10 days after inoculation. The colony is flat.

  development of aerial hyphae and the formation of key-

  thecies are both very weak The surface and the reverse

  colony are colored in dark red to reddish-brown.

  The development on Czapek agar medium at OC is very slow and the colony diameter reaches 1.6 to 1.8 cm 10 days after inoculation.

  The development rates on each of the above

  above at 37 OC are almost equal to those at 25 C.

  2 Morphological Properties Cleistothecia are spherical and are 30 to 60 microns in diameter; their walls are thin and membranous; their stems have septal walls and each consists of a hypha of 3, 5 to 4.5 microns in diameter and 15 to 80 microns

  The ascus is 8 spores and is almost spherical.

  evanescent Ascospores are ovoid or ellipsoid

  of; they have a dimension of 4 4 x 4 7 microns and their surfaces are united The conidia are colorless and spherical

  or pyriforms; their size reaches 6 9 x 6 11

  cron; the bases are truncated and their walls are relatively

  The conidiophores resemble a vegetative hypha and are branched or unbranched, the conidia being formed on the top The mycelia are branched and

  have septal walls; most of them have a di-

meter from 3 to 5 microns.

  From the observation of its characteristics, as mentioned above, this microorganism has been identified

  as a strain of Monascus ruber van Tieghem.

  -The microbiological properties of Monascus ruber have been reported in the following literature: van Tieghem,

  Bull Soc Botan France 31, 227 (1884); Cole et al, The Ca-

  nadian Journal of Botany 46, 987 (1968), and Takada, Transac-

  tions of the Micological Society of Japan 9, 128 (1969).

  Dihydromonacoline L is produced by a culture of

  the strain producing dihydromonacoline L, in

  aerobic conditions, in a nutrient medium, according to the method known as method of cultivation of fungi For example, the microorganism producing dihydromonacoline L is cultured in series on medium containing 2% soluble starch, 1% glucose, 2% of peptone and 2% agar For the purpose of

  to produce dihydromonacoline L, cell bodies de-

  grown on this agar medium are directly inoculated on the production medium and cultured.

  developed on the production medium are

  on a new production environment in which dihydro-

monacoline L can be produced.

  The microorganism producing dihydromonacoline L develops at a temperature between 7 and 40 C; but it is normally preferred to produce dihydromonacoline L at a temperature of between 20 and 35 ° C. For cultivation

  of the microorganism producing dihydromonacoline L,

  As regards the Monascus genus, the nutritive sources used for the cultivation of fungi and other microorganisms may all be used. For example, as a carbon source, glucose, maltose, destrin,

  starch, lactose, sucrose, glycerin and the like.

  These carbon sources include glucose and starch

  present favorable carbon sources for the production of

dihydromonacoline L.

  All nitrogen sources known for the development of

  microorganisms belonging to the genus Monascus or

  can be used for the production of dihydro-

  For example, peptone, an ex-

  meat, yeast, yeast extract,

  soymilk, peanut flour, a syrup infusion of

  mals, rice bran and an inorganic nitrogen source and

  In the production of dihydromonacoline L by

  of the microorganism producing dihydromonacoline L,

  if necessary, a mineral salt and a metal salt are added.

  A quantity of metal can also be added as needed

heavy in trace.

  Dihydromonacoline L is obtained by culturing the microorganism producing dihydromonacoline L in

  aerobic conditions, and generally using

  aerobic culture dice, for example a culture in a

  lide, a culture with agitation, and a culture under aeration

  and agitation If an antifoam agent proves necessary

  In the culture or sterilization of the medium, antifoaming agents such as silicone oil, surfactants and the like can be used. A temperature of 20 to OC is preferable for the culture.

  continuously until dihyciromonacoline L is

  normally accumulated and normally lasts 4 to 17 hours.

  The extraction of the substance concerned from the

  cultivated material can be carried out by associating

  various processes depending on the properties of the

  as described by the Applicant.

  That is, these methods include extraction with

  a solvent such as ether, ethyl acetate, chloroform

  me, benzene and the like; a dissolution in a soil

  having a strong polarity such as acetone, an alcohol,

  and the like; an elimination of impurities by the use

  petroleum ether, hexane and other low polarity solvents; gel filtration using a

  Sephadex column; an adsorption chromatography in use

  reading active charcoal, silica gel and the like The substance is isolated from the culture medium as a homogeneous substance using an appropriate combination of

these techniques.

