DE3112566A1 - MONACOLINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE DERIVATIVES - Google Patents

Description

The invention relates to new monacoline derivatives which are derived from the compounds ML-263A and MB-53OA and which Inhibiting cholesterol biosynthesis, as well as processes for their preparation and pharmaceuticals containing these derivatives.

Hyperlipemia, especially hypercholesterolemia, is known to be one of the main causes of heart disease, like heart attack or arteriosclerosis. Considerable efforts have therefore been made to establish connections to discover the lipid and especially the cholesterol level lower the blood. One group of such compounds is described in US Pat. No. 3,983,140. These Group of compounds is isolated from microorganisms of the genus Penicillium and collectively referred to as ML-236.

In USSN 121 515 of 02/14/1980 and 137 821 of 04/04/1980 (DE-OS 30 06 215 and 30 06 216) describes another such compound, which is referred to as Monacolin K or MB-53OB and by growing microorganisms of the genus Monascus, in particular the strains Monascus ruber, is obtained.

A new set of compounds has now been isolated that are related to ML-236 and MB-53OB and because of them better absorption when administered orally and their easier availability than per-drug. (i.e. drug that after administration by chemical or biochemical

- 8 - ■ * ■ "■

Body reactions are converted into an active or more active form, show better activity development.

ML-236A and ML-236B (two compounds of the ML-236 complex described in U.S. Patent 3,983,140) have the formulas

II or III:

CH

CH ₃

while MB-53OB (or Monacolin K) has the following Formula IV Has:

(IV]

The compounds according to the invention have the formula I.

1 2

in which R and R, identically or differently, denote hydrogen atoms or acyl groups and R denotes a hydrogen atom or a methyl group, with the proviso that when R

2 3

is a hydrogen atom, R and R are not water at the same time

are hydrogen atoms, and R does not represent an α-methylbutyryl group.

1 2

The compound of the invention in which R and R are both Are hydrogen atoms and R is a methyl group, i.e. the Compound of Formula V

(Previous year

was designated as MB-5 30A and can be manufactured by it be that one ΜΒ-53ΟΛ producing microorganism of the genus Monascus in a suitable culture medium

- 10 and the MB-53OA produced is recovered from the culture medium.

The other compounds of the invention that are viewed as 3- and / or 8'-acylated derivatives of ML-236A or ΜΒ-53ΟΆ can be prepared by acylating ML-236A, ML-236B, MB-53OA, or M3-53OB. For clarification these acylated derivatives are hereinafter referred to as esters of the compound (ML-236A, ML-236B, MB-53OA or MB-53OB), from which they are obtained by acylation became.

When defining the compounds according to the invention, the following numbering was used:

1 2

If one or both of the radicals R and R are an acyl group, this is preferably a saturated or unsaturated acyl group, an aromatic acyl group or an araliphatic group Acyl group.

Preferred aliphatic acyl groups are formyl, straight chain or branched alkanoyl with 2 to 20, preferably 2 to 6 carbon atoms and straight-chain or branched

Alkenoyl with 3 to 20, preferably 2 to 6 carbon atoms.

Preferred saturated aliphatic acyl groups are Formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, Isovaleryl, hexanoyl, 2-methylvaleryl, 3-methylvaleryl, 4-methylvaleryl, 2-ethylbutyryl, heptanoyl, octanoyl, 2-rethylhexanoyl, nonamoyl, isononanoyl, decanoyl, undecanoyl, Dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, Palmitoyl, stearoyl, isostearoyl, nonadecanoyl, eicosanoyl and pivaloyl.

Examples of suitable unsaturated aliphatic acyl groups are acryloyl, 3-butenoyl, methacryloyl, 2-pentenoyl, 4-pentenoyl, 2-undecenoyl, 4-undecenoyl, 2-trideceneoyl, 2-tetradecenoyl, 2-hexadecenoyl, linolenoyl, linoleyl, Arachidonoyl, propioloyl, crotonoyl, tigloyl, angeloyl, Senecionoyl, 2-heptenoyl, 2-octenoyl and 2-nonenoyl.

1 2

If R and / or R are aromatic acyl groups, this is preferably a Benzoy! Phenyl nucleus has one or more substituents. Such substituents are preferably CL-C'-alkyl, C. -C - alkoxy, Hydroxy, methylenedioxy, halogen and / or trifluoromethyl. The substituents can be in the ortho, meta or para position. When two or more substituents are present, they can be the same or different.

Examples of benzoyl groups with a substituent are Methylbenzoyl, ethylbenzoyl, propylbenzoyl, bufcylbenzoyl, Methoxybenzoyl, ethoxybenzoyl, propoxybenzoyl, butoxybenzoyl, Hydroxybenzoyl, chlorobenzoyl, bromobenzoyl and fluorobenzoyl, it being possible for the substituents to be in the ortho, meta or para position. Examples of benzoyl groups with two or several substituents are 2,3-dimethoxybenzoyl,

2,4-diraethoxybenzoyl, 2,5-dimethoxybenzoyl, 2,6-dimethoxybenzoyl, 2,4,6-trimethoxybenzoyl, 3,4,5-trimethoxybenzoyl, 3,4-methylenedioxybenzoyl and 2,3-methylenedioxybenzoyl.

1 2

When R and / or R are araliphatic acyl groups, is this is preferably a phenylalkanoyl group which optionally has one or more substituents on the phenyl nucleus. The alkanoyl group of this phenylalkanoyl group is preferably a C 1-4 alkanoyl group, preferably acetyl, Propionyl or butyryl, and the substituents are preferably Cj-C ^ -alkyl, Cj-C.-alkoxy, hydroxy, methylenedioxy, Halogen and / or trifluoromethyl. These substituents can be in the ortho, meta or para position. If two or several substituents are present, these can be the same or different.

Examples of araliphatic acyl groups are cinnamoyl, Chlorinenamoyl, bromocinnamoyl, methoxycinnamoyl, methy1-cinnamoyl, Phenylacetyl, phenoxyacetyl and phenylpropionyl, where the substituents of the cinnamoyl groups can be in the ortho, meta or para position.

Alternatively, although less preferred, R and / or R can represent a heterocyclic acyl radical (e.g. 2-furoyl, 2-thenoyl, 3-thenoyl, nicotinoyl and isonicotinoyl) or a heterocyclically substituted aliphatic acyl radical, (e.g. 2-thienylacetyl, 3-thienylacetyl, 2-Fury! acetyl, 3-furylacetyl, 2-thienylacryloyl, 3-thienylacryloyl, 2-Furylacryloyl and 3-Furylacryloyl) or an alicyclic Acyl radical (preferably cyclopropane carbonyl, cyclobutane carbonyl, cyclopentane carbonyl, cyclohexane carbonyi, cyclohoptane carbonyl, Cyclooctanecarbonyl, Cyclohexanacetyl, 3-cyclohexane propionyl, 4-cyclohexane butyryl and 1-adamantane carbonyl).

