DE3114242A1 - CARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE DERIVATIVES - Google Patents

Abstract

Compounds of the formula I in which R [high] 1 denotes a hydrogen atom or a methyl group, R [high] 2 denotes a hydrogen atom, the alcohol group of an ester or the cation group of a salt, R [high] 3, R [high] 4 and R [high] 5 are identical or different hydrogen atoms or organic or inorganic acyl groups, with the proviso that when R [high] 3 is a 2-methylbutyryl group, R [high] 4 and R [high] 5 are both acyl groups, and n are the Valence of R [high] 2 is produced by growing microorganisms of the genera Penicillium or Monascus or by salt formation or esterification of the corresponding carboxylic acids or lactones or, in the case of esters of formula I, by esterification of a corresponding salt of formula I.

Description

The invention relates to a number of new compounds which inhibit cholesterol biosynthesis and are therefore suitable for the prophylactic and therapeutic treatment of diseases which are based on high cholesterol levels.

The hyperlipemia, in particular the hypercholesterolemia, are known to be the main causes of heart diseases, such as myocardial infarction or arteriosclerosis. Considerable research has therefore been carried out to discover compounds which lower lipid and especially cholesterol levels in the blood. One group of such compounds isolated from microorganisms of the genus Penicillium is described in US Pat. No. 3,983,140. This group of compounds is collectively referred to as ML-236. In USSN 121 515 of February 24, 1980 and 137 821 of April 4, 1980 (DE-OS 3 006 215 and 3 006 216) a structurally similar compound is described, which is referred to as Monacolin K or MB-530B. Certain salts and esters of MB-530B are described in USSN 172 231 of 07/25/1980 (P ..).

MB-530B and its salts can be obtained by culturing microorganisms belonging to the genus Monascus, particularly with strains of Monascus ruber. Another compound of the MB-530 group, designated MB-530A, as well as compounds related to groups ML-236 and MB-530, are in the patent application P. described.

A new set of compounds has now been discovered which are related to groups ML-236 and MB-530 and which inhibit the biosynthesis of cholesterol. The compounds according to the invention have the formula I. in which R [high] 1 denotes a hydrogen atom or a methyl group, R [high] 2 denotes a hydrogen atom, the alcohol group of an ester or the cation group of a salt, and R [high] 3, R [high] 4 and R [high] 5 are the same or different hydrogen atoms or organic or inorganic acyl groups, with the proviso that when R [high] 3 is a 2-methylbutyryl group, R [high] 4 and R [high] 5 are both acyl groups, and n is the valence of R [high] 2 is.

The invention also relates to processes for producing the compounds according to the invention by fermentation, using microorganisms of the genus Penicillium or Monascus, or by hydrolysis, salt formation or esterification of the fermentation products obtained.

The compounds according to the invention are derivatives of compounds of groups ML-236 and MB-530 in which the lactone ring has been opened. They are therefore called derivatives of

ML-236 carboxylic acids or MB-530 carboxylic acids, that is, carboxylic acids obtained by hydrolysis of ML-236 or MB-530 compounds. According to the invention, the numbering is based on the following structural formula:

In compounds of the formula I in which R [high] 2 is the cation of a salt, this can be, for example, a metal atom, such as an alkali metal atom (such as sodium or potassium), an alkaline earth metal atom (such as calcium, magnesium or barium), a transition metal atom (such as Iron, nickel or cobalt) or another metal atom (such as aluminum, zinc or copper). In this case, n is the valence of these metals, which is usually 1 to 3. Alternatively, R [high] 2 can also be an ammonium group or a substituted ammonium group, preferably an alkyl-substituted ammonium group, such as the methylammonium, ethylammonium, isopropylammonium, dimethylammonium, diethylammonium, trimethylammonium, triethylammonium, tetramethylammonium, or dhexamethylammonium group. In this case n = 1. Other cation groups R [high] 2 are, for example, salt-forming groups which are derived from a basic amino acid such as lysine, arginine or ornithine.

Alternatively, R [high] 2 can be the alcohol group of an ester, the value of n depending on the type of hydroxy compound from which R [high] 2 is derived. In the case of monoalcohols, for example, n has the value 1, in the case of glycols the value 2 and in the case of glycerol the value 3. If R [high] 2 is a monovalent group, it is preferably a substituted or unsubstituted alkyl group, aralkyl group or phenacyl group .

Examples of alkyl groups R [high] 2 are straight-chain or branched alkyl groups with preferably 1 to 8 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, tert-pentyl, isopentyl, neopentyl, hexyl, heptyl, 2-methylhexyl and octyl.

Examples of aralkyl groups R [high] 2 are benzyl and benzhydryl, both of which are either unsubstituted or have one or more substituents on the benzene ring. Examples of such substituents are C [deep] 1-C [deep] 4-alkyl groups (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl), C [deep] 1-C [deep] 4-alkoxy groups (such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert-butoxy), halogen atoms (such as chlorine, bromine or fluorine) or trifluoromethyl groups. If two or more substituents are present, they can be the same or different. Examples of such aralkyl groups are benzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-ethylbenzyl, 3-ethylbenzyl, 4-ethylbenzyl, 2-propylbenzyl, 3-propylbenzyl, 4-propylbenzyl, 2-butylbenzyl, 3-butylbenzyl , 4-butylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-propoxybenzyl, 3-propoxybenzyl, 4-propoxybenzyl, 4-butoxybenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, 3 -Bromobenzyl, 4-bromobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl and benzhydryl.

If R [high] 2 is a phenacyl group, this can be unsubstituted or have one or more substituents on the benzene ring. Examples of such substituents are C [deep] 1-C [deep] 4-alkyl groups, C [deep] 1-C [deep] 4-alkoxy groups, halogen atoms and the trifluoromethyl group, specific substituents being mentioned above. Preferred examples of such phenacyl groups are phenacyl, 2-methylphenacyl, 3-methylphenacyl, 4-methylphenacyl, 2-ethylphenacyl, 3-ethylphenacyl, 4-ethylphenacyl, 2-propylphenacyl, 3-propylphenacyl, 4-propylphenacyl, 2-butylphenacyl, 3- Butylphenacyl, 4-butylphenacyl, 2-methoxyphenacyl, 3-methoxyphenacyl, 4-methoxyphenacyl, 2-ethoxyphenacyl, 3-ethoxyphenacyl, 4-ethoxyphenacyl, 2-propoxyphenacyl, 3-propoxyphenacyl, 4-propoxyphenacyl, 2-butylphenacyl, 2-propoxyphenacyl, 4-butoxyphenacyl, 2-chlorophenacyl, 3-chlorophenacyl, 4-chlorophenacyl, 2-bromophenacyl, 3-bromophenacyl, 4-bromophenacyl, 2-fluorophenacyl, 3-fluorophenacyl, 4-fluorophenacyl, 2-trifluoromethylphenacyl and 4-trifluoromethylphenacyl, 3-trifluoromethyl Trifluoromethylphenacyl.

If R [high] 2 denotes a dihydric alcohol group, this is preferably a C [low] 2-C [low] 6-alkylene or alkylidene group, for example ethylene, ethylidene, propylene, propylidene, trimethylene, tetramethylene, butylidene, pentamethylene or pentylidene , as well as corresponding groups with one or more substituents, for example hydroxyl groups, halogen atoms or trifluoromethyl groups.

When R [high] 2 is a trihydric alcohol group, it is preferably a saturated aliphatic hydrocarbon group having 2 to 6 carbon atoms, which may optionally have one or more substituents, e.g., hydroxyl groups, halogen atoms or trifluoromethyl groups.

When R [high] 3, R [high] 4 and R [high] 5 are acyl groups, these can be, for example, organic acyl groups such as aliphatic, aromatic, araliphatic, alicyclic, heterocyclic or heterocyclic substituted aliphatic acyl groups, aliphatic or aromatic sulfonyl groups, aliphatic, aromatic or araliphatic phosphoryl groups, or inorganic acyl groups such as acyl groups derived from phosphoric acid, sulfuric acid or nitric acid.

If the acyl group is an aliphatic acyl group, this can be saturated or unsaturated, such as, for example, straight-chain or branched C [deep] 2 -C [deep] 20 -alkanoyl groups (e.g. acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl) , 2-methylvaleryl, heptanoyl, isoheptanoyl, octanoyl, isoocatnoyl, 2-methyloctanoyl, nonanoyl, isononanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, palmitoyl, stearoyl, and isostearoyl); C [deep] 3-C [deep] 20-alkenoyl groups (e.g. acryloyl, crotonoyl, 3-butenoyl, methacryloyl, 3-methyl-2-butenoyl, 2-pentenoyl, 4-pentenoyl, tigloyl, angeloyl, 2-hexenoyl, 2 -Heptenoyl, hept-2,4-dienoyl, 2-octenoyl, 2-nonenoyl, 2-decenoyl, 2-undeconoyl, linolenoyl, oleoyl, linoleyl and arachidonoyl); or C [deep] 3-C [deep] 20-alkinoyl groups (e.g. propioloyl, 2-butinoyl, 3-butinoyl, 2-pentinoyl, 2-hexinoyl, 2-heptinoyl, 2-octinoyl, 2-nonionyl and 2-decinoyl) . These acyl groups can be unsubstituted or have one or more substituents, for example halogen atoms such as chlorine or bromine, trifluoromethyl groups, nitro groups, carboxyl groups, alkoxycarbonyl groups such as methoxycarbonyl or ethoxycarbonyl, aralkoxycarbonyl groups such as benzyloxycarbonyl, cyano groups, amino groups, alkanoylamino groups such as alkylamino groups, such as alkylamino groups Methylamino, dimethylamino or ethylamino, aralkylamino groups such as benzylamino, hydroxyl groups, alkanoyloxy groups such as acetoxy or pivaloyloxy, alkoxy groups such as methoxy or ethoxy, sulfhydryl groups, alkylthio groups such as methylthio or ethylthio, and acylthio groups such as acetoxy or benzylthiothio.

When the acyl groups R [high] 3, R [high] 4, or R [high] 5 are aromatic acyl groups, the aromatic ring can be a simple ring (ie, benzene ring) or a condensed ring such as naphthalene, anthracene, or indane . This ring may optionally have one or more substituents, e.g. alkyl groups, alkoxy groups, halogen atoms, trifluoromethyl groups, nitro groups, cyano groups, amino groups or hydroxyl groups. If two or more substituents are present, these can be the same or different. Specific examples of such aromatic acyl groups are 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-anisoyl, m-anisoyl, p-anisoyl, 2,4-dimethoxybenzoyl, 2-ethoxybenzoyl, 3-ethoxybenzoyl, 4-ethoxybenzoyl, 2-propoxybenzoyl, 3-propoxybenzoyl, 4 Propoxybenzoyl, 2-butoxybenzoyl, 3-butoxybenzoyl, 4-butoxybenzoyl, piperonyloyl, 2-chlorobenzoyl, 3-chlorobenzoyl, 4-chlorobenzoyl, 2,3-dichlorobenzoyl, 3,4-dichlorobenzoyl, 2,4-dichlorobenzoyl, 2-bromobenzoyl , 3-bromobenzoyl, 4-bromobenzoyl, 2-fluorobenzoyl, 3-fluorobenzoyl, 4-fluorobenzoyl, 2-trifluoromethylbenzoyl, 3-trifluoromethylbenzoyl, 4-trifluoromethylbenzoyl, 2-nitrobenzoyl, 3-nitrobenzoyl, 4-nitrobenzoyl, 2,4-dinzoyl , 3,5-dinitrobenzoyl, salicyloyl, 3-hydroxybenzoyl, 4-hydroxybenzoyl, 2-acetoxybenzoyl, 3-acetoxybenzoyl, 4-acetoxybenzoyl, anthraniloyl, 2-acetamidobenzoyl, 4-acetamidobe nzoyl, vanilloyl, veratroyl, protocatechuoyl, galloyl, 1-naphthoyl, 2-naphthoyl, 2-anthranoyl, 4-indanecarbonyl, 5-indanecarbonyl and 4-indene carbonyl.

When the acyl groups R [high] 3, R [high] 4, or R [high] 5 are araliphatic acyl groups, the aromatic ring of this araliphatic acyl group can be a simple or a condensed ring, as explained above for the aromatic acyl groups, while the aliphatic group can be saturated or unsaturated. The aromatic ring may optionally have one or more substituents as described above for the aromatic acyl groups are mentioned. Examples of such araliphatic acyl groups are phenylacetyl, 2-methylphenylacetyl, 3-methylphenylacetyl, 4-methylphenylacetyl, 2-ethylphenylacetyl, 2-methoxyphenylacetyl, 3-methoxyphenylacetyl, 4-methoxyphenylacetyl, 2-ethoxyphenylacetyl, 2-ethoxyphenylacetyl, 2-ethoxyphenylacetyl, 3-ethoxyphenylacetyl, 2-ethoxyphenylacetyl, 2-ethoxyphenylacetyl Propoxyphenylacetyl, 3-propoxyphenylacetyl, 4-propoxyphenylacetyl, 2,4-dimethoxyphenylacetyl, 3,4-methylenedioxyphenylacetyl, 2-hydroxyphenylacetyl, 3-hydroxyphenylacetyl, 4-hydroxyphenylacetyl, 2-chlorophenylacetyl, 3-chlorophenylacetyl, 2,3- chlorophenylacetyl Dichlorophenylacetyl, 2,4-dichlorophenylacetyl, 3,5-dichlorophenylacetyl, 2-bromophenylacetyl, 3-bromophenylacetyl, 4-bromophenylacetyl, 2-nitrophenylacetyl, 3-nitrophenylacetyl, 4-nitrophenylacetyl, 4-aminophenylacetyl, 2-phenylpropionyl, 3- -Methylphenyl) propionyl, 3- (3-methylphenyl) propionyl, 3- (4-methylphenyl) propionyl, 3- (2-methoxyphenyl) propionyl, 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, m-methylcinnamoyl, p-methylcinnamoyl, o- Methoxycinnamoyl, m-methoxycinnamoyl, p-methoxycinnamoyl, o-hydroxycinnamoyl, m-hydroxycinnamoyl, p-hydroxycinnamoyl, o-chlorocinnamoyl, m-chlorocinnamoyl, p-chlorocinnamoyl, o-bromocinnamoyl, m-bromocinnamoyl and p-bromocinnamoyl.