  More concretely, the substances concerned can be isolated from the culture medium by the combination of the following operations: extraction from the medium of

  with a solvent such as ethyl acetate and similarly

  res, evaporation of the extract to dryness, dissolution of the extract in an organic solvent such as benzene and the like,

  extraction with an aqueous solution of alkaline hydroxide,

  of the aqueous solution by adding an acid and

  pulling the solution with an organic solvent such as

  ethyl ketate, evaporation of the extract to dryness, dissolution of the extract in benzene, separation of the crystals formed

  concentration, dry evaporation of the solution, dissolu-

  of the dried product in an organic solvent such as

  benzene and finally purification of the crude product by chromato-

  ordinary column writing to obtain a purified product.

  The physicochemical properties of dihydromonato

line L are described below.

  Dihydromonacoline L represented by the general formula

  above (III) is a white crystalline powder, so-

  soluble in solvents such as lower alcohols, by

  methanol, ethanol, propanol and the like, the

  ketone, chloroform, ethyl acetate, benzene and

  It is insoluble in hexane, petroleum ether and the like. This substance is neutral and is not soluble in neutral or acidic water.

  opening of the cycle by a usual saponification with an al-

  cali and is converted to a water-soluble acidic substance.

  This acidic substance is extracted with a solvent such as

  ethyl ketate, chloroform and the like in the range of p H acid and reconverted to dihydromonacoline L by evaporation

dried up.

  The elemental analysis of dihydromonacoline L indicates the following values * carbon 74.50%; 9.85% hydrogen; and oxygen 15.65% The substance has a molecular weight of 306 and for molecular formula: C H O Figures 1, 2 and 3 of the accompanying drawings show respectively the spectrum

  infrared absorption, the NMR spectrum and the spectrum of

mass analysis of this substance.

  Thin layer chromatography using silica gel (manufactured by Merck and Co No. 5715 Silica Gel (e) 60-F 254) gives a single spot at a Rf value of 0.48.

  using as the developing solvent hexane / acetone

  ne (1: 1) Said stain can be detected by a sulfuric acid spray (staining in reddish brown by light

heating) and iodine.

  The tetrahydromonacoline L represented by the general formula mentioned above (IV) is a white crystalline product and is soluble in lower alcohols such as methanol, ethanol, propanol and the like, and other

  solvents such as acetone, chloroform, ethyl acetate,

  le, benzene and the like, but it is insoluble in hexane, petroleum ether and the like This substance is neutral and insoluble in water, but easily converted into a water-soluble acidic substance by opening the nucleus of the lactone structure with an alkaline treatment

usual.

  Elemental analysis of tetrahydromonacoline L

  the following values: carbon 74.03%, hydrogen 10.39%;

  oxygen 15.58% It has a molecular weight of 308 and its

molecular mule is C 19 H 3203 o

  The tetrahydromonacoline L can be obtained by dissolving

  monacolin L or dihydromonacoline L represented by the general formula (III) above in an organic solvent such as, for example, tetrahydrofuran, ethyl acetate

  and the like, and hydrogenating the dissolved compound

  This is a catalyst such as, for example, platinum oxide, palladium carbone and the like. The hydrogenation is carried out at a temperature of 10 to 60 ° C, preferably at 15 to 40 ° C and is normally complete in 10 to 24 hours. The amount of catalyst is normally from 1 to 60% by weight, preferably from 2 to 30% by weight, based on the weight of monacolin L or dihydromonacoline L. The monacolin L used as starting material is a known compound and can be obtained by isolation from the culture medium of Monascus ruber n 1005 (FERM-P-NO 4822),

  as described in the Japanese patent application, put in the form of

Public Notice N 57798/81.

  As metal salts of dihydro and tetrahydro-

  monacolines L may be mentioned alkali metal salts such as sodium, potassium and the like; salts

  alkaline earth metals such as calcium salts,

  gnesium and the like; aluminum salts, iron salts,

_518546

  zinc salts, copper salts, nickel salts, and cobalt salts and the like. Among these salts, alkali metal salts, alkaline earth metal salts and aluminum salts are especially preferred. salts

  S sodium, calcium salts and aluminum salts.

  As examples of alkyl esters, mention may be made of

  methyl, ethyl, n-propyl, isopropyl,

  lique, n-butyl, n-hexyl and the like.

  The list below is representative of these compounds.