- 13 examples of compounds according to the invention are:

ML-236A and MB-53OA-3,8'-diformiate ML-236A and MB-53OA-3,8'-diacetate ML-236A and MB-53OA-3,8'-dipropionate ML-236A and MB-53OA-3,8'-dibutyrate ML-236A and MB-5 3OA-3,8'-diisobutyrate ML-236A and MB-53OA-3,8'-divalerate ML-236A and MB-53OA-3,8'-diisovalerate ML-236A and MB-53OA-3,8'-dipivalate ML-236A and MB-5 30E-3,8'-dihexanoate ML-236A and MB-53OA-3,8'-diheptanoate ML-236A and MB-5 3OA-3,8'-bis (2-methylvalerate) ML-236A and MB-53OA-3,8'-bis (3-methylvalerate) ML-236A and MB-53OA-3,8'-bis (2-ethylbutyrate) ML-236A and MB-5 3OA-3,8'-dioctanoate ML-236A and MB-53OA-3,8'-bis (2-ethylhexanoate) ML-236A and MB-5 3OA-3,8'-dinonanoate M1-236A and MB-53OA-3,8'-diisononanoate ML-236A and MB-53OA-3,8'-diundecanoate ML-236A and MN-530A-3,8'-ditetradecanoate ML-236A and MB-53OA-3,8'-dipentadecanoate ML-236A and MB-53OA-3,8'-dipalmitate ML-236A and MB-5 3OA-3,8'-distearate ML-236A and MB-53OA-3,8'-diisostearate ML-236A and MB-53OA-3,8'-dinonadecanoate ML-236A and MB-53OA-3,8'-dieicosanoate ML-236A and MB-53OA-3,8'-bis (1-adamantane carboxylate) ML-236A and MB-53OA-3,8'-dicyclopropanecarboxylate ML-236A and MB-53OA-3,8'-dicyclobutane carboxylate ML-236A and MB-53OA-3,8'-dicyclopentanecarboxylate ML-236A and MB-53OA-3,8'-dicyclohexane carboxylate ML-236A and MB-5 3OA-3,8'-dicyeloheptane carboxylate ML-236A and MB-53OA-3,8'-dicyclooctane carboxylate ML-236A and MB-53OA-3,8'-bis (cyclohexane acetate) ML-236A and MB-5 3OA-3, 8 '-bis (3-cyclohaxane propionate)

ML-236A and MB-53OA-3,8'-bis (4-cyclohexane butyrate ML-236A and MB-53OA-3,8'-diacrylate ML-236A and MB-5 3OA-3,8'-dipropiolate ML-236A and MB-53OA-3,8'-dicrotonate ML-236A and MB-53OA-3,8'-bis (3-butenoate) ML-236A and MB-5 3OA-3,8'-dimethacrylate ML-236A and MB-53OA-3,8'-bis (2-pentenoate) ML-236A and MB-53OA-3,8'-bis (4-pentenoate) ML-236A and MB-5 3OA-3,8'-digiglate ML-236A and MB-5 3Oa-3,8'-diangelate ML-236A and MB-53OA-3,8'-disenecionate ML-236A and MB-53OA-3,8'-bis (2-heptenoate) ML-236A and MB-53OA-3,8'-bis (2-octenoate) ML-236A and MB-53OA-3,8'-bis (2-nonenoate) ML-236A and MB-53OA-3,8'-dilinoleate ML-236A and MB-53OA-3,8'-dioleate ML-236A and MB-53OA-3,8'-dilinolenate ML-236A and MB-53OA-3,8'-dicinnamate ML-236A and MB-5 3OA-3,8'-bis (o-chlorocinnamate) ML-236A and MB-5 3OA-3,8'-bis (m-chlorocinnamate) ML-236A and MB-5 3OA-3,8'-bis (p-chlorocinnamate) ML-236A and MB-53OA-3,8'-bis (o-bromocinnamate) ML-236A and MB-53OA-3,8'-bis (m-bromocinnamate) ' ML-236A and MB-53OA-3,8'-bis (p-bromocinnamate) ML-236A and MB-53OA-3, 8 '-bis (o-iuethoxycinnamate) ML-236A and MB-53OA-3,8'-bis (m-raethoxycinnamate) ML-236A and MB-53OÄ-3,8'-bis (p-methoxycinnamate) ML-236A and MB-53OA-3,8'-bis (o-methylcinnamate) ML-236A and MB-53OA-3,8'-bis (ra-methylcinnamate) ML-236A and MB-53OA-3,8'-bis (p-methylcinnamate) ML-236A and MB-5 3QA-3,8'-bis (phenyl acetate) ML-236A and MB-5 3OA-3, 8 '-bis (phenoxyacet.it) ML-236A and MB-5 3OA-3,8'-bis (3-phenylpropionate) ML-236A and MB-53OA-3,8'-bis (2-thienyl acetate) ML-236A and MB-53OA-3,8'-bis (2-furylacetate) ML-236A and MB-53OA-3,8'-bis (2-thiophenecarboxylate)

ML-236A and MB-53OA-3,8 ¹ -bis (2-furoate) ML-236A and MB-53OA-3,8'-bis (2-thienyl acrylate) ML-236A and MB-53OA-3,8 ' -bis (2-furylacrylate) ML-236A and MB-53OA-3,8'-bis (3-furoate) ML-236A and MB-53OA-3,8'-dinicotinate ML-236A and MB-53OA-3, 8'-diisonicotinate ML-236A and MB-53OA-3,8'-dibenzoate ML-236A and MB-53OA-3,8'-bis (o-methylbenzoate) ML-236A and MB-53OA-3,8'- bis (m-methylbenzoate) ML-236A and MB-53OA-3,8'-bis (p-methylbenzoate) ML-236A and MB-53OA-3,8'-bis (o-ethylbenzoate) ML-236A and MB- 53OA-3,8'-bis (m-ethylbenzoate) ML-236A and MB-53OA-3,8'-bis (p-ethylbenzoate) ML-236A and MB-53OA-3,8'-bis (o-propylbenzoate ) ML-236A and MB-53OA-3,8'-bis (m-propylbenzoate) ML-236A and MB-53OA-3,8'-bis (p-propylbenzoate) ML-236A and MB-53OA-3,8 '-bis (o-butyl benzoate) ML-236A and MB-5 3OA-3,8'-bis (m-butyl benzoate) ML-236A and MB-53OA-3,8'-bis (p-butyl benzoate) ML-236A and MB-53OA-3,8'-bis (o-methoxybenzoate) ML-236A and MB-53OA-3,8'-bis (m-methoxybenzoate) ML-236A and MB-53OA-3,8'-bis ( p-methoxybenzoate) ML-236A and MB-53OA-3,8'-bis (o-ethoxybenzoate) ML-236A and MB-53OA-3,8'-bis (m-ethoxybenzoate) ML-236A and MB-53OA-3,8'-bis (p-ethoxybenzoate) ML-236A and MB-53OA -3,8'-bis (o-propoxybenzoate) ML-236A and MB-53OA-3,8'-bis (m-propoxybenzoate) ML-236A and MB-53OA-3,8'-bis (p-propoxybenzoate) ML-236A and MB-53OA-3,8'.bis (o-butoxybenzoate) ML-236A and MB-53OA-3,8'.bis (m-butoxybenzoate) ML-236A and MB-53OA-3,8 ' -bis (p-butoxybenzoate) ML-236A and MB-53OA-3,8'-bis (o-hydroxybenzoate) ML-236A and MB-5 3OA-3,8'-bis (m-hydroxybenzoate) ML-23 ( ) A and MB-53OA-3, 8 '-bis (p-hydroxybenzoate :) ML-23f ") A and MB-53OA-3, 8' -bis (2, 3-dirnel: hoxyberr.: Oat)

ML-2 36A and MB-53OA-3,8'-bis (2,4-dimethoxybenzoate) ML-236A and MB-53OA-3,8'-bis (2,5-dimethoxybenzoate) ML-236A and MB-5 3OA-3,8'-bis (2,6-dimethoxybenzoate) ML-236A and MB-53OA-3,8'-bis (2,4,6-trimethoxybenzoate) ML-236A and MB-53OA-3,8'-bis (3,4,5-trimethoxybenzoate) ML-236A and MB-53OA-3,8'-bis (3,4-methylenedioxybenzoate) ML-236A and MB-53OA-3,8'-bis (2,3-methylenedioxybenzoate) ML-236A and MB-53OA-3,8'-bis (o-chlorobenzoate) ML-236A and MB-53OA-3,8'-bis (m-chlorobenzoate) ML-236A and MB-53OA-3,8'.bis (p-chlorobenzoate) ML-236A and MB-53OA-3,8'-bis (o-bromobenzoate) ML-236A and MB-5 3OA-3,8'-bis (m-bromobenzoate) ML-236A and MB-53OA-3,8'-bis (p-bromobenzoate) ML-236A and MB-53OA-3,8'-bis (o-fluorobenzoate) ML-236A and MB-53OA-3,8'-bis (m-fluorobenzoate) ML-236A and MB ^ 53OA-3v, 8'-bis. (P-f luorbenzoate) ML-2 36B and MB-5 3OB acetate