When the acyl groups R [high] 3, R [high] 4, or R [high] 5 are alicyclic acyl groups, the alicyclic ring may be saturated or unsaturated and preferably contain 3 to 7 carbon atoms. Examples of such alicyclic acyl groups are cyclopropanecarbonyl, cyclobutanecarbonyl, cyclobut-1-ene carbonyl, cyclobut-2-ene carbonyl, cyclopentanecarbonyl, cyclopent-1-ene carbonyl, cyclopent-2-ene carbonyl, cyclopent-1,3-diene carbonyl, cyclopent-2,4- diene carbonyl, cyclohexane carbonyl, cyclohex-1-ene carbonyl, cyclohex-2-ene carbonyl, cyclohex-3-ene carbonyl, cyclohex-1,3-diene carbonyl, cyclohex-2,4-diene carbonyl, cycloheptane carbonyl, cyclohept-1-ene carbonyl, cyclohept-2- encarbo- nyl, cyclohept-3-ene carbonyl, cyclohept-1,3-diene carbonyl, cyclohept-2,4-diene carbonyl, cyclohept-2,5-diene carbonyl, cyclohept-1,4-diene carbonyl, cyclohept-1,5-diene carbonyl, cyclohept- 1,3,5-triene carbonyl, cyclohept-2,4,6-triene carbonyl and adamantane carbonyl. These rings can optionally have one or more substituents such as those mentioned above for the aromatic acyl groups. These substituents can form one or more rings which are fused onto said alicyclic ring system.

When the acyl groups R [high] 3, R [high] 4 or R [high] 5 are heterocyclic acyl groups, the heterocyclic ring preferably contains five or six ring atoms, one or more of which are heteroatoms, for example nitrogen, oxygen, sulfur - or selenium atoms. This heterocyclic ring may optionally be fused with a carbocyclic ring or another heterocyclic ring which may or may not be identical to the first-mentioned heterocyclic ring to form a condensed heterocyclic ring system. The heterocyclic acyl group can have one or more substituents as mentioned above for the aromatic acyl groups. Specific examples of such heterocyclic acyl groups are 2-thenoyl, 3-thenoyl, 5-methylthen-2-oyl, 5-chlorothen-2-oyl, 4,5-dimethylthen-3-oyl, 2-furoyl, 3-furoyl, 5 -Methylfur-2-oyl, 5-chlorofur-2-oyl, pyridine-2-carbonyl, 3-methylpyridine-2-carbonyl, 4-methylpyridine-2-carbonyl, 5-methylpyridine-2-carbonyl, 6-methylpyridine-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-tetrazole-1-carbonyl, piperidine carbonyl, 4-methyl-1 -piperazine carbonyl, 1-pyrrolidine carbonyl, benzofuran-2-carbonyl and benzothiophene-2-carbonyl.

When the acyl groups R [high] 3, R [high] 4 or R [high] 5 are heterocyclic-substituted aliphatic acyl groups, the same heterocyclic groups as mentioned above for the heterocyclic acyl groups and the same saturated or unsaturated aliphatic groups, as mentioned above for the aliphatic acyl groups are present. Examples of such heterocyclically substituted aliphatic acyl groups are 2-thienylacetyl, (5-methylthiophen-2-yl) -acetyl, (5-chlorothiophen-2-yl) -acetyl, 3-thienylacetyl, 2-furylacetyl, 3-furylacetyl, 2 -Pyridylacetyl, 3-pyridylacetyl, 4-pyridylacetyl, 2-furylacryloyl, 3-furylacryloyl, 2-thienylacryloyl, 3-thienylacryloyl, piperidinoacetyl, 4-methylpiperidinoacetyl, 2-amino-3- (indol-2-yl and 2-propionyl) -Amino-3- (indol-3-yl) -propionyl.

When the acyl group R [high] 3, R [high] 4, or R [high] 5 is a sulfonyl group, it can be an aliphatic sulfonyl group such as methanesulfonyl or ethanesulfonyl, or an aromatic sulfonyl group such as benzenesulfonyl or toluenesulfonyl.

When the acyl group R [high] 3, R [high] 4 or R [high] 5 is a phosphoryl group, it can be an aliphatic phosphoryl group such as dimethylphosphoryl or diethylphosphoryl, an aromatic phosphoryl group such as ditolylphosphoryl, or an araliphatic phosphoryl group such as dibenzylphosphoryl , p-methylbenzylphosphoryl, p-bromobenzylphosphoryl or p-methoxybenzylphosphoryl.

According to the invention, compounds are preferred in which R [high] 1 denotes a hydrogen atom or a methyl group, R [high] 2 denotes a hydrogen atom, a metal atom (in particular an alkali metal, alkaline earth metal, aluminum, zinc, iron or germanium atom), an ammonium group, an alkyl-substituted ammonium group, a group capable of forming salts and derived from a basic amino acid, an alkyl group (preferably a straight-chain or branched C [deep] 1-C [deep] 8-alkyl group), an aralkyl group, which optionally has one or more substituents on the aryl radical, or a phenacyl group, which optionally has one or more substituents on the phenyl radical, where the substituents C [low] 1-C [low] 4-alkyl groups, C [low] 1-C [low] 4-alkoxy groups, halogen atoms and / or trifluoromethyl groups, and R [high] 3, R [high ] 4 and R [high] 5 identical or different hydrogen atoms, aliphatic acyl groups (preferably C [low] 2-C [low] 20-alkanoyl groups, C [low] 3-C [low] 20-alkenoyl groups or C [low] 3 -C [deep] 20-alkinoyl groups), aromatic acyl groups (preferably C [deep] 7-C [deep] 15 groups) or araliphatic acyl groups (preferably C [deep] 8- or C [deep] 9-aralkanoyl groups or C [ low] 9-aralkenoyl groups), with the proviso that when R [high] 3 is a 2-methylbutyryl group, R [high] 4 and R [high] 5 are both acyl groups.

Particularly preferred compounds of the formula I are those in which R [high] 1 denotes a hydrogen atom or a methyl group, R [high] 2 denotes a hydrogen, alkali metal or alkaline earth metal atom, an ammonium group, a group which is capable of forming salts and is derived from a basic amino acid , represents a C [low] 1-C [low] 4-alkyl group, benzyl group or phenacyl group and R [high] 3, R [high] 4 and R [high] 5 are the same or different hydrogen atoms, C [low] 2-C [low] 6-alkanoyl groups, C [low] 3-C [low] 6-alkenoyl groups or benzoyl groups, with the proviso that when R [high] 3 is a 2-methylbutyryl group, R [high] 4 and R [high ] 5 are both acyl groups.

Most preferred are compounds in which R [high] 1 denotes a hydrogen atom or a methyl group, preferably a hydrogen atom, R [high] 2 denotes a C [low] 1 -C [low] 4-alkyl group, benzyl group or phenacyl group, in particular a C [lower] 1-C [lower] 4-alkyl group, R [high] 3 represents a C [lower] 2-C [lower] 6-alkanoyl group or C [lower] 3-C [lower] 6-alkenoyl group , in particular a C [low] 2-C [low] 6-alkanoyl group and R [high] 4 and R [high] 5 are identical or different C [low] 2-C [low] 6-alkanoyl groups or benzoyl groups, in particular one Acetyl or benzoyl group.

One class of compounds according to the invention are compounds of the formula II in which R [high] 1 denotes a hydrogen atom or a methyl group, R [high] 2a denotes a hydrogen, alkali metal or alkaline earth metal atom, an ammonium group, a group which is capable of forming salts and is derived from a basic amino acid, a C [low] 1- C [low] 4-alkyl group, benzyl group or phenacyl group, R [high] 3 represents a C [low] 2-C [low] 6-alkanoyl group (but no 2-methylbutyryl group) or a C [low] 3-C [low ] Means 6-alkenoyl group and m is the valence of the metal or the group R [high] 2a.

Particularly preferred are compounds of the formula II in which R [high] 2a is a C [low] 1-C [low] 4-alkyl group, benzyl group or phenacyl group, and compounds of the formula II in which R [high] 2a is an alkali metal atom is.

Another class of compounds according to the invention are compounds of the formula III

in which R [high] 1 is a hydrogen atom or a methyl group and M is a hydrogen or alkali metal atom, preferably a sodium atom.

Specific compounds according to the invention are mentioned below. The compounds are referred to as derivatives of ML-236A, ML-236B, MB-530A or MB-530B or their corresponding carboxylic acids:

1. Sodium ML-236A carboxylate

2. Calcium bis (ML-236A carboxylate)

3. Sodium MB-530A carboxylate

4. Calcium bis (MB-530A carboxylate)

5. ML-236A carboxylic acid methyl ester

6. ML-236A carboxylic acid ethyl ester

7. ML-236A butyl carboxylate

8. ML-236A Benzyl Carboxylate

9. ML-236A carboxylic acid p-bromobenzyl ester

10. ML-236A carboxylic acid p-methoxybenzyl ester

11. ML-236A phenacyl carboxylate

12. ML-236A carboxylic acid p-methoxyphenacyl ester

13. MB-530A methyl carboxylate

14. Ethyl MB-530A carboxylate

15. MB-530A butyl carboxylate

16. MB-530A benzyl carboxylate

17. MB-530A carboxylic acid p-methoxybenzyl ester

18. Phenacyl MB-530A carboxylate

19. MB-530A carboxylic acid p-methoxyphenacyl ester

20. Sodium 8'-O-acetyl-ML-236A-carboxylate

21. 8'-O-acetyl-ML-236A-carboxylic acid methyl ester

22. Ethyl 8'-O-acetyl-ML-236A-carboxylate

23. 8'-O-acetyl-ML-236A-carboxylic acid butyl ester

24. 8'-O-Acetyl-ML-236A-carboxylic acid benzyl ester

25. 8'-O-acetyl-ML-236A-carboxylic acid p-methoxybenzyl ester

26. 8'-O-acetyl-ML-236A-carboxylic acid phenacyl ester

27. 8'-O-acetyl-ML-236A-carboxylic acid p-methoxyphenacyl ester

28. Sodium 8'-O-acetyl-MB-530A-carboxylate

29. 8'-O-acetyl-MB-530A-carboxylic acid methyl ester

30. Ethyl 8'-O-acetyl-MB-530A-carboxylate

31. 8'-O-Acetyl-MB-530-carboxylic acid butyl ester

32. 8'-O-acetyl-MB-530A-carboxylic acid benzyl ester

33. 8'-O-acetyl-MB-530A-carboxylic acid p-methoxybenzyl ester

34. 8'-O-acetyl-MB-530A-carboxylic acid phenacyl ester

35. 8'-O-acetyl-MB-530A-carboxylic acid p-methoxyphenacyl ester

36. Sodium 8'-O-propionyl-ML-236A-carboxylate

37. 8'-O-propionyl-ML-236A-carboxylic acid methyl ester

38. 8'-O-propionyl-ML-236A-carboxylic acid ethyl ester

39. 8'-O-propionyl-ML-236A-carboxylic acid benzyl ester

40. 8'-O-propionyl-ML-236A-carboxylic acid phenacyl ester

41. Sodium 8'-O-propionyl-MB-530A-carboxylate

42. 8'-O-propionyl-MB-530A-carboxylic acid methyl ester

43. 8'-O-propionyl-MB-530A-carboxylic acid ethyl ester

44. 8'-O-propionyl-MB-530A-carboxylic acid butyl ester

45. 8'-O-propionyl-MB-530A-carboxylic acid benzyl ester

46. 8'-O-propionyl-MB-530A-carboxylic acid phenacyl ester

47. Sodium 8'-O-butyryl-ML-236A-carboxylate

48. Magnesium bis (8´-O-butyryl-ML-236A-carboxylate)

49. Aluminum tris (8´-O-butyryl-ML-236A-carboxylate)

50. 8'-O-butyryl-ML-236A-carboxylic acid methyl ester

51. 8'-O-butyryl-ML-236A-ethyl carboxylate

52. 8'-O-Butyryl-ML-236A-carboxylic acid butyl ester

53. 8'-O-Butyryl-ML-236A-carboxylic acid benzyl ester

54. Phenacyl 8'-O-Butyryl-ML-236A-carboxylate

55. 8'-O-butyryl-ML-236A-carboxylic acid dimethylaminoethyl ester

56. Sodium 8'-O-butyryl-MB-530A-carboxylate

57. Calcium bis (8´-O-butyryl-MB-530A-carboxylate)

58. 8'-O-butyryl-MB-530A-carboxylic acid methyl ester

59. 8'-O-butyryl-MB-530A-carboxylic acid ethyl ester

60. 8'-O-butyryl-MB-530A-butyl carboxylate

61. 8'-O-Butyryl-MB-530A-carboxylic acid benzyl ester

62. 8'-O-butyryl-MB-530A-carboxylic acid phenacyl ester

63. Sodium 8'-O- (4-pentenoyl) -ML-236A-carboxylate

64. 8'-O- (4-pentenoyl) -ML-236A-carboxylic acid methyl ester

65. 8'-O- (4-pentenoyl) -ML-236A-carboxylic acid ethyl ester

66. 8'-O- (4-pentenoyl) -ML-236A-butyl carboxylate

67. 8'-O- (4-pentenoyl) -ML-236A-carboxylic acid benzyl ester

68. Phenacyl 8'-O- (4-pentenoyl) -ML-236A-carboxylate

69. Sodium 8'-O- (4-pentenoyl) -MB-530A-carboxylate

70. 8'-O- (4-pentenoyl) -MB-530A-carboxylic acid methyl ester

71. 8'-O- (4-pentenoyl) -MB-530A-carboxylic acid ethyl ester

72. 8'-O- (4-pentenoyl) -MB-530A-butyl carboxylate

73. 8'-O- (4-pentenoyl) -MB-530A-carboxylic acid benzyl ester

74. Phenacyl 8'-O- (4-pentenoyl) -MB-530A-carboxylate

75. Sodium 8'-O-isovaleryl-ML-236A-carboxylate

76. 8'-O-isovaleryl-ML-236A-carboxylic acid methyl ester

77. 8'-O-isovaleryl-ML-236A-carboxylic acid ethyl ester

78. 8'-O-isovaleryl-ML-236A-carboxylic acid butyl ester

79. 8'-O-isovaleryl-ML-236A-carboxylic acid benzyl ester

80. 8'-O-isovaleryl-ML-236A-carboxylic acid phenacyl ester

81. Sodium 8'-O-isovaleryl-MB-530A-carboxylate

82. 8'-O-isovaleryl-MB-530A-carboxylic acid methyl ester

83. 8'-O-isovaleryl-MB-530A-carboxylic acid ethyl ester

84. 8'-O-isovaleryl-MB-530A-carboxylic acid butyl ester

85. 8'-O-Isovaleryl-MB-530A-carboxylic acid benzyl ester

86. 8'-O-isovaleryl-MB-530A-carboxylic acid phenacyl ester

87. Sodium 8'-O-hexanoyl-ML-236A-carboxylate

88. 8'-O-hexanoyl-ML-236A-carboxylic acid methyl ester

89. 8'-O-hexanoyl-ML-236A-carboxylic acid ethyl ester

90. 8'-O-hexanoyl-ML-236A-carboxylic acid butyl ester

91. 8'-O-hexanoyl-ML-236A-carboxylic acid benzyl ester

92. 8'-O-hexanoyl-ML-236A-carboxylic acid phenacyl ester

93. Sodium 8'-O-hexanoyl-MB-530A-carboxylate

94. 8'-O-hexanoyl-MB-530A-carboxylic acid methyl ester

95. 8'-O-hexanoyl-MB-530A-carboxylic acid ethyl ester

96. 8'-O-hexanoyl-MB-530A-carboxylic acid butyl ester

97. 8'-O-hexanoyl-MB-530A-carboxylic acid benzyl ester

98. 8'-O-hexanoyl-MB-530A-carboxylic acid phenacyl ester

99. Sodium 8'-O-palmitoyl-ML-236A-carboxylate

100. 8'-O-palmitoyl-ML-236A-carboxylic acid methyl ester

101. 8'-O-palmitoyl-ML-236A-carboxylic acid benzyl ester

102. 8'-O-palmitoyl-ML-236A-carboxylic acid phenacyl ester

103. Sodium 8'-O-palmitoyl-MB-530A-carboxylate

104. 8'-O-palmitoyl-MB-530A-carboxylic acid methyl ester

105. 8'-O-palmitoyl-MB-530A-carboxylic acid ethyl ester

106. 8'-O-palmitoyl-MB-530A-carboxylic acid benzyl ester

107. Sodium 8'-O-stearoyl-ML-236A-carboxylate

108. Sodium 8'-O-stearoyl-MB-530A-carboxylate

109. Sodium 8'-O-linolenoyl-ML-236A-carboxylate

110. 8'-O-linolenoyl-ML-236A-carboxylic acid methyl ester

111. Sodium 8'-O-linolenoyl-MB-530A-carboxylate

112. 8'-O-linolenoyl-MB-530A-carboxylic acid methyl ester

113. Sodium 8'-O-benzoyl-ML-236A-carboxylate

114. Potassium 8'-O-benzoyl ML-236A-carboxylate

115. Aluminum tris (8´-O-benzoyl-ML-236A-carboxylate)

116. 8'-O-Benzoyl-ML-236A-carboxylic acid methyl ester

117. 8'-O-Benzoyl-ML-236A-carboxylic acid ethyl ester

118. 8'-O-Benzoyl-ML-236A-carboxylic acid butyl ester

119. 8'-O-Benzoyl-ML-236A-carboxylic acid benzyl ester

120. 8'-O-Benzoyl-ML-236A-carboxylic acid p-methoxybenzyl ester

121. 8'-O-Benzoyl-ML-236A-carboxylic acid phenacyl ester

122. 8'-O-Benzoyl-ML-236A-carboxylic acid p-methoxyphenacyl ester

123. Sodium 8'-O-benzoyl-MB-530A-carboxylate

124. Potassium 8'-O-benzoyl-MB-530A-carboxylate

125. Aluminum tris (8´-O-benzoyl-MB-530A-carboxylate)

126. 8'-O-Benzoyl-MB-530A-carboxylic acid methyl ester

127. 8'-O-Benzoyl-MB-530A-carboxylic acid ethyl ester

128. 8'-O-Benzoyl-MB-530A-carboxylic acid butyl ester

129. 8'-O-Benzoyl-MB-530A-carboxylic acid benzyl ester

130. 8'-O-Benzoyl-MB-530A-carboxylic acid p-methoxybenzyl ester

131. 8'-O-Benzoyl-MB-530A-carboxylic acid phenacyl ester

132. 8'-O-Benzoyl-MB-530A-carboxylic acid p-methoxyphenacyl ester

133. Sodium 8'-O- (p -toluoyl) -ML-236A-carboxylate

134. Calcium bis [8´-O- (p-toluoyl) -ML-236A-carboxylate]

135. 8'-O- (p-Toluoyl) -ML-236A-carboxylic acid ethyl ester

136. 8'-O- (p-Toluoyl) -ML-236A-butyl carboxylate

137. 8'-O- (p-Toluoyl) -ML-236A-carboxylic acid benzyl ester

138. Phenacyl 8'-O- (p-Toluoyl) -ML-236A-carboxylate

139. Sodium 8'-O- (p -toluoyl) -MB-530A-carboxylate

140. 8'-O- (p-Toluoyl) -MB-530A-carboxylic acid methyl ester

141. 8'-O- (p-Toluoyl) -MB-530A-butyl carboxylate

142. 8'-O- (p-Toluoyl) -MB-530A-benzyl carboxylate

143. 8'-O- (p-Toluoyl) -MB-530A-carboxylic acid phenacyl ester

144. Sodium 8'-O- (2-chlorobenzoyl) ML-236A-carboxylate

145. Sodium 8'-O- (2-chlorobenzoyl) -MB-530A-carboxylate

146. Sodium 8'-O- (3-chlorobenzoyl) ML-236A carboxylate

147. Sodium 8'-O- (3-chlorobenzoyl) -MB-530A-carboxylate

148. Sodium 8'-O- (4-chlorobenzoyl) ML-236A-carboxylate

149. Sodium 8'-O- (4-chlorobenzoyl) -MB-530A-carboxylate

150. Sodium 8'-O-salicyloyl-ML-236A-carboxylate

151. Potassium 8'-O-salicyloyl-ML-236A-carboxylate

152. 8'-O-salicyloyl-ML-236A-carboxylic acid methyl ester

153. 8'-O-salicyloyl-ML-236A-carboxylic acid ethyl ester

154. 8'-O-salicyloyl-ML-236A-carboxylic acid butyl ester

155. 8'-O-salicyloyl-ML-236A-carboxylic acid benzyl ester

156. 8'-O-salicyloyl-ML-236A-carboxylic acid phenacyl ester

157. Sodium 8'-O-salicyloyl-MB-530A-carboxylate

158. Potassium 8'-O-salicyloyl-MB-530A-carboxylate

159. 8'-O-salicyloyl-MB-530A-carboxylic acid methyl ester

160. 8'-O-salicyloyl-MB-530A-carboxylic acid ethyl ester

161. 8'-O-salicyloyl-MB-530A-carboxylic acid butyl ester

162. 8'-O-salicyloyl-MB-530A-carboxylic acid benzyl ester

163. 8'-O-salicyloyl-MB-530A-carboxylic acid phenacyl ester

164. Sodium 8'-O-phenylacetyl-ML-236A-carboxylate

165. 8'-O-phenylacetyl-ML-236A-carboxylic acid methyl ester

166. Ethyl 8'-O-phenylacetyl-ML-236A-carboxylate

167. 8'-O-Phenylacetyl-ML-236A-carboxylic acid benzyl ester

168. Sodium 8'-O-phenylacetyl-MB-530A-carboxylate

169. 8'-O-phenylacetyl-MB-530A-carboxylic acid methyl ester

170. 8'-O-phenylacetyl-MB-530A-carboxylic acid ethyl ester

171. 8'-O-Phenylacetyl-MB-530A-carboxylic acid benzyl ester

172. Sodium 8'-O-cinnamoyl-ML-236A-carboxylate

173. Sodium 8'-O-cinnamoyl-MB-530A-carboxylate

174. Sodium 8'-O- (p-hydroxycinnamoyl) -ML-236A-carboxylate

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

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

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

178. Sodium 8'-O- (2-thenoyl) -ML-236A-carboxylate

179. 8'-O- (2-thenoyl) -ML-236A-carboxylic acid methyl ester

180. 8'-O- (2-thenoyl) -ML-236A-carboxylic acid ethyl ester

181. Sodium 8'-O- (2-thenoyl) -MB-530A-carboxylate

182. 8'-O- (2-thenoyl) -MB-530A-carboxylic acid methyl ester

183. Ethyl 8'-O- (2-thenoyl) -MB-530A-carboxylate

184. Sodium 8'-O- (2-furoyl) -ML-236A-carboxylate

185. 8'-O- (2-furoyl) -ML-236A-carboxylic acid methyl ester

186. Ethyl 8'-O- (2-furoyl) -ML-236A-carboxylate

187. Sodium 8'-O- (2-furoyl) -MB-530A-carboxylate

188. 8'-O- (2-furoyl) -MB-530A-carboxylic acid methyl ester

189. 8'-O- (2-furoyl) -MB-530A-carboxylic acid ethyl ester

190. Sodium 8'-O- (2-thienylacetyl) -ML-236A-carboxylate

191. 8'-O- (2-Thienylacetyl) -ML-236A-carboxylic acid methyl ester

192. 8'-O- (2-thienylacetyl) -ML-236A-carboxylic acid ethyl ester

193. 8'-O- (2-thienylacetyl) -ML-236A-carboxylic acid butyl ester

194. Benzyl 8'-O- (2-Thienylacetyl) -ML-236A-carboxylate

195. Phenacyl 8'-O- (2-Thienylacetyl) -ML-236A-carboxylate

196. Sodium 8'-O- (2-thienylacetyl) -MB-530A-carboxylate

197. 8'-O- (2-thienylacety) -MB-530A-carboxylic acid methyl ester

198. Ethyl 8'-O- (2-thienylacety) -MB-530A-carboxylate

199. Sodium 8'-O-methanesulfonyl-ML-236A-carboxylate

200. 8'-O-methanesulfonyl-ML-236A-carboxylic acid methyl ester

201. 8'-O-methanesulfonyl-ML-236A-carboxylic acid ethyl ester

202. Sodium 8'-O-methanesulfonyl-MB-530A-carboxylate

203. 8'-O-methanesulfonyl-MB-530A-carboxylic acid methyl ester

204. 8'-O-methanesulfonyl-MB-530A-carboxylic acid ethyl ester

205. Trisodium 8'-O-phosphoryl-ML-236A-carboxylate

206. Trisodium 8'-O-phosphoryl-MB-530A-carboxylate

207. Sodium 3-0-acetyl-ML-236A-carboxylate

208. 3-O-Acetyl-ML-236A-carboxylic acid methyl ester

209. 3-O-Acetyl-ML-236A-carboxylic acid ethyl ester

210. 3-O-Acetyl-ML-236A-carboxylic acid butyl ester

211. 3-O-Acetyl-ML-236A-carboxylic acid benzyl ester

212. Sodium 3-0-acetyl-MB-530A-carboxylate

213. 3-0-Acetyl-MB-530A-carboxylic acid methyl ester

214. 3-O-Acetyl-MB-530A-carboxylic acid butyl ester

215. 3-O-Acetyl-MB-530A-carboxylic acid benzyl ester

216. Sodium 3-O-butyryl-ML-236A-carboxylate

217. 3-0-Butyryl-ML-236A-carboxylic acid methyl ester

218. 3-O-butyryl-ML-236A-carboxylic acid butyl ester

219. 3-O-butyryl-ML-236A-carboxylic acid benzyl ester

220. Sodium 3-O-butyryl-MB-530A-carboxylate

221. 3-0-Butyryl-MB-530A-carboxylic acid methyl ester

222. 3-0-Butyryl-MB-530A-carboxylic acid ethyl ester

223. 3-O-butyryl-MB-530A-carboxylic acid benzyl ester

224. Sodium 3-0-benzoyl-ML-236A-carboxylate

225. 3-0-Benzoyl-ML-236A-carboxylic acid methyl ester

226. 3-0-Benzoyl-ML-236A-carboxylic acid ethyl ester

227. 3-0-Benzoyl-ML-236A-carboxylic acid butyl ester

228. 3-0-Benzoyl-ML-236A-carboxylic acid benzyl ester

229. Sodium 3-0-benzoyl-MB-530A-carboxylate

230. 3-0-Benzoyl-MB-530A-carboxylic acid methyl ester

231. 3-0-Benzoyl-MB-530A-carboxylic acid ethyl ester

232. 3-0-Benzoyl-MB-530A-carboxylic acid butyl ester

233. 3-O-Benzoyl-MB-530A-carboxylic acid benzyl ester

234. Sodium 3,8'-di (O-acetyl) ML-236A-carboxylate

235. 3,8'-Di- (O-acetyl) -ML-236A-carboxylic acid methyl ester

236. Ethyl 3,8'-di- (O-acetyl) -ML-236A-carboxylate

237. 3,8'-Di- (O-acetyl) -ML-236A-carboxylic acid benzyl ester

238. Sodium 3,8'-di- (O-acetyl) -MB-530A-carboxylate

239. 3,8'-Di- (O-acetyl) -MB-530A-carboxylic acid methyl ester

240. 3,8'-Di- (O-acetyl) -MB-530A-carboxylic acid butyl ester

241. 3,8'-Di- (O-acetyl) -MB-530A-carboxylic acid benzyl ester

242. Sodium 3,8'-di (O-butyryl) ML-236A carboxylate

243. 3,8'-Di- (O-butyryl) -ML-236A-carboxylic acid methyl ester

244. 3,8'-Di- (O-butyryl) -ML-236A-carboxylic acid butyl ester

245. 3,8'-Di- (O-butyryl) -ML-236A-carboxylic acid benzyl ester

246. Sodium 3,8 '-di- (O-butyryl) -MB-530A-carboxylate

247. 3,8'-Di- (O-butyryl) -MB-530A-carboxylic acid methyl ester

248. 3,8'-Di- (O-butyryl) -MB-530A-butyl carboxylate

249. 3,8'-Di- (O-butyryl) -MB-530A-carboxylic acid benzyl ester

250. Sodium 3,8'-di (O-benzoyl) ML-236A-carboxylate

251. 3,8'-Di- (O-benzoyl) -ML-236A-carboxylic acid methyl ester

252. 3,8'-Di- (O-benzoyl) -ML-236A-carboxylic acid ethyl ester

253. 3,8'-Di- (O-benzoyl) -ML-236A-carboxylic acid butyl ester

254. Benzyl 3,8'-Di- (O-benzoyl) -ML-236A-carboxylate

255. Sodium 3,8'-di- (O-benzoyl) -MB-530A-carboxylate

256. 3,8'-Di- (O-benzoyl) -MB-530A-carboxylic acid methyl ester

257. 3,8'-Di- (O-benzoyl) -MB-530A-butyl carboxylate

258. 3,8 '- (O-Benzoyl) -MB-530A-carboxylic acid benzyl ester

259. Sodium 3-0-acetyl-8'-O-butyryl-ML-236A-carboxylate

260. Sodium 3-0-acetyl-8'-O-butyryl-MB-530A-carboxylate

261. Sodium 3-0-butyryl-8'-O-acetyl-ML-236A-carboxylate

262. Sodium 3-0-butyryl-8'-O-acetyl-MB-530A-carboxylate

263. Sodium 3-0-benzoyl-8'-O-acetyl-ML-236A-carboxylate

264. Sodium 3-0-benzoyl-8 '-O-acetyl-MB-530A-carboxylate

265. Sodium 3-0-benzoyl-8'-O-butyryl-ML-236A-carboxylate

266. Sodium 3-0-benzoyl-8'-O-butyryl-MB-530A-carboxylate

267. Sodium 3-0-acetyl-8'-O -benzoyl-ML-236A-carboxylate

268. Sodium 3-0-acetyl-8'-O -benzoyl-MB-530A-carboxylate

269. Sodium 3-0-butyryl-8'-O -benzoyl-ML-236A-carboxylate

270. Sodium 3-0-butyryl-8'-O -benzoyl-MB-530A-carboxylate

271. Sodium 3,5,8'-tri- (O-acetyl) -ML-236A-carboxylate

272. Potassium 3,5,8'-tri- (O-acetyl) -ML-236A-carboxylate

273. 3,5,8'-Tri- (O-acetyl) -ML-236A-carboxylic acid methyl ester

274. 3,5,8'-Tri- (O-acetyl) -ML-236A-carboxylic acid ethyl ester

275. 3,5,8'-tri- (O-acetyl) -ML-236A-carboxylic acid butyl ester

276. Benzyl 3,5,8'-tri- (O-acetyl) -ML-236A-carboxylate

277. Phenacyl 3,5,8'-tri- (O-acetyl) -ML-236A-carboxylate

278. Sodium 3,5,8'-tri- (O-butyryl) -ML-236A-carboxylate

279. 3,5,8'-tri- (O-butyryl) -ML-236A-carboxylic acid methyl ester

280. 3,5,8'-tri- (O-butyryl) -ML-236A-carboxylic acid ethyl ester

281. 3,5,8'-tri- (O-butyryl) -ML-236A-carboxylic acid butyl ester

282. Benzyl 3,5,8'-tri- (O-butyryl) -ML-236A-carboxylate

283. Pivaloyloxymethyl 3,5,8'-tri- (O-butyryl) -ML-236A-carboxylate

284. Phenacyl 3,5,8'-tri- (O-butyryl) -ML-236A-carboxylate

285. Sodium 3,5,8'-tri- (O-butyryl) -MB-530A-carboxylate

286. Potassium 3,5,8'-tri- (O-butyryl) -MB-530A-carboxylate

287. 3,5,8'-tri- (O-butyryl) -MB-530A-carboxylic acid methyl ester

288. 3,5,8'-tri- (O-butyryl) -MB-530A-carboxylic acid ethyl ester

289. 3,5,8'-tri- (O-butyryl) -MB-530A-carboxylic acid butyl ester

290. Benzyl 3,5,8'-tri- (O-butyryl) -MB-530A-carboxylate

291. Pivaloyloxymethyl 3,5,8'-tri- (O-butyryl) -MB-530A-carboxylate

292. Phenacyl 3,5,8'-tri- (O-butyryl) -MB-530A-carboxylate

293. Sodium 3,5-di (O-acetyl) ML-236B-carboxylate

294. Potassium 3,5-di (O-acetyl) ML-236B-carboxylate

295. Aluminum tris [3,5-di- (O-acetyl) -ML-236B-carboxylate]

296. Calcium bis [3,5-di- (O-acetyl) -ML-236B-carboxylate]

297. 3,5-Di- (O-acetyl) -ML-236B-carboxylic acid methyl ester

298. 3,5-Di- (O-acetyl) -ML-236B-carboxylic acid ethyl ester

299. Isopropyl 3,5-di- (O-acetyl) -ML-236B-carboxylate

300. 3,5-Di- (O-acetyl) -ML-236B-carboxylic acid butyl ester

301. Benzyl 3,5-Di- (O-acetyl) -ML-236B-carboxylate

302. Pivaloyloxymethyl 3,5-di- (O-acetyl) -ML-236B-carboxylate

303. 3,5-Di- (O-acetyl) -ML-236B-carboxylic acid ethoxymethyl ester

304. Phenacyl 3,5-di- (O-acetyl) -ML-236B-carboxylate

305. Sodium 3,5-di- (O-acetyl) -MB-530B-carboxylate

306. Potassium 3,5-di- (O-acetyl) -MB-530B-carboxylate

307. Calcium bis [3,5-di- (O-acetyl) -MB-530B-carboxylate]

308. Aluminum tris [3,5-di- (O-acetyl) -MB-530B-carboxylate]

309. 3,5-Di- (O-acetyl) -MB-530B-carboxylic acid methyl ester

310. 3,5-Di- (O-acetyl) -MB-530B-carboxylic acid ethyl ester

311. 3,5-Di- (O-acetyl) -MB-530B-carboxylic acid isopropyl ester

312. 3,5-Di- (O-acetyl) -MB-530B-carboxylic acid butyl ester

313. 3,5-Di- (O-acetyl) -MB-530B-carboxylic acid benzyl ester

314. 3,5-Di- (O-acetyl) -MB-530B-carboxylic acid pivaloyloxymethyl ester

315. 3,5-Di- (O-acetyl) -MB-530B-carboxylic acid methoxymethyl ester

316. 3,5-Di- (O-acetyl) -MB-530B-carboxylic acid ethoxymethyl ester

317. 3,5-Di- (O-acetyl) -MB-530B-carboxylic acid phenacyl ester

318. Sodium 3,5-di (O-propionyl) ML-236B-carboxylate

319. 3,5-Di- (O-propionyl) -ML-236B-carboxylic acid methyl ester

320. 3,5-Di (O-propionyl) -ML-236B-carboxylic acid butyl ester

321. Benzyl 3,5-di (O-propionyl) -ML-236B-carboxylate

322. Sodium 3,5-di- (O-propionyl) -MB-530B-carboxylate

323. 3,5-Di- (O-propionyl) -MB-530B-carboxylic acid methyl ester

324. 3,5-Di- (O-propionyl) -MB-530B-carboxylic acid butyl ester

325. 3,5-Di- (O-propionyl) -MB-530B-carboxylic acid benzyl ester

326. Sodium 3,5-di (O-butyryl) ML-236B-carboxylate

327. 3,5-Di- (O-butyryl) -ML-236B-carboxylic acid methyl ester

328. Sodium 3,5-di- (O-butyryl) -MB-530B-carboxylate

329. 3,5-Di- (O-butyryl) -MB-530B-carboxylic acid methyl ester

330. Sodium 3,5-di (O-valeryl) ML-236B-carboxylate

331. Potassium 3,5-di (O-valeryl) ML-236B-carboxylate

332. Sodium 3,5-di- (O-valeryl) -MB-530B-carboxylate

333. Potassium 3,5-di- (O-valeryl) -MB-530B-carboxylate

334. Sodium 3,5-di (O-isovaleryl) ML-236B-carboxylate

335. Sodium 3,5-di- (O-isovaleryl) -MB-530B-carboxylate

336. Sodium 3,5-di- (O-stearoyl) -ML-236B-carboxylate

337. Sodium 3,5-di- (O-stearoyl) -MB-530B-carboxylate

338. Sodium 3,5-di (O-oleoyl) ML-236B-carboxylate

339. Sodium 3,5-di (O-linoleoyl) ML-236B-carboxylate

340. Sodium 3,5-di- (O-linoleoyl) -MB-530B-carboxylate

341. Sodium 3,5-di (O-benzoyl) ML-236B-carboxylate

342. Sodium 3,5-di- (O-benzoyl) -MB-530B-carboxylate

343. Sodium 3,5-di (O-phenylacetyl) ML-236B-carboxylate

344. 3,5-Di- (O-phenylacetyl) -ML-236B-carboxylic acid methyl ester

345. Sodium 3,5-di- (O-phenylacetyl) -MB-530B-carboxylate

346. 3,5-Di- (O-phenylacetyl) -MB-530B-carboxylic acid methyl ester

347. Sodium 3,5-di (O-cyclopentanecarbonyl) ML-236B-carboxylate

348. Sodium 3,5-di- (O-cyclopentanecarbonyl) -MB-530B-carboxylate

349. Sodium 3,5-di (O-cyclohexanecarbonyl) ML-236B-carboxylate

350. Sodium 3,5-di- (O-cyclohexanecarbonyl) -MB-530B-carboxylate

351. Sodium 3,5-di (O-thenoyl) ML-236B-carboxylate

352. Sodium 3,5-di- (O-thenoyl) -MB-530B-carboxylate

353. Sodium 3,5-di (O-furoyl) ML-236B-carboxylate

354. Sodium 3,5-di- (O-furoyl) -MB-530B-carboxylate

355. Sodium 3,5-di (O-thienylacetyl) ML-236B-carboxylate

356. Sodium 3,5-di- (O-thienylacetyl) -MB-530B-carboxylate

357. Sodium 3,5-di (O-methanesulfonyl) ML-236B-carboxylate

358. Sodium 3,5-di- (O-methanesulfonyl) -MB-530B-carboxylate

359. Trisodium 3,5-di (O-phosphoryl) ML-236B-carboxylate

360. Trisodium 3,5-di- (O-phosphoryl) -MB-530B-carboxylate

361. Sodium 3,5-di- (O-acetyl) -8 '-O-propionyl-ML-236A-carboxylate

362. 3,5-Di- (O-acetyl) -8 '-O-propionyl-ML-236A-carboxylic acid methyl ester

363. 3,5-Di- (O-acetyl) -8 '-O-propionyl-ML-236A-butyl carboxylate

364. Benzyl 3,5-di- (O-acetyl) -8 '-O-propionyl-ML-236A-carboxylate

365. Sodium 3,5-di- (O-acetyl) -8 '-O-propionyl-MB-530A-carboxylate

366. 3,5-Di- (O-acetyl) -8 '-O-propionyl-MB-530A-carboxylic acid methyl ester

367. Sodium 3,5-di- (O-acetyl) -8 '-O-butyryl-ML-236A-carboxylate

368. 3,5-Di- (O-acetyl) -8 '-O-butyryl-ML-236A-carboxylic acid methyl ester

369. Butyl 3,5-di- (O-acetyl) -8'-O-butyryl-ML-236A-carboxylate

370. Sodium 3,5-di- (O-acetyl) -8 '-O-butyryl-MB-530A-carboxylate

371. 3,5-Di- (O-acetyl) -8 '-O-butyryl-MB-530A-carboxylic acid methyl ester

372. Butyl 3,5-di- (O-acetyl) -8'-O-butyryl-MB-530A-carboxylate

373. Sodium 3,5-di- (O-butyryl) -8 '-O-acetyl-ML-236A-carboxylate

374. Sodium 3,5-di- (O-butyryl) -8 '-O-acetyl-MB-530A-carboxylate

375. Sodium 3,5-di- (O-acetyl) -8 '-O -benzoyl-ML-236A-carboxylate

376. Sodium 3,5-di- (O-acetyl) -8 '-O -benzoyl-MB-530A-carboxylate

377. Sodium 3,5-di- (O-benzoyl) -8 '-O-acetyl-ML-236A-carboxylate

378. 3,5-Di- (O-benzoyl) -8 '-O-acetyl-ML-236A-carboxylic acid methyl ester

379. Sodium 3,5-di- (O-benzoyl) -8 '-O-acetyl-MB-530A-carboxylate

380. 3,5-Di- (O-benzoyl) -8 '-O-acetyl-MB-530A-carboxylic acid methyl ester

Of these compounds, the following are particularly preferred:

Sodium ML-236A carboxylate

Sodium MB-530A carboxylate

Sodium 8'-O-butyryl-ML-236A-carboxylate

Sodium 8'-O-hexanoyl-ML-236A-carboxylate

Ethyl 8'-O-butyryl-ML-236A-carboxylate

Ethyl 8'-O-hexanoyl-ML-236A-carboxylate

8'-O-butyryl-ML-236A-carboxylic acid butyl ester

8'-O- (4-pentenoyl) -ML-236A-carboxylic acid butyl ester

8'-O-isovaleryl-MB-530A-carboxylic acid butyl ester

Benzyl 8'-O-butyryl-MB-236A-carboxylate

Benzyl 8'-O-hexanoyl-ML-236A-carboxylate

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

3,5-Di- (O-acetyl) -ML-236B-carboxylic acid butyl ester

3,5-Di- (O-benzoyl) -ML-236B-carboxylic acid butyl ester

The compounds according to the invention can be prepared by various processes, all of which ultimately start from ML-236A, MB-236B, MB-530A, MB-530B, ML-236A-carboxylic acid and MB-530A-carboxylic acid. These starting compounds are obtained by cultivating suitable microorganisms, as described in the literature references already mentioned and explained in the preparation examples. These compounds have the following chemical structures:

Metal salts, and particularly the alkali metal salts of ML-236A and MB-530A, can be obtained by cultivating a suitable microorganism and recovering the desired salt from the culture broth. For example, the salts of ML-236A carboxylic acid can be obtained by cultivating an ML-236A producing microorganism belonging to the genus Penicillium and recovering the ML-236A carboxylic acid salt from the culture broth, while MB-530A carboxylic acid salts can be obtained by cultivating an MB-530A producing microorganism Microorganism of the genus Monascus and recovering the MB-530A carboxylic acid salt from the culture broth.

The microorganisms of the genus Penicillium are preferably Penicillium citrinum, Penicillium chrysogenum or Penicillium notatum and, in particular, Penicillium citrinum SANK 18767 (FERM 2609), Penicillium citrinum SANK 24467, Penicillium citrinum SANK 24567, Penicillium chrysogenum SANK 24567, Penicillium chrysogenum SANK12768.

The microorganisms of the genus Monascus are preferably strains of Monascus ruber, Monascus anka, Monascus paxii, Monascus purpureus or Monascus vitreus, and in particular Monascus ruber SANK 11272 (IFO 9203), Monascus ruber SANK 17075 (CBS 832.70), Monascus ruber SANK 175 503.70), 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) and Monascus vitreus SANK 10960 (NIHS 609, e-609, FERM 4960).

All of these microorganisms are available from the following recognized depositories:

IFO = Institute for Fermentation, Osaka, Japan

FERM = Fermentation Research Institute, Agency of Industrial Science and Technology, Minstry of International Trade and Industry, Japan

NIHS = National Institute of Hygenic Sciences, Japan

CBS = Centraal Bureau voor Schimmelcultures, Netherlands

ATCC = American Type Culture Collection, Maryland, U.S.A.

In addition to the microorganism strains mentioned, any microorganisms of the genus Penicillium or Monascus, including varieties and mutants, which are capable of producing ML-236A or MB-530A, can also be used.

The ML-236A and MB-530A salts can be prepared by culturing the selected microorganism in a culture broth under aerobic conditions using known methods for cultivating fungi and other microorganisms. For example, the selected strain of Penicillium or Monascus can first be cultivated in a suitable medium, then the microorganism obtained can be collected and inoculated into another culture medium and cultivated there further in order to produce the desired ML-236A or MB-530A. The same or different culture media can be used for the reproduction of the microorganism and for the production of ML-236A or MB-530A. Any culture media known for the cultivation of fungi can be used, provided that they contain the known essential len nutrients, particularly an assimilable carbon source and an assimilable nitrogen source. Examples of suitable assimilable carbon sources are glucose, maltose, dextrin, starch, lactose, sucrose and glycerin. Of these, glucose and glycerin are particularly preferred for producing ML-236A and MB-530A. Examples of suitable assimilable nitrogen sources are peptone, meat extract, yeast, yeast extract, soy flour, peanut flour, corn steep liquor, rice bran and inorganic nitrogen source. For the production of the ML-236A and MB-530A, inorganic salts and / or metal salts can optionally be added to the culture medium. Furthermore, a small amount of heavy metal can optionally be added. In some cases it is possible that the fungus of the genus Penicillium or Monascus will directly yield the desired ML-236A or MB-530A carboxylic acid salt, while in other cases the fungus will first produce ML-236A or MB-530A, which will then over the course the separation and purification is converted into the desired salt. If the salts are to be produced directly by the fungus, metal ions which correspond to the metal salt to be produced must be present in the culture medium or in the fungal mycelium.

The microorganism is preferably grown under aerobic conditions by methods known per se, e.g. as a solid culture, shaking culture or aerated stirring culture. The microorganisms grow within a wide temperature range, e.g. 7 to 35 ° C, but cultivation temperatures of 20 to 30 ° C are preferably used for the production of ML-236A or MB-530A or their carboxylic acid salts.

During the cultivation of the microorganism, the production of the desired ML-236A or MB-530A or their carboxylic acid salts can be monitored by taking samples from the culture medium and measuring the physiological activity of the medium using suitable test methods. Breeding can then continue be set until a significant amount of the desired material has accumulated in the culture medium, whereupon the ML-236A or MB-530A carboxylic acid salt is isolated from the culture medium and the mycelium by any suitable combination of isolation methods and obtained with regard to its physical and chemical properties are selected. For example, any or all of the following isolation methods can be used:

Extraction of the liquid portion of the culture broth with a hydrophilic solvent (such as diethyl ether, ethyl acetate or chloroform); Extraction of the microorganism with a hydrophilic solvent (such as acetone or an alcohol); Concentration, e.g., partial or complete evaporation of the solvent under reduced pressure; Mixing with a more polar solvent (such as acetone or an alcohol); Removing impurities with a less polar solvent (such as petroleum ether or hexane); Gel filtration, e.g., with Sephadex (trademark of Pharmacia Co. Ltd., USA); Absorption chromatography with activated charcoal or silica gel; Rapid liquid chromatography; Conversion to ML-236A or MB-530A or their parent acid; direct cleaning in the form of the metal salt; as well as similar methods. By using a suitable combination of these methods, the desired salt can be obtained as a pure substance from the culture broth.

As described in the references mentioned, ML-236A, ML-236B, MB-530A, MB-530B, ML-236A-carboxylic acid and ML-530A-carboxylic acid, which are important starting materials for the preparation of certain compounds according to the invention, can also be produced using the the above microorganisms and methods are produced.

Other compounds of the invention can be prepared by the following methods.

Procedure 1

Manufacture of salts

Carboxylic acid salts of the formula IV in which R [high] 1, R [high] 3 and R [high] 4 have the above meaning, M [high] 1 represents that cation of a salt and m 'is the valence of M [high] 1, are thereby obtained that you can get a lactone of the formula V

in which R [high] 1, R [high] 3 and R [high] 4 have the above meaning, hydrolyzed and, if necessary, the carboxyl group of the product obtained is converted into the corresponding salt.

The hydrolysis can be carried out by any known method for converting lactones to the corresponding hydroxy acids. If necessary, the hydroxy acid can then be extracted with a suitable organic solvent and converted into the desired salt by reaction with a base, for example a metal hydroxide or carbonate, ammonia, an organic amine or an amino acid. For the production of metal salts (M [high] 1 = metal atom), however, it is often preferred to carry out the hydrolysis and salt formation in a single stage using a basic compound of the metal, preferably the metal hydroxide, in at least an equimolar amount, based on the lactone Formula V to perform. In this case, the metal salt of the formula IV is formed directly and can be obtained from the reaction mixture by simply distilling off the solvent.

The hydrolysis can be carried out by conventional methods, e.g. by contacting the lactone V with a dilute (e.g. 0.1 to 0.2 N) aqueous solution of the metal hydroxide, preferably an alkali metal hydroxide, such as sodium or potassium hydroxide, in water or an aqueous organic solution, e.g. aqueous alcohol or aqueous dioxane. The hydrolysis takes place over a wide temperature range, e.g. room temperature or an elevated temperature of e.g. 50 to 100 ° C. The required reaction time varies within a wide range depending on the reactants and the reaction temperature, but is usually a few hours.

In a preferred embodiment of this process, an alkali metal salt of the formula VI

in which R [high] 1 has the above meaning and M [high] 2 is an alkali metal atom, produced by a lactone of the formula VII in which R [high] 1 has the above meaning, hydrolyzed in an alkali solution containing the alkali metal atom. In this case, M [high] 2 is preferably a sodium atom, and the alkali solution is preferably an aqueous sodium hydroxide solution.

Procedure 2

Production of esters from the corresponding lactone

Carboxylic acid esters of the formula VIII in which R [high] 1 denotes a hydrogen atom or a methyl group, R [high] 3 and R [high] 4 are the same or different hydrogen atoms or acyl groups, with the proviso that when R [high] 3 is a 2-methylbutyryl group, R [high] 4 is an acyl group and R [high] 2b is an alkyl or aralkyl group are prepared by adding a lactone of the formula V

in which R [high] 1, R [high] 3 and R [high] 4 have the above meaning, reacts with an alcohol in the presence of an acidic catalyst.

Suitable acidic catalysts are, for example, inorganic acids such as hydrochloric or sulfuric acid, Lewis acids such as boron trifluoride, and acidic ion exchange resins. The reaction can be carried out in the presence of a suitable inert organic solvent such as benzene, diethyl ether or chloroform. However, if the alcohol, i.e. one of the reactants, is liquid, it is preferably used as the solvent. Although the reaction takes place over a wide range of temperatures, it is preferably carried out with heating, for example at a temperature of 50 ° C to the boiling point of the solvent. After the reaction has ended, the desired product is obtained from the reaction mixture in a customary manner. If, for example, the catalyst used is an ion exchange resin, this can be filtered off and the desired compound can be obtained by distilling off the solvent. When the catalyst is an inorganic acid or a Lewis acid, it can be neutralized, the solvent distilled off, the residue extracted with a suitable solvent and then distilled off from the extract to obtain the desired product.

The same process can also be applied to the preparation of esters other than the alkyl and aralkyl esters by using suitable hydroxy compounds or their functional equivalents, for example compounds of the formula I in which R [high] 2 is a divalent aliphatic hydrocarbon group by using of a glycol can be prepared in place of the alcohol in the above process. Furthermore, instead of the acid-catalyzed solvolysis process described, any other conventional solvolysis methods can be used to prepare compounds of the formula I in which R [high] 2 is an ester radical which is accessible by solvolysis of a lactone.

Procedure 3

Production of esters from the corresponding metal salt

Carboxylic acid esters of the formula IX in which R [high] 1, R [high] 3, R [high] 4 and R [high] 5 have the above meaning, R [high] 2c represents the alcohol group of an ester and p the valence of R [high] 2c is obtained by using a metal salt of the formula X

in which R [high] 1, R [high] 3, R [high] 4 and R [high] 5 have the above meaning, M [high] 3 represents a metal atom, preferably an alkali metal or alkaline earth metal atom, and q is the valence of M [high] 3 with an esterifying agent, preferably an esterifying agent of the formula R [high] 2c-X, where X is a halogen atom, for example a chlorine or bromine atom.

The reaction can be carried out by customary methods for alkylating carboxylic acid metal salts. For example, the metal salt of the formula X can be contacted with the esterifying agent in the presence of an inert organic solvent in order to obtain the desired ester of the formula IX. The type of solvent used is not subject to any particular restriction, but it must not adversely affect the reaction. Preferred solvents are dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, hexamethylphosphoryl triamide, acetone and methyl ethyl ketone. The reaction will take place over a wide range of temperatures, such as room temperature or elevated temperatures, but room temperature will normally be used. The required reaction time depends on the reaction temperature and the reactants used, but is usually 1 to 20 hours. The desired product can be obtained from the reaction mixture in a conventional manner, for example by diluting the reaction mixture with water, extracting the mixture with a water-immiscible solvent and distilling off the solvent from the extract.

The esterifying agent used is preferably an alkyl halide, aralkyl halide or phenacyl halide and the metal salt of formula X is preferably an alkali metal salt; i.e., M [high] 3 is an alkali metal atom. This alkali metal salt is preferably formed in situ by another reaction, e.g., by Method 1, prior to the reaction with the esterifying agent.

In particularly preferred starting compounds, R [high] 1 is a hydrogen atom or a methyl group, R [high] 3 is a hydrogen atom, a C [low] 2-C [low] 6-alkanoyl group or C [low] 3-C [low] 6 -Alkenoyl group, R [high] 4 and R [high] 5 are identical or different hydrogen atoms, C [low] 2-C [low] 6-alkanoyl groups or benzoyl groups, with the proviso that when R [high] 3 is a 2-methylbutyryl group R [high] 4 and R [high] 5 are both acyl groups, and M [high] 3 is an alkali metal atom. Benzyl halides and phenacyl halides are particularly preferred as esterifying agents.

Procedure 4

Production of 3-acyl, 5-acyl and 8´-acyl derivatives

Triacyl compounds of the formula XI in which R [high] 1, R [high] 2 and n are as defined above, and R [high] 3b, R [high] 4b and R [high] 5b represent the same or different acyl groups are obtained by a compound of the formula XII

in which R [high] 1, R [high] 2 and n have the above meaning and R [high] 3c, R [high] 4c and R [high] 5c represent the same or different hydrogen atoms or acyl groups, with the proviso that at least one of the radicals R [high] 3c, R [high] 4c and R [high] 5c is a hydrogen atom, acylated.

Compounds of formulas XIII, XIV and XV

in which R [high] 1, R [high] 2 and n are as defined above, R [high] 4 represents a hydrogen atom or an acyl group, R [high] 3b represents an acyl group, and R [high] 4b represents an acyl group, are obtained by acylation of a compound of formula XVI

in which R [high] 1, R [high] 2, n and R [high] 3b have the above meanings. By suitable choice of the conditions it is possible either to prepare one of the compounds of the formulas XIII, XIV and XV or else a mixture of two or all three compounds. The desired compound (s) can then be isolated from the reaction mixture.

The acylation is preferably carried out by one of the following methods:

(A) Acylation with a reactive acid derivative

In this process, the compound of formula XII or XVI is reacted with a reactive derivative of an acid having the desired acyl group, e.g. an acid halide (such as the acid chloride or bromide), an acid anhydride or a mixed acid anhydride (e.g. a mixed anhydride of the acid with a Chloroformic acid ester or a sulfonic acid chloride). The reaction is preferably carried out in the presence of a solvent and also preferably in the presence of a base. The type of solvent used is not particularly limited, but it must not adversely affect the reaction. Suitable solvents are, for example, chloroform, methylene chloride, diethyl ether, tetrahydrofuran and dioxane. Preferred bases are, for example, organic amines such as pyridine, 4- (N, N-dimethylamino) pyridine, quinoline, triethylamine, N-methylmorpholine, N-methylpiperidine and N, N-dimethylaniline. If the amine used is liquid at the reaction temperature, such as pyridine, it can be used as a solvent. The reaction is preferably carried out at room temperature or with cooling in order to control side reactions. However, it also proceeds at elevated temperatures. The reaction time depends on the reaction temperature and the reactants used, but is normally 10 minutes to 10 hours. After the reaction has ended, the desired product is obtained in the usual way, e.g. by diluting the reaction mixture with water. ser, extracting the mixture with a water-immiscible solvent and distilling off the solvent from the extract.

(B) Acylation with a condensing agent

This reaction takes place under customary conditions using a free acid which has the acyl group to be introduced, in the presence of a condensing agent. Here, the compounds of the formula XII or XVI are simply brought into contact with the acid in the presence of the condensing agent. The condensing agent is preferably a dehydrating agent, for example a carbodiimide such as dicyclohexylcarbodiimide. The reaction is normally carried out in the presence of a solvent, the nature of which is not critical as long as it does not adversely affect the reaction. Suitable solvents are, for example, dimethylformamide, dimethylacetamide, acetonitrile, pyridine, methylene chloride, chloroform and dioxane. The reaction can be carried out within a wide temperature range, but in order to control side reactions, it is preferably carried out at room temperature or with cooling. However, the reaction also takes place at elevated temperatures. The reaction time depends on the reaction temperature and the reactants, but is usually 1 to 20 hours. The desired compound can then be obtained from the reaction mixture in a conventional manner, e.g. by filtering off insoluble constituents, diluting the filtrate with water, extracting the resulting mixture with a water-immiscible solvent and distilling off the solvent from the extract.

In both of the acylation processes described, when the starting material contains two or more free hydroxyl groups, mono-, di- or triacyl derivatives can be obtained by adjusting the amount of the acylating agent used will. If a mixture of these compounds is obtained, the individual compounds can be isolated by conventional methods, for example by chromatography on silica gel.

The compounds according to the invention can be obtained from the fermentation products ML-236A, ML-236B, MB-530A and MB-530B or the corresponding carboxylic acids or carboxylic acid salts by any combination of the reactions mentioned. These reactions are summarized in the following reaction scheme, whereby the chemical structures of the compounds are simplified as follows:

In this reaction scheme, Ac [high] 1, Ac [high] 2 and Ac [high] 3 mean the same or different acyl groups.

The compounds according to the invention inhibit the activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), which is the rate-limiting enzyme in the biosynthesis of cholesterol. According to the method of Knauss et al. [J. Biol. Chem., Vol. 234, p. 2835 (1959)] are the inhibitory concentrations of the compounds according to the invention in cholesterol biosynthesis, expressed as ID [low] 50 values (ie concentrations at which cholesterol biosynthesis is 50% is inhibited), 1.0 to 0.03 µg / ml. It was also found that sodium salts of the compounds of the formula I (R [high] 2 = sodium) were absorbed significantly better in an in vivo test than the corresponding lactones, and it is generally assumed that the compounds according to the invention have a better bioavailability than the corresponding lactones.

For the treatment of hypercholesterolemia, the compounds according to the invention can be administered by known methods, preferably in the form of tablets or capsules. The daily dose depends on the age, body weight and condition of the patient, but in general the compounds according to the invention are preferably administered in an amount of 1 to 10 mg / day as single or partial doses.

The following examples illustrate the preparation of the compounds according to the invention. The preparation of certain starting materials used in the examples is illustrated in Preparation Examples 1 to 4. Other starting materials can be prepared by similar methods. The preparation of ML-236A and ML-236B is described in U.S. Patent 3,983,140.

Production example 1

3-0-Butyryl-ML-236A

1 ml of butyranhydride is added dropwise at room temperature to a solution of 918 mg of ML-236A in 5 ml of pyridine. The reaction mixture is left to stand overnight, then diluted with water and extracted with diethyl ether. The extract is washed successively with water, saturated aqueous sodium bicarbonate solution, water, 1 N hydrochloric acid and water and dried over sodium sulfate. By distilling off the solvent and column chromatography of the residue on silica gel with benzene / ethyl acetate (volume ratio 5: 1) as the eluant, 930 mg of the desired product are obtained as a colorless oily substance.

Elemental analysis for C [deep] 22H [deep] 32O [deep] 5:

C H

calc .: 70.21% 8.51%

found: 69.95% 8.69%

Nuclear Magnetic Resonance Spectrum (CDCl3 [low] 3) delta ppm: 0.95 (3H, t); 4.27 (1H, m); 5.32 (1H, m).

IR spectrum (film) ny [deep] max cm [high] -1: 3460, 1740.

Production example 2

3,8'-Di (O-butyryl) -ML-236A

0.5 ml of butyryl chloride is added dropwise to a solution of 306 mg of ML-236A and 0.5 ml of pyridine in 3 ml of methylene chloride while cooling with ice. The mixture is stirred at room temperature for 1 hour and then washed with water. The organic layer is separated off and dried over sodium sulfate, whereupon the solvent is distilled off and the residue obtained is chromatographed on a silica gel column with benzene / ethyl acetate (volume ratio 10: 1) as the eluent. 384 mg of the desired product are obtained as a colorless oily substance.

Elemental analysis for C [deep] 26H [deep] 38O [deep] 6:

C H

ber .: 69.96% 8.52%

found: 70.14% 8.31%

Nuclear Magnetic Resonance Spectrum (CDCl3 [low] 3) delta ppm: 0.93 (6H, t); 5.2 - 5.5 (2H, m).

IR spectrum (film) ny [deep] max cm [high] -1: 1735, 1250, 1175.

Production example 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, whereupon the solution is cooled in an ice bath and 0.35 ml of butyryl chloride is added dropwise. After stirring for one hour, the mixture is diluted with water and the organic layer is separated, washed with water and dried over sodium sulfate. The residue obtained by distilling off the solvent is chromatographed on a silica gel column. The 3,8'-diacyl compound (preparation example 2) is eluted with benzene / ethyl acetate (volume ratio 10: 1), the 3-acyl compound (preparation example 1) is eluted with benzene / ethyl acetate (volume ratio 5: 1) and 395 mg des desired product are obtained from the eluate of benzene / ethyl acetate (volume ratio 2: 1) in the form of colorless crystals, melting point 124 to 125 ° C.

Elemental analysis for C [deep] 22H [deep] 32O [deep] 5:

C H

calc .: 70.21% 8.51%

found: 70.25% 8.50%

Nuclear Magnetic Resonance Spectrum (CDCl3 [low] 3) delta ppm: 0.95 (3H, t); 4.42 (1H, m).

IR spectrum (Nujol) ny [deep] max cm [high] -1: 3400, 1730, 1710.

Other acyl derivatives can be prepared according to the methods described in these Preparation Examples.

Production example 4

Manufacture of MB-530A

300 liters of a culture medium which has a pH of 5.5 before sterilization and contains 5% w / v glucose, 0.5% w / v corn steep liquor, 2% w / v peptone ("Kyokuto" from Kyokuta Seiyaku KK, Japan ) and contains 0.5% ammonium chloride, are placed in a 600 liter fermenter and inoculated with a culture of Monascus ruber SANK 15177 (FERM 4956, NRRL 12081). The cultivation of the microorganism is continued for 120 hours at 27 ° C. with an aeration rate of 300 liters / min and with stirring at 190 rpm. The culture broth is then filtered using a filter press, a filtrate and a filter cake of moist microorganism cells being obtained.

The filtrate is adjusted to a pH of 3.0 by adding 6N hydrochloric acid and then extracted with 400 liters of ethyl acetate. The extract (about 400 liters) is concentrated under reduced pressure and then dehydrated over sodium sulphate, whereupon it is evaporated to dryness and about 60 g of an oily product are obtained. This is washed with ethylcyclohexane and hexane, and the residue (20 g) is separated by chromatography with a large volume liquid chromatograph (System 500 liquid chromatograph from Waters Co., USA) and eluting with 60% v / v aqueous methanol . The fractions with a chromatographic retention time of 6 minutes are collected and concentrated under reduced pressure. This gives 100 mg of the desired MB-530A as an oily product which is recrystallized from acetone / diethyl ether. 57 mg of the desired product are obtained in the form of colorless needles with the following properties:

1st F.: 92 to 93 ° C.

2. Elemental analysis for C [low] 19H [low] 28O [low] 4:

C H

ber .: 69.76% 8.68%

found: 71.22% 8.81%.

3. Molecular weight: 320 (mass analysis).

4. Molecular formula: C [deep] 19H [deep] 28O [deep] 4.

5. UV absorption spectrum: see Figure 1.

6. IR absorption spectrum: see Figure 2.

7. NMR spectrum: see FIG. 3.

8. Solubility: Easily soluble in methanol, ethanol, acetone and ethyl acetate; soluble in benzene; insoluble in hexane and petroleum ether.

9. Color reaction: In thin-layer chromatography on silica gel, developing with 50% V / V sulfuric acid produces a pink color.

10. Inhibitory effect against cholesterol biosynthesis: At a concentration of 0.04 µg / ml, a 50 percent inhibition of cholesterol synthesis is observed in the rat liver.

example 1

Sodium ML-236A carboxylate

0.4 g of ML-236A are added to 12 ml of 0.1 N sodium hydroxide solution, whereupon the mixture is heated to 80 to 90 ° C. for 2 hours. After the reaction has ended, the insoluble constituents are filtered off and the filtrate is lyophilized. 0.41 g of the desired product is obtained as a colorless powder.

Elemental analysis for C [deep] 18H [deep] 27O [deep] 5NA:

C H

ber .: 62.43% 7.80%

found: 62.58% 7.72%

Example 2

Sodium 8'-O-butyryl-ML-236A-carboxylate

0.75 g of 8'-O-butyryl-ML-236A are added to 20 ml of 0.1 N sodium hydroxide solution, whereupon the mixture is heated to 80 to 90 ° C. for 2 hours. After the reaction has ended, the insoluble constituents are filtered off and the filtrate is lyophilized. 0.83 g of the desired product are obtained as a colorless powder.

Elemental analysis for C [deep] 22H [deep] 33O [deep] 6Na:

C H Na

ber .: 63.46% 7.93% 5.53%

found: 63.54% 7.90% 5.50%

Nuclear Magnetic Resonance Spectrum (D [low] 2O) delta ppm: 0.95 (3H, t); 4.15 (2H, t), 3.5-4.5 (2H, m).

IR spectrum (mujol) ny [deep] max cm [high] -1: 3450, 1730, 1580.

Example 3

Sodium 8'-O-hexanoyl-ML-236A-carboxylate

0.88 g of 8'-O-hexanoyl-ML-236A are added to 20 ml of 0.1 N sodium hydroxide solution. By processing the mixture according to Example 1, 0.84 g of the desired product is obtained as a colorless powder.

Elemental analysis for C [deep] 24H [deep] 37O [deep] 6Na:

C H Na

calc .: 64.86% 8.33% 5.18%

found: 64.75% 8.37% 5.25%.

Nuclear Magnetic Resonance Spectrum (O [low] 2O) delta ppm: 0.87 (3H, t); 4.13 (2H, m); 3.5-4.5 (2H, m).

IR spectrum (Nujol) ny [deep] max cm [high] -1: 3450, 1730, 1580.

Example 4

Ethyl 8'-O-butyryl-ML-236A-carboxylate

0.79 g of 8'-O-Butyryl-ML-236A are dissolved in 10 ml of ethanol and mixed with 1 g of a strongly acidic cation exchange resin of the sulfonic acid type (Dowex 50 W). The mixture is heated to 60 to 70 ° C for 3 hours. After the reaction has ended, the mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel and gives 0.41 g of the desired product as a colorless oily substance.

Elemental analysis for C [deep] 24H [deep] 38O [deep] 6:

C H

ber .: 68.25% 9.00%

found: 68.19% 9.06%

Nuclear Magnetic Resonance Spectrum (CDCl3 [low] 3) delta ppm: 0.95 (3H, t); 1.23 (3H, t); 4.12 (2H, q); 3.5-4.5 (2H, m).

IR spectrum (film) ny [deep] max cm [high] -1: 3450, 1740.

Example 5

Ethyl 8'-O-hexanoyl-ML-236A-carboxylate

0.9 g of 8'-O-hexanoyl-ML-236A are dissolved in 10 ml of ethanol and 1.5 g of a strongly acidic cation exchange resin of the sulfonic acid type are added. When working up the mixture according to Example 3, 0.55 g of the desired product is obtained as a colorless oily substance.

Elemental analysis for C [deep] 26H [deep] 46O [deep] 6:

C H

calc .: 69.33% 9.33%

found: 69.21% 9.39%.

Nuclear Magnetic Resonance Spectrum (CDCl3 [low] 3) delta ppm: 0.87 (3H, t); 1.25 (3H, t); 4.13 (2H, q); 3.5-4.5 (2H, m).

IR spectrum (film) ny [deep] max cm [high] -1: 3400, 1730, 1720.

Example 6

8'-O-butyryl-ML-236A-carboxylic acid butyl ester

0.79 g of 8'-O-butyryl-ML-236A are dissolved in 10 ml of butanol and mixed with 1.0 g of a strongly acidic cation exchange resin of the sulfonic acid type. When working up the mixture according to Example 3, 0.59 g of the desired product is obtained as a colorless oily substance.

Elemental analysis for C [deep] 26H [deep] 42O [deep] 6:

C H

calc .: 69.33% 9.33%

found: 69.25% 9.40%.

Nuclear Magnetic Resonance Spectrum (CDCl3 [low] 3) delta ppm: 0.95 (3H, t); 1.24 (3H, t); 4.12 (2H, t); 3.5-4.5 (2H, m).

IR spectrum (film) ny [deep] max cm [high] -1: 3440, 1730.

Example 7

8'-O- (4-pentenoyl) -ML-236A-carboxylic acid butyl ester

According to Example 3, using 0.92 g of 8'-O- (4-pentenoyl) -ML-236A, 10 ml of butanol and 1.0 g of ion exchange resin, 0.45 g of the desired product is obtained as a colorless oily substance.

Elemental analysis for C [deep] 27H [deep] 42O [deep] 6:

C H

ber .: 70.13% 9.09%

found: 70.04% 9.13%

Nuclear Magnetic Resonance Spectrum (CDCl3 [low] 3) delta ppm: 1.24 (3H, m); 3.5-4.5 (4H, m); 4.8 - 6.2 (8H, m);

IR spectrum (film) ny [deep] max cm [high] -1: 3400, 1730.

Example 8

8'-O-isovaleryl-MB-530A-carboxylic acid butyl ester

According to Example 3, 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 as a colorless oily substance.

Elemental analysis for C [deep] 27H [deep] 44O [deep] 6:

C H

ber .: 69.83% 9.48%

found: 69.77% 9.46%

Nuclear Magnetic Resonance Spectrum (CDCl3 [low] 3) delta ppm: 0.89 (1H, d); 1.24 (3H, t); 4.12 (2H, t); 3.5-4.5 (2H, m).

IR spectrum (film) ny [deep] max cm [high] -1: 3430, 1730.

Example 9

Benzyl 8'-O-Butyryl-ML-236A-carboxylate

1.0 g of sodium 8'-O-butyryl-ML-236A-carboxylate are dissolved in 5 ml of dimethylformamide and mixed with 1 ml of benzyl chloride. The mixture is left to stand overnight, then diluted with water and extracted with ethyl acetate. The organic layer is separated, washed with water and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure is purified by column chromatography on silica gel, whereby 1.2 g of the desired product are obtained as a colorless oily substance.

Elemental analysis for C [deep] 29H [deep] 40O [deep] 6:

C H

calc .: 71.90% 8.26%

found: 71.84% 8.25%

Nuclear Magnetic Resonance Spectrum (CDCl3 [low] 3) delta ppm: 0.94 (3H, t); 1.24 (3H, t); 4.11 (2H, t); 3.5-4.5 (2H, m); 5.20 (2H, s); 7.42 (5H, s).

IR spectrum (film) ny [deep] max cm [high] -1: 3540, 1730.

Example 10

Benzyl 8'-O-hexanoyl-ML-236A-carboxylate

According to Example 8, using 1.2 g of sodium 8'-O-hexanoyl-ML-236A-carboxylate and 1 ml of benzyl chloride, 1.3 g of the desired product are obtained as a colorless oily substance.

Elemental analysis for C [deep] 31H [deep] 44O [deep] 6:

C H

ber .: 72.66% 8.59%

found: 72.58% 8.50%

Nuclear Magnetic Resonance Spectrum (CDCl3 [low] 3) delta ppm: 0.89 (3H, t); 4.14 (2H, t); 3.5-4.5 (2H, m); 5.21 (2H, s); 7.44 (5H, s).

IR spectrum (film) ny [deep] max cm [high] -1: 3400, 1730.

Example 11

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

According to Example 8, using 0.86 g of sodium 8'-O-butyryl-MB-530A-carboxylate and 0.45 g of phenacyl bromide, 1.0 g of the desired product is obtained as a colorless oily substance.

Elemental analysis for C [low] 31H [low] 42O [low] 7:

C H

ber .: 70.72% 7.98%

found: 70.65% 8.04%

Nuclear Magnetic Resonance Spectrum (CDCl3 [low] 3) delta ppm: 0.95 (3H, t), 4.13 (2H, t), 3.5-4.5 (2H, m); 5.44 (2H, s); 7.4 - 8.2 (5H, m).

IR spectrum (film) ny [deep] max cm [high] -1: 3450, 1730, 1700.

Example 12

3,5-Di- (O-acetyl) -ML-236B-carboxylic acid butyl ester

0.32 g of butyl ML-236B carboxylate are dissolved in 1 ml of pyridine, 1 ml of acetic anhydride is added and the mixture is left to stand at room temperature for 1 hour. The reaction mixture is then diluted with water and extracted with ethyl acetate, the solvent is distilled off from the extract under reduced pressure and the residue is purified by column chromatography on silica gel. This gives 0.35 g of the desired product as a colorless oily substance.

Elemental analysis for C [low] 31H [low] 48O [low] 8:

C H

ber .: 67.88% 8.76%

found: 67.74% 8.81%.

Nuclear Magnetic Resonance Spectrum (CDCl3 [low] 3) delta ppm: 2.00 (3H, s), 2.03 (3H, s).

IR spectrum (film) ny [deep] max cm [high] -1: 1740.

Example 13

3,5-Di- (O-benzoyl) -ML-236B-carboxylic acid butyl ester

According to Example 11, 0.38 g of the desired product are obtained as a colorless oily substance from 0.34 g of butyl ML-236B carboxylate, 0.3 ml of benzoyl chloride and 1 ml of pyridine.

Elemental analysis for C [low] 41H [low] 52O [low] 8:

C H

calc .: 73.21% 7.74%

found: 73.10% 7.89%

Nuclear Magnetic Resonance Spectrum (CDCl3 [low] 3) delta ppm: 7.2-7.6 (3H, m); 7.8 - 8.2 (2H, m).

IR spectrum (film) ny [deep] max cm [high] -1: 1720.

Example 14

Sodium ML-236A carboxylate

300 liters of a culture medium that has a pH of 5.5 before sterilization and contains 2% w / v glucose, 0.1% w / v peptone ("Kyokuto") and 3% w / v malt extract is poured into a 600 Liter fermenter introduced and inoculated with Penicillium citrinum SANK 18767. Cultivation is continued for 96 hours under aerobic conditions at 26 ° C with an aeration rate of 300 liters / min and with stirring at 145 rpm. The culture broth containing the organism is then adjusted to pH 3.4 with 6N hydrochloric acid and extracted with 800 liters of ethyl acetate. The extract is washed with 200 liters of saturated aqueous sodium chloride solution and concentrated to 18 liters by evaporation in vacuo. The resulting solution is extracted with 600 liters of ethyl acetate, whereupon 50 g of trifluoroacetic acid are added to the extract and it is reacted at 80 ° C. for 30 minutes. The reaction mixture is washed each other 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, followed by evaporation under reduced pressure to obtain 130 g of an oily substance. This oil is dissolved in 400 ml of methanol. 20 ml of the methanol solution containing 6.5 g of oil is subjected to preparative flash liquid chromatography (System 500 by Waters Co., Ltd.) with a Prepac C [deep] 18 column (reverse phase column). The development takes place with methanol / water (60: 40 V / V). The development at a flow rate of 200 ml / min (development time: about 10 minutes) is observed with a differential refractometer connected to the device, and the part giving the main peak on the differential refractometer is separated. This procedure is repeated and the main peak fractions obtained are collected and concentrated. This gives 9.2 g of an oily substance which is dissolved in 30 ml of methanol. 6 ml of the methanol solution containing about 1.8 g of the oil is chromatographed in the same way, but developing with methanol / water (55:45 v / v) at a flow rate of 200 ml / min. The part showing the main peak is cut off. This procedure is repeated and the main peak fractions are collected and concentrated to give 1020 mg of ML-236A as an oily substance. 33.2 ml of 0.1 N aqueous sodium hydroxide solution are added to the substance and the mixture is stirred at 50 to 60 ° C. for 3 hours. After the insoluble constituents have been filtered off, the filtrate is lyophilized and 1090 mg of sodium ML-236A carboxylate is obtained.

Example 15

Sodium ML-236A carboxylate

1030 liters of an ethyl acetate extract of the culture broth obtained in Example 14 are washed with 200 liters of saturated aqueous sodium chloride solution. Of the

The extract is dried over sodium sulfate and concentrated to dryness to give 120 g of an oily substance containing ML-236A carboxylic acid.

This oil is mixed with methanol up to a total volume of 200 ml. 20 ml of the solution are subjected to preparative high-speed liquid chromatography on the reverse phase column of Example 14 and eluted with a 20% v / v aqueous methanol solution containing 2% acetic acid at a flow rate of 200 ml / min. The part showing a main peak on the differential refractometer is separated (7 to 10 minutes). The remaining 120 ml are treated in the same way. The main peak fractions obtained are collected, concentrated and extracted with ethyl acetate. After adding heptane, the filtrate is concentrated to dryness and 8.7 g of an oily substance are obtained, which is dissolved in 20 ml of methanol and chromatographed in the above manner. This gives 930 mg of ML-236A carboxylic acid, to which 2 ml of methanol and 100 ml of water are added. The resulting solution is adjusted to pH 8.0 with 1N sodium hydroxide solution, a clear aqueous solution being formed which, on lyophilization, yields 980 mg of sodium ML-236A carboxylate as a white powder.

Example 16

Sodium MB-530A carboxylate

300 liters of a culture medium which, prior to sterilization, has a pH of 5.5 and contains 5% w / v glucose, 0.5% w / v corn steep liquor, 2% w / v peptone ("Kyokuto") and 0.5% w / V containing ammonium chloride are placed in a 600 liter fermenter and inoculated with Monascus ruber SANK 18174. Cultivation is continued for 116 hours at 26 ° C. under aerobic conditions with an aeration rate of 300 liters / min and with stirring at 190 rpm. The microorganisms Culture broth containing nism is adjusted to pH 3.4 with 6 N hydrochloric acid and extracted with 800 liters of ethyl acetate. The extract is washed with 200 liters of saturated aqueous sodium chloride solution and dried over anhydrous sodium phosphate. It is then concentrated to 18 liters by evaporation under reduced pressure. The resulting solution is extracted with 600 liters of ethyl acetate, whereupon 50 g of trifluoroacetic acid are added to the extract and it is reacted at 80 ° C. for 30 minutes. The reaction mixture is washed successively with 10 liters of a 2% w / v aqueous sodium bicarbonate solution and 10 liters of a 10% w / v aqueous sodium chloride solution, and then concentrated to 105 g of an oily substance. The oil is dissolved in 400 ml of methanol. 20 ml of the methanol solution containing about 5.3 g of the oil is subjected to preparative rapid liquid chromatography with the reversed-phase column of Example 14. The development takes place at a flow rate of 200 ml / min (development time: about 15 minutes) with methanol / water (65: 35 V / V). A differential refractometer is connected to the device. The part showing a main peak on the differential refractometer is cut off. This procedure is repeated and the main peak fractions obtained are collected and concentrated. This gives 7.9 g of an oily substance which is dissolved in 30 ml of methanol. 60 ml of the methanol solution, which contains about 1.6 g of the oil, is chromatographed again, but developed with methanol / water (60:40 V / V) at a flow rate of 200 ml / min. The part showing a main peak is cut off. This procedure is repeated and the main peak fractions are collected and concentrated. This gives 679 mg of MB-530A as an oily substance. This substance is mixed with 21 ml of 0.1 N sodium hydroxide solution and stirred at 50 to 60 ° C. for 3 hours. By filtering off the insoluble constituents and lyophilizing the filtrate, 720 mg of sodium MB-530A-carboxylate are obtained.

Elemental analysis for C [low] 19H [low] 29O [low] 5Na:

C H

ber .: 63.33% 8.06%

found: 63.51% 7.97%

Example 17

Sodium MB-530A carboxylate

300 liters of a culture medium which has a pH of 7.4 before sterilization and contains 1.5% w / v soluble starch, 1.5% w / v glycerin, 2% w / v fish meal and 0.2% w / v Contains calcium carbonate, is placed in a 600 liter fermenter and inoculated with Monascus ruber SANK 17075 (CBS 832.70). Cultivation is continued for 120 hours at 26 ° C. under aerobic conditions at an aeration rate of 300 liters / min and with stirring at 190 rpm. The culture broth obtained is filtered with a filter press and gives 35 kg of a moist microorganism to which 100 liters of water are added. The mixture is adjusted to pH 12 with sodium hydroxide while stirring and left to stand at room temperature for 1 hour. The mixture is then treated with 2 kg of Hyflo Super Cel filter aid and filtered with a filter press. The filtrate is adjusted to pH 10 with hydrochloric acid and applied to a column which is filled with 5 liters of HP-20 resin. It is then washed with 15 liters each of water and 10% V / V aqueous methanol and then eluted with 60% V / V aqueous methanol. The eluate is concentrated to a volume of about 10 liters, whereupon the residue is adjusted to pH 2 with hydrochloric acid and extracted with ethyl acetate. The extract is washed with a saturated sodium chloride aqueous solution, dried over sodium sulfate and concentrated to dryness to obtain 20 g of an oily substance containing MB-530A carboxylic acid. This oil is mixed with methanol up to a total volume of 100 ml. 20 ml of the solution are subjected to the preparative high-speed liquid chromatography with the reversed-phase column of Example 14 fen and eluted with 13% v / v aqueous methanol containing 2% acetic acid at a flow rate of 200 ml / min. The part showing a main peak on the differential refractometer is separated (7 to 10 minutes). The remaining 80 ml are treated in the same way. The main peak fractions obtained are collected, concentrated and extracted with ethyl acetate. After adding heptane, the extract is concentrated to dryness, 920 mg of an oily substance being obtained, which is dissolved in 20 ml of methanol and subjected to chromatography under the above conditions. This gives 120 mg of MB-530A carboxylic acid, to which 2 ml of methanol and 100 ml of water are added. By adjusting the pH to 8.0 with 1N sodium hydroxide solution, a clear aqueous solution is obtained which, on lyophilization, gives 110 mg of sodium MB-530A carboxylate as a white powder.

Claims (41)

1. Carboxylic acid derivatives of the formula I. in which R [high] 1 represents a hydrogen atom or a methyl group, R [high] 2 represents a hydrogen atom, the alcohol group of an ester or the cation of a salt and R [high] 3, R [high] 4 and R [high] 5 are identical or different hydrogen atoms or organic or inorganic acyl groups with Provided that when R [high] 3 is 2-methylbutyryl, R [high] 4 and R [high] 5 are both acyl groups, and n is the valence of R [high] 2. 2. Compounds according to claim 1, characterized in that R [high] 1 denotes a hydrogen atom or a methyl group, R [high] 2 denotes a hydrogen atom, a monovalent metal atom, an ammonium group, an alkyl-substituted ammonium group, one capable of salt formation, from a basic one Amino acid-derived group, an alkyl group, an aralkyl group which optionally has a substituent on the aryl radical, or a phenacyl group which optionally has a substituent on the phenyl radical, the substituents being C [deep] 1-C [deep] 4-alkyl groups, C [low] 1-C [low] 4-alkoxy groups, halogen atoms and / or trifluoromethyl groups, and R [high] 3, R [high] 4 and R [high] 5 are identical or different hydrogen atoms or aliphatic, aromatic or araliphatic acyl groups provided that when R [high] 3 is 2-methylbutyryl, R [high] 4 and R [high] 5 are both acyl groups. 3. Compounds according to claim 1, characterized in that R [high] 1 is a hydrogen atom or a methyl group, R [high] 2 is a hydrogen, alkali metal, alkaline earth metal, aluminum, zinc, iron or germanium atom, a Ammonium group, a group derived from a basic amino acid capable of forming salts, a C [deep] 1-C [deep] 8-alkyl group, an aralkyl group which may have a substituent on the aryl radical, or a phenacyl group which may have a substituent on the phenyl radical has, where the substituents are C [deep] 1-C [deep] 4-alkyl groups, C [deep] 1-C [deep] 4-alkoxy groups, halogen atoms and / or trifluoromethyl groups, and R [high] 3, R [high] 4 and R [high] 5 identical or different hydrogen atoms, C [low] 2-C [low] 20-alkanoyl groups, C [low] 3-C [low] 20-alkenoyl groups, C [low] 3-C [deep] 20-alkinoyl groups, aromatic C [deep] 7-C [deep] 15-acyl groups, C [deep] 8-C [deep] 9-aralkanoyl groups or C [deep] 9-aralkenoyl groups, mi t the Provided that when R [high] 3 is 2-methylbutyryl, R [high] 4 and R [high] 5 are both acyl groups. 4. Compounds according to claim 1, characterized in that R [high] 1 is a hydrogen atom or a methyl group, R [high] 2 is a hydrogen, alkali metal or alkaline earth metal atom, an ammonium group, one capable of salt formation and derived from a basic amino acid Group, a C [low] 1-C [low] 4-alkyl group, a benzyl group or phenacyl group and R [high] 3, R [high] 4 and R [high] 5 are identical or different hydrogen atoms, C [low] 2 -C [low] 6-alkanoyl groups, C [low] 3-C [low] 6-alkenoyl groups or benzoyl groups, with the proviso that when R [high] 3 is a 2-methylbutyryl group, R [high] 4 and R [high] 5 are both acyl groups. 5. Compounds according to claim 1, characterized in that R [high] 1 is a hydrogen atom or a methyl group, R [high] 2 is a C [low] 1-C [low] 4-alkyl group, benzyl or phenacyl group, R [high] 3 denotes a C [low] 2-C [low] 6-alkanoyl group or C [low] 3-C [low] 6-alkenoyl group, and R [high] 4 and R [high] 5 are the same or different C [deep] 2-C [deep] 6-alkanoyl groups or benzoyl groups. 6. Compounds according to claim 1, characterized in that R [high] 1 is a hydrogen atom, R [high] 2 is a C [low] 1-C [low] 4-alkyl group, R [high] 3 is a C [low] 2 -C [low] 6-alkanoyl group and R [high] 4 and R [high] 5, identically or differently, represent acetyl or benzoyl groups. 7. Compounds of the formula II in which R [high] 1 denotes a hydrogen atom or a methyl group, R [high] 2a denotes a hydrogen, alkali metal or alkaline earth metal atom, an ammonium group, a group which is capable of forming salts and is derived from a basic amino acid, a C [low] 1- C [lower] 4-alkyl group, a benzyl or phenacyl group, R [high] 3a represents a C [lower] 2-C [lower] 6-alkanoyl group, but no 2-methylbutyryl group, or a C [lower] 3-C [low] means 6-alkenoyl group and m is the valence of R [high] 2a. 8. Compounds according to claim 7, characterized in that R [high] 2a is a C [low] 1-C [low] 4-alkyl group, a benzyl or phenacyl group. 9. Compounds according to claim 7, characterized in that R [high] 2a is an alkali metal atom. 10. Compounds of the formula III in which R [high] 1 denotes a hydrogen atom or a methyl group and M denotes a hydrogen or alkali metal atom. 11. Compounds according to claim 10, characterized in that M is an alkali metal atom. 12. Compounds according to claim 10, characterized in that M is a sodium atom. 13. Sodium ML-236A carboxylate Sodium MB-530A carboxylate Sodium 8'-O-butyryl-ML-236A-carboxylate Sodium 8'-O-hexanoyl-ML-236A-carboxylate Ethyl 8'-O-butyryl-ML-236A-carboxylate Ethyl 8'-O-hexanoyl-ML-236A-carboxylate 8'-O-butyryl-ML-236A-carboxylic acid butyl ester 8'-O- (4-pentenoyl) -ML-236A-carboxylic acid butyl ester 8'-O-isovaleryl-MB-530A-carboxylic acid butyl ester Benzyl 8'-O-butyryl-MB-236A-carboxylate Benzyl 8'-O-hexanoyl-ML-236A-carboxylate Phenacyl 8'-O-butyryl-MB-530A-carboxylate 3,5-Di- (O-acetyl) -ML-236B-carboxylic acid butyl ester and 3,5-Di- (O-benzoyl) -ML-236B-carboxylic acid butyl ester. 14. A process for the production of an ML-236A-carboxylic acid salt, characterized in that a ML-236A-producing microorganism of the genus Penicillium is cultivated in a suitable culture medium and the ML-236A-carboxylic acid salt is obtained from the culture broth. 15. The method according to claim 14, characterized in that a microorganism of the strain Penicillium citrinum, Penicillium chrysogenum or Penicillium notatum is used. 16. The method according to claim 15, characterized in that the microorganism Penicillium citrinum SANK 18767 (FERM 2609), Penicillium citrinum SANK 24467, Penicillium citrinum SANK 24567, Penicillium chrysogenum SANK 12768 (ATCC 100020) or Penicillium notatum SANK 24867 is used. 17. The method according to any one of claims 14 to 16, characterized in that the salt is an alkali metal salt. 18. Process for the production of an MB-530A-carboxylic acid salt, characterized in that an MB-530A-producing microorganism of the genus Monascus is cultivated in a suitable culture medium and the MB-530A-carboxylic acid salt is obtained from the culture broth obtained. 19. The method according to claim 18, characterized in that a microorganism of the strain Monascus ruber, Monascus anka, Monascus paxii, Monascus purpureus or Monascus vitreus is used. 20. The method according to claim 19, characterized in that the microorganism 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 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. The method according to any one of claims 18 to 20, characterized in that the salt is an alkali metal salt. 22. Process for the preparation of carboxylic acid salts of the formula IV in which R [high] 1 denotes a hydrogen atom or a methyl group, R [high] 3 and R [high] 4 represent the same or different hydrogen atoms or acyl groups, with the proviso that when R [high] 3 is a 2-methylbutyryl group, R [high] 4 is an acyl group, M [high] 1 is the cation of a salt and m 'is the valence of M [high] 1, characterized in that a lactone of the formula V in which R [high] 1, R [high] 3, R [high] 4, M [high] 1 and m 'have the above meaning, hydrolyzed and, if necessary, the carboxyl group of the product obtained is converted into the corresponding salt. 23. The method according to claim 22, characterized in that the hydrolysis takes place in an alkali solution and M [high] 1 denotes an alkali metal atom. 24. The method according to claim 22 and 23, characterized in that R [high] 1 is a hydrogen atom or a methyl group, R [high] 3 is a hydrogen atom, a C [low] 2-C [low] 6-alkanoyl group or a C [ low] 3-C [low] 6-alkenoyl group and R [high] 4 denotes a hydrogen atom, a C [low] 2-C [low] 6-alkanoyl group or a benzoyl group. 25. Process for the preparation of carboxylic acid derivatives of the formula VI in which R [high] 1 denotes a hydrogen atom or a methyl group and M [high] 2 denotes an alkali metal atom, characterized in that a compound of the formula VII in which R [high] 1 has the above meaning, hydrolyzed in an alkali solution. 26. The method according to claim 25, characterized in that M [high] 1 is a sodium atom and an aqueous sodium hydroxide solution is used as the alkali solution. 27. Process for the preparation of carboxylic acid esters of the formula VIII in which R [high] 1 denotes a hydrogen atom or a methyl group, R [high] 3 and R [high] 4 represent the same or different hydrogen atoms or acyl groups, with the proviso that when R [high] 3 is a 2-methylbutyryl group, R [high] 4 is an acyl group, and R [high] 2b denotes an alkyl or aralkyl group, characterized in that a lactone of the formula V in which R [high] 1, R [high] 3 and R [high] 4 have the above meaning, reacts with an alcohol in the presence of an acidic catalyst. 28. The method according to claim 27, characterized in that the acidic catalyst used is an inorganic acid, a Lewis acid or a cation exchange resin. 29. The method according to claim 28, characterized in that a strongly acidic cation exchange resin is used as the acidic catalyst. 30. The method according to any one of claims 27 to 29, characterized in that R [high] 1 is a hydrogen atom or a methyl group, R [high] 3 is a hydrogen atom, a C [low] 2-C [low] 6-alkanoyl group or a C [low] 3-C [low] 6-alkenoyl group, R [high] 4 is a hydrogen atom, a C [low] 2-C [low] 6-alkanoyl group or a benzoyl group (with the proviso that when R [high] 3 is a 2-methylbutyryl group, R [high] 4 is an acyl group) and the alcohol is a C [low] 1-C [low] 4-alkanol. 31. Process for the preparation of carboxylic acid esters of the formula IX in which R [high] 1, R [high] 3, R [high] 4 and R [high] 5 have the meaning given in claim 1, R [high] 2c is the alcohol group of an ester and p is the valence of R [high ] 2c, characterized in that a carboxylic acid salt of the formula X. in which R [high] 1, R [high] 3, R [high] 4 and R [high] 5 have the above meaning, M [high] 3 is an alkali or alkaline earth metal atom and q is the valence of M [high] 3 is reacted with an esterifying agent. 32. The method according to claim 31, characterized in that the esterifying agent used is an alkyl halide, an aralkyl halide or a phenacyl halide. 33. The method according to claim 31 or 32, characterized in that M [high] 3 is an alkali metal atom. 34. The method according to claim 33, characterized in that the salt (X), in which M [high] 3 is an alkali metal atom, is formed in situ prior to the reaction with the esterifying agent. 35. The method according to any one of claims 31 to 34, characterized in that R [high] 1 is a hydrogen atom or a methyl group, R [high] 3 is a hydrogen atom, a C [low] 2-C [low] 6-alkanoyl group or a C [low] 3-C [low] 6-alkenoyl group, R [high] 4 and R [high] 5 identical or different hydrogen atoms, C [low] 2-C [low] 6-alkanoyl groups or benzoyl groups, with the proviso that when R [high] 3 is 2-methylbutyryl, R [high] 4 and R [high] 5 are both acyl groups, and M [high] 3 is an alkali metal atom, and the esterifying agent is a benzyl halide or phenacyl halide. 36. Process for the preparation of triacyl compounds of the formula XI in which R [high] 1, R [high] 2 and n have the meaning given in claim 1 and R [high] 3b, R [high] 4b and R [high] 5b are the same or different acyl groups, characterized in that a compound of the formula XII in which R [high] 1, R [high] 2 and n have the above meaning and R [high] 3c, R [high] 4c and R [high] 5c are the same or different hydrogen atoms or acyl groups, with the proviso that at least one of the radicals R [high] 3c, R [high] 4c and R [high] 5c is a hydrogen atom, acylated. 37. Process for the preparation of compounds of the formulas XIII, XIV and / or XV n in which R [high] 1, R [high] 2, R [high] 4 and n have the meaning given in claim 1, R [high] 3b represent an acyl group and R [high] 4b represent an acyl group, characterized in that a compound of the formula XVI in which R [high] 1, R [high] 2, R [high] 3b and n have the above meaning, acylated to give compounds of the formulas XIII, XIV and XV, respectively, and these are isolated from the reaction mixture. 38. The method according to claim 37, characterized in that in compound XVI R [high] 1 is a hydrogen atom or a methyl group, R [high] 2 is an alkali metal atom, a C [low] 1-C [low] 4-alkyl group, benzyl group or phenacyl group and R [high] 3b denote a C [low] 2-C [low] 6-alkanoyl group or C [low] 3-C [low] 6-alkenoyl group and the acylation with a C [low] 2-C [ low] 6-alkanoic acid, benzoic acid or their reactive derivatives is carried out, so that compounds XIII and / or XIV are formed in which R [high] 4b is an alkanoyl group or benzoyl group. 39. The method according to claim 37, characterized in that the acylation is carried out with a reactive derivative of a carboxylic acid or sulfonic acid. 40. The method according to claim 39, characterized in that the acylation is carried out with an acid halide, acid anhydride or mixed anhydride of a carboxylic acid or sulfonic acid. 41. Medicaments containing at least one compound according to Claim 1 in addition to customary carriers, auxiliaries and / or diluents.