  1 Sodium salt of dihydromonacoline L 2 Sodium salt of tetrahydromonacoline L 3 Calcium salt of dihydromonacoline L 4 Calcium salt of tetrahydromonacoline L Aluminum salt of tetrahydromonacoline L 6 Methyl ester of dihydromonacoline L 7 Methyl ester tetrahydromonacoline L 8 Ethyl ester of tetrahydromonacoline L

  The synthesis of these compounds is carried out

next.

  An alkyl ester of tetrahydromonacoline L is

  presented by the following general formula (V) HOOROR H

(V

  CH. Wherein R is an alkyl group having 1 to 6 carbon atoms, and is obtained by catalytic reduction of an ester

  monacolin L or corresponding dihydromonacoline L

  represented by the following general formula (VI): ## STR1 ## in which there is a double bond in the case of monacolin L and a single bond in the case of dihydromonacoline L; R has the same meaning as above,

  in an organic solvent such as for example an alcohol, especially

  methanol, ethanol and the like, tetrahydrofuran

  ne, ethyl acetate and the like, in the presence of a

  such as platinum oxide, palladium-carbon and

  The reduction is carried out at a temperature

  between 10 and 60 Cs, preferably between 15 and 40 C.

  The catalyst is normally used in an amount of 1 to 60% by weight, preferably 2 to 30% by weight, based on the weight of monacolin L ester or dihydromonacoline L. The ester can also be obtained by reacting the tetrahydromonacoline L with an alcohol (ROH in which R has the meaning indicated above) corresponding to the ester

longed for.

  An alkyl ester of dihydro-

  monacoline L by reacting dihydromonacoline L with a

  corresponding alcohol to the desired ester In the reaction

  above, a mineral acid such as hydrochloric acid, sulfuric acid and the like is used as the catalyst; the

  boron fluoride, an acid ion exchange resin and the like.

  res, and as solvent an alcohol of the same type or benzene, chloroform, ether and the like, provided that it does not

not participate in the reaction -

  An alkyl ester of monacolin L and an alkyl ester

  Dihydromonacoline L used as depaxt materials can be obtained by reacting monacolin L or dihydromonacoline L with an alcohol corresponding to the desired ester.

  Metal salts of dihydro and tetrahydromona

  L columns are represented by the general formula (VII) HO On M (VII) X

  in which X, M and N have the meanings given below.

  above, and are synthesized in the following manner;

  They are obtained by dissolving the dihydro or tetra-

  hydromonacoline L represented by the general formula (I) CH (I)

  wherein X is -CH = CH or -CH 2 -CH 2, in a sol-

  such as methanol, ethanol, acetone and the like, and reacting the compound with a metal hydroxide represented by the general formula (VIII) M (OH) n (VIII) wherein M represents an alkali metal such as as sodium, potassium and the like; an alkaline earth metal such as

  calcium, magnesium and the like; or a metal element

  such as aluminum, iron, zinc, copper, nickel,

  kel, cobalt and the like; N is an atomic valency of the metal element The metal hydroxide is normally used as an aqueous solution.

  Physiological activity of dihydronooacoline L, tetihydromo

  L and their derivatives according to the invention can be evaluated by the

  following process in which hypochlorous activity is determined

  desterolemic in the blood in rats are injected

  T (R) w R-1339 (4- (1,1,3,3-tetramethylbutyl) polymer)

  nol with formaldehyde and oxirane, a tensive agent

  manufactured by Rohm & Haas Co, US) with hyperchromic activity

  desterolemic in the blood, intravenously to a group

* 5 rats in a dose of 400 mg / kg and at the same time

  minister orally a certain amount of each compound.

  The rats are bled to death after 14 hours and the dose is

  the sterol in the blood by the classical method (Group treated).

  On the other hand, rats that have only been administered

  your (R) WR-1339 intravenously, are treated the same

  way to measure cholesterol in the blood (control group).

  The effect of dihydromonacoline 1 can be determined quantitatively

  by comparing cholesterol levels in both groups. The hypocholesterolemic activity in the serum,

  effective dose and toxicity are given below.

  (1) Hypocholesterolemic Activity in Serum (A) Triton (R) WR-1339 was injected intravenously in an amount of 400 mg / kg and at the same time dihydromonacoline L was administered orally. of

  tetrahydromonacoline L or a derivative thereof (in the form of

  of an aqueous solution or an aqueous suspension)

  bled the rats to death after 14 hours and dosed the choles-

  terol in the blood by the classical method The results

are reported in Table 1.

  TABLE 1 Hypocholesterolemic Activity in Serum

in rats.

  (B) Triton (R) WR-1339 was injected intravenously in an amount of 400 mg / kg and at the same time

  10 mg / kg of monacolin L, dihydrogen,

  monacolin L, tetrahydromonacoline L or one of their derivatives

  (as an aqueous solution or aqueous suspension) Orally a dose of 10 mg / kg

  of each of the above compounds after 8 hours (the total

  up to 20 mg / kg) The rats were then bled to death after 12 hours (20 hours after administration of Triton WR-1339)

  and serum cholesterol was assayed by the conventional method.

  The results are reported in Table 2.

  Compound Dose Percentage reduction of serum cholesterol mg / kg (%) Dihydromonacoline L 20 23.4

30.6

Tetrahydromonacoline L 5 21

29

  Methyl ester of tetrahydromonacoline L 5 19

31

  Sodium salt of tetrahydromonacoline L 5 20

29

TABLE 2

  The results above show that the compounds of

  the invention possess excellent hypocholesterol activity.

  and in particular the methyl ester of the dihydro-

  monacoline Let latetahydromonacoline L and its derivatives exert

one hundred excellent effect.

(2) Acute toxicity

  Acute toxicity was determined by oral

  and intraperitoneally an aqueous solution or

  aqueous suspension of dihydromonacoline L, tetrahydromona-

  coline L and their derivatives The results are reported

in Table 3.

Percentage of reductions

  cholesterol concentration ___ -serial (%) Monacoline L 18.9 Dihydromonacoline sodium salt L 31.3 Dihydromonacoline methyl ester L 34, 1 Tetrahydromonacoline sodium salt L 34.2 Tetrahydromonacoline methyl ester L 38.0 o TABLAU 3 Acute toxicity compound Animal Method of administration LD 50 (mg / kg) Mouse Oral route> 1000 Intraperitoneal route; 7500 Dihydromonacolin L Oral route 71 000 R at_ _ _ _ _ _ _ _ _ _ _ _ _ _ Intraperitoneal route 7500 Oral route 72 000 So Iris Intraperitoneal route 7500 T 6 Trahydronxonacoline L Oral route 72 000 Rat Intraperitoneal route - 500 mice Oral route 72,000 Methyl ester of the intraperitoneal route 4a> 7500 tetrahydromonacoline L Rat Oral route -72000 Intraperitoneal route 7,500 Oral route> 2,000 Sodium salt of tetrahydromnacolin L mouse Initialipteritoneal route 7500 Oral route> 2000 Rat Intraperitoneal route> 500 H o 'wb oe LA ON.

TABLE 3

  According to the table above, it has been found that

  hydromonacoline L, tetrahydromonacoline L and their derivatives

had a very low toxicity.

  As mentioned above, dihydromonacoline L, tetrahydromonacoline L and their derivatives have an activity.

  hypocholesterolemia in the blood and can be used

  as pharmaceuticals, for example as an agent

  anti-hyperlipemia and as anti-atherosclerosis agent.

  These compounds are administered as an intravenous injection or by oral administration and the like.

  dose varies with age, body weight, symptoms,

  for example, dihydromonacoline L is administered to adults in a dose of 10 to 2000 mg, preferably 50 to 300 mg per day in 1 to 3 partial doses, and tetrahydromonacoline L and its derivatives is administered in a dose of 5 to 3000 mg,

  preferably from 10 to 300 mg per day in 1 to 3 partial doses.

  However, if necessary, other doses may be administered

  Trees. Dihydromonacoline L, tetrahydromonacoline L and

  their derivatives can be prepared in the form of doses of

  optional way and current by analogy with another lipid-lowering agent such as for example Clofibrate or Simfibrate Accordingly, the invention also relates to the

  preparation of a composition containing at least one of the

  dihydromonacoline L, tetrahydromonoline L and their derivatives, which can be used as pharma-

  These compositions may be adapted for use in a

  the addition of an optional or ne-

necessary, or an excipient.

  This composition is desirably presented in a form suitable for absorption by the tract

  gastrointestinal tablets and capsules for

  Oral administration is a unit dose form and may contain customary excipients, for example binders such as syrup, gum arabic, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; excipients such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; lubricants such as, for example, magnesium stearate, talc, polyethylene glycol, or silica; disintegrants such as, for example, potato starch, or authorized wetting agents, such as, for example, sodium lauryl sulfate Tablets may be coated by the conventional method known in the art Liquid preparation for use oral form may be in the form of an aqueous or oily suspension, solution, syrup, elixir and the like or may be a dry product ready to be redissolved

  with water or other suitable vehicles before use.

  These liquid preparations may contain the usual additives

  used, for example suspending agents such as

  sorbitol syrup, methylcellulose, glucose syrup

  cose / sugar, gelatin, hydroxyethylcellulose, carbox-

  methylcellulose, an aluminum stearate gel or a grease

  edible hydrogenated; emulsifiers such as lecithin

  thine, sorbitan magnesium, or gum arabic; of the

  non-aqueous vehicles such as almond oil, coconut oil,

  fractional prah, an oily ester, propylene glycol or ethyl alcohol; preservatives such as methyl p-hydroxybenzoate, propyl p-hydroxybenzoate

or sorbic acid.

  An injectable composition is provided in the form of an ampoule containing a unit dose or a container for multiple doses, a preservative having been

  added to the composition The composition may be in the form of

  of a suspension, a solution, an emulsion in an oily or aqueous vehicle, and may contain a prescribed agent such as a suspending agent, a stabilizer and / or a dispersing agent. the active ingredient can be a powder ready to be redissolved in a suitable vehicle, for example

  example of the pyrogen-free and sterilized water, before use.

  Examples and examples of non-limiting

  following examples are given as an illustration of the in-

vention.

EXAMPLE 1

  Monascus ruber # 1005 (FERM-P 4822, ATCC 20657) is inoculated in a liquid medium containing 3% glucose, 1% peptone, 3% defatted soybean powder, 7% glycerol, 0.2% sodium and 0.1% magnesium sulphate heptahydrate (Mg SO 4 7H 2 O) and is cultivated at 28 ° C. under aerobic conditions for 10 days. The filtrate resulting from the culture (50 l) is admixed with hydrochloric acid. 6 N for

  obtain a pH of 3, then the filtrate is extracted with a quantity of

  equal amount of ethyl acetate The extract is concentrated to dryness

  and the residue is dissolved in 1 liter of benzene, and then separated

  The insoluble material is filtered off. The filtrate is washed twice with 500 ml of an aqueous solution of sodium bicarbonate.

  To the benzene solution, 1% sodium

  0.2 N sodium hydroxide solution and shake the mixture

  resulting mixture at room temperature A separation of

  after confirming the disappearance of dihydro-

  nacoline L of the benzene layer by chromatography in

  The pH of this aqueous layer is adjusted to a range of

  3.0 of them with 6 N hydrochloric acid and extracted with 2 times 1 liter of ethyl acetate. The extract is concentrated to dryness to obtain 3.1 g of an oily material.

  oily material in benzene and subjected to a crystalline

  to precipitate monacolin K produced simultaneously.

  The mother liquor was dried from which the crystals were separated, the residue was dissolved in benzene and adsorbed on a column packed with 80 g of silica gel (Wako C-200 gel). The column was developed successively with 400 g. ml of dichloromethane, 5 liters of a mixture of dichloromethane and

  of ethyl acetate (9: 1) and 7 liters of a mixture of dichloromethane

  methane and ethyl acetate (8: 2) Dissolve in

  zene a fraction containing dihydromonacoline L (a fraction

  giving a brown spot by spraying with sulfuric acid

18546

  and heating at 120 ° C. to the Rf value of 0.45, developed by thin layer chromatography on silica gel

  5715, Silica gel (R) 60 F 254 / manufactured by Merck & C /,

  CH 2 C 12 / acetone = 9: 1) and adsorbed on a column packed with 40 g of silica gel (Wako C-200 gel), followed by

  veloppe with 250 ml of hexane and 4 liters of a mixture of hexa-

  and acetone (9: 1). A fraction containing dihydromonacoline L is dried and dissolved in 60 ml of benzene before washing with twice 30 ml of 5% sodium bicarbonate solution. benzene solution and

  concentrated to dryness to obtain 30 mg of a white powder.

  This white powder is subjected to a high-speed liquid chromatography (column of silica gel type

  ODS, development with a solvent consisting of acetonitrile -

  0.1% phosphoric acid solution, 1: 1) to collect a dihydromonacoline L fraction.

  solvent by distillation, 18 mg of dihydro-

  not L in the form of a crystalline white powder.

  Elemental analysis: Calculated: C, 74.50%; H, 9.85% Found: C, 74.63%; H 9, 79%

  Molecular weight: 306 (C 19 H 3003).

EXAMPLE 2

  100 mg of monacolin L is dissolved in 5 ml of tetrahydrofuran.

  dry hydrofuran and to this solution 5 mg of oxide is added

  platinum and the resulting solution is hydrogenated.

  hydrogen with stirring at room temperature for 15 hours. The catalyst is filtered off and

  crystallizes the resulting product in a mixture of acetate of

  thyle and hexane to obtain 63 mg of white crystals of

  trahydromonacoline L. Elemental analysis: Calculated: C 74.03%; H, 10.39% Found: C, 74.13%; H 10.42% Molecular Weight: 308 (C 19 H 3203)

  Ultraviolet Absorption Spectrum (MeOH): Tertiary absorption

  min Infrared absorption spectrum (k Br): v 3500, 1730 cm 1

Melting point: 101 to 105 OC.

EXAMPLE 3

  60 mg of dihydromonacoline L obtained according to the method of Example 1 are dissolved in 5 ml of dry tetrahydrofuran

  and to the resulting solution is added S mg of platinum oxide.

  The procedure of Example 2 is then repeated to obtain 33 mg of white crystals of tetrahydromonacoline L. Elemental analysis: Found: C 74.11%; H 10.44% Molecular weight: 308 Ultraviolet absorption spectrum: terminal absorption Infrared absorption spectrum (k Br): 3500, 1730 cm

EXAMPLE 4

  200 mg of monacolin L methyl ester are dissolved in 30 ml of methanol and 10 mg of platinum oxide is added as catalyst before the resulting solution is reduced by

  catalytic way according to the conventional method.

  the catalyst, the concentrated residue is purified by chromatography.

  silica gel graphite (benzene-ethyl acetate,

  9: 1 and 8: 2) to obtain 195 mg of methyl ester of

  trahydromonacoline L in the form of an oily substance.

  Elemental analysis: Calculated: C 70.59%; H, 9.59 Found: C, 70.60%; H 10, 61% Molecular weight: 340 (C 20 H 3604) Ultraviolet absorption spectrum (methanol): terminal absorption Infrared absorption spectrum: -3200, 1740, 1730 cm

EXAMPLE 5

  120 mg of tetrahydromonacoline L are dissolved in 5 ml of benzene and 0.4 ml of a hydroxide solution is added.

  0.1N sodium, and the resulting mixture is stirred at 40 ° C.

  After 2 hours, an aqueous layer is separated from the mixture and washed with 3 times 2 ml of benzene before freeze-drying to obtain 104 mg of the sodium salt of tetrahydromionacoline.

in the form of a white powder.

  Elemental analysis: Calculated: C 65.52 5; H 9.48% Found: C 65.98%; H 9, 61%

  Ultraviolet Absorption Spectrum (H20): terminal absorption

  Infrared Absorption Spectrum (k Br): 3420, 2930, 1720, 1650 cml. Repeating the procedure of this example and replacing

  tetrahydromonacoline L by dihydromonacoline L, we obtain

  holds the sodium salt of dihydromonacoline L e Elemental Analysis: Calculated: C 65.87%; H, 9.02% Found: C, 66.16%; H 9.14% Ultraviolet Absorption Spectrum (H20): terminal absorption Infrared Absorption Spectrum (k Br): 3420, 2930, 1720 ef -1 1650 cm Using calcium hydroxide or hydroxide

  magnesium instead of sodium hydroxide in the example below.

  above, the calcium salt and the salt are respectively obtained

magnesium.

EXAMPLE 6

  Synthesis of dihydromonacoline methyl ester L: 90 mg of dihydromonacoline L are dissolved in 10 ml of methanol and the resulting solution is added 200 mg of an acidic ion exchange resin (Dowex (R) 50, type H) and shake

  the mixture between 60 and 70 ° C. for 3 hours.

  After completion, the resin is separated from the mixture by filtration.

  and the filtrate is evaporated under reduced pressure to remove the solvent, and the resulting residue is purified by column chromatography using 10 g of

  silica gel (developing solvent, benzene-acetate

  thyl, mixtures 9: 1 and 8: 2) to obtain 63 mg of methyl ester.

  dihydromonacoline L in the form of a water-soluble substance

  Leuse. Elemental analysis: Calculated: C 70.97%; H, 10.12% Found: C, 71.37%; H 10.83% Ultraviolet Absorption Spectrum (H 20): terminal absorption Infrared Absorption Spectrum (k Br): 3100, 1740 and -1 1725 cm Composition Example 1 Capsules for oral administration: Tetrahydromonacoline L 250 mg Lactose 75 mg Magnesium stearate 15 mg Total 340 mg

  The powder corresponding to the above formula is mixed

  and passed over a sieve with an opening of

  0.250 mm, then 340 mg of the powder is introduced into a capsule of gelatin n 1 to obtain the capsule composition. Reference Example Synthesis of monacoline methyl ester L: 1 g of monacolin L is dissolved in 15 ml of methanol and 2 g of an ion exchange resin are added to this solution,

  (Dowex (R) 50 W, Type H, in dry form), then heat

  the resulting mixture and stir at 60.degree. to 70.degree.

  3 hours When the reaction is over, the resi-

  of the mixture by filtration, the filtrate is evaporated under pressure.

  reduced to remove the solvent and the residue obtained is purified by column chromatography using 10 g of

  silica gel (developing solvent: benzene-acetate

  thyl, 9: 1 and 8: 2 mixtures) to obtain 650 mg of methyl ester.

  Monacoline L in the form of an oily substance.

  Elemental analysis: Calculated: C 71.39%; H, 9.59% Found: C, 71.44%; H 9, 68%

  Ultraviolet Absorption Spectrum (H20): Tertiary absorption

  min Infrared Absorption Spectrum 3400, Z-3100, 1710 cm 1

N E V E N D I C A T IO N S

  Dihydro and tetrahydroalkanolacoline L represented by the following general formula (I) HO (I) CH 3 in which X represents -CH = CH or -CH 2 -CH 2, as well as the metal salts and the alkyl esters of dihydro and tetrahydromonacolines L represented by the following general formula (II) HO Y (Ii) CH 3. X wherein Y is -M (o M is a metallic element and nn

  is an atomic valence of the metallic element) or a group

  alkyl having 1 to 6 carbon atoms and X has the meaning

cation indicated above.

  Dihydromonacoline L according to claim 1, wherein X is CH = CH- and represented by the formula

HO O

\ (III)

CH

  The tetrahydromonacoline L according to claim 1, wherein X is -CH 2 -CH 2 and having the formula

HO O

(IV) a CH 3 CH 3

  4 Dihydro and tetrahydromona metal salt

  colines L according to claim 1, characterized in that the

  salt is a sodium salt, a calcium salt or an aluminum salt

  minium. Methyl ester of dihydro and tetrahydromonato

lines L according to claim 1.

  6 Process for the preparation of dihydromonato

  line L represented by the following formula (III) Ho \, 0 t (III) CH 3 characterized in that it consists in cultivating a microorganism producing dihydromonacoline L, belonging to the genus

  Monascus, on a nutrient medium and to isolate dihydromona-

coline L produced.

  Process according to Claim 6, characterized in that the microorganism producing dihydromonacoline L,

  belonging to the genus Monascus, is Monascus ruber.

  8 Process according to claim 7, characterized in that the Monascus ruber is Monascus ruber n 1005 (FERM-P

4822, ATCC 20657).

  9 Process for the preparation of tetrahydromonato

  line L represented by the following formula (IV) or one of its

  alkyl esters represented by the following general formula (V):

  wherein R represents an alkyl group having from 1 to 6 carbon atoms, characterized in that it consists in catalytically reducing the monacolin L or the dihydromonacoline L

  or an alkyl ester thereof in an organic solvent.

  Process for the preparation of a metal salt

  or an alkyl ester of dihydro or tetrahydro-

  monacoline L represented by the general formula (VII) HO (VII) CH 3 X i wherein Y represents -M (where M is a metal element n and N is an atomic valence of the metal element) or an alkyl group having 1 to 6 carbon atoms; and X is -CH = CH or -CH 2 -H 2, characterized in that it consists in dissolving the dihydro or tetrahydromonacoline L represented by the following general formula (I) (I) in which X has the meaning indicated below. above, in an organic solvent and reacting the dissolved compound with an aliphatic alcohol having 1 to 6 carbon atoms or a metal hydroxide represented by the general formula (VIII) M (OH) n (VIII)

  in which M and N have the meanings indicated below.

  above. 11 Composition for the treatment of hyperlipemia

  containing a compound according to any one of the claims

  1 to 5, as an active ingredient.