FR2479809A1 - CHOLESTEROL BIOSYNTHESIS INHIBITOR COMPOUNDS, PROCESS FOR PREPARING THEM AND THERAPEUTIC APPLICATION THEREOF - Google Patents

Abstract

THE SUBJECT OF THE INVENTION IS COMPONENTS OF INTEREST AS THERAPEUTIC AGENTS AND CHEMICAL INTERMEDIATE PRODUCTS, RESPONDING TO THE FORMULA: (CF DRAWING IN BOPI) IN WHICH: R, R, R, R, R AND N HAVE SPECIAL MEANINGS. THESE COMPOUNDS MAY BE PREPARED BY CULTIVATION OF MICROORGANISMS OF THE GENUS PENICILLIUM OR MONASCUS OR BY SALIFYING OR ESTERIFYING THE CORRESPONDING CARBOXILIC ACID OR LACTONE OR, IN THE CASE OF ESTERS OF THE ABOVE FORMULA, BY ESTERIFYING A CORRESPONDING SALT OF THE FORMULA.

Description

The present invention relates to a series of

  new compounds that have been shown to inhibit the biosynthesis

  cholesterol thesis and which are, thus, usable for the treatment and prevention of disorders due to high levels of cholesterol in the body. The invention aims

  also a process for preparing these compounds.

  Hyperlipemia and, in particular, hypercholesterolemia

  is known as one of the main causes of

  heart disease such as cardiac infarction

  that or arteriosclerosis. As a result, considerable research has been conducted to discover compounds capable of reducing lipid levels, including cholesterol, in the body. A group of such compounds is described in U.S. No. 3,983,140, isolated from microorganisms of the genus Penicillium, this

  group of compounds being collectively designated ML-236.

  In addition, in US patent applications. 121,515 filed February 14, 1980 and 137,821 filed April 4, 1980, describes a compound having a similar structure,

  designated Monacoline K or MB-530B, and certain salts and esters

  MB-530B are described in U.S. patent application. No. 172. 231 filed July 25, 1980. MB-530B

  and its salts can be prepared by cultivating microorganisms

  Monascus, in particular, but not ex-

  only strains of Monascus ruber.Another

  The group MB-530, designated MB-530A, and other compounds related to ML-236 and MB-530 are described in A. Sato's patent application.

  et al., entitled "Inhibitors of the biosynthesis of choles-

  terol, their preparation and their applications ".

  The Applicant has now discovered a series of

  compounds related to groups ML-236 and MB-530 which

  also feel a valuable inhibitory activity of

the biosynthesis of cholesterol.

  The compounds according to the invention correspond to formula (I):

R4O COD -R2

OR 5

OR3 11)

  Wherein R 1 represents a hydrogen atom or a methyl group; R2 represents a hydrogen atom, the alcohol moiety of an ester or the cationic moiety

  a salt; R3, R4 and R5, which may be the same or different

  are, independently of one another, a hydrogen atom or an organic or inorganic acyl group,

  provided that when R3 represents a 2-methyl group

  butyryl, R4 and R are both groups

acyl; and n is the valence of R2.

  The invention also relates to a preparation process

  compounds according to the invention, by fermentation, used

  microorganisms of the genus Penicillium or Monascus

  or by hydrolysis, salification or

  pricing starting with these fermentation products.

  Since the compounds according to the invention are derivatives of

  compounds ML-236 and MB-530 in which the lactone ring was opened, they are named as

  derivatives of ML-236 carboxylic acids or MB-acids

  530 carboxylic acids (i.e. carboxylic acids obtained by hydrolysis of 2 compounds of ML-236 or MB-530) and the numbering system is that shown in the following structure (in which R1 and R have the above mentioned 3C 7 $ 31 G, 8 ''

  In the compounds of formula (I), when R2 represents

  the cationic moiety of a salt, it may represent a metal atom, for example an alkali metal atom

  (especially sodium or potassium), alkali metal

  earth (especially calcium, magnesium or barium) of transition metal (such as an iron, nickel or cobalt atom) or other metal atoms (especially

  aluminum, zinc or copper); in this case, n represents

  the well-known valence of these metals which, in the

  given examples, normally varies from 1 to 3. R2 can also

  represent an ammonium group or an ammo-

  substituted nium (preferably an alkylammonium

  substituted), for example methylammonium, ethylammonium,

  isopropylammonium, dimethylammonium, diethylammonium, tri-

  methylammonium, triethylammonium, tetramethylammonium, or

  dicyclohexylammonium; in this case, n = 1. Another fragment

  The cationic agent that can be represented by R2 is the salifying group derived from a basic basic amino acid.

  such as lysine, arginine or ornithine.

  R2 may also represent the alcoholic moiety of an ester, in which case the value of n depends on the nature of the hydroxylic compound from which R is derived; for example, in the case of monoalcohols, n would be 1, in the case of glycols n would be 2 and, in the case of glycerol, n

  would be equal to 3. When R2 represents a monovalent group

  slow, it is preferably an alkyl unsubsti-

  killed or replaced by an unsubstituted aralkyl group or

  substituted or unsubstituted or substituted phenacyl group

kill.

  Examples of alkyl groups that can be represented

1 2

  R 2 are selected from linear and branched, preferably C 1 to C 8, alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.butyl, t-butyl, pentyl, sec-pentyl, t-butyl, and the like. pentyl, isopentyl, neopentyl, hexyl, heptyl, 2-methylhexyl

and octyl.

  Examples of aralkyl groups that can be

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  R will be benzyl and benzhydryl, both of which may be unsubstituted or

  carry one or more substituents on the benzene ring

  than. Examples of such substituents are: C1-C4 alkyl groups (methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl or t-butyl), C1-C4 alkoxy groups (methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy or t-butoxy), halogen atoms (for example chlorine, bromine or fluorine) or trifluoromethyl group. When there are 2

  substituents or more, they may be identical or different

  ent. Examples of these aralkyl groups are:

  benzyl, 2-methylbenzyl, 3-methylbenzyl,

  4-methylbenzyl, 2-ethylbenzyl, 3-ethylbenzyl, 4-ethyl-

  benzyl, 2-propylbenzyl, 3-propylbenzyl, 4-propylbenzyl, 2-butylbenzyl, 3-butylbenzyl, 4-butylbenzyl, 2-methoxy

  benzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-propoxy-

  benzyl, 3-propoxybenzyl, 4-propoxybenzyl, 4-butoxybenzyl

  zyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl,

  2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-fluoromethyl

  benzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-trifluoro-

  methylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethyl

benzyl and benzhydryl.

  When R2 represents a phenacyl group, this

  may be unsubstituted or carry one or more substitutes

  killing on the benzene nucleus. As examples of these sub-

  Examples are: (1-4C) alkyl groups, (1-4C) alkoxy groups, halogen atoms and trifluoromethyl group. As particular examples of

  these groups are those mentioned above. As an example

  Preferred of these phenacyl groups are: phenacyl, 2-methylphenyl, 3-methylphenyl,

  4-methylphenacyl, 2-nacyl, enacyl, 3-ethylphenacyl, 4-

  ethylphenacyl, 2-propylphenacyl, 3-propylphenacyl, 4-

  propylphenacyl, 2-butylphenacyl, 3-butylphenacyl, 4-

  butylphenacyl, 2-methoxyphenacyl, 3-methoxyphenacyl, 4methoxyphenacyl, 2-ethoxyphenacyl, 3-ethoxyphenacyl, 4ethoxyphenacyl, 2-propoxyphenacyl, 3-propoxyphenacyl, 4propoxyphenacyl, 2-butoxyphenacyl, 3-butoxyphenacyl, 4-butoxyphenacyl, 2-chlorophenacyl, 3 -chlorophénacyle,

  4-chlorophenacyl, 2-bromophenacyl, 3-bromophenacyl, 4-

  bromophenacyl, 2-fluorophenacyl, 3-fluorophenacyl, 4-

  fluorophenacyl, 2-trifluoromethylphenacyl, 3-trifluoro-

  methylphenacyl and 4-trifluoromethylphenyl.

  When R represents a divalent alcohol moiety

  it is preferably an alkylene or alkyl group

  C2 to C6 iden, for example an ethylene group, ethyl

  propylene, propylidene, trimethylene, tetramethylene, butylidene, pentamethylene or pentylidene, as well as those groups bearing one or more substituents such as

  hydroxy groups, halogen atoms or tri-groups

fluoromethyl.

  When R represents a trivalic alcoholic moiety

  it preferably represents a C2-C6 saturated aliphatic hydrocarbon group optionally bearing one or more substituents such as hydroxy groups,

  halogen atoms or trifluoromethyl groups.

3 4 5

  When R 3, R or R is an acyl group, it may be an organic acyl group (for example an aliphatic acyl group, an aromatic acyl group, a group

  araliphatic acyl, an alicyclic acyl group, a

  heterocyclic acyl, an aliphatic acyl group with

  heterocyclic substitution, an aliphatic sulfonyl group

  an aromatic sulphonyl group, an aliphatic phosphoryl group, an aromatic phosphoryl group or an araliphatic phosphoryl group) or an inorganic acyl group (for example an acyl group derived from phosphoric acid,

  sulfuric acid or nitric acid).

  When the acyl group is an aliphatic acyl group

  It may be saturated or unsaturated and, as examples, linear or saturated C 2 to C 20 alkanoyl groups (for example acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, 2-methylvaleryl). , heptanoyl, isoheptanoyl, octanoyl, isooctanoyl, 2-methyloctanoyl, nonanoyl, isononanoyl,

  decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetra-

  decanoyl, pentadecanoyl, palmitoyl, stearoyl, isostearate

  royle, nonadecanoyl and dicosanoyl); alkenoy groups

  C 3 to C 20 (e.g., acryloyl, crotonoyl, 3-butenoyl, methacryloyl, 3-methyl-2-butenoyl, 2-pentenoyl,

  4-pentenoyl, tigloyl, angeloyl, 2-hexenoyl, 2-heptenoyl

  oyl, hept-2,4-dienoyl, -2-octanoyl, 2-nonenoyl, 2-decane

  nuclei, 2-undecenoyl, linolenoyl, oleoyl, linoleyl and arachidonoyl); as well as C3-C20 alkynoyl groups (for example 2-butynoyl, 3-butynoyl, 2-pentynoyl,

  2-hexynoyl, 2-heptynoyl, 2-octynoyl, 2-nonynoyl and 2-

  décynoyle). These acyl groups may be unsubstituted or carry one or more substituents, in particular: halogen atoms (for example chlorine or bromine); the

  trifluoromethyl group; the nitro group; the group car-

  boxy; alkoxycarbonyl groups such as methylene

  xycarbonyl or ethoxycarbonyl; aralkoxycarbo groups

  nyl such as benzyloxycarbonyl; the cyano group; the amino group; alkanoylamino groups (for example acetylamino); alkylamino groups (for example methyl

  amino, dimethylamino or ethylamino); aralcoyl groups

  amino (for example benzylamino); the hydroxy group; alkanoyloxy groups (for example acetoxy or pivaloyloxy); alkoxy groups (for example methoxy or ethoxy); the sulfhydryl group; alkylthio groups (for example methylthio or ethylthio); as well as acylthio groups

  (eg acetylthio or benzylthio).

3 4 5

  When the acyl group represented by R 3, R or R is an aromatic acyl group, the aromatic ring may be a single ring (i.e., a benzene ring) or a fused ring (e.g., a naphthalene ring, a

  anthracene nucleus or an indane nucleus). This nucleus may

  have one or more substituents, for example

  ple of alkyl groups, alkoxy groups, atoms

  halogen, trifluoromethyl groups, nitro groups,

  tro, cyano groups, amino groups or groups

  hydroxy; when there are two or more substituents, they may

  may be identical or different. As examples

  of these aromatic acyl groups, mention may be made of

  benzoyl, o-toluoyl, m-toluoyl, p-toluoyl, 2,4-

  dimethylbenzoyl, 3,4-dimethylbenzoyl, 2-ethylbenzoyl,

  3-ethylbenzoyl, 4-ethylbenzoyl, 2-propylbenzoyl, 3-

  propylbenzoyl, 4-propylbenzoyl, 4-butylbenzoyl, o-anis

  oyl, m-anisoyl, p-anisoyl, 2,4-dimethoxybenzoyl, 2-

  ethoxybenzoyl, 3-ethoxybenzoyl, 4-ethoxybenzoyl, 2-pro-

  poxybenzoyl, 3-propoxybenzoyl, 4-propoxybenzoyl, 2-bu-

  toxybenzoyl, 3-butoxybenzoyl, 4-butoxybenzoyl, piperazole

  Nyloyl, 2-chlorobenzoyl, 3-chlorobenzoyl, 4-chlorobenzene

  zoyl, 2,3-dichlorobenzoyl, 3,4-dichlorobenzoyl, 2,4-di-

  chlorobenzoyl, 2-bromobenzoyl, 3-bromobenzoyl, 4-bromobenzoyl

  benzoyl, 2-fluorobenzoyl, 3-fluorobenzoyl, 4-fluoro

  benzoyl, 2-trifluoromethylbenzoyl, 3-trifluoromethyl

  benzoyl, 4-trifluoromethylbenzoyl, 2-nitrobenzoyl, 3-

  nitrobenzoyl, salicyloyl, 3-hydroxybenzoyl, 4-hydroxy-

  benzoyl, 2-acetoxybenzoyl, 3-acetoxybenzoyl, 4-acetoxy-

  benzoyl, anthraniloyl, 2-acetamidobenzoyl, 4-acetamido

  benzoyl, vanilloyl, veratroyl, protocatachuoyl, gal-

  mole, 1-naphthoyl, 2-naphthoyl, 2-anthranoyl, 4-indanyl

  carbonyl, 5-indanecarbonyl and 4-indenecarbonyl.

3 4 5

  When the acyl group represented by R3, R or R is an araliphatic acyl group, the aromatic nucleus of this araliphatic acyl group may be a single ring or a fused ring, examples of which are the same.

  than those mentioned above with regard to the acyl group

  while the aliphatic fragment can be

  saturated or unsaturated. The aromatic ring may optionally carry one or more substituents as indicated above with respect to aromatic acyl groups. Examples of such araliphatic acyl groups include

  phenylacetyl, 2-methylphenylacetyl, 3-methylphenylacetyl

  4-methylphenylacetyl, 2-ethylphenylacetyl, 2-methoxy-

  phenylacetyl, 3-methoxyphenylacetyl, 4-methoxyphenylacetate

  tyl, 2-ethoxyphenylacetyl, 3-ethoxyphenylacetyl, 4-

  ethoxyphenylacetyl, 2-propoxyphenylacetyl, 3-propoxy-

  phenylacetyl, 4-propoxyphenylacetyl, 2,4-dimethoxyphenyl

  acetyl, 3,4-methylenedioxyphenylacetyl, 2-hydroxyphenyl

  acetyl, 3-hydroxyphenylacetyl, 4-hydroxyphenylacetyl, 2chlorophenylacetyl, 3-chlorophenylacetyl, 4-chloroacetyl,

  phenylacetyl, 2,3-dichlorophenylacetyl, 2,4-dichloro-

  phenylacetyl, 3,5-dichlorophenylacetyl, 2-bromophenyl-

  acetyl, 3-bromophenylacetyl, 4-bromophenylacetyl, 2-

  nitrophenylacetyl, 3-nitrophenylacetyl, 4-nitrophenyl

  acetyl, 4-aminophenylacetyl, 2-phenylpropionyl, 3- (2-

  methylphenyl) propionyl, 3- (3-methylphenyl) propionyl,

  3- (4-methylphenyl) propionyl, 3- (2-methoxyphenyl) propionic acid

  Nyl, 3- (3-methoxyphenyl) propionyl, 3- (4-methoxyphenyl) -

  propionyl, 3- (3,4-methylenedioxyphenyl) propionyl, 3- (2-

  chlorophenyl) propionyl, 3- (3-chlorophenyl) propionyl, 3- (4-chlorophenyl) propionyl, phenoxyacetyl, cinnamoyl, o-methylcinnamoyl, mmethylcinnamoyl, p-methylcinnamoyl,

  o-methoxycinnamoyl, m-methoxycinnamoyl, p-methoxycinna-

  av, o-hydroxycinnamoyl, m-hydroxycinnamoyl, p-hydroxy

  cinnamoyl, o-chlorocinnamoyl, m-chlorocinnamoyl, p-

  chlorocinnamoyl, o-bromocinnamoyl, m-bromocinnamoyl,

and p-bromocinnamoyl.

  When the acyl group represented by R3, R4 or R5 is an alicyclic acyl group, the alicyclic ring may

  be saturated or unsaturated and is preferably C3-C7.

  Examples of such alicyclic acyl groups are cyclopropanecarbonyl, cyclobutanecarbonyl,

  cyclobut-1-enecarbonyl, cyclobut-2-enecarbonyl, cyclohexyl

  pentanecarbonyl, cyclopent-1-enecarbonyl, cyclopent-2-

  decarbonyl, cyclopent-1,3-dienecarbonyl, cyclopent-2,4-

  dienecarbonyl, cyclohexanecarbonyl, cyclohex-1-enecarbonyl

  Nyl, cyclohex-2-enecarbonyl, cyclohex-3-enecarbonyl, cyclohex-1,3-diecarbonyl, cyclohex-2,4-dienecarbonyl,

  cycloheptanecarbonyl, cyclohept-1-enecarbonyl, cyclohept-

  2-enecarbonyl, cyclohept-2,4-dienecarbonyl, cyclohept-

  2,5-dienecarbonyl, cyclohept-1,4-dienecarbonyl, cyclopentyl

  hept-1,5-dienecarbonyl, cyclohept-1,3,5-trienecarbonyl,

  cyclohept-2,4,6-trienecarbonyl and adamantanecarbonyl.

  These nuclei may eventually carry one or more

  substituents as indicated above with respect to groups

  aromatic acyls, and these substituents can form one or more fused rings on the ring system

alicyclic aforesaid.

  When the acyl group represented by R3, R or R

  is a heterocyclic acyl group, the heterocyclic ring

  preferably 5 or 6 ring atoms, one or more of which is (or are) heteroatom (s)

  for example nitrogen, oxygen, sulfur or selenium.

  This heterocyclic ring can optionally be condensed

  with a carbocyclic ring or with another hetero ring.

  cyclical (which may be the same as the first one or may be different from this) by forming a

  condensed heterocyclic ring. The heterocyclic acyl group

  that one or more substituents such as those mentioned above may be carried with regard to aromatic acyl groups. As particular examples of these heterocyclic acyl groups

  there will be mentioned 2-thenoyl, 3-thenoyl, 5-methylthenyl

  2-oyl, 5-chlorothen-2-yl, 4,5-dimethylthen-3-oyl,

  2-furoyl, 3-furoyl, 3-methylfur-2-oyl, 5-chlorofur-2-

  oy, pyridine-2-carbonyl, 3-methylpyridin-2-carbonyl, 4-methylpyridin-2-carbonyl, 5-methylpyridin-2-carbonyl, 6-methylpyridin-2-carbonyl, nicotinoyl, isonicotinoyl,

  isoxazole-3-carbonyl, isoxazole-4-carbonyl, oxazole-2-

  carbonyl, oxazole-4-carbonyl, 4-acetylaminothiazole-2

  carbonyl, 1,3,4-thiadiazole-2-carbonyl, 5-methyl-1,3,4-

  thiadiazole-2-carbonyl, 1,2,3-triazole-1-carbonyl, 1,2,

  3,4-Tetrazol-1-carbonyl, piperidinecarbonyl, 4-methyl-

  1-piperazinecarbonyl, 1-pyrrolidinecarbonyl, benzofuran

  Ran-2-carbonyl and benzothiophene-2-carbonyl.

  When the acyl group represented by R3, R4 or R5

  is a heterocyclic substituted aliphatic acyl group

  the heterocyclic group may be as described above with respect to the heterocyclic acyl groups and the aliphatic moiety may be saturated or unsaturated and may be as described above with respect to the acyl groups

  aliphatic. Examples of such aliphatic acyl groups are

  heterocyclic-substituted ticks, the groups

  2-thienylacetyl, (5-methylthiophen-2-yl) acetyl, (5-chlorothiophene-2-yl) acetyl, 3-thienylacetyl, 2-furyl

  acyl, 3-furylacetyl, 2-pyridylacetyl, 3-pyridylacetate,

  yl, 4-pyridylacetyl, 2-furylacryloyl, 3-furylacryloyl, 2-thienylacryloyl, 3-thienylacryloyl, piperidinoacetyl

  and 4-methylpiperidinoacetyl, 2-amino-3- (indol-2-yl) -

  propionyl and 2-amino-3- (indol-3-yl) propionyl.

3 4 5

  When the acyl group represented by R 3, R or R is a sulfonyl group, it may be an aliphatic sulfonyl group (for example a methanesulfonyl or ethanesulfonyl group) or an aromatic sulfonyl group (for example,

  benzenesulphonyl or toluenesulfonyl).

3 4 5

  When the acyl group represented by R3, R or R

  is a phosphoryl group, it can be a phospho-

  aliphatic ryle (for example dimethylphosphoryl or di-

  ethylphosphoryl), an aromatic phosphoryl group (eg

  ditolylphosphoryl example) or a phosphoryl group

  lipid (for example dibenzylphosphoryl, p-methyl-

benzylphosphoryl, p-bromobenzylphosphoryl or p-methoxy-

benzylphosphoryle).

  Among the compounds according to the invention, are preferably

  compounds in which: R 1 represents a hydrogen atom or a methyl group; R2 represents a hydrogen atom, a metal atom (in particular an alkali metal atom, an alkaline earth metal atom or an aluminum, zinc, iron or germanium atom), an ammonium group or an ammonium group; alkyl substituted, a group capable of forming a salt derived from an amino acid

  basic alkyl group (preferably an alkyl group

  linear or branched C1 to C8), an aralkyl group optionally bearing one or more substituents on the

  aryl moiety or a phenacyl group

  one or more substituents on the phenyl moiety, said substituents being selected from C1 to C4 alkyl groups, C1 to C4 alkoxy groups, halogen atoms and trifluoromethyl groups; and R3 R and

  R, which may be the same or different, represent

  independently of each other a hydrogen atom, an aliphatic acyl group (preferably a C2-C20 alkanoyl group, a C3-C20 alkenoyl group or

  C3-C20 alkynoyl), an aromatic acyl group,

  (preferably C 7 -C 15) or araliphatic acyl (preferably C 8 -C 9 aralkanoyl or C 9 aralkenoyl) provided that when R 3 is 2-methylbutyryl, R 4 -

  and R are both acyl groups.

  The compounds of formula (I) in which R represents a hydrogen atom or a methyl group are still preferable; R2 represents a hydrogen atom, an alkali metal atom, an alkaline earth metal atom, an ammonium group, a group capable of forming a salt derived from a basic amino acid, a C1-C4 alkyl group, a benzyl group or a phenacyl group; and R3, R4

  and R5, which may be the same or different, represent

  independently of one another are hydrogen, C 2 -C 6 alkanoyl, C 3 -C 6 alkenoyl or benzoyl, provided that when R 3

  represents a 2-methylbutyryl group, R4 and R5 represent

both acyl groups.

  The most preferable compounds are those in which R 1 represents a hydrogen atom or a methyl group (in particular a hydrogen atom); R represents a C1-C4 alkyl group, a benzyl group or a phenacyl group (in particular a C1-C4 alkyl group); R3 represents a C2-C6 alkanoyl group or a C3-C6 alkenoyl group (particularly an alkanoyl group);

4 5

  C2 to C6); and R and R5, which may be the same or different, represent independently of one another

  a C2-C6 alkanoyl group or a benzoyl group (for example

  especially an acetyl group or a benzoyl group).

  An interesting class of compounds according to the present

  the invention is that of the compounds of formula (II): ## STR2 ## wherein: R 1 represents a hydrogen atom or a methyl group; R2a represents a hydrogen atom, an alkali metal atom, an alkaline earth metal atom, an ammonium group, a group capable of forming a salt derived from a basic amino acid, a C1-alkyl group;

  at C4, a benzyl group or a phenacyl group; R3a

  C2-C6 alkanoyl (other than a

  eg 2-methylbutyryl) or a C 3 -C 6 alkenoyl group; and 2a

  m is the valence of the atom or group represented by R2a.

  Especially preferable are the compounds of

  wherein R 2a represents an alkyl group

  C1 to C4, a benzyl group or a phenacyl group as well as the compounds of formula (II) in which R2a

  represents an alkali metal atom.

  Another particularly interesting class of

  compounds according to the present invention are those

poses of formula (III):

HO COOM

-H

  Wherein R1 represents a hydrogen atom or a methyl group and M represents a hydrogen atom or a hydrogen atom.

  alkali metal atom, preferably a sodium atom.

  Examples of compounds according to the invention are

  in the following list in which, as indicated above, the compounds are named as derived from

  ML-236A, ML-236B, MB-530A or MB-530B or their carboxylic acids

  corresponding boxylics: 1. ML-236A-sodium carboxylate 2. calcium bis (ML236A-carboxylate) 3. MB-530A-sodium carboxylate 4. calcium bis (MB530A-carboxylate) 5. ML-236A-methyl carboxylate 6. ML-236A-ethylcarboxylate

14 2479809

  7. Butyl ML-236A-carboxylate 8. Benzyl ML-236A-carboxylate 9. P-Bromobenzyl ML236A-carboxylate 10. Methoxybenzyl ML-236A-carboxylate 11. Phenacyl ML-236A-carboxylate 12. ML-236A carboxylate p-methoxyphenacyl 13. Methyl MB-530A-carboxylate 14. MB-530A-ethyl carboxylate 15. Butyl MB-530A-carboxylate 16. Benzyl MB530A-carboxylate 17. p-Methoxybenzyl MB-530A-carboxylate 18. Phenacyl MB-530A-carboxylate 19. Methoxyphenacyl MB-530A-carboxylate 20. Methyl 8'-OO-acetyl-ML-236A-carboxylate 21. Methyl 8'-Oacetyl-ML-236A-carboxylate 22. Ethyl 8'-OO-acetyl-ML-236A carboxylate 23. Butyl 8 '-O-acetyl-ML-236A-carboxylate 24. Benzyl 8'-O-acetyl-ML-236A-carboxylate 25. 8'- P-Methoxybenzyl O-acetyl-ML-236carboxylate 26. Phenyl 8 '-O-acetyl-ML-236A-carboxylate 27. 8'-O-acetyl-ML-236A-carboxylic acid 4-methoxyphenacyl 28. 8'- Sodium 0-acetyl-MB-530A-carboxylate 29. 8'-OO-acetyl-MB-530A-carboxylate ethyl 30. Ethyl 8'-O-acetyl-MB-530A-carboxylate 31. 8'-OO-acetyl-MB-530A-butyl carboxylate 32. 8'-O-acetyl-MB-530Baryyl carboxylate 33. Phosphenyl 8'-O-acetyl-MB-530A-carboxylate 34. Phenacyl 8 '-O-acetyl-MB-53OA-carboxylate 35. 8-O-acetyl-MB-530A-p-methoxyphenacyl carboxylate 36. 8'- Sodium O-propionyl-ML236A-carboxylate 37. Ethyl 8 '-O-propionyl-ML-236A-carboxylate 38. 8-O-propionyl-ML-236A-ethyl carboxylate 39. 8'-Opropionyl-ML- Benzyl benzyl α-carboxylate 40. 8'-O-propionyl-ML-236Phenacyl carboxylate 41. 8'-O-propionyl-MB-530A-carboxylate 42. 8'-O-pronionyl-MB-530A-carboxylate methyl 43. ethyl 8'-Opropionyl-MB-530A-carboxylate 44. 8'-O-propionyl-MB-530A butyl carboxylate 45. 8'-O-nropionyl-MB-530A-benzyl carboxylate 46. 8 ' 47. 8'-O-butyryl-ML236A-sodium carboxylate 48. bis (8'-O-butyryl-ML-236A-carboxylate) 49. tris (8-phenolyl) -O-propionyl-MB-530A-carboxylate '-O-butyryl-ML-23 6A-carboxylate) aluminum 50. 8'-O-butyryl-ML-236A-carboxylate methyl 51. 8'-O-butyryl-ML-236A carboxylate ethyl 52. 8'-O-butyryl-ML-236A-carboxylate butyl ester 53. Benzyl 8'-O-butyryl-ML-236A-carboxylate 54. 8'-O-butyryl-ML-236Phenacyl carboxylate 55. Dimethylamino 8'-O-butyryl-ML-236A-carboxylate

  Ethyl 56. 8'-O-butyryl-MB-530A-carboxylate 57. bis (8'-O-butyryl-MB-530A-carboxylate) calcium 58. 8'-O-butyryl-MB-530Carboxylate 59. Ethyl 8'-O-butyryl-MB-530A-carboxylate 60. 8'-O-butyryl-MB-530A-butyl carboxylate 61. 8'-O-butyryl-MB-530Baryyl carboxylate 62. 8'- Phenacyl 0-butyryl-MB-530A-carboxylate 63. sodium 8'-O- (4-pentenoyl) -MML-236A-carboxylate 64. Methyl 8'-O- (4-pentenoyl) -MML-236A-carboxylate 65 Ethyl 8'-O- (4-pentenoyl) -M.-236-carboxylate 66. Butyl 67. 8'-O- (4-pentenoyl) -MML-236A-carboxylate 67. 8'-Q- (4-pentenoyl) Benzyl Mg-236A-carboxylate 68. 8'-O- (4-pentenoyl) -MR-236A-phenoxy carboxylate 69. sodium 8'-O- (4-pentenoyl) -MB530A-carboxylate 70. 8'-O Methyl (4-pentenoyl) -MB-530A-carboxylate 71. Ethyl 8'-O- (4-pentenoyl) -MB-530A-carboxylate 72. 8'-O- (4-pentenoyl) -MB-530A- butyl carboxylate 73. 8'-O- (4-pentenoyl) -MB-530Baryyl carboxylate 74. Phenacy 8'-O- (4-pentenoyl) -MB-530A-carboxylate 75. 8'-O-isovaleryl-ML-236A-sodium carboxylate 76. 8'-Oisovaleryl-ML-236A-methyl carboxylate 77. 8'-O-isovaleryl-ML-236Carboxylate 78. 8 ' Butyl 79-isovaleryl-ML-236A-carboxylate 79. 8'-O-isovaleryl-ML-236A-benzyl carboxylate 80. 8'-O-isovaleryl-ML236A-phenoxy carboxyate 81. 8'-O-isovaleryl Sodium methyl-82-B-530A-carboxylate 82. Methyl 8 '-O-isovaleryl-MB-530A-carboxylate 83. 8'-isovaleryl-MB-530A-ethyl carboxylate 84. 8'-O-isovaleryl-MB- 530Butyl carboxylate 85. 8'-O-isovaleryl-MB-530A-benzyl carboxylate 86. 8'-O-isovaleryl-MB-530A-carboxylate of phenacyl 87. 8'-O-hexanoyl-ML236A-sodium carboxylate 88 Methyl 8'-O-hexanoyl-ML-236A-carboxylate 89. Ethyl 8 '-O-hexanoyl-ML-236A-carboxylate 90. 8'-O-hexanoylML-236A-butyl carboxylate 91. 8' Benzophenyl O-hexanoyl-ML-236A-carboxylate 92. 8'-O-hexanoyl-ML-236A-phenacyl carboxylate 93. 8'-Ohexanoyl-MB-530A-sodium carboxylate 94. 8'-O-hexanoyl -MB53O methylcarboxylate 95. Ethyl 8'-O-hexanoyl-MB-530A-carboxylate 96. 8'-O-hexanoyl-MB-530A-Butyl carboxylate 97. 8'-O-hexanoyl-MB-530Baryyl carboxylate 98. Phenacyl 8'-O-hexanoyl-MB-530A-carboxylate 99. 8'-O-palmitoyl-ML-236A-sodium carboxylate 100. Methyl 8 '-O-almitoyl-ML236A-carboxylate 101. 8'-0 Benzyl alginate-ML-236A-carboxylate 102. Phenolyl 8'-O-palmitoyl-ML-236A-carboxylate 103. 8 '-Opalmitoyl-MB-530A-sodium carboxylate 104. 8'-O-palmitoyl-MB Methyl 5-carboxylate 105. Ethyl 8 '-O-palmitoyl-MB-530A-carboxylate 106. 8'-O-palmitoyl-MB-530A-benzyl carboxylate 107. 8'-O-stearoyl-ML236A-carboxylate sodium 108. sodium 8'-O-stearoyl-MB-530A-carboxylate 109. 8'-O-linolenoyl-ML-236A-sodium carboxylate 110. 8'-Olinolenoyl-ML-236A-methyl carboxylate 111. 8 Methyl α-O-linolenoyl-MB-530A carboxylate 112. 8'-O-linolenoyl-MB-530A-carboxylate 113. 8'-O-benzoyl-ML-236A-sodium carboxylate 114. 8'-0 -benzoyl-ML236A-carboxylate potassium 115. Tris (8'-O-benzoyl-ML-236A carboxylate) aluminum 116. Methyl 8'-O-benzoyl-ML-236A-carboxylate 8'-O-benzoyl-ML-236A-ethyl carboxylate Butyl 8 '-O-benzoyl-ML-236Abutyl carboxylate 8'-OO-benzoyl-ML-236A-carboxylate 8'-Obenzoyl-ML-236A-carboxylate D-methoxybenzyl 8'-O-benzoyl-ML-236A carboxylate of phenophyl 8'-O-benzoyl-ML-236A-carboxylic acid methoxyphenacyl 8'-O-benzoyl-MB-530A-sodium carboxylate 8'-O-benzoylMB-530A-potassium carboxylate tris (8'-O-benzoyl) Methyl 8 '-O-benzoyl-MB-530A-carboxylate 8'-O-benzoyl-MB530A-ethyl carboxylate 8'-O-benzoyl-MB-530A-carboxylate benzyl 8-butylbenzoyl-MB-530A-carboxylate 8'-Obenzoyl-MB-8'-O-benzoyl-MB-530A-carboxylic acid 8'-O-benzoyl-MB-530A-carboxylate p-methoxybenzyl 8'-O-benzoyl-MB-530A carboxylate 5'-methoxyphenacyl 530A-carboxylate 8'-O- (-toluoyl) -ML-236A-carboxylate 7'-O- (-toluoyl) 8'-O- (-toluoyl) -ML236A- sodium carboxylate; -ML Ethyl -236A-carboxylate 8'-O- (D-toluoyl) ML-236A-Butyl carboxylate 8'-O- (p-toluoyl) -MML-236A -benzyl carboxylate 8'-O- (-toluoyl) Phenacyl Mg-236A-carboxylate 8'-O- (toluoyl) -MB-530A-carboxylate 8'-O- (p-toluoyl) -MB-530A methylcarboxylate 8'-O- (-toluoyl) Benzyl 8'O- (p-toluoyl) -MB-530A-carboxylate 8'-O- (p-toluoyl) -MB-530A carboxylate 8'-O- (p-toluoyl) -MB-530A-phenacyl carboxylate 8'-O- (2-chlorobenzoyl) Sodium 8 '-O- (2-chlorobenzoyl) -MB-530A-sodium carboxylate sodium 8' -O- (3chlorobenzoyl) -MML-236A-carboxylate sodium 8'-O- sodium chlorobenzoyl) -MB530A-carboxylate sodium 8 '-O- (4-chlorobenoyl) -MML-236A-carboxylate sodium 8'-O- (4-chlorobenzoyl) -MB-530A-carboxylate 8'-Osalicyloyl- ML-236A-sodium carboxylate 8'-O-salicyloyl-ML-236Carboxylate of potassium 8'-OO-salicyloyl-ML-236A-carboxylate of methyl 8'-O-salicyloyl-ML-236A-ethyl carboxylate 117. 118. 119. 120. 121. 122. 123. 124. 125.

126.

127. 128. 129. 130.

131.

132. 133. 134. 135.

136.

137. 138. 139. 140.

141.

142. 143. 144. 145.

146.

147. 148. 149. 150.

151.

152. 153.

18 2479809

  154. Butyl 8'-O-salicyloyl-ML-236A-carboxylate 155. Benzine 8'-O-salicyloylML-236A-carboxylate 156. Phenyl-157. 8'-O-salicyloyl-ML-236A-carboxylate 157. 8 ' Sodium 158. 8'O-salicyloyl-MB-530A-carboxylate 158. 8'-O-salicyloyl-MB-530A-carboxylate 159. methyl 8'-O-salicyloyl-MB530A-carboxylate 160. 8'-O-salicyloyl- 161. 8'-O-salicyloyl-MB-530A-carboxylic acid butyl ester 162. 8'-Osalicyloyl-MB-530A-benzyl carboxylate 163. 8'-O-salicyloyl-MB-530Acarboxylate of phenicyl 164. 8 '-O-phenylacetyl-ML-236A-carboxylate of sodium 165. Methyl 8' -O-Dhenylacetyl-ML-236A-carboxylate 166. 8'-Phenylacetyl-ML-236A-carboxylate ethyl 167. 8'-O-phenylacetyl-ML-236Benzyl carboxylate 168. 8'-O-phenylacetyl-MB-530A-carboxylate of sodium 169. methyl 8'-O-phenylacetyl-MB-530A-carboxylate 170. 8 17-Benzylphenylacetyl-MB-530A-ethyl carboxylate 171. 8'-O-phenylacetyl-MB-53Ocarboxylate benzyl 172. 8'-O-cinnamoyl-ML-23 Sodium 6a-carboxylate 173. sodium 8'-O-cinnamoyl-MB-530A-carboxylate

  174. 8 '-O- (-hydroxycinnamoyl) -L-236-carboxylate-carboxylate

dium

  175. 8'-O- (p-hydroxycinnamoyl) -MB-530A-carboxylate of

dium

  176. 8'-O-cyclohexanecarbonyl-ML-236A-carboxylate of

dium

  177. 8'-O-cyclohexanecarbonyl-MB-530A-carboxylate of

  178. methyl 8'-O- (2-thénovyl) -M-236A-carboxylate 179. methyl 8'-O- (2thenoyl) -MML-236A-carboxylate 180. 8'-O- (2-thenoyl) 181. 8'-O- (2-thenoyl) -MB-530A-carboxylate 182. 8 '- (2-thenoyl) -MB-530A-carboxylate 183. 8-O- (2-thenoyl) -MB-530A-carboxylate. 184. 8'-O- (2-furoyl) -MML-236 Sodium carboxylate 185. 8'-O- (2-furoyl) -MML-236A Methylcarboxylate 186. Ethyl 8 '-O- (2-furoyl) -M.-236A-carboxylate 187. 8'-O- (2-furoyl) -MB-530A-sodium carboxylate 188. 8'-O- Methyl (2-furoyl) -MB-530carboxylate 189. Ethyl 8 '-O-- (2-furoyl) -MB-530A-carboxylate 190. 8'-O- (2-thienylacetyl) -MML-236A- sodium carboxylate 191. 8'-O- (2-thienylacetyl) -MR-236A-carboxylate methyl 192. 8'-O- (2-thienylacetyl) -MML-236A-ethyl carboxylate 193. 8'-O- ( 2-thienylacetyl) Butyl ML-236A-carboxylate 194. Benzyl 8'-O- (2-thienylacetyl) -M-236Barboxylate

  195. Phenyl 8 '-O- (2-thienylacetyl) -M4L-236A-carboxylate

  Methyl 196. 8'-O- (2-thienylacetyl) -MB-530A-carboxylate 197. Methyl 8'-O (2-thienylacetyl) -MB-530A-carboxylate 198. 8'-O- (2-thienylacetyl) 199 -MB-53OA-ethyl carboxylate 199. sodium 8'-O-methanesulphonyl-ML236A-carboxylate 200. methyl 8'-O-methanesulphonyl-ML-236A-carboxylate 201. 8'-O-methanesulphonyl-ML- 236A-ethyl carboxylate 202. 8'-O-methanesulphonyl-MB-530A-carboxylate of sodium 203. 8'-O-methanesulphonyl-MB-530A-carboxylate 204. 8'-O-methanesulphonyl-MB-530A-carboxylate 205. Trisodium 20 '8' -O-phosphoryl-ML236A-trisodium carboxylate 206. 8'-O-phosphoryl-MB-530A-trisodium carboxylate 207. 3-0-acetyl-ML-236A-sodium carboxylate 208. 3-0- Methyl acetylML-236A-carboxylate 209. Ethyl 3-0-acetyl-ML-236A-carboxylate 210. Butyl 3-0-acetyl-ML-236A-carboxylate 211. 3-O-acetyl-ML236A-carboxylate sodium benzyl 212. 3-0-acetyl-MB-530A-carboxylate 213. Methyl 3-O-acetyl-MB-530A-carboxylate 214. 3-O-acetyl-MB-530 Butyl acarboxylate 215. 3-0-acetyl-MB-530A-benzyl carboxylate 216. 3-0-butyryl-ML-530A-sodium carboxylate 217. 3-O-butyryl-ML-236Carboxylate, methyl 218. 3- Butyl 0-butyryl-ML-236A-carboxylate 219. Benzyl 3-0-butyryl-ML-236A-carboxylate 220. 3-0-butyryl-MB-530Sodium carboxoxide 221. 3-O-butyryl-MB-530A methyl carboxylate 222. Ethyl 3-O-butyryl-MB-530A-carboxylate

2479809 -

  223. 3-0-Butyryl-MB-530A-Benzyl Carboxylate 224. 3-O-benzoyl-ML-236Carboxylate Sodium 225. Methyl 3-O-benzoyl-ML-236A-carboxylate 226. 3-O-benzoyl 227. 3-O-benzoyl-ML-236Butyl carboxylate 228. 3-O-benzoyl-ML-236A-carboxylate 229. 3-O-benzoyl-MB-53OA-carboxylate of sodium 230. 3-O-benzoyl-MB-530A methyl carboxylate 231. 3-O-benzoyl-MB-530A-ethyl carboxylate 232. 3-O-benzoyl-MB-530A-butyl carboxylate 233. 3- Benzyl benzyl-benzoyl-MB-530carboxylate 234. 3'-di (O-acetyl) -MR-236A-sodium carboxylate 235. 3,8'-di (O-acetyl) -MML-236A-carboxylate methyl 236. 3,8'-di (O-acetyl) -MR-236A-ethyl carboxylate 237. 3,8'-di (O-acetyl) -MML-236Barbyl carboxylate 238. 3,8'-di ( Sodium O-acetyl) -MB-530A-carboxylate 239. Methyl 3,8'-di (O-acetyl) -MB-530A-carboxylate 240. 3,8'di (O-acetyl) -MB-530A- butyl carboxylate 241. 3,8'-di (O-acetyl) -MB530A-benzyl carboxylate 242. 3,8'-di (O-butyryl) -MML-236A-carboxyl sodium ate 243. methyl 3,8'-di (O-butyryl) -M-236A-carboxylate 244. 3, 8'-di (O-butyryl) -M-236-butyl carboxylate 245. 3.8 Benzyl 246-di (O-butyryl) ML-236A-carboxylate 246. 3,8'-Di (O-butyryl) -MB-530Carboxylate 247. 3,8'-Di (O-butyryl) -MB- Methyl 530A-carboxylate 248. 3,8'-Di (O-butyryl) -MB-530A-butyl carboxylate 249. 3,8 'di-O-butyryl) -MB-530A-benzyl carboxylate 250. 3, Methyl 8'-di (O-benzoyl) -ML236A-carboxylate 251. Methyl 3,8'-di (O-benzoyl) -MML-236A-carboxylate 252. 3,8'-di (O-benzoyl) - Ethyl ML-236A-carboxylate 253. Benzyl 3 ', 8'-di (O-benzoyl) -M-236A-carboxylate 254. Benzyl 3,8'-di (O-benzoyl) ML-236A-carboxylate 255 Sodium 3,8'-di (O-benzoyl) MB-530carboxylate A256. Methyl 3,8'-di (O-benzoyl) -MB-53OA-carboxylate 257. Butyl 3,8'-di (O-benzoyl) -MB-530A-carboxylate 258. 3,8'di (O- benzoyl) -MB-530A-benzyl carboxylate 259. 3-O-acetyl-8'-Obutyryl-ML-236A-carboxylate sodium 3-0-acetyl-8'-O-butyryl-MB-530carboxylate sodium 3- Sodium 0-butyryl-8'-O-acetyl-ML-236A-carboxylate 3-0-Butyryl-8'-O-acetyl-MB-530A-sodium carboxylate 3-O-benzoyl-8 '-acetyl-ML- Sodium 236-carboxylate 3-O-benzoyl-8'-O-acetyl-MB530A-sodium carboxylate 3-O-benzoyl-8'-O-butyryl-ML-236A-sodium carboxylate 3-O-benzoyl-8 Sodium 3-O-butyryl-MB-530A-carboxylate sodium 3-acetyl-8'-O-benzoyl-ML-236A-carboxylate sodium 3-O-acetyl-8 '-benzoyl-MB-530A-carboxylate 3-0-Butyryl-8'-O-benzoyl-ML-236Carboxylate Sodium 3-O-butyryl-8'-O-benzoyl-MB-530A-carboxylate 3,5,8 '-tri (O-acetyl) ) -Methyl Sodium 3,5,8'-tri (acetyl) -ML-236A-carboxylate methyl 3,5,8'-tri (O-acetyl) -M-236-carboxylate methyl ester , 8'-tr ethyl (α-acetyl) -MIT-236A-carboxylate 3,5,8'-tri (O-acetyl) -M-236-butyl carboxylate 3,5,8 '-tri (acetyl) -ML-236A 1,3,5'-3,5,8'-trifluoromethyl-3,5,8'-tri (O-acetyl) -M-236-carboxylic acid benzylcarboxylate 3,5,8'-tri (Q-butyryl) -M-236A-carboxylate carboxylate methyl tri (0-butyryl) -M-236A-carboxylate 3,5,8'-tri (0-butyryl) -MML-236A-ethyl carboxylate 3,5,8'-tri (O-butyryl) -ML -236Butyl benzyl 3,5,8 '-tri (0-butyryl) -M-236A-carboxylate

  3,5,8'-tri (-butyryl) -MR-236A-carboxylate

  Sodium phenacyl 3,5,8'-tri (O-butyryl) -MB-530A-carboxylate loyloxymethyl 3,5,8'-tri (Q-butyryl) -M-236A-carboxylate

  3,5,8'-tri (0-butyryl) -MB-530A-carboxylate from potassium

  ethyl 3,5,8'-tri (Q-butyryl) -MB-530A-carboxylate methyl 3,5,8'-tri (butyryl) -MB-530A-ethyl carboxylate 3,5,8'-tri (B-Butyryl) -MB-530Butyl Butyl 3,5,8 '-tri (Q-butyryl) -MB-530A-carboxylate carboxylate

  3,5,8 '-tri (0-butyryl) -MB-530A-carboxylate from

  sodium 3,5-di (3,5-tert-butyryl) -MB-530A-carboxylic acid 3,5-di (O-acetyl) -M-234B-sodium carboxylate, loxoxymethyl 3,5,8'-cyclic 260. 261. 262. 263. 264. 265. 266. 267. 268.

269.

270. 271. 272. 273.

274.

275. 276. 277. 278.

279.

280. 281. 282. 283. 284. 285. 286.

287.

  288. 289. 290. 291. 292. 293. 294. Potassium 3,5-di (0-acetyl) -M-236B-carboxylate

  295. aluminum trisZ ', 5-di (0-acetyl) -MML-236B-carboxylate;

  Calcium bis (3,5-di (Oacetyl) -MML-236B-carboxylate 3,5-di (O-acetyl) -MML-236B-alium 296. bisD, 5-di (D-acetyl) -MML-236B-carboxylate] carboxylate 3,5di (O-acetyl) -MML-236B-carboxylate 3,5-di (O-acetyl) -MML-236B-carboxylate 3,5-di (O-acetyl) -MML-236B-carboxylate 3,5 Methyl 3,5-di (O-acetyl) -MML-236B-carboxylate 3,5-di (Oacetyl) -M-236B-carboxylate 3,5-di (O-acetyl) -M-236B-carboxylate benzyl butyl ethyl isopropyl 3,5-di (O-acetyl) -MB-530B-carboxylic acid -MB-530B-carboxylate

of pivaloyloxy-

  ethoxymethyl potassium bis (3,5-di (O-acetyl) MB-530B-carboxylate calcium trisZ, 5-di (O-acetyl) -MB-530Bcarboxylate, 3,5-di (0 -acetyl) -MB-530B-carboxylate 3,5-di (0acetyl) -MB-530B-carboxylate 3,5-di (O-acetyl) -MB-530B-carboxylate 3,5-di (0acetyl) -MB- 530B-carboxylate 3,5-di (O-acetyl) -MB-53OB-carboxylate 3,5-di (2-acetyl) -MB-530B-carboxylate methyl 3,5-di (O-acetyl) -MB-530B carboxylate Benzyl butyl isopropyl ethyl 3,5-di (0-acetyl) -MB-530B-carboxylate 3,5-diO 0-acetyl) -MB530B-carboxylate

of pivaloyloxy-

  methoxymethyl ethoxymethyl methyl phenoxyl 3,5-di (O-propionyl) -ML236B-carboxylate 3,5-di (O-propionyl) -MML-236B-carboxylate 3,5-di (O-propionyl) ) -3,5-di (O-propionyl) -MB-530B-3,5-di (O-propionyl) -benzyl 3,5-di (Opropionyl) -ML-236B-carboxylate butyl ester ) -MB-530B-Methyl 3,5-di (-propionyl) -MB-530B-Butyl 3,5-di (O-propionyl) -MB-530B-carboxylate 3,5-di-methyl ester Methyl 0-butyryl) -MML-236B-carboxylate 3,5-di (0-butyryl) -MML-236B-carboxylate 297. 298. 299. 300. 301.

302.

303. 304. 305.

306.

307. 308. 309. 310.

311.

312. 313. 314.

315.

316. 317. 318.- 319.

320.

321. 322. 323. 324.

325.

326. 327.

23 2479809

  328. 3,5-di (-butyryl) -MB-530B-sodium carboxylate 329. Methyl 3,5-di (butyryl) -MB-530B-carboxylate 330. 3,5-di (O-valeryl) - ML-236B sodium carboxylate 331. 3,5-di (0-valeryl) -M-236B-potassium carboxylate 332. 3,5-di (0-valeryl) -MB-530B-sodium carboxylate 333. 3,5di (0-valeryl) -MB-530B-potassium carboxylate 334. 3,5-di (O-isovaleryl) -MR-236B-carboxylate 335. 3,5-di (O-isovaleryl) -MB-530B carboxylate sodium 336. 3,5-di (0-stearoyl) -MR-236B-sodium carboxylate 337. 3,5-di (0-stearoyl) -MB-530B-sodium carboxylate 338. 3,5-di (O) sodium oleoyl) -MN-236B-carboxylate 339. 3,5-di (0-linoloyl) -MR-236B sodium carboxylate 340. 3,5-di (0-sinoloyl) -MB-530B-sodium carboxylate 341 Sodium 3,5-di (0-benzoyl) -MML-236B-carboxylate 342. 3,5-di (0-benzoyl) -MB-530B-sodium carboxylate 343. 3,5-di (O-phenylacetyl) - ML236B-sodium carboxylate

  344. Methyl 3,5-di (O-phenylacetyl) -MML-236B-carboxylate

  345. 3,5-di (0-phenylacetyl) -MB-530B-sodium carboxylate 346. 3,5-di (O-phenylacetyl) -MB-530B-carboxylate 347. 3,5-di (0cyclopentanecarbonyl) -ML Sodium 248-bicarboxylate 348. 3,5-di (0cyclopentanecarbonyl) -MB-530B-sodium carboxylate 349. 3,5-di (0cyclohexanecarbonyl) -MR-236B-sodium carboxylate 350. 3,5-di ( Sodium 35cyclohexanecarbonyl) -MB-530B-carboxylate 351. 3,5-di (0-thenoyl) ML-236B-sodium carboxylate 352. 3,5-di (O-thenoyl) -MB-530B-sodium carboxylate 353 3,5-di (O-furoyl) -MR-236B-sodium carboxylate 354. 3,5di (O-furoyl) -MB-530B-sodium carboxylate 355. 3,5-di (O-thienylacetyl) ML Sodium 2,336B-carboxylate 356. 3,5-di (-thienylacetyl) -MB-530B sodium carboxylate

  357. 3,5-di (O-methanesulphonyl) -MML-236B-carboxylate

dium

  358. 3,5-di (O-methanesulphonyl) -MB-53OB-carboxylate of

dium

2479809

  Trisodium 3,5-di (0.phosphoryl) -MB-530B-trisodium 3,5-di (0-acetyl) -8'-opropionyl tri-3,5-di (O-phosphoryl) -M-236B-trisodium carboxylate Methyl ML-236A-carboxylate 3,5-di (0-acetyl) -8'-O-proDionylML-236A-carboxylate methyl 3,5-di (O-acetyl) -8'-O-Oropionyl-ML- 236Butylcarboxylate 3,5-di (0-acetyl) -8'-Q-pronionyl-ML-236Benzylcarboxylate 3,5-di (0-acetyl) -8'-O-propionyl-MB-530Sodium carboxylate Sodium 3,5-di (0-acetyl) -8'-o-proplonyl-MB-530 alkylcarboxylate 3,5-di (0-acetyl) -8'-O-butyryl-ML-236A-carboxylate 3, Methyl 5-di (0-acetyl) -8'-1-butyryl-ML-236A-carboxylate 3,5-di (0-acetyl) -8'-O-butyryl-ML-236A-butyl carboxylate 3, Methyl 3,5-di (0-acetyl) -8'-O-butyryl-MB-530A-carboxylate, 5-di (0-acetyl) -8'-o-butyryl-4B-530A, methyl 3,5-di-carboxylate sodium 3,5-di (O-acetyl) -8'-O-acetyl-ML-236-carboxylate 3,5-di (0) -di (O-acetyl) -8'-O-butyryl-MB530A-carboxylate -butyryl) -8'-O-acetyl-MB-530A-carboxylate 3,5-di (0-acetyl) Sodium 3,5-di-O-benzoyl-ML-236A-carboxylate 3,5di (O-acetyl) -8'-O-benzoyl-MB-530A-carboxylate 3,5-di (O-benzoyl) 8 Sodium O-acetyl-ML-236A-carboxylate 3,5-di (O-benzoyl) -8'-O-acetylML-236A-carboxylate of 359. 360. 361.

362.

363. 364. 365. 366.

367.

368. 369. 370. 371.

372.

373. 374. 375. 376.

377.

378.

2479809

  Methyl 379. sodium 3,5-di (O-benzoyl) -8'-O-acetyl-MB-530A-carboxylate 380. 3,5-di (O-benzoyl) -8'-O-acetyl-MB- Among these compounds, the compounds that are particularly preferred are the following: sodium ML-236A-carboxylate MB-530A-sodium carboxylate 8'-O-butyrylML-236A-sodium carboxylate 8'-O-hexanoyl Sodium ML-236A-carboxylate Ethyl 8'-O-butyryl-ML-236A-carboxylate Ethyl 8'-O-hexanoyl-ML-236Acarboxylate 8'-O-butyryl-ML-236A-Butyl carboxylate 8 Butyl 8'-O-isovaleryl-MB-530 Butylcarboxylate 8'-O-butyryl-MB-236A-benzyl carboxylate 8'-Ohexanoyl-ML-236A-Butyl 8'-O-isovaleryl-MB-5B benzyl carboxylate phenyl 8'-O-butyryl-MB-530A-carboxylate 3,5-di (0-acetyl) -M-236B-butyl carboxylate

2479809

  Butyl 3,5-di (O-benzoyl) -M-236B-carboxylate.

  The compounds according to the invention can be prepared

  various ML-236A, ML-236B, MB-530A, MB-530B, ML-236A carboxylic acid and ML-530A carboxylic acid which

  can all be prepared by growing microorganisms

  my appropriate, as described in the aforementioned prior documents and as particularly described hereinafter in the Preparations. The chemical structures of these compounds are as follows:

ML-236A ML-236B

ff, t 0.n _A '. not

ML-530A

MB-530B

  ML-236A carboxylic acid acid ffl-530A carboxyl that

27 2479809

  The metal salts, and especially the alkali metal salts,

  ML-236A and MB-530A can be prepared in

  an appropriate microorganism and then separating the salt

looked for culture broth.

  In particular, salts of the acid can be prepared

  ML-236A carboxylic acid by cultivating a microorganism

  ML-236A producer of the genus Penicillium and separating the ML236A acid salt from the culture broth, while salts of MB-530A carboxylic acid can be prepared by cultivating an MB-530A-producing microorganism of the genus

  Monascus and separating the acid salt MB-530A carboxyli-

only culture broth.

  The microorganisms of the Penicillium genus are pre-

  Penicillium citrinum, Penicillium chrysogenum or Penicillium notatum and, better still, Penicillium citrinum SANK

  18767 (FERM 2609), Penicillium citrinum SANK 24467, Peni-

  cillium citrinum SANK 24567, Penicillium chrysogenum SANK

  12768 (ATCC 10002) or Penicillium notatum SANK 24867.

  Microorganisms of the genus Monascus are preferably

  the strains of Monascus ruber, Monascus anka, Monas-

  cus paxii, Monascus purpureus or Monascus vitreus, pre-

  Monascus ruber SANK 11272 (IFO 9203), Monascus ruber SANK 17075 (CBS 832.70), Monascus ruber SANK 17175 (CBS 503.70), Monascus ruber SANK 17275 (ATCC 18199), Monascus ruber SANK 15177 (FERM 4956), Monascus ruber SANK 13778 (FERM 4959), Monascus ruber SANK 10671 (FERM 4958), Monascus ruber SANK (FERM 4957), Monascus anka SANK 10171 (IFO 6540), Monascus paxii SANK 11172 (IFO 8201), Monascus purpureus SANK 10271 (IFO 4513) or Monascus vitreus SANK

10960 (NIHS 609, e-609, FERM 4960).

  All these microorganisms can be obtained from

  from known culture collections, as indicated by the following codes: IFO = Institute for Fermentation, Osaka, Japan FERM = Fermentation Research Institute, Ministry of International Trade and Industry, Japan

2 & 2479809

  NIHS = National Institute of Hygienic Sciences, Japan CBS = Central Bureau voor Schimmelcultures, Netherlands ATCC = American Type Culture Collections, Maryland,

USA.

  Apart from the aforementioned microorganism strains, it is possible, in the method according to the invention, to use any microorganism of the genus Penicillium or Monascus, including

  varieties and mutants capable of producing

ML-236A or MB-530A.

  The salts of ML-236A and MB-530A can be produced in

  cultivating the selected microorganism in a broth of

  in the aerobic environment, using the techniques

  known for the cultivation of fungi and other microorganisms

  my. For example, we can first cultivate the strain

  of Penicillium or Monascus in a suitable environment.

  requested, then collect the microorganism produced and the

  cull in - and cultivate it on - another culture medium.

  to produce the desired ML-236A or MB-530A, the

  culture medium used for the proliferation of micro-

  organism and the culture medium used for the production

  ML-326A or MB-530A may be identical or different

  ent. Any culture medium can be used well

  known in the art of fungi cultivation, provided that

  it contains, as is well known, the elements

  necessary nutrients, in particular a source of car-

  assimilable bone and a source of assimilable nitrogen. Examples of suitable sources of assimilable carbon are: glucose, maltose, dextrin, starch, lactose, sucrose and glycerine. Among these sources,

  glucose and glycerin are particularly preferred.

  for the production of ML-236A and MB-530A. As an example

  sources of assimilable nitrogen include: peptone, meat extract, yeast,

  yeast, soy flour, peanut flour, li-

  maceration of maize, rice bran and mineral sources of nitrogen. When ML-236A or MB-530A is prepared, a mineral salt and / or a metal salt can

29 2479809

  if necessary, be added to the culture medium. In-

  if necessary, it is also possible to add a minor amount of a heavy metal. In some cases, it is thought that it is possible that Penicillium or Monascus fungus may directly produce ML-236A or MB-530A carboxylic acid salt, while in other cases fungus will produce first the ML-236A or MB-530A which

  will then be converted to the salt sought during a pro-

  cessation of separation and routine purification. Lors-

  that the salts must be produced directly by the

  it is important to be in the middle

  in the fungal organism of metal ions.

  corresponding to the metal salt that one seeks to obtain

  ne. The microorganism is preferably grown in an aerobic environment, using culture methods well known in the art, for example, by solid culture, shaking culture, or aerating and shaking culture. Microorganisms proliferate over a wide range of temperatures, for example. example, from 7 to 35 ° C, but in particular when culturing the microorganism to obtain ML-236A or MB-530A or a carboxylic acid salt thereof,

  Preferred culture temperature is 20 to 300C.

  During the culture of the microorganism, it is possible

  ensure the production of the ML-236A or MB-530A sought, or

  their carboxylic acid salt, by taking samples of

  lons on the culture medium and by measuring the physiological activity of the medium by appropriate tests. The culture can then be continued until a substantial accumulation of active substance is obtained in the culture medium, and the ML-236A or MB530A carboxylic acid salt can be isolated and separated from the culture medium and the tissues of the culture medium. microorganism, using any appropriate combination of isolation techniques chosen for their physicochemical properties. For example, any or all of the following isolation techniques may be used: extraction of the liquor from the culture broth using a hydrophilic solvent

  (such as diethyl ether, ethyl acetate or chloro

  roforme); extraction of the body with a hydrophilic solvent (such as acetone or an alcohol); concentration, for example by total or partial evaporation of the solvent under reduced pressure; dissolving in a more polar solvent (such as acetone or an alcohol); removal of impurities with a less polar solvent (such as petroleum ether or hexane); gel filtration, on a column of a material such as Sephadex (trade name of a product supplied by Pharmacia Co. Limited, U.A.); absorption chromatography with activated carbon

  or silica gel; fast liquid chromatography; con-

  version in ML-236A or MB-530A itself or the corresponding acid

  laying; direct purification in the form of a metal salt

  Metallic; and other similar procedures. By using

  an appropriate combination of these techniques, the desired salt can be isolated from the culture medium in the form of

of a pure substance.

  As described in prior art, ML-23614 ML-236B, MB-530A, MB-530B, ML-236A carboxylic acid

  and MB-530A carboxylic acid, all of which are

  important starting points for the preparation of certain

  compounds according to the present invention, may also

  be prepared using microorganisms and

the techniques described above.

  Other compounds according to the invention may be

  prepared by the following procedures.

OPERATIVE MODE 1 M1

  R -0 00 -M1 Preparation of salts It is possible to prepare salts YOn of carboxylic acid of formula (IV) in which R, R3 and R4 have the above-mentioned significances, M1 represents R1 the cationic fragment of a mi salt and m 'represents the valence of M1 by hydrolyzing a lactone of formula (V): IV) OR3' s N RI in which R1, R3 and R4 have the precise meanings

  and, if necessary, by converting the carbon group

  xyl of the product thus obtained in the corresponding salt.

  The following hydrolysis can be carried out

  procedure well known in the art of converting

  lactones to the corresponding hydroxy acid. Then, optionally, the hydroxy acid can be extracted with a suitable organic solvent and then salified by reaction with a base corresponding to the desired salt.

  obtain, for example with a hydroxide or carbonate metal-

  ion, ammonia, an organic amine or an amino acid.

  However, when it is desired to prepare a metal salt

  (i.e., where M is a metal atom

  that), it is most often necessary to carry out hydrolysis and salification in a single step, by using a basic compound of the metal, preferably the hydroxide, in an amount at least equimolar with respect to the lactone of formula ( V), to effect the hydrolysis. In this case, the metal salt of formula (IV) is obtained directly and is simply collected by removing the solvent from the

  reaction mixture, by distillation.

* The hydrolysis can be carried out in a conventional manner by

  example by putting the lactone (V) in contact with a solution

  diluted aqueous solution (eg 0.1 to 0.2N) of the hy-

  metal dioxide, preferably a metal hydroxide

  alkali such as sodium hydroxide or potassium hydroxide

  potassium, in water or in hydro-organic solution, for example in an aqueous solution of an alcohol or dioxane. The hydrolysis can be carried out in an extended temperature range, for example at room temperature or at an elevated temperature, for example from 50 to 1000 ° C. The time required for the reaction is very variable, depending on the nature of the reagents and the reaction temperature, but

  normally, the reaction takes several hours.

  According to a preferred embodiment of this procedure, an alkali metal salt of formula (VI) may be prepared: VIII H3CL

  wherein R 'has the above meaning and M2 represents

  an alkali metal atom, by hydrolysing, in an alkaline solution containing said alkali metal atom, a lactone of formula (VII): wherein R 1 has the meaning mentioned above, in which case

  M2 preferably represents a sodium atom and the solu-

  alkaline solution is preferably an aqueous solution of hy-

sodium droxide.

OPERATIVE MODE 2

  Preparation of an ester from the corresponding lactone

  Reactive carboxylic acid esters can be prepared.

  formula (VIII): wherein R1 represents a hydrogen atom or a methyl group; R3 and R4 are the same or different and each represents a hydrogen atom or an acyl group, provided that when R3 is 2-methylbutyryl, R4 is acyl; and R2b represents an alkyl or aralkyl group, by reacting a lactone of formula (V):

IV)

OR3 N N Rl

1 3 4

  in which R, R and R have the precise meanings

  with an alcohol in the presence of an acid catalyst.

  Examples of suitable acid catalysts include: mineral acids such as hydrochloric acid or

  sulfuric acid; Lewis acids such as trifluoro-

  boron chloride; as well as acidic ion exchange resins

  of. The reaction can be carried out in the presence of a sol-

  suitable inert organic material, such as

  zene, diethyl ether or chloroform. However,

  alcohol - which is one of the reagents - is a

  it is better to use it as a solvent.

  Although the reaction is carried out over a wide temperature range, it is preferable to operate by heating, for example at a temperature of 50 ° C at the boiling point of the solvent. Once the reaction is complete, the desired product can be separated from the reaction mixture by conventional means. For example, when the catalyst used is an ion exchange resin, the latter is removed by filtration, and then the solvent is distilled to obtain

  the compound sought. If the catalyst is a mineral acid

  or a Lewis acid, the residue is extracted with a suitable solvent which is then distilled, obtaining

thus the product sought.

  The same can be done to prepare other esters as alkyl and aralkyl esters, using appropriate hydroxyl compounds or their functional equivalents, for example: compounds of formula (I) in which R 2 represents an aliphatic hydrocarbon group

  divalent can be prepared by replacing the alcohol used

  in the above procedure by a glycol. Similarly, instead of the acid catalyzed solvolysis described above, any other

  classical technique of solvolysis to produce any

  embedded image of formula (I) in which R 2 represents an ester residue

  obtainable by solvolysis of a lactone.

OPERATIVE MODE 3

  Preparation of esters from the corresponding metal salt Carboxylic acid esters of formula (IX) can be prepared:

R DO _ _ _ - R2C

OR 5

OR311% X

113C Ri p

  wherein R1, R3, R and R have the meanings

  cited; R represents the alcoholic moiety of an ester; 2c and p represents the valence of R, by reacting a metal salt of formula (X):

CDO - -M3

oR5 (1) O3 1H3c

1, 4 5

  wherein R, R, R and R have the meanings

  cited; M3 represents a metal atom, preferably

  an alkali metal or alkaline earth metal atom; and q represent

  the valence of M3 with an esterifying agent, preferably an esterification agent in accordance with

  formula R2c-X in which X represents a halogen atom

  gene, for example a chlorine or bromine atom.

  This reaction can be carried out using standard procedures for the alkylation of metal salts of carboxylic acids. For example, one can put the metal salt (X) in contact with the agent

  esterification in the presence of an inert organic solvent.

  te, in order to obtain the desired ester of formula (IX). The na-

  The solvent used is not particularly limited as long as it does not affect the reaction. Examples of preferable solvents are: dimethylformamide,

  dimethylsulfoxide, tetrahydrofuran, hexamethylphosphoric acid,

  phoryltriamide, acetone and methyl ethyl ketone. We

  can perform the reaction in a wide range of temperatures

  erature, for example at room temperature, or at a

  high temperature, but it is normally preferable to

  at about room temperature. The required time

  reaction depends, of course, on the temperature of

  reaction and reagents used, but it is normally

  maliciously from 1 to 20 hours. The desired product can be separated from the reaction mixture by conventional means, for example by diluting the reaction mixture with water, extracting the mixture with a nonmiscible solvent at room temperature.

  water and removing the solvent from the extract,

  tillation. The esterification agent used is preferably an alkyl halide, or an aralkyl halide, or

  a phenacyl halide and the metal salt of

  (X) is preferably an alkali metal salt (i.e.

  say: M3 represents an alkali metal atom). This salt of

  alkali metal is preferably formed in situ by another

  reaction, for example that described in the procedure

  1, before reaction with the esterification agent.

  It is particularly preferred that the compounds used are compounds in which: R 1 represents a hydrogen atom or a methyl group; R3 represents a hydrogen atom, a C2-C6 alkanoyl group or a C3-C6 alkenoyl group; R and R5 are the same or different and each represents a hydrogen atom, a C2-C6 alkanoyl group or a benzoyl group,

  provided that when R3 represents a 2-methyl-

  butyryl, R4 and R5 are both acyl groups and M3 is an alkali metal atom; and that the agent

  esterification either a benzyl halide or a halogenide

phenacyl genius.

PROCEDURE 4

  Preparation of 3-acylated, 5-acylated and 8'-acylated derivatives A triacylated compound of formula (XI) can be prepared: R coR eib

{H3CC

  n in which R1 R and n have the aforementioned meanings

  and R3b, R4b and R5b are the same or different and represent

  each have an acyl group, acylating a compound of formula (XII): wherein R1, R1 and n have the meanings and R3c, R4c and R5c are identical or different, each of which is a hydrogen atom or a group 3c provided that at least one of the radicals R3,

  R5c represents a hydrogen atom.

  Compounds corresponding to (XIII), (XIV) and (XV) can be prepared:

{XIII)

fn above

and represent

  acyl, R4c and formulas R2 (Mi (n R2 fuEi R1 RU In

  in which: R, R and n have the precise meanings

  FOA; R represents a hydrogen atom or an acyl group; R3b is an acyl group; and R4b represents an acyl group, by acylating a compound of formula (XVI):

HO COO R2

  In which R, R, n and R3b have the abovementioned meanings. By choosing the operating conditions appropriately, it is possible to prepare either one of the compounds of formulas (XIII), (XIV) and (XV), or a mixture of two of them, or a mixture of all three. . The desired compound (s) may then be

isolated) from the reaction mixture.

  It is preferable to carry out the acylation reaction itself by using one or other of the following procedures: (A) Acylation with a reactive derivative of an acid

  According to this procedure, the compound of formula

  mule (XII) or (XVI) in contact with a reactive derivative of the acid containing the desired acyl groups, for example an acid halide (such as an acid chloride or an acid bromide), a acid or a mixed acid anhydride (for example a mixed acid anhydride of

  acid with a chlorocarbonic ester or an acid chloride

  sulfonic acid). It is better to carry out the reaction

  in the presence of a solvent and also, preferably, in

  sence of a base. The nature of the solvent to be used is not particularly limited as long as it does not affect the reaction. Examples of suitable solvents include

  chloroform, methylene chloride, diethyl ether,

  tetrahydrofuran and dioxane. As examples

  preferable bases, mention will be made of organic amines com-

  pyridine, 4- (N, N-dimethylamino) pyridine, the

  nicotine, triethylamine, N-methylmorpholine, N-methyl

  methylpiperidine and N, N-dimethylaniline. When the friend

  not used is a liquid at the reaction temperature, for example pyridine, it can also serve as

  solvent. The reaction is preferably carried out at the

  room temperature, or while cooling, in order to

  avoid side reactions, but it may

  kill at high temperature. The reaction time depends on the reaction temperature and the nature of the reactants, but the reaction is normally completed in one.

  lapse of time from 10 minutes to 10 hours. Once the reaction

  After completion, the desired product can be recovered by conventional means, for example by diluting the reaction mixture with water, extracting the mixture with a water-immiscible solvent and removing the solvent.

by distillation.

  (B) Acylation using a condensing agent It is possible to operate under standard conditions, using a free acid corresponding to the acyl group which

  it is desired to introduce in the presence of a condensing agent

  tion, and in this case simply put the compound of

  mule (XII) or (XVI) in contact with the acid in the presence of the condensing agent. The condensing agent is

  preferably a dehydrating agent, for example a car-

  bodiimide such as dicyclohexylcarbodiimide. The reaction is normally carried out in the presence of a solvent whose

  nature is not critical, as long as it does not affect the

  action. Examples of suitable solvents are: dimethylformamide, dimethylacetamide, acetonitrile, pyridine, methylene chloride, chloroform and dioxane. The reaction can be carried out over a wide temperature range, but in order to control side reactions, it is normally preferable to operate at room temperature or cool; however, the

  The reaction can also be carried out at elevated temperature.

  The time required for the reaction varies according to the temperature

  reaction and the nature of the reagents used, but the reaction is normally finalized

  lapse of time from one to twenty hours. We can then separate

  recover the desired compound from the reaction mixture, by conventional means, in particular: by filtering the insoluble matters, by diluting the filtrate with water, extracting the resulting mixture with a solvent which is not removable with water, then by removing the solvent by distillation,

in order to obtain the sought product.

  In the case of either of the above acylation reactions, when the starting material contains two or more free hydroxy groups, any of the mono-, di- or tri-acyl derivatives can be obtained. by adjusting the amount of acylating agent used. If we get a

  mixtures of these compounds, the compounds

  using class isolation techniques.

  such as silica gel chromatography.

  The compounds according to the invention can finally be prepared from fermentation products

  ML-236A, ML-236B, MB-530A and MB-530B or their carboxylic acids

  corresponding carboxylic acid or carboxylic acid salts

  by any combination of the above reactions. These reactions

  These are summarized in the following reaction scheme, wherein the chemical structures of the compounds are simplified as follows:

41 2479809

HO OH

COH COOH CO

OOH 1OH

OH

H3C R1

R OH OH OAcl

O COOR2 X COOR2

OH OAcI OH OAc OAc

R1 R1 R1

  OAcl OH OAcl OAcl O / - O COOR2 OA OH, OAcl OAc OAc

R1 R1 to R1

  OAc1 OAc1 OH OAc1 1, A.O I. r.nnR2 -, - rnnR2I. CnnR2 * OAc OAc1 Oc OAcl OAc2

A1 2 3

  In the above reaction scheme, Ac, Ac and Ac are the same or different and each represents a

acyl group.

  The compounds of the invention have been found to inhibit the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), which is the enzyme

  determining the rate in the biosynthesis of choles-

  terol. According to the operative protocol of Knauss et al.

  (J. Biol Chem., 234, 2835 (1959)), the inhibitory activities

  of the compounds according to the invention on the biosynthesis

  cholesterol, expressed in their DI50 values (ie

  say the concentration needed to inhibit by 50% the

  cholesterol biosynthesis) range from 1.0 to 0.03> ag / ml.

  In addition, the sodium salts, that is to say the compounds of formula (I) in which R2 represents a sodium atom, have proved, in an in vivo test, to be adsorbed much better than the lactone corresponding and, in general, it is believed that the compounds according to the invention have a better biodisposibility than

the corresponding lactones.

  The compounds can be administered for the treatment of

  Preferably, they are administered in the form of tablets or capsules. The daily dosage varies according to the age, the weight and the state of the patient, but, in general, the compounds according to the invention are preferably administered at a rate of 1 to 10 mg per day in

  a single shot or several shots.

  The preparation of the compounds according to the invention is illustrated by the following nonlimiting examples. The

  preparation of some of the starting substances used

  in these examples is illustrated by the Preparations

  1-4 and other starting substances may be

  trimmed in a manner similar to that described in these Preparations. The preparations of ML-236A and ML-236B are

  described in more detail in the U.S. Patent.

No. 3,983,140.

43 2479809

  Preparation 1 3-O-Butyryl-ML-236A 918 mg of ML-236A was dissolved in 5 ml of pyridine, and 1 ml of butyric anhydride was added dropwise at room temperature. After giving up the mixture

  overnight, diluted with water and the ex-

  related to diethyl ether. The extract is washed, successively

  water, with a saturated aqueous solution of bicarbonate, with water, with 1N hydrochloric acid and

  water, and dried over anhydrous sodium sulfate. We elect

  solvent from the solution by distillation and the residue is subjected to chromatography on a column of

  silica gel, eluting with a 5/1 mixture

  lume of benzene and ethyl acetate, thus obtaining 930

  mg of the product sought, in the form of an oil substance

lous colorless.

  Elemental analysis CH for C22H3O5 Calcd.% 70.21 8.51 Found% 69.95 8.69 NMR Spectrum (CDCl3) dppm: 0.95 (3H, multiplet) 4.27 (1H, multiplet), 32 (1H, multiplet) IR absorption spectrum (liquid film) max cm-: max

3460, 1740.

  Preparation 2 3,8'-Di (O-butyryl) -MML-236A 306 mg of ML-236A and 0.5 ml of pyridine are dissolved in 3 ml of methylene chloride, and the following are added:

  drop 0.5 ml of butyryl chloride while cooling

  on ice. The mixture is stirred at room temperature for one hour and then washed with

  the water. The organic layer is separated and dried over

  anhydrous sodium fate, and then the solvent is distilled off. We

  subject the resulting residue to a chromatography on

  silica gel, eluting with a 1: 1 mixture of benzene and ethyl acetate,

  384 mg of the product sought, in the form of a

oily colorless matter.

  Elemental analysis C H for C26H3806 Calcd.% 69.96 8.52 Found% 70,14 8.31 NMR spectrum (CDCl3) 6 ppm: 0.93 (6H, triplet), 2 - 5.5 (2H, multiplet). IR absorption spectrum (liquid film) -max cm-1 max

1735, 1250, 1175.

  Preparation 3 8'-O-Butyryl-ML-236A 918 mg of ML-236A and 0.36 ml of pyridine are dissolved

  in 10 ml of methylene chloride. The solution is cooled

  on an ice bath and add drop by drop

  0.35 ml of butyryl chloride. After stirring the

  lange for one hour, dilute with water. We separate

  the organic layer which is washed with water and dries

  Anhydrous sodium. We distil the solvent and submit

  the residue at a column chromatography gel gel

  contention. The compound 3,8'-diacylated (described in

  2), eluting with a 10: 1 by volume mixture of benzene and ethyl acetate, the 3-acylated compound (described in Preparation 1) was obtained by eluting with

  of a 5/1 mixture by volume of benzene and ethyl acetate.

  1a, and 395 mg of the desired product (as colorless crystals, mp 124 ° -125 ° C.) are obtained from the eluate, using a 2: 1 by volume mixture of benzene.

and ethyl acetate.

  Elemental analysis C H for C22H3205 Calcd.% 70.21 8.51 Found% 70.25, 8.50 NMR Spectrum (CDCl3) I ppm: 0.95 (3H, triplet)

4.42 (iH, multiplet).

  IR absorption spectrum (Nujol, trade name) - max cm:

3400, 1730, 1710.

  Other acylated derivatives can be prepared by operating

  following the procedures described in these prepara-

  tions. Preparation 4 Preparation of MB-530A

  In a fermenter of 600 liters 300 liters are introduced

  very much of a culture medium having a pH of 5.5 before

  and containing 5% wt / vol glucose, 0.5 wt / vol corn liquor, 2% peptone pds.vol (Kyokuto brand, supplied by Kyokuto Seiyaku KK, Japan) and 0.5% chloride ammonium, and inoculated with a Monascus ruber culture SANK 15177 (FERM 4956, NRRL 12081). The culture of the microorganism is continued for hours at 270 ° C., aerating at a rate of 300 liters / minute.

and stirring at 190 rpm.

  At the end of this time, the culture broth is filtered on a filter press and thus a filtrate and a filter cake containing wet cells of the microorganism are obtained. The filtrate is brought to pH 3.0 by addition of 6N hydrochloric acid and then extracted with 400 liters of ethyl acetate. The extract is concentrated (approximately 400 liters) by evaporation under reduced pressure and then dried over anhydrous sodium sulphate, after which

  evaporates to dryness, which gives approximately 60 g of a

  lous. The oily product is washed with ethylcyclohexane and

  hexane, and the residue (20 g) is separated by chromatography.

  Using a liquid chromatograph for large sample collection ("System 500 liquid chromatography" supplied by Waters Co., U.A.), eluted with 60% vol / vol aqueous methanol. Fractions having a chromatographic retention time of 6 minutes were collected and concentrated by evaporation under reduced pressure, thus obtaining 100 mg of the desired MB-530A in the form of an oily product. MB-530A is recrystallized from a mixture of acetone and diethyl ether, which gives 57 mg of the desired product, in the form of colorless needles having the following properties:

1. Melting point: 92-93C.

  2. Elemental analysis: C H for C19H2804 Calculated% 69.76 8.68 5. Found% 71.22 8.81 3. Molecular weight: 320 (by mass analysis)

4. Gross formula: C19H2804.

  5. UV absorption spectrum: as shown in FIG. 1 of the accompanying drawing 6. IR absorption spectrum: as shown in FIG.

of the attached drawing.

  7. NMR spectrum: as shown in Fig. 3 of the accompanying drawing. 8. Solubility: very soluble in methanol, ethanol,

  acetone and ethyl acetate; soluble in the ben-

  zene; insoluble in hexane and petroleum ether.

  9. Color reaction: a pink color appears when developing a thin layer chromatogram

  on silica gel of the compound using sulfuric acid

than 50% vol / vol.

  10. Inhibitory activity of cholesterol biosynthesis

  rol: 50% inhibition of cholesterol synthesis in a rat liver at a concentration

* 0.04 μg / ml.

Example 1

  ML-236A-sodium carboxylate 0.4 g of ML-236A is added to 12 ml of a solution

  0.1N aqueous sodium hydroxide, and the mixture is heated

  at 80-90 ° C for 2 hours. Once the reaction

  finished, the insoluble substances are filtered and

  the filtrate, thus obtaining 0.41 g of the product

  in the form of a colorless powder.

  Elemental analysis C H for C18H2705Na Calcd.% 62.43 7.80 Found% 62, 58 7.72

Example 2

  8'-O-butyryl-ML-236A-sodium carboxylate 0.75 g of 8'-Obutyryl-ML-236A are added to 20 ml of a 0.1N aqueous solution of sodium hydroxide and the mixture is heated. resulting at 80-90 C for 2 hours. Once the reaction is complete, the insoluble substances are filtered and the filtrate is lyophilized, thus obtaining 0.83 g of

  product sought, in the form of a colorless powder.

  Elemental analysis CH Na for C22H3306Na Calcd.% 63.46 7.93 5.53 Found% 63.54 7.90 5.50 NMR Spectrum (D20) <ppm: 0.95 (3H, triplet) 4.15 (2H) , triplet) 3.5 - 4.5 (2H, multiplet) IR absorption spectrum (Nujol) cm-1 max

3450, 1730, 1580.

Example 3

  8'-O-Hexanoyl-ML-236A-sodium carboxylate 0.88 g of 8'-Ohexanoyl-ML-236A is added to 20 ml

  0.1N aqueous solution of sodium hydroxide. We treat

  mixture as described in Example 1, thus obtaining

  0.84 g of the desired product, in the form of an

  colored. Elemental analysis: CH Na for C24H3706Na Calcd.% 64.86 8.33 5.18 Found% 64.75 8.37 5.25 NMR Spectrum (D20) sppm: 0.87 (3H, triplet) 4.13 (2H) , multiplet)

3.5 - 4.5 (2H, multiplet).

  IR absorption spectrum (Nujol) max m

3450, 1730, 1580.

Example 4

  8'-O-Butyryl-ML-236A-ethyl carboxylate 0.79 g of 8'-Obutyryl-ML-236A are dissolved in 10 ml

  of ethanol, and 1 g of a

  strongly acidic, sulfonic acid type (supplied under the trade name Dowex 50 W). The mixture is heated at 60-70 ° C. for 3 hours. Once the reaction is over,

  the mixture is filtered and the filtrate is concentrated by evaporation.

  ration under reduced pressure. The residue is purified by chromatography on a column of silica gel, thus obtaining 0.41 g of the desired product, in the form of a subsp.

oily colorless matter.

  Elemental analysis CH for C24 386 0 Calcd.% 68.25 9.00 Found% 68, 19 9.06 NMR spectrum (CDCl3) 6 ppm: 0.95 (3H, triplet) 1.23 (3H, triplet) 4, 12 (2H, quadruplet)

3.5 - 4.5 (2H, multiplet).

  IR absorption spectrum (liquid film) max cm1

3450, 1740.

Example 5

  Ethyl 8'-O-Hexanoyl-ML-236A-carboxylate 0.9 g of 8'-hexanoyl-ML-236A are dissolved in 10 ml of ethanol and 1.5 g of a sodium hydroxide exchange resin are added.

  strongly acidic sulfonic acid type cations. We treat

  the mixture as described in Example 3, thus obtaining 0.55 g of the desired product, in the form of a substance

oily colorless.

  Elemental analysis CH for C26 46a6 Calcd.% 69.33 9.33 Found% 69.21 9.39 NMR spectrum (CDCl3) ppm: 0.87 (3H, triplet) 1.25 (3H, triplet) 4.13 ( 2H, quadruplet) 3.5 - 4.5 (2H, multiplet) IR absorption spectrum (liquid film) max cm-1 max

3400, 1730, 1720.

Example 6

  Butyl 8'-O-butyryl-ML-236A-carboxylate 0.79 g of 8'-Obutyryl-ML-236A was dissolved in 10 ml of butanol, and 1.0 g of a

  strongly acidic cations, of the sulfonic acid type. We treat

  mix it in the same way as in example 3, obtain

  thus 0.59 g of the desired product as a colorless oily substance. Elemental analysis: C H for C26H42 6 Calculated% 69.33 9.33

26 42 6

  Found% 69.25 9.41 NMR Spectrum (CDCl3): ppm: 0.95 (3H, triplet) 1.24 (3H, triplet) 4.12 (2H, triplet)

3.5 - 4.5 (2H, multiplet).

  IR absorption spectrum (liquid film) cm1 max

3440, 1730.

Example 7

  Butyl 8'-O- (4-Pentenoyl) -MTH-236A-carboxylate

  Operating as described in Example 3, but using

  (0.92 g of 8'-O-pentenoyl) -MML-236A, 10 ml of butanol and 1.0 g of the ion exchange resin, 0.45 g of the desired product are obtained in the form of Colorless oily substance Elemental analysis CH for C27H4206 Calcd.% 70.13 9.09 Found% 70.04 9.13 NMR spectrum (CDCl3) 6 ppm: 1.24 (3H, multiplet) 3.5-4, 5 (4H, multiplet)

4.8 - 6.2 (8H, multiplet).

  IR absorption spectrum (liquid film) max cm-: max

3400, 1730.

Example 8

  Butyl 8'-O-Isovaleryl-MB-530A-carboxylate

  Operating as described in Example 3, but using

  Using 0.9 g of 8'-O-isovaleryl-MB-530A, 10 ml of butanol and 1.0 g of the ion exchange resin, 0.52 g of the desired product is obtained in the form of colorless oily substance. Elemental analysis CH for C274406 Calcd.% 69.83 9.48 Found% 69.77 9.46 NMR Spectrum (CDCl3) 6 ppm: 0.89 (1H, doublet) 1.24 (3H, triplet) 4.12 ( 2H, triplet)

3.5 - 4.5 (2H, multiplet).

  IR absorption spectrum (liquid film) max cm1 max c

3430, 1730.

Example 9

  Benzyl 8'-O-Butyryl-ML-236A-carboxylate 1.0 g of sodium 8'-Obutyryl-ML-236A-carboxylate are dissolved in 5 ml of dimethylformamide and 1 ml of benzyl chloride is added. The mixture is left standing overnight. The reaction mixture is diluted with water and extracted with ethyl acetate. We separate the layer

  organic, washed with water and dried over sodium sulphate

  anhydrous dium. The solvent is distilled under reduced pressure and the residue is purified by column chromatography on silica gel, thus obtaining 1.2 g of the desired product.

  in the form of a colorless oily substance.

  Elemental analysis CH for C29 4006 Calcd.% 71.90 8.26 Found% 71.84 8.25 NMR spectrum (CDCl3) δ ppm: 0.94 (3H, triplet) 1.24 (3H, triplet) 4.11 (2H, triplet) 3.5 - 4.5 (2H, multiplet), 20 (2H, singlet)

7.42 (5H, singlet).

  IR absorption spectrum (liquid film) ma) my:

3540, 1730.

Example 10

  Benzyl 8'-O-Hexanoyl-ML-236A-carboxylate -1 cm: xK

  Operating as described in Example 8, but using

  1.2 g of sodium 8'-O-hexanoyl-ML-236A-carboxylate

  and 1 ml of benzyl chloride give 1.3 g of the

  sought, in the form of an oily substance

  lore. Elemental analysis CH for C31 H4406 Calcd.% 72.66 8.59 Found% 72.58 8.50 NMR Spectrum (CDCl3) 1 ppm: 0.89 (3H, triplet) 4.14 (2H, triplet) 3.5 4.5 (2H, multiplet), 21 (2H, singlet)

7.44 (5H, singlet).

  IR absorption spectrum (liquid film) max cm: max

3400, 1730.

Example 11

  Phenacyl 8'-O-butyryl-MB-530A-carboxylate

  Operating as described in Example 8, but using

  reading 0.86 g of 8'-O-butyryl-MB-530A-carboxylate from

  dium and 0.45 g of phenacyl bromide, 1.0 g of the desired product is obtained in the form of a colorless oily substance. Elemental analysis CH for C31 H4207 Calcd.% 70.72 7.98 Found% 70.65 8.04 NMR Spectrum (CDCl3) e ppm: 0.95 (3H, triplet) 4.13 (2H, triplet) 3.5 4.5 (2H, multiplet), 44 (2H, singlet)

7.4 - 8.2 (5H, multiplet.

  IR absorption spectrum (liquid film) max cm-:

3450, 1730, 1700.

Example 12

  Butyl 3,5-di (O-acetyl) -ML-236B-carboxylate 0.32 g of butyl ML236B-carboxylate was dissolved in 1 ml of pyridine. After addition of 1 ml of anhydride

  acetic acid, the mixture is allowed to stand at room temperature

  ante for an hour. Then the reaction mixture is diluted

  This is washed with water and extracted with ethyl acetate. We distill

  the solvent under reduced pressure and the residue is purified.

  by chromatography on a column of silica gel, obtained

  0.35 g of the product sought, in the form of a

colorless oily substance.

  Elemental analysis C H for C31H4808 Calcd.% 67.88 8.76 Found% 67.74 8.81 NMR Spectrum (CDCl3) δ ppm: 2.00 (3H, singlet)

2.03 (3H, singlet).

  IR absorption spectrum (liquid film) cm'1 max

Example 13

  Butyl 3,5-di- (O-benzoyl) -M-236B-carboxylate

  Operating as described in Example 11, but using

  reading 0.34 g of butyl ML-236B-carboxylate, 0.3 ml of benzoyl chloride and 1 ml of pyridine, 0.38

  g of the product sought, in the form of a water-soluble substance

lous colorless.

  Elemental analysis C H for C41H52 Calcd.% 73.21 7.74 Found A 73.10 7.89 NMR Spectrum (CDCl3) δ ppm: 7.2-7.6 (3H, multiplet)

7.8 - 8.2 (2H, multiplet).

  IR absorption spectrum (liquid film) max cm maxcm: 1720.

Example 14

  ML-236A-sodium carboxylate In a 600-liter fermenter, 300 liters of culture medium (pH 5.5 before sterilization) containing 2% w / v glucose, 0.1% w / v peptone are introduced. ("Kyokuto") and 3% w / v of malt extract, and is inoculated

  with the organism Penicillium citrinum SANK 18767. It is

  follows the culture at 260C for 96 hours in an aerobic environment by aerating at a rate of 300 liters / minute and stirring at

  revolutions / minute. Broth of culture is brought

  the body) at pH 3.4 with hydrochloric acid

  6N and extracted with 800 liters of ethyl acetate.

  The extract is washed with 200 liters of saturated aqueous sodium chloride solution and concentrated by evaporation in vacuo at -18 liters. The resulting solution is extracted using 600 liters

  of ethyl acetate. The extract of 50 g of

  trifluoroacetic acid, and reacted at 800C for 30 minutes. The reaction mixture is washed successively with 20 liters of a 2% w / v aqueous solution of sodium bicarbonate and 20 liters of a 10% w / v aqueous solution of sodium chloride. after which it is concentrated by evaporation under reduced pressure to give 130 g of an oily substance. We dissolve this

  oil in 400 ml of methanol. 20 ml of the solution are

  methanolic solution (containing 6.5 g of the oil) to a System 500 type preparative quick liquid chromatography (produced by Waters Co., Ltd.) equipped with a Prepac C18 column (reverse phase column). We use a

  mixture of methanol and water (60/40 vol / vol) as a

  loppateur. The development is carried out at a rate of 200 ffl / minute (development time: about 10 minutes),

  monitoring a differential refractometer connected to the

  mera; the portion having a main peak is separated from the differential refractometer. This procedure is repeated, the resulting main peak fractions are collected and concentrated, thereby obtaining 9.2 g of

  oily substance which is dissolved in 30 ml of methanol.

  6 ml of the methanolic solution (

  holding about 1.8 g of the oil) at the same chromatography but is developed using a 55/45 vol / vol mixture of methanol and water at a rate of 200 ml / minute. We separate

  a portion having a main peak. The operation is repeated

  The main peak fractions were collected and concentrated, thereby obtaining 1020 mg of ML-236A as an oily substance. This substance is added with 33.2 ml of an aqueous solution

  0.1N sodium hydroxide and the mixture is stirred at 50.degree.

   C for 3 hours. The insoluble substances are filtered and the filtrate is freeze-dried, which gives 1090 mg of

ML-236A-sodium carboxylate.

Example 15

  ML-236A-sodium carboxylate 1030 liters of an ethyl acetate extract are washed with

  broth of culture obtained by operating as described in the ex-

  Example 14, using 200 liters of an aqueous solution

saturated with sodium chloride.

  The extract is dried over anhydrous sodium sulphate

  and concentrated to dryness, thus obtaining 120 g of a substance

  this oily product containing ML-236A carboxylic acid.

  The methanol oil is added to give a total volume of 200 ml. 20 ml of the solution are

  preparative rapid liquid chromatography with

  not reversed phase (the same as in Example 14) and eluted with a 20% vol / vol aqueous solution of methanol (containing 2% acetic acid) at a rate of 200

  ml / minute. A portion with a main peak is separated

  pal on the differential refractometer (7-10 minutes). We

  treat the remaining 120 ml following the same procedure.

  The resulting fractions with a peak are collected

  main, concentrated and extracted with ethyl acetate.

  the. The filtrate is concentrated to -sec after addition of hepta-

  thus obtaining 8.7 g of an oily substance which is dissolved in 20 ml of methanol and chromatography under the same conditions as above, which provides 930 mg of ML-236A carboxylic acid. This product is added with 2 ml of methanol and 100 ml of water, the resulting solution is brought to pH 8.0 with a 1N aqueous solution of sodium hydroxide; in this way a clear aqueous solution is obtained which is lyophilized to provide 980 mg of sodium ML-236A-carboxylate as a white powder.

Example 16

MB-530A-sodium carboxylate

  In a fermenter of 600 liters 300 liters are introduced

  very culture media (pH 5.5 before sterilization) containing 5% w / v glucose, 0.5% w / v corn broth liquor, 2% w / vol peptone (brand "Kyokuto" ) and 0.5% w / v ammonium chloride and is inoculated with Monascus ruber SANK 18174. The culture is continued at 26 C for 116 hours in aerobic medium aerating at a rate of 300 liters / minute and stirring at 190 rpm. The culture broth (containing the organism) is brought to pH 3.4 with 6N hydrochloric acid and extracted with 800 liters of ethyl acetate. The extract is washed with 200 liters of a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulphate. It is then concentrated to 18 liters by evaporation under reduced pressure. The resulting solution is extracted with 600 liters of acetate

  ethyl. 50 g of trifluoroacetic acid are added to the ex-

  quenched and reacted at 80 ° C. for 30 minutes. The reaction mixture is washed successively with the aid of

  liters of a 2% w / v aqueous solution of bicarbonate

  sodium nate and 10 liters of a 10% w / v aqueous solution of sodium chloride, and then concentrated to give 105 g of an oily substance. We dissolve this

  oil in 400 ml of methanol. 20 ml of the solution are

  methanol (containing approximately 5.3 g of the oil) to

  rapid preparative liquid chromatography with co-

  reversed phase bar (the same as in example 14). It is developed using a 65/35 vol / vol mixture of methanol and water. The development is carried out at a rate of 200 ml / minute (development time: approximately 15 minutes),

  by monitoring a differential refractometer connected to the

  the same; the portion with a main peak is separated

  on the differential refractometer. This operation is repeated

  and collect and concentrate the resulting fractions having a main peak, thus obtaining 7.9 g

  of an oily substance which is dissolved in 30 ml of

  ethanol. 60 ml of this methacrylate solution are again

  nolic (containing about 1.6 g of the oil) at the same chromatography, but developing with a mixture / 40 vol / vol of methanol and water at a flow rate of 200 ml /

  minute. A fraction having a main peak is separated

  pal. This operation is repeated and we collect and concentrate

  the fractions with a main peak. We obtain

  679 mg of MB-530A in the form of an oily substance.

  This substance is added with 21 ml of a 0.1N aqueous solution of sodium hydroxide and the mixture is stirred at 50-600 ° C. for one hour. The insoluble substances are filtered off and the filtrate is lyophilized, thereby obtaining

  720 mg of MB-530A-sodium carboxylate.

  Elemental Analysis C H for C19H2905Na Calcd.%: 63.33 8.06 Found%: 63.51 7.97

Example 17

  MB-350A-sodium carboxylate 300 liters of a culture medium (pH 7.4 before sterilization) containing 1.5% w / v of soluble starch, 1.5% w / w are introduced into a 600 liter fermenter. glycerin theft, 2% wt / vol fishmeal and 0.2% w / v

  of calcium carbonate, and inoculated with Monas-

  cus ruber SANK 17075 (CBS 832.70). The culture is continued at a temperature of 260 ° C. for 120 hours in an aerobic medium, aerating at a rate of 300 liters / minute and

  stirring at 190 rpm. We filter the broth of

  resulting in a filter press, thus obtaining 35 kg of the wet body, and 100 liters of water are added. The mixture is brought to pH 12 with sodium hydroxide, with stirring, and left at room temperature for one hour. The mixture of 2 kg of Hyflo Super Cel, a filter aid, is added and filtered on a filter press. The filtrate is brought to pH 10 using

  hydrochloric acid and adsorbed on a column

  5 liters of HP-20 resin. We wash with 15

  liters of water and 15 liters of an aqueous solution of metha-

  10% vol / vol, after which it is eluted with 60% vol / vol aqueous methanol. The elution product is concentrated to a volume of about 10 liters. The residue is brought to pH 2 with hydrochloric acid and extracted with acetate.

  ethyl. The extract is washed with an aqueous solution

  saturated with sodium chloride, dried over anhydrous sodium sulphate and concentrated to dryness, thus obtaining 20 g

  an oily substance containing MB-530A acid

  boxylique. Methanol is added to the oil to give a total volume of 100 ml. 20 ml of the solution are submitted

  preparative fast liquid chromatography with co-

  reverse phase (the same as in example 14) and

  eluted with a 13% aqueous methanol solution.

  vol / vol (containing 2% acetic acid) at a rate of 200

  ml / minute. A fraction having a main peak is separated

  by on differential refractomers (7-10 minutes). The remaining 80 ml is treated in the same way. The resulting fractions having a principal peak are collected, concentrated and extracted with ethyl acetate. The extract is concentrated to dryness after addition of heptane. 920 mg of an oily substance are obtained which are dissolved in 20 ml of methanol and chromatography under the same conditions as

  above, and 120 mg of MB-530A carboxylic acid are obtained.

  than. This product is added with 2 ml of methanol and 100

  ml of water, the solution is brought to pH 8.0 with a solution of

  aqueous solution of 1N sodium hydroxide. We obtain

  a clear aqueous solution which is freeze-dried, which

  nit 110 mg of MB-530A-sodium carboxylate in the form

a white powder.

Claims (41)

  1. Compounds of interest as therapeutic agents and chemical intermediate products, characterized in that they correspond to the formula: Rte Con R2 OR5 OR3 I   Wherein R1 represents a hydrogen atom or a methyl group; R represents a hydrogen atom, the alcoholic moiety of an ester or the cationic moiety of a salt; and R3, R4 and R5 are the same or different and each represents a hydrogen atom or an organic or inorganic acyl group, provided that when R3   represents a 2-methylbutyryl group, R and R5 represent   both are acyl groups and n represents the valence of R2.   2. Compounds according to claim 1, characterized in that: R1 represents a hydrogen atom or a methyl group; R2represents a hydrogen atom, a monovalent metal atom, an ammonium group, an ammonium group   alkyl, a group capable of forming a derivatized salt   a basic amino acid, an alkyl group, an aralkyl group optionally substituted on the   aryl moiety or a phenacyl group   substituent on the phenyl moiety, said   substituents are selected from C1 to C4 alkyl groups, C1 to C4 alkoxy groups, halogen atoms, and the like. 3 4 5   and trifluoromethyl groups; and R, R and R are the same or different and each represents a hydrogen atom, an aliphatic acyl group, an aromatic acyl group or an araliphatic acyl group, subject to 3 4   that when R is 2-methylbutyryl, R   and R5 are both acyl groups.   3. Compounds according to claim 1, characterized in that: R1 represents a hydrogen atom or a methyl group; R2 represents a hydrogen atom, an atom of   alkali metal, an alkaline earth metal atom, an atom   of aluminum, zinc, iron or germanium, an ammonium group, a group capable of forming a salt deriving from a   basic amino acid, a C1 to C8 alkyl group, a group   aralkyl optionally carrying a substituent sur.le   aryl moiety, or a phenacyl group   a substituent on the phenyl moiety, said substituents being selected from C1 to C4 alkyl groups, C1 to C4 alkoxy groups, halogen atoms and trifluoromethyl groups; and R3, R4 and R5 are the same or different and each represents a hydrogen atom, a C2-C20 alkanoyl group, a C3-C20 alkenoyl group, a C3-C20 alkynoyl group,   a C 7 to C 15 aromatic acyl group, an aralkal group   C8 - C9 nucleus or a C9 aralkenoyl group, under   that when R3 represents a 2-methylbutyryl-   the, R4 and R5 are both acyl groups.   4. Compounds according to claim 1, characterized in that: R1 represents a hydrogen atom or a methyl group; R2 represents a hydrogen atom, an alkali metal atom, an alkaline earth metal atom, a   ammonium group, a group capable of forming a distillate salt   from a basic amino acid, a C1 to C4 alkyl group, a benzyl group or a phenacyl group; and R3, R4 and R5 are the same or different and each represents a hydrogen atom, a C2-C6 alkanoyl group, a C3-C6 alkenoyl group or a benzoyl group,   provided that when R3 represents a 2-methylbutyl-   R14, R4 and R5 are both acyl groups.   5. Compounds according to claim 1, characterized in that: R1 represents a hydrogen atom or a methyl group; R2 represents a C1-C4 alkyl group, a benzyl group or a phenacyl group; R3 represents a C2-C6 alkanoyl group or a C3 alkenoyl group   at C6; and R and R are the same or different and represent   each have a C 2 -C 6 alkanoyl group or a benzoyl group. 6. Compounds according to claim 1, characterized in that: R1 represents a hydrogen atom; R2 represents   C1 to C4 alkyl; R3 represents a group   eg C 2 -C 6 alkanoyl; and R4 and R4 are the same or different and each represents an acetyl group or a benzoyl group.   Compounds according to claim 1, characterized in that they correspond to formula (II): HO CDOQ R1   in which: R1 represents a hydrogen atom or a methyl group; R2a represents a hydrogen atom, an alkali metal atom, an alkaline earth metal group, an ammonium group, a group capable of forming a salt derived from a basic amino acid, a C1-alkyl group   at C4, a benzyl group or a phenacyl group; R3a represents   C2 to C6 alkanoyl, which is not 2-methylbutyryl, or C3-C6alkenoyl; and m represents the valence of R2a 8. Compounds according to Claim 7, characterized in that R2a represents a C1 to C4 alkyl group, a   benzyl group or a phenacyl group.   9. Compounds according to claim 7, characterized   in that R2a represents an alkali metal atom.   10. Compounds according to claim 1, characterized in that they correspond to formula (III) HO COOM OH OH ti H03 R ' R1   wherein: R1 represents a hydrogen atom or a methyl group; M represents a hydrogen atom or a alkali metal atom.   11. Compounds according to claim 10, characterized   in that M represents an alkali metal atom.   12. Compounds according to claim 10, characterized   in that M represents a sodium atom.   13. Compounds according to claim 1, characterized in that they are: ML-236A-sodium carboxylate,   MB-530A-sodium carboxylate, 8'-O-butyryl-ML-236A-car-   sodium boxylate, 8'-O-hexanoyl-ML-236A-carboxylate   sodium, ethyl 8'-O-butyryl-ML-236A-carboxylate, 8'-O-   hexanoyl-ML-236A-ethyl carboxylate, 8'-O-butyryl-ML-   236A-Butyl carboxylate, 8'-O- (4-pentenoyl) -MML-236A-   butyl carboxylate, butyl 8'-O-isovaleryl-MB-530A-carboxylate, benzyl 8'-butyryl-ML-236A-carboxylate, benzyl 8'-O-hexanoyl-ML-236Acarboxylate, 8'-O butyryl   -MB-530A-phenacyl carboxylate, 3,5-di (O-acetyl) -LM-   236B-Butyl carboxylate, and 3,5-di (O-benzoyl) -MML-236B- butyl carboxylate.   14. Process for preparing an ML-236A acid salt   carboxylic acid, characterized in that a microorganism is cultivated   producing ML-236A, of the genus Penicillium, in a suitable culture medium, and collect the salt   ML-236A carboxylic acid from the stock broth. resulting ture.   15. Process according to claim 14, characterized in that the microorganism is a strain of Penicillium   citrinum, Penicillium chrysogenum or Penicillium notatum.   16. Process according to claim 15, characterized in that the microorganism is Penicillium citrinum SANK   18767 (FERM 2609), Penicillium citrinum SANK 24467, Peni-   cillium citrinum SANK 24567, Penicillium chrysogenum SANK 12768 (ATCC 100020) or Penicillium notatum SANK 24867.   17. Process according to any one of the claims   14 to 16, characterized in that the salt is a salt of alkali metal.   18. Process for preparing an MB-530A acid salt   carboxylic acid, characterized in that a microorganism is cultivated   MB-530A producer, of the genus Monascus, in a suitable culture medium and the acid salt is collected   MB-530A carboxylic acid from the culture broth   sultant. 19. Process according to claim 18, characterized in that the microorganism is a strain of Monascus ruber, Monascus anka, Monascus paxii, Monascus purpureus or Monascus vitreus.   20. Process according to claim 19, characterized in that the microorganism is Monascus ruber SANK 11272   (IFO 9203), Monascus ruber SANK 17075 (CBS 832.70), Monas-   cus ruber SANK 17175 (CBS 503.70), Monascus ruber SANK 17275 (ATCC 18199), Monascus ruber SANK 15177 (FERM 4956), Monascus ruber SANK 13778 (FERM 4959), Monascus ruber SANK 10671 (FERM 4958), Monascus ruber SANK 18174 ( FERM 4957), Monascus anka SANK 10171 (IFO 6540), Monascus paxii SANK 11172 (IFO 8201), Monascus purpureus SANK 10271 (IFO 4513) or Monascus vitreus SANK 10960 (NIHS 609, e-609, FERM 4960).   21. Process according to any one of the claims   18 to 20, characterized in that the salt is a salt of alkali metal.   22. Process for the preparation of a carboxylic acid salt   which corresponds to formula (IV): wherein: R 1 represents a hydrogen atom or a methyl group; R3 and R4 are the same or different and each represents a hydrogen atom or an acyl group, provided that when R3 represents a group   2-methylbutyryl, R4 is acyl; M re-   shows the cationic moiety of a salt, and m 'is the valency of -M1, characterized in that a lactone of formula (V): IV) i 3 4 i in which R 1, R, R 4, M is hydrolyzed is hydrolyzed; and I have the meanings   above mentioned, and the carbohydrate group   xy of the product thus obtained in the corresponding salt.   23. Process according to claim 22, characterized in that the hydrolysis is carried out in a solution   alkaline and M1 represents an alkali metal atom.   24. The method of claim 22 or 23, wherein   characterized in that: R represents a hydrogen atom or a methyl group; R3 represents a hydrogen atom, a C2-C6 alkanoyl group or a C3-C6 alkenoyl group; and R4 represents a hydrogen atom, a group   C2-C6 alkanoyl or benzoyl group.   25. Process for the preparation of a carboxylic acid derivative   xyl corresponding to formula (VI): wherein R1 represents a hydrogen atom or a methyl group and M2 represents an alkali metal atom, characterized in that a compound of formula (VII):   [in which R1 has the above meaning, in a alkaline solution.   26. Process according to claim 25, characterized in that M2 represents a sodium atom and the solution   alkaline is an aqueous solution of sodium hydroxide.   27. Process for the preparation of a carboxylic acid ester   xyl compound of the formula (VIII): RI00 wherein R1 represents a hydrogen atom or a methyl group; R3 and R4 are the same or different and each represents a hydrogen atom or an acyl group, provided that when R3 is 2-methylbutyryl, R4 is acyl; and R2b represents an alkyl group or an aralkyl group, characterized in that a lactone (V) is reacted: RtO IV) - I OR3 IV}. RI 1,341   in which R1, R3 and R4 have the precise meanings   with an alcohol in the presence of an acid catalyst.   28. Process according to claim 27, characterized in that the acidic catalyst is a mineral acid, a   Lewis acid or a cation exchange resin.   29. The process according to claim 28, characterized in that the acidic catalyst is a water-exchange resin. strongly acidic cations.   30. Process according to any one of the claims   27 to 29, characterized in that: R1 represents a hydrogen atom or a methyl group; R3 represents a hydrogen atom, a C2-C6 alkanoyl group or a   C3 to C6 alkenoyl group; R4 represents a hydrogen atom   a C2-C6 alkanoyl group or a ben-   zoyl - with the proviso that when R 3 is 2-methylbutyryl, R 4 is acyl; and   the alcohol is a C1 to C4 alkanol.   31. A process for the preparation of an R 5 carboxylic acid ester having the formula (IX): wherein R, R, R and R are as defined in claim 1. 1; R represents the alcoholic moiety of an ester; and p is the valence of R 2c, characterized in that a carboxylic acid salt having the formula (X) is reacted with an esterification agent: neck - M3 ORS   wherein R1, R3, R4 and R5 have the meanings   M3 represents an alkali or alkali metal atom   no-earthy, and q is the valence of M3.   32. A process according to claim 31, characterized in that the esterifying agent is an alkyl halide, an aralkyl halide or a halogenide. phenacyl.   33. The process of claim 31 or 32, wherein   characterized in that M represents an alkali metal atom.   34. Process according to claim 33, characterized in that the salt (X) in which M3 represents an alkali metal atom is formed in situ prior to reaction with an esterification agent.   35. Process according to any one of the claims   compositions 31 to 34, characterized in that: R1 represents a hydrogen atom or a methyl group; R3 represents a hydrogen atom, a C2-C6 alkanoyl group or a C3-C6 alkenoyl group; R4 and R5 are identical   or different and each represent a hydrogen atom   gene, a C2-C6 alkanoyl group or a benzoyl group, with the proviso that when R is 2-methyl-butyryl, R4 and R5 are both acyl groups; M3 represents an alkali metal atom; and the agent   esterification is a benzyl halide or a halo phenacyl genius.   36. Process for the preparation of a triacylated compound   laying down in formula (XI): I tu] L i   wherein R1, R2 and n are as defined in the   3b b 5b claim 1, and R3b, R4b and R5b are the same or different and each represents an acyl group; characterized in that a compound of formula (XII): R "CO0O k 0., R5c R1 ..   in which R1, R2 and n have the precise meanings   R3c 4c 5c tees and R3c, R4c and R5c are the same or different and each represents a hydrogen atom or a 3c acyl group, provided that at least one of R3c radicals,   R4c and R5c represents a hydrogen atom.   37. A process for the preparation of one or more compounds corresponding to formulas (XIII), (XIV) and (XV): wherein R1, R1, R3, RR and n are as defined in claim 1, R3b is acyl and R4b is acyl, wherein acyl is a compound of formula (XVI): _- A. (xvI) R1 2 3b   wherein R1, R3b and n have the meanings   cited, thus obtaining compounds corresponding to the formulas   (XIII), (XIV) or (XV) which is isolated from the reaction mixture.   38. Process according to claim 37, characterized in that in the compound (XVI): R1 represents a hydrogen atom or a methyl group; R2 represents a hydrogen atom or a methyl group; R represents an atom - R2 IY! I!)   R 1 is alkali metal, C 1 -C 4 alkyl, benzyl or phenacyl, and R 3b is C 2 -C 6 alkanoyl or C 3 -C 6 alkenoyl, the acylation being carried out using a C 2 to C 6 alkanolic acid, benzoic acid or a reactive derivative thereof, and the compounds (XIII) are obtained   and / or (XIV) in which R4b represents an alkaline group nucleus or a benzoyl group.   39. Process according to claim 37, characterized in that the acylation is carried out using a derivative   reagent of a carboxylic or sulfonic acid.   40. Process according to claim 39, characterized in that the acylation is carried out using an acid halide, an acid anhydride or a mixed anhydride of carboxylic or sulfonic acid.   41. Medicines having, inter alia, inhibitory activity   that of the biosynthesis of cholesterol characterized in that it contains as active ingredient a compound according to one of   any of claims 1 to 13.