ML-236B and MB-530B propionate ML-2 36B and MB-5 3OB butyrate ML-238B and MB-530B isobutyrate ML-236B and MB-5 3OB-valerate ML-236B and MB-530B-isovalerate ML-236B and MB-5 3OB-pivalate ML-236B and MB-530B-hexanoate ML-236B and MB-530B-heptanoate ML-236B and MB-53OB- (2-ethylvalerate) ML-236B and MB-53OB- (3-methylvalerate) ML-236B and MB-53OB- (2-ethylbutyrate) ML-236B and MB-530B-octanoate ML-236B and MB-530B- {2-ethylhexanoate) ML-236B and MB-530B nonanoate ML-236B and MB-5 30B isononanoate ML-236B and MB-5 30B undecanoate ML-236B and MB-5 30B tetradecanoate ML-2 36B and MB-530B pentadecanoate ML-236B and MB-5 3OB palmitate ML-236B and MB-5 3OB stearate ML-236B and Mß-530B isostearate

ML-236B and MB-530B-nonadecanoate ML-236B and MB-530B-eicosanoate ML-236B and MB-53OB- (1-adamantane carboxylate) ML-236B and MB-SSOB-cyclopropanecarboxylate ML-236B and MB-S.SOB cyclobutane carboxylate ML-2 36B and MB-SSOB cyclopentane carboxylate ML-236B and MB-SSOB cyclohexane carboxylate ML-236B ~ and MB-SSOB-cycloheptane carboxylate ML-236B and MB-SSOB cyclooctane carboxylate ML-236B and MB-530B-cyclohexane acetate ML-236B and MB-53OB- (3-cyclohexane propionate) ML-236B and MB-53OB acrylate ML-236B and MB-530B propiolate ML-236B and MB-530B crotonate ML-236B and MB-SSOB-inethacrylate ML-2 36B and MB-53OB-tiglat ML-236B and MB-53OB-angelat ML-236B and MB-530B-senecionate ML-236B and MB-53OB- (3-butenoate) ML-236B and MB-53OB (2-pentenoate) ML-236B and MB-530B linoleate ML-236B and MN-530B oleate ML-236B and MB-530B linolenate ML-236B and MB-5 3OB-cinnamate ML-2368 and MB-53OB- (o-chlorocinnamate) ML-236B and MB-53OB- (m-chlorocinnamate) ML-236B and MB-53OB- (p-chlorocinnamate) ML-236B and MB-53OB- (o-bromocinnamate) ML-236B and MB-53OB- (m-bromocinnamate) ML-236B and MB-53OB- (p-bromocinnamate) ML-236B and MB-53OB- (o-methoxycinnamate) ML-236B and MB-5 3OB- (m-methoxycinnamate) ML-236B and MB-53OB- (p-methoxycinnamate) ML-236B and MB-53OB- (o-methylcinnamate) ML-23bB and MB-53OB- (m-methylcinnamate) ML-236B and MB-53OB- (p-methylcinnamate)

ML-236B and MB-53OB-phenyl acetate ML-236B and MB-530B phenoxyacetate ML-236B and MB-5 3OB- (3-phenylpropionate) ML-236B and MB-53OB- (2-thienyl acetate) ML-236B and MB-5 3OB- (2-furylacetate) ML-236B and MB-53OB- (2-thiophene carboxylate) ML-236B and MB-5 3OB- (2-furoate) ML-2 36B and MB-5 3OB- (2-thienyl acrylate) ML-236B and MB-5 3OB- (2-furylacrylate) ML-236B and MB-53OB- (3-furoate) ML-236B and MB-5 30B-nicotinate ML-236B and MB-530B isonicotinate ML-236B and MB-5 30B-benzoate ML-236B and MB-5 3OB- (o-methylbenzoate) ML-236B and MB-53OB- (m-methylbenzoate) ML-236B and MB-53OB- (p-methylbenzoate) ML-236B and MB-5 3OB- (o-ethylbenzoate) ML-236B and MB-53OB- (m-ethylbenzoate) ML-236B and MB-5 3OB- (p-ethylbenzoate) ML-236B and MB-53OB- (o-propylbenzoate) ML-236B and MB-53OB- (m-propylbenzoate) ML-236B and MB-53OB- (p-propylbenzoate) ML-236B and MB-5 30B- {o-butylbenzoate) ML-236B and MB-53OB- (m-butylbenzoate) ML-236B and MB-5 3OB- (p-butylbenzoate) ML-236B and MB-53OB- (o-methoxybenzoate) ML-2 36B and MB-530B- (m-methoxybenzoate) ML-236B and MB-53OB- (p-m.ethoxybenzoate) ML-236B and MB-5 3OB- (o-ethoxybenzoate) ML-236B and MB-5 3OB- (m-ethoxybenzoate) ML-236B and MB-53OB- (p-ethoxybenzoate) ML-236B and MB-53OB- (o-propoxybenzoate) ML-236B and MB-53OB- (m-propoxybenzoate) ML-2 36B and MB-5 3OB- (p-propoxybenzoate) ML-236B and MB-53OB- (o-butoxybenzoate) ML-236B and MB-53OB- (m-butoxybenzoate)

ML-236B and MB-53OB- (p-butoxybenzoate) ML-236B and MB-236B- (o-hydroxybenzoate) ML-236B and MB-53OB- (m-hydroxybenzoate) ML-236B and MB-53OB- (p-hydroxybenzoate) ML-236B and MB-53OB- (2,3-dimethoxybenzoate) ML-236B and MB-53OB- (2,4-dimethoxybenzoate) ML-236B and MB-53OB- (2,5-dimethoxybenzoate) ML-236B and MB-5 3OB- (2,6-dimethoxybenzoate) ML-236B and MB-53OB- (2,4,6-trimethoxybenzoate) ML-236B and MB-53OB- (3,4,5-trimethoxybenzoate) ML-236B and MB-53OB- (3,4-methylenedioxybenzoate) ML-2 36B and MB-53OB- (2,3-methyledioxybenzoate) ML-236B and MB-53OB- (o-chlorobenzoate) ML-236B and MB-53OB- (m-chlorobenzoate) ML-236B and MB-53OB- (p-chlorobenzoate) ML-236B and MB-53OB- (o-bromobenzoate) ML-236B and MB-53OB- (m-bromobenzoate) ML-236B and MB-53OB- (p-bromobenzoate) ML-236B and MB-53OB- (o-fluorobenzoate) ML-236B and MB-53OB- (ra-fluorobenzoate) ML-236B and MB-53OB- (p-fluorobenzoate)

The above are only the diesters of ML-236A and MB-5 30A listed, but the invention also includes the corresponding 3-monoesters and 8'-monoesters. From these connections the following are particularly preferred:

ML-236A - δ'-butyrate

ML-2 36A - 8'-isobutyrate ML-236A - δ'-isovalerate MB-53OB - 8'-butyrate

MB-53OB - 8'-isovalerate ML-236A - 8 '- (4-pentenoate) ML-236A - 3,8'-diacetate ML-236A - 3,8'-dibutyrate and ML-2: 6A - 3,8'-di (4-pentenoate).

MB-53OA, one of the compounds of the invention, can by cultivating an MB-53OA producing microorganism belonging to the genus Monascus, preferably a strain Monascus ruber and in particular Monascus ruber SANK 15177 can be produced. This strain was registered on April 27, 1979 under the entry no. FERM 4956 at the Fermentation Research Institute, Agency of Industrial Science and Technology, Ministry of International Trade and Industry, Japan, as well as on January 25, 1980 under the entrance no. NRRL 12081 at the Agricultural Research Service Culture Collection, Northern Regional Research Laboratory, Peoria, Illinois, USA. The morphology and physiology of this strain are detailed described in USSN 137 821 of April 4, 1980.

The desired MB-53OA can be obtained by growing the selected one Microorganism under aerobic conditions in a culture broth according to methods known per se for cultivating fungi and other microorganisms. For example, you can first see the selected Monascus strain in culture in a suitable medium, then collect the cultured microorganisms and inoculate them into another culture medium and continue breeding there to obtain the desired MB-5 3OA to obtain. The culture medium used for the multiplication of the microorganism and the culture medium used for the production of MB-5 30A can be the same or different. Any culture media known for cultivating fungi can be used be used, provided it contains the known necessary nutrients, especially assimilable carbon and Nitrogen sources. Examples of suitable assimilable carbon sources are glucose, maltose, dextrin, starch, Lactose, sucrose and glycerin. Of these, glucose, glycerin and starch are particularly preferred for the production of MB-53OA. Examples of suitable assimilable nitrogen sources are peptone, meat extract, yeast, yeast extract, soy flour, Peanut meal, corn steep liquor, rice bran and inorganic nitrogen sources, of which are corn steep liquor and

112566

Peptone is particularly preferred. For the production of MB-5 3OA Inorganic SaIae can optionally be added to the culture medium and / or metal salts are added. In addition, small amounts of heavy metals can optionally be added.

The microorganism is preferably grown under aerobic conditions using known culture methods, e.g. as a festival culture, shaking culture or aerated stirring culture. The microorganisms grow over a wide temperature range, e.g. about 7 to 40 C, but for the production of MB-53OA a growth temperature of 20 am is required 30 ° C is particularly preferred.

During the cultivation of the microorganism, the production of MB-5 3OA can be determined by taking samples from the culture medium and measuring the physiological activity of the medium can be monitored by known methods. The culture can then be continued until sufficient MB-53OA has accumulated in the culture medium, whereupon the MB-53OA can be removed by a appropriate combination of insulation techniques, considering its physical and chemical properties are selected, isolated from the culture medium and the tissues (mycelium) of the microorganism and recovered. For example one or more of the following isolation methods can be used:

Extraction of the liquid from the culture broth with a hydrophilic solvent (e.g. diethyl ether, ethyl acetate, Chloroform or benzene); Extraction of the organism with a hydrophilic solvent (e.g. acetone or an alcohol); Concentration, e.g., evaporation of part or all of the solvent under reduced pressure; Dissolve in one more polar solvents (e.g. acetone or an alcohol); Separate the impurities with a less polar one Solvents (e.g. petroleum ether or hexane); Gel filtration, for example with Sephadex (product of Pharmacia Co. Limited, USA);

Absorption chromatography with activated carbon or silica gel
and similar methods. By using an appropriate combination of these methods, the desired MB-53OA
isolate from the culture broth as a pure substance.

In a similar manner, the other known starting materials of the acylation process according to the invention, ie ML-236A, ML-236B and MB-53OB, can be obtained from culture media containing the respective microorganism by the above methods or by the methods described in US Pat
3 983 140, USSN 121 515 dated 02/14/1980 or the
USSN 137 821 of 04/04/1980 described methods.

The acylated derivatives according to the invention can be prepared from ML-236A, ML-236B, MB-5 3OA, or MB-5 3OB using one of the following methods getting produced.

Procedure 1

ML-236A, ML-236B, MB-53OA or ML-53OB are reacted with a suitable acid chloride or acid anhydride to give the desired acyl derivative. The reaction is preferably carried out in the presence of a base (which binds the acid), preferably
an organic alkali such as pyridine, triethylamine, N, N-dimethylaminopyridine, N-methylpyrrolidone or N-methylmorpholine. The reaction is preferably carried out in the presence of a solvent, the choice of which is not critical as long as it does not adversely affect the reaction. Suitable solvents are, for example, chloroform, methylene chloride and dimethyl ether. In some cases it is possible to carry out the reaction using an excess of one of the reactants
or the base as a solvent. The reaction succeeds over a wide temperature range, but it is usually preferred for reaction control to use a relatively low temperature, for example -20 ° C. to room temperature, especially -20 ° C. to ⁰ ° C. If desired, can. however, higher temperatures can also be used.

- 23 Procedure 2

A carboxylic acid is reacted with a chlorocarbonic acid ester or a sulfonic acid chloride in the presence of a base, e.g. of the organic amines mentioned above, converted to a mixed acid anhydride, which can then be mixed with ML-236A, ML-236B, MB-53OA or MB-53OB implements. The reaction takes place preferably in the presence of a solvent, the choice of which is not critical, as long as it does not adversely affect the reaction influenced. Suitable solvents are, for example, diethyl ether, benzene, chloroform and methylene chloride. The implementation takes place within a wide temperature range, e.g. -20 ° C to room temperature, in particular -20 to 0 C.

Procedure 3

ML-236A, ML-236B, MB-53OA or MB-53OB are mixed with a carboxylic acid and a diazoalkyl dicarboxylate in the presence of, for example, dicyclohexylcarbodiimide, triphenylphosphine or dimethyl phosphoric acid amide implemented. The reaction is preferably carried out in the presence of a solvent, the selection thereof is not critical as long as it does not adversely affect the reaction. Suitable solvents are e.g. chloroform, Methylene chloride, benzene and diethyl ether.

The above reactions are usually complete within 30 minutes to 5 hours, however each depends required reaction time depends on the reactants and the reaction temperature. After the implementation is complete, the the desired product is separated off from the reaction mixture in the usual way, e.g. by evaporating off the solvent a solution of the desired product (this solution can simply be the reaction mixture or a solution created by Extraction of the reaction mixture with an organic solvent was obtained), the solution given case κ was washed and dried beforehand. The pro-

the product can be cleaned in the usual way, e.g. by column chromatography, Thin layer chromatography and / or recrystallization.

When the starting material for the acylation reaction contains two hydroxyl groups, i.e. in the case of ML-236A or MB-53OA, the above reactions can give the 3-monoester, the 3,8'-diester, the 8'-monoester, or mixtures thereof. The nature of the product obtained may depend on the amounts of the reactants, the reaction temperature and other reaction conditions are influenced, it being assumed, for reasons not yet cleared, that the 3-monoester is preferred is formed, followed by the 3,8'-diester and the 8'-monoester. For each individual reaction, the person skilled in the art can however, it is easy to determine the optimal conditions for producing the particular desired product. Generally will get the following result:

The 3-Monoester and / or 8'-Monoester are mainly formed when halide carrying out the reaction using an acid anhydride as acylating agent or in the presence of an organic base at a temperature of -20 to 0 ⁰ C. The amount of the acylating agent, preferably the acid halide, is preferably about 1 equivalent per equivalent of ML-236A, ML-236B, MB-5 30A, or MB-53OB.

The 3,8'-diester is mainly formed when one is used as Acylating agent an acid anhydride or halide in an amount of at least 2 equivalents per equivalent of ML-236A, ML-2 36B, MB-5 30A or MB-53OB begins and the acylation carried out in the presence of an organic base at a temperature above room temperature.

The compounds according to the invention have a specific inhibitory effect against 2-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), which is the rate-limiting enzyme in the biosynthesis of cholesterol. The inhibiting action of some compounds according to the invention in cholesterol biosynthesis is shown in the table below based on their I ₁ . Values (concentration in μΐη / πιΐ, which causes a 50 percent inhibition of cholesterol biosynthesis). The measurement is carried out according to the method of Knaus et al., J. Biol.Chem. Vol. 234, p. 2835 (1959).

Tabel

^R i ^R 2 ^R 3 I ₅₀ (ng / ml) Acetyl H H 0.21 Butyryl H H O, 10 Isobutyryl H H O, 29 Butyryl H CH ₃ O, 39 4-pentenoyl H H 0.17 H Butyryl H O, O17 H Butyryl CH ₃ O, O21 H Isobutyryl H 0.061 H Isovaleryl H 0.039 H Isovaleryl CH ₃ 0.026 H 4-pentenoyl H O, O96 H Hexanoyl H 0.13 H Octanoyl H 0.34 H Palmityl H 0.24 H Linolyl H O, 16 Acetyl Acetyl H 0.12 Butyryl Butyryl H 0.065 4-pentenoyl 4-pentenoyl H O, 12

The preparation of the compounds according to the invention is in explained in the following examples. The manufacture and properties of MB-53OB (Monacolin K) used as the starting material Used in some examples are detailed in USSN 121 515 dated 02/14/1980 and US Pat USSN 137 821 of 04.04.198O described. The manufacture and the properties of ML-236A and ML-236B are in the U.S. Patent 3,983,140.

example 1
Manufacture of MB-53OA

300 liters of a culture medium that has a pH of 5.5 before sterilization and contains 5% w / v glucose, 0.5% w / v corn squeegee liquid, 2% w / v peptone (Kyokuto brand from Kyokuto Seiyaku KK, Japan) and containing 0.5% ammonium chloride are placed in a 600 liter fermenter and inoculated with a culture of Monascus ruber SANK 15177 (FERM 49 56, NRRL 12081). The microorganism is grown 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 through a filter press, a filtrate and a filter cake being obtained which consists of moist microorganism cells. The filtrate is adjusted to pH by adding 6N hydrochloric acid set of 3.0 and then extracted with 400 liters of ethyl acetate. The extract (about 400 liters) is evaporated under reduced pressure, dried over sodium sulfate and then added evaporated to dryness to give about 60 g of an oily product. This is done with ethylcyclohexane and washed with hexane, whereupon the residue (20 g) is chromatographed using a liquid chromatograph for large volume samples (System 500 for liquid chromatography from Waters Co., USA.) and KIu Loren rail:

60% v / v aqueous methanol separates. The fractions with a chromatographic retention time of 6 minutes will be collected and evaporated under reduced pressure to give 100 mg of the desired MB-53OA as an oily product will. The oily MB-53OA is made from acetone / The thy lether recrystallized to give 57 mg of the desired product in the form of colorless needles with the following Characteristics:

1. Melting point: 92-93 ° C.

2. Elemental analysis for C _ig K "0 .: CH

calc .: ■ 69.76%; 8.68% found: 71.22%; 8.81%.

3. Molecular weight: 320 (mass analysis)

4. Molecular formula ·: C. "!!" "O. .

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, ethyl acetate, chloroform and carbon tetrachloride; soluble in benzene; insoluble in hexane and petroleum ether.

9. Coloring reaction: In thin layer chromatography on silica gel, development occurs at 50% v / v Sulfuric acid turns pink.

10. Inhibitory effect in cholesterol biosynthesis: With a Concentration of 0.04 μΐη / ml will result in 50% inhibition of cholesterol synthesis was observed in the rat liver.

Example 2
ML-236A-3-acetate

918 mg of ML-236A and 0.36 ml of pyridine are dissolved in 10 ml of methylene chloride and treated dropwise at a temperature from -20 to -10 ⁰ C with 1.0 ml of acetic anhydride. When the reaction has ended, water is added to the reaction mixture, the methylene chloride layer is separated off, washed with water and dried over sodium sulfate. The residue obtained by evaporating the methylene chloride is separated by column chromatography on silica gel (10 g) and recrystallized from diethyl ether, 780 mg of the desired product being obtained, mp 138 to 139 ^° C.

Elemental analysis ^{for C 2o H} 28 ° 5 ^{: CH}

calc .: 68.97%; 8.05%. found: 68.99%; 8.01%.

-Spectrum (CDCl-) 6 ppm: 1.98 (3H, s); 5.10 (1H, m)

NMRp (l) ppm:

IR spectrum (Nujol) υ cm: 3400, 1740.

Max

Example 3
ML-236A-3-butyrate

1 ml of butyranhydride is added dropwise to a solution of 918 mg of ML-236A in 5 ml of pyridine. After the mixture bo.i. Was left to stand at room temperature, water is added and the mixture is extracted with diethyl ether. The ether layer is with a saturated aqueous sodium bicarbonate solution, 1 N HCl and water and then washed over sodium sulfate dried. The residue obtained by evaporating the diethyl ether is separated by chromatography on silica gel and thereby gives 930 mg of the desired product.

Elemental analysis for ^C 22 ^H 32 ° 5 ^{: CH}

calc .: 70.21%; 8.51% found: 69.96%; 8.69%.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) rpm: 0.95 (3H, t); 4.27 (1H, m); 5.32 (1H, m).

IR spectrum (film) v _mnv cm " ¹ : 3480, 1740.

Iu el λ

Example 4 ML-236A-3-butyrate

According to Example 2, 853 mg of the desired product, which has the same properties as the product of Example 3 made from 918 mg of ML-236A and 0.32 ml of butyryl chloride.

Example 5 ML- 236A-3-isobutyrate

According to Example 2, 841 mg of the desired product are prepared from 918 mg of ML-236A and 0.32 ml of isobutyryl chloride.

Elemental analysis for ^C ₂ 2 ^H 32 ° 5 ^{: CH}

ber .:. 70.21%; 8.51%.

found: 69.84%; 8.32%.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm: 1.17 (6H, d); 4.27 (1H, m);

5.25 (1H, m).

IR spectrum (film) ν cm " ¹ : 3440, 1730, 1720.

Max

Example 6

According to Example 2, 834 mg of the desired product are prepared from 918 mg of ML-236A and 0.39 ml of 4-pentenoyl chloride.

Elemental analysis for C ₇₃ H ₃₂ O-: CH

calc .: 71.13 %; 8.25% found: 71.43%; 8.00%.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) 5 ppm: 4.27 (1H, m); 4.8 - 6.2 (7H, m).

IR spectrum (film) v _max cm " ¹ : 3400, 1730, 1640.

Example 7

ML-236A-3-isova lerat

According to Example 2, 894 mg of the desired product are prepared from 918 mg of ML-236A and 0.40 ml of isovaleryl chloride.

Elemental analysis for C ₇₃ H ₃₄ O ₁ -: CH

calc .: 70.77%; 8.72%.

found: 70.61%; 8.80%.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ pp _m : 0.95 (6H, d); 4.23 (1H, m);

5.27 (1H, m).

IR spectrum (film) υ cm ": 3460, 1740.

Example 8

ML-236A-3-hexanoate

(M.p. 70 to 72 ° C) from 2.70 g ML-236A and 1.36 ml hexanoyl

According to Example 2, 2.90 g of the desired product (melting point 70 to 72 ° C.) are obtained
Chloride produced.

Elemental analysis for

H ,, 0 _c : 71 C. %; 8th II %. ber .: 71 , 29 %; 8th , 91 %. found : , 04 , 79

Example 9 ML-236A-3-octanoate

According to Example 2, 690 mg of the desired product are prepared from 612 mg of ML-236A and 0.54 ml of octanoyl chloride.

Elemental ^{analysis for c} ₂ g ^H 40 ° 5 ^{: CH}

calc .: 7 2.22%; 9.26%: found: 72.45%; 9.12%.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm: 0.88 (3H, br t); 4.28 (1H, πι); 5.33 (1H, m).

IR spectrum (film) ν cm ": 3450, 1735.

ItIcLJC

Example 10 ML-236A-3 palmitate

According to Example 2, 749 mg of the desired product are prepared from 827 mg of ML-236A and 0.82 g of palmitoyl chloride.

Elemental analysis for C ₃₄ H ₅₆ O: CH

calc .: 75.00%; 10.29%.

found: 74.89%; 10.35%.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δρρπι: 0.90 (3H, br t); 1.27 (24H, br s);

4.27 (1H, m); 5.32 (1H, m).

IR spectrum (film) ½ cm " ¹ : 3460, 1735.

Max

Example 11 ML-236A-3 linoleate

According to Example 2, 897 mg of the desired product are prepared from 918 mg of ML-236A and 1.03 g of linoleyl chloride.

Elemental analysis for ^C 3g ^H 5g ° 5 ^{: c H}

calc .: 76.06%; 9.86%: found: 76.24%; 9.96%.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) 6 ppm: 0.90 (3H, br. T); 1.32 (18H, br s);

4.27 (1H ₇ m). ·

IR spectrum (film) ν cm " ¹ : 3460, 1740.

ΠΙ 3.x

Example 12 MB-5 3 OA-3-butyrate

According to Example 2, 250 mg of the desired product are prepared from 300 mg of MB-53OA and 0.47 ml of butyryl chloride.

Elemental analysis for C ₂₃ HO ₅ : CH

calc .: 70.77%; . 8.72%. "Found: 70.60%; 8.89%.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm: 0.90 (3H, t); 4.17 (1H, m); 5.22 (1H, m).

IR spectrum (film) V ^ cm ": 3450, 1730.

Example 13 MB-530A-3 isovalerate

According to Example 2, 235 mg of the desired product are prepared from 320 mg of MB-53OA and 0.47 ml of isovaleryl chloride.

Elemental ^{analysis for C} 24 ^H 3fi ° 5 ^:

calc .: 71.29%; 8.91%.

found: 71.20%; 8.87%.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm: 0.89 (6H, d); 4.16 (1H, m); 5.22 (1H, m).
IR spectrum (Nujol) ν cm " ¹ : 3510, 1730, 1710.

Example 14
MB-5 3 OA-3-hexanoate

According to Example 2, 410 mg of the desired product are prepared from 420 mg of MB-53OA and 0.21 ml of hexanoyl chloride.

Elemental analysis for C ₃₅ H "0-: CH

calc .: 71.77%; 9.09%

found: 71.55%; 9.19%.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δρρπι: 0.88 (3H, br t); 4.19 (1H, m);

5.25 (1H, m).

IR spectrum (film) υ cm ": 3400, 1730. ^ max

Example 15
MB-5 30A-3-octanoate

According to Example 2, 340 mg of the desired product are obtained 322 mg MB-53OA and 0.28 ml octanoyl chloride prepared:

Elemental analysis for C ₂₇ H ₄ ^ O ₁ -: CH

calc .: 72.65%; 9.42%.

found: 72.44%; 9.34%.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm: 0.84 (3H, br t); 1.21 (12H, br s);

4.18 (1H, m); 5.23 (1H, m).

IR spectrum (film) v ^ "cm" ¹ : 3400, 1730.

Example 16
ML-2 3 6 A-8'-butyrate

918 mg of ML-236A and 0.36 ml of pyridine are dissolved in 10 ml of methylene chloride. Butyryl chloride is added dropwise to the solution, which has been cooled to 0 ^{° C.} After the reaction has ended, water is added to the reaction mixture, the methylene chloride layer is separated off, washed with water and dried over

■ sodium sulfate. The through. Evaporation of the methylene chloride obtained The residue is separated by column chromatography on silica gel (10 g). By recrystallization from diethyl ether 395 mg of the desired product are obtained, P. 124 to 125 ° C.

Elemental analysis for ^ 22 ^Η 32 ° ^Γ : C II

calc .: 70.21%; 8.51%. found: 70.25%; 8.50%.

Nuclear Magnetic Resonance Spectrum (CDCl3) δ ppm: 0.95 (3H, t); 4.42 (1H, m), 5.43 (1H, m).

IR spectrum (Nujol) ν cm " ¹ : 3400, 1730, 1710.

JUdLX

Example 17 ML-236A-8'-isobutyrate

According to Example 16, 100 mg of the desired product made from 285 mg of ML-236A and 0.11 ml of isobutyryl chloride.

Elemental analysis for ^C 22 ^H 32 ° 5 ^{: CH}

calc .: 70.21%; 8.51%. found: 70.05%; 8.67%.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm: 1.14 (6H, d); 4.35 (1H, m); 5.32 (1H, m).

IR spectrum (film) ν cm " ¹ : 3400, 1730, 1700.

ΓΩ.3.Χ

Example 18 ML-236A-8 '- (4-pentenoate)

According to Example 16, 370 mg of the desired product are prepared from 918 mg of ML-236A and 0.39 ml of 4-pentenoyl chloride.

Elemental analysis for C.-H ^ -Oj-: C H

calc .: 71.13%; 8.25 S. found: 70.82%; 8.33%.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm: 4.14 (1H, 'm); 4.8 - 6.2 (8H, m).

IR spectrum (film) v _{m = v} cm " ¹ : 3400, 1730.

Max

Example 19 ML-236A-8'-isovalerate

According to Example 16, 365 mg of the desired product are prepared from 918 mg of ML-236A and 0.47 ml of isovaleryl chloride.

Elemental analysis for C ₃₃ H ₃₄ O ₅ : CH

calc .: 70.77%; 8.72%. found: 70.59%; 8.90%.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm: 0.93 (6H, d), -4.35 (1H, m), -5.35 (1H, m).

IR spectrum (film) ν. cm " ¹ : 3430, 1730, 1710.

ill 3, X

Example 20 ML-236A-8'-hexanoate

According to Example 16, 408 mg of the desired product are prepared from 918 mg of ML.-236A and 0.46 ml of hexanoyl chloride.

Elemental analysis for ^C 24 ^H 36 ° 5 ^: "CH

calc .: 71.29%; 8.91%. found: 71.07%; 9.01%.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm: 0.87 (3H, t); 4.32 (1H, m); 5.32 (1H, m).

IR spectrum (film) ν cm " ¹ : 3400, 1720, 1710.

Max

Example 21 ML-236A-8'-octanoab

According to Example 16, 462 mg of the desired product are prepared from 918 mg of ML-236A and 0.54 ml of octanoyl chloride.

Elemental ^{analysis for C} 26 ^H 4O ° 5 ^{: CH}

calc .: 72.22%; 9.26%.

found: 72.04%; 9.10%.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm: 0.88 (3H, br t); 1.28 (12ίΙ, br s);

4.42 (1H, m); 5.42 (1H, m).

IR spectrum (film) ν cm " ¹ : 3470, 1735.

ITlclX

Example 22 ML-236A-8'-palmitate

According to Example 16, 490 mg of the desired product are prepared from 918 mg of ML-236A and 640 mg of palmitoyl chloride.

Elemental analysis for C ₃₄ H ₅ OO ₅ : CH

calc .: 74.73%; 10.62%.

found: 74.56%; 10.78%.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm: 0.88 (3H, br t); 1.28 (24H, br s);

4.38 (1H, m); 5.40 (1H, m).

IR spectrum (film) ν cm " ¹ : 3450, 1735.

Example 23 ML-236A-8'-linoleate

According to Example 16 there are 415 mg of the desired product made from 918 ml ML-236A and 1.0 g linoleyl chloride.

Elemental analysis for C ₃₆ H ₅₆ O ₅ : CH

calc .: 76.06%; 9.86%.

found: 76.23%; 10.03%.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm: 0.90 (3H, br t); 1.32 (18H, br s);

4.40 (1H, m); 5.2 - 5.5 (5H, m).

IR spectrum (film) ν cm " ¹ : 3440, 1735.

ITl clX

Example 24 MB-5 3OA-8'-butyrate

According to Example 16, 154 mg of the desired product are prepared from 309 mg of MB-53OA and 0.16 ml of butyryl chloride.

Elemental analysis for C ₃₃ H .O ₅ : CH

calc .: 70.77%; 8.72%.

found: 70.58%; 8.61%.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) rpm: 0.90 (3H, t); 4.17 (1H, m);

5.22 (1H, m).

IR spectrum (film) ν cm " ¹ : 3450, 1730.

Max

Example 25 MB-53OA-8'-isovalerate

According to Example 16, 109 mg of the desired product are prepared from 308 mg of MB-53OA and 0.12 ml of isovaleryl chloride.

Elemental analysis for ^C 24 ^H 36 ° 5 ^{: CH}

calc .: 71.29%; 8.91%.

found: 71.17%; 8.69%.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm: 0.88 (6H, d); 4.15 (1H, m);

5.22 (1H, m).

IR spectrum (film) ν cm " ¹ : 3420, 1730.

Max

Example 26 MB-53OA-8'-hexanoate

According to Example 16, 87 mg of the desired product are prepared from 308 mg of MB-53OA and 0.15 ml of hexanoyl chloride.

Elemental analysis for. C-cH ^ O,.: C H

calc .: 71.77%; 9.09%.

found: 71.95%; 9.17%.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm: 0.90 (3H, t); 4.33 (1H, m),

5.33 (1H, m).

IR spectrum (film) ν cm " ¹ : 3440, 1735.

Max

Example 27

MB-53OA-8'-octanoa b

According to Example 16, 96 mg of the desired product are prepared from 304 mg of MB-53OA and 0.11 ml of octanoyl chloride.

Elemental analysis for Cp ₇ H ^ ^ Oc. '· ^ - ^

calc .: 72.65%; 9.42%.

found: 72.52%; 9.50%.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm: 0.85 (3H, br t); 1.22 (12H, br s);

4.19 (1H, m); 5.23 (1H, m).

IR spectrum (film) ν cm " ¹ : 3400, 1735. ^ ' max

Example 28 ML-236A-3,8'-diacetate

According to Example 3, 914 mg of the desired product are obtained made from 918 mg ML-236A, 5 ml pyridine and 1 ml acetic anhydride.

Elemental ^{analysis for c} ₂ 2 ^H 3O ° 6 ^{: CH}

calc .: 67.69%; 7.69%.

found: 67.44%; 7.79%.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm: 1.89 (6H, s); 5.10 (2H, m).

IR spectrum (film) ν cm " ¹ : 1735, 1250, 11701

ms χ

Example 29
ML-236E-3,8'-dibutyrate

306 mg of ML-236A and 0.5 ml of pyridine are dissolved in 3 ml of methylene chloride dissolved, whereupon the resulting solution is treated with 0.5 ml of butyryl chloride while cooling with ice. The mixture is stirred for 1 hour at room temperature and then processed according to Example 2 further. The residue obtained gives on chromatography, 384 mg of the desired product.

Elemental analysis for C ", H_" O _fi : CH

calc .: 69.96%; 8.52%. found: 70.14%; 8.31 %.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm: 0.93 (6H, t); 5.2 - 5.5 (2H, m).

IR spectrum (film) ν cm " ¹ : 1735, 1250, 1175.

Example 30
ML-236A-3,8'-bis (4-pentenoate)

According to Example 29, 405 mg of the desired product are obtained from 306 mg of ML-236A, 0.5 ml of pyridine and 0.4 ml of 4-pentenoyl chloride manufactured.

Elemental ^{analysis for C} 28 ^H t8 ° 6 ^{: CH}

calc .: 71.48%; 8.09%. found: 71.25%; 8.30%.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm: 4.8-6.2 (11H, m). 'IR spectrum (film) ν cm " ¹ : 1735, 1640, 1460, 1240, 1170.

Example 31
ML-2 36A-3,8'-dioctanoate
According to Example 29, 1.7 g of the desired product are obtained

- Prepared 41,918 mg of ML-236A and 1.4 ml of octanoyl chloride.

Elemental analysis for C_, H _C .O: CH

calc .: 73.12%; 9.68%. found: 72.95%; 9.79%.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm: 0.88 (6H, br t); 1.32 (24H, br s); 5.2 - 5.5 (2H, m).

IR spectrum (film) ν cm " ¹ : 1735, 1460, 1250, 1165.

ItI 3. X

Example 32 ML-236A-3,8'-dipalmitate

According to Example 29, 1.0 g of the desired product is prepared from 415 mg of ML-236A and 0.71 ml of palmitoyl chloride.

Elemental analysis for C ₅₀ Ho ₆ O ₁ -: CH

calc .: 76.73%; 11.00%. found: 76.99%; 10.81%.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm: 0.87 (6H, br t); 1.25 (52H, br s); 5.2 - 5.5 (2H, m).

IR spectrum (film) ν. cm ": 1735, 1460.

Example 33 ML-236A 3,8'-dilinoleate

According to Example 29, 804 mg of the desired product are prepared from 306 mg of ML-236A and 0.6 ml of linoleyl chloride.

Elemental analysis for C ₅₄ Hn ^ O ₆ : CH

calc .: 78.07%; 10.36%. found: 78.30%: 10.19%

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm: 0.90 (6H, br t) 1.30 (36H, br s); 5.1 - 6.2 (13H, m).

IR spectrum (film) ν cm " ¹ : 1740, 1460, 1240, 1170.

IQcL X

Example 34 MB-5 30A-3,8'-dihexanoate

According to Example 29, 440 mg of the desired product are prepared from 330 mg of MB-53OA and 0.5 ml of hexanoyl chloride.

Elemental analysis ^{for C 3o H} 4R ° 6 ^{: CH}

calc .: 71.43%; 9.52%.

found: 71.58%; 9.30%.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm: 0.86 (3H, br t); 0.91 (3H, br t);

5.0 - 6.1 (5H, m).

IR spectrum (film) v cm ": 1730.

^c max

Example 35 MB-5 30A-3,8'-dioctanoate

According to Example 29, 498 mg of the desired product, made from 330 mg of MB-53OA, 0.5 ml of pyridine and 0.5 ml of octanoyl chloride.

Elemental analysis for C ₃₄ H ₅₆ O ₆ : CH

calc .: 72.85%; 10.00%.

found: 72.58%; 10.18%.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm: 0.82 (3H, br t), -0.91 (3H, br m);

5.0 - 6.1 (5H, m).

IR spectrum (film) v cm " ¹ : 1730. ^ max

Example 36 ML-236B acetate

7.8 g of ML-236B are dissolved in 10 ml of dry pyridine, and 4.5 ml of distilled acetic anhydride are added. The reaction mixture is heated to 40 to 45 ° C. for 1 hour while stirring.

The reaction mixture is then poured into ice water acidified with hydrochloric acid and extracted with benzene. The benzene layer is washed with water and dried over sodium sulfate. That obtained by evaporation of the solvent Oily product is separated by chromatography on silica gel with benzene / ethyl acetate as the eluent and this gives 7.3 g of ML-236B acetate as an oily product. This is recrystallized from aqueous ethanol and gives 6.6 g of ML-236B acetate in the form of white crystals, mp 48 to 51 ° C.

Elemental analysis for C ₃₅ H ^ ₆ O ,: CH

calc .: 69.44%; 8.33%.

found: 69.35%; 8.50%.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm: 6.05 (1H, d); 5.80 (1H, dd);

2.8 (2H, d); 2.1 (3H, s).

IR spectrum (KBr) ν cm " ¹ : 1740, 1710.

Max

Example 37
ML-236B benzoate

7.8 g of ML-236B are dissolved in 20 ml of dry pyridine, and 4.2 g of benzoyl chloride are added while cooling with ice. The mixture is stirred for 15 hours at room temperature, then poured into ice water acidified with hydrochloric acid and with benzene extracted. The benzene layer is washed with water, dried over sodium sulfate and under reduced pressure evaporated. The oily concentrate obtained is purified by chromatography on silica gel with benzene / ethyl acetate Eluent separated and purified. Recrystallization from diethyl ether / hexane gives 9.1 g of ML-236B-benzoate in Form of white crystals, m.p. 102 to 104 ° C.

Elemental analysis for ^C 3O ^H 38 ° 6 ^: 73 C. 7th H ber .: 72 , 00%; 7th , 70 found : , 81 ft; , 75

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm: 7.2 (5H, m); 6.10 (1H, d);

5.82 (1H, d); 2.82 (2H, d).

IR spectrum (paraffin oil) v _{ra => v} cm " ¹ : 1745, 1708

Example 38
ML-236B pivaloate

7.8 g of ML-236B are dissolved in 20 ml of dry pyridine and 3.6 g of pivaloyl chloride were added while cooling with ice. The mixture is stirred for 1 hour at room temperature and then in Poured ice water acidified with hydrochloric acid. The reaction product is extracted with benzene, whereupon the benzene extract is obtained Washed with water, dried over sodium sulfate and concentrated under reduced pressure. The oily concentrate will purified by chromatography on silica gel. Recrystallization from aqueous ethanol gives 4.9 g ML-236B pivaloate in the form of white crystals, m.p. 104 to 105 ° C.

Elemental analysis for

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) 6 ppm: 6.00 (1H, d), 5.93 (1H, dd); 5.52 (1H, m); 5.22 (2H, m); 4.38 (1H, m); 2.63 (2H, d); 1.14 (9H, s).

IR spectrum (paraffin oil) ν cm " ¹ : '1735, 1720.

Max

Example 39
ML-236 B-phenoxyacetate

7.8 g of ML-236B are dissolved in 20 ml of dry pyridine and 5.1 g of phenoxyacetyl chloride were added while cooling with ice. The mixture is stirred at room temperature for 1 hour and then poured into ice water acidified with hydrochloric acid. The reaction product is extracted with ethyl acetate, whereupon the Wash the extract with water, dry over sodium sulfate and

42 6 ^: 70 C. 8th H ber .: 70 , 55%; 8th , 92%. found: , 53%; , 86%.

constricts under reduced pressure. The oily concentrate is purified by chromatography on silica gel with a solvent system separated from hexane, diethyl ether and ethyl acetate and cleaned. Recrystallization from aqueous ethanol gives 2.5 g of ML-236B-phenoxyacetate in the form of white Crystals, P. 42 to 44 ° C.

Elemental analysis for C ^ ₁ H ₄₀ O ₇ : CH

calc .: 70.97%; 7.69%. found: 70.89%; 7.68%.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm: 6.6-7.4 (5H, m); 5.86 (1H, d); 5.65 (1H, dd); 4.51 (2H, s); 4.15 (1H, m).

IR spectrum (paraffin oil) ν cm ": 174Ο (shoulder), 1725.

ICl 3.X

Example 40 MB-53OB acetate

0.081 g of MB-53OB are dissolved in 0.2 ml of dry pyridine and 0.05 ml of acetic anhydride are added. The mixture is stirred for 2 hours at room temperature, then in hydrochloric acid Poured acidified salt water and extracted with benzene. The benzene layer is washed with water over sodium sulfate dried and concentrated under reduced pressure. The oily concentrate is placed on a silica gel column (Rover column from Merck Co., USA) separated and cleaned. Recrystallization from diethyl ether / hexane gives 0.076 g MB-53OB acetate in the form of white needles, m.p. 92 to 93 ° C.

Elemental analysis for ^C 26 ^H 38 ° 6 ^:

ber .:

found :

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm: 6.06 (1H, d); 5.88 (1H, dd); 2.73 (2H, d); 2.10 (3H, s).
IR spectrum (paraffin oil) ν cm " ¹ : 1736, 1720.

Iu 3 X

C. 8th H 69 , 93%; 8th , 58%. 69 , 71%; , 60%.

Example 41 MB-5 30B-benzoate

According to Example 40, 0.081 g of MB-53OB and 0.044 g Benzoyl chloride 0.09 g of MB-530B benzoate prepared.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) rpm: 8.1 (2H, m); 7.6 (3H, m); 6.01 (1H, d); 5.85 (1H, dd); 2.78 (2H, d). IR spectrum (film) ν cm " ¹ : 1750-1720, 1600, 1580.

ΙΏ. 3.x

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Claims (26)

SHIP ν. FÜNER STREHL SCHÜ BEL-HOPF EBBINGHAUS FlNCK MARIAHILFPLATZ 2 & 0, MUNICH SO POST ADDRESS: POST BOX 95 O1 6O, D-8OOO MUNICH 95 ALSO PROFESSIONAL RBF> R & SENTATIVE-: S ÖEFORE THE EUROPE5 "-04FICN -1Ο7Β) DIPL.CHi = M. DR. ALEXANDER V. F-ÜNKM DIPL.ING.PETER STREHL DIPL.CHEM.DR.UHSULA SCHOBEL-HOPF DIPL.ING. DIETE COMPANY = R KaBlNGHAUS DR. ING. OIETKR FINCK SANKYO LIMITED TELEPHONE (ÜB ») 482O5» TELEX 5-235BS AURO D TELEGRAMS AUHOMARCPAT MliNCHf.N DEA-13 543 March 30, 1981 "Monacoline derivatives, process for their preparation and pharmaceuticals containing these derivatives" claims 1.I monacoline derivatives of the formula I. 1 2 in which R and R, identically or differently, denote hydrogen atoms or acyl groups and R denotes a hydrogen atom or a methyl group with the proviso that if 2 3 R is a hydrogen atom, R and R are not both water 2
are stoffatorae and R does not represent an a-methylb \ ityryl group. stall. 2. Compounds according to claim 1, characterized in cj. » 1 2 that at least one of the radicals R and R is a saturated or unsaturated aliphatic acyl group, an aromatic Is acyl group or an araliphatic acyl group. 3. Compounds according to claim 1, characterized in that 1 2 that at least one of the radicals R and R is a formyl group, a straight-chain or branched C ₂ -C "-alkanoy! group, a straight-chain or branched C -.- Cp ^ -alkenoyl group, a benzoyl group, a benzoyl group with one or more substituents on the phenyl group, a phenylalkanoyl group, a phenylalkanoyl group with one or more substituents on the phenyl group. represents a plienylalkenoyl group or a phenylalkenoyl group having one or more substituents on the phenyl group. , where the substituents are C -C ₄ alky groups, C -C alkoxy groups, hydroxyl groups, methylenedioxy groups, halogen atoms and / or trifluoromethyl groups. 4. Compounds according to claim 1, characterized in that 1 2 that R is a hydrogen atom and R is a straight-chain or branched C ₃ -C ₂ -alkanoyl group, a straight-chain or branched C.-Cp - ^ - alkenoyl group or an unsubstituted benzoyl group. 5. Compounds according to claim 4, characterized in that 2
that R is a linear or branched C "-C _fi alkanoyl group or a linear or branched C _.- C -Alkenoy _fi! group. 6. Compounds according to claim 5, characterized in that 2
that R is a butyryl, isobutyryl, 4-propenoyl or isovalery! group. 7. Compounds according to claim 1, characterized in that that R is a straight-chain or branched Cp-C "alkanoyl group, a straight-chain or branched C_-C "-alkenoyl group or represents an unsubstituted benzoyl group 2
and R is a hydrogen atom or an α-methylbutyryl group 8. Compounds according to claim 7, characterized in that R is a straight-chain or branched C ₂ -C, - alkanoyl group, a straight-chain or branched C -.- C -.- alkenoyl group or an unsubstituted benzoyl group. 9. Compounds according to claim 7, characterized in that R is an acetyl, butyryl, isobutyryl, 4-propenoyl, Isovaleryl, hexanoyl or benzoyl group means and 2
R is α-methylbutyryl group. 10. Compounds according to claim 1, characterized in that 1 2
that R and R identically or differently straight-chain or branched C "-C -alkanoyl groups, straight-chain or branched Δ 6 te C_-C _fi -alkenoyl groups or unsubstituted benzoyl groups. 11. Compounds according to claim 10, characterized in that that R is acetyl, butyryl, isobutyryl, 4-propenoyl, 2 is an isovaleryl, hexanoyl or benzoyl group and R is a butyryl, isobutyryl, 4-propenoyl or isovaleryl group is. 12. MB-5 30A; ML-236A-8'-butyrate; ML-236A-8'-isobutyrate; ML-236A-8'-isovalerate; MB-53OB-8'-butyrate; MB-530B-8'-isovalerate; ML-236A-8 '- (4-pentenoate); ML-236A-3,8'-diacetate; ML-236A-3,8'-dibutyrate and ML-236A-3,8'-di (4-pentenoate). 13. A method for the production of MB-53OA, characterized in that that a MB-53OA producing microorganism of the genus Monascus is cultivated in a suitable culture medium and recovering MB-53OA from the obtained culture broth. 14. The method according to claim 13, characterized in that a microorganism of the species Monascus ruber is used. 15. The method according to claim 14, characterized in that the microorganism Monascus ruber SANK 15177 (FERM 4956, NRRL 12081) is used. 16. Process for the preparation of compounds of the formula I. 1 2 according to claim 1, in which one of the radicals R and R is a hydrogen atom and the other means an acyl group (with 1 2 with the proviso that R is not a hydrogen atom when R is a 1 2 a-methylbutyry group) or R and R both acyl groups and R is a hydrogen atom or a methyl group is, characterized in that a connection of the 1 2 Formula I in which one or both radicals R and R are hydrogen atoms mean, acylated with an Acylierungsmxttel. 17. The method according to claim 16, characterized in that the acylation is carried out with a reactive carboxylic acid derivative or a carboxylic acid in the presence of a condensation agent. 18. The method according to claim 17, characterized in that an acid anhydride or acid halide is used as the acylating agent used and the acylation carried out in the presence of an organic base. 19. The method according to claim 18, characterized in that pyridine is used as the organic base. 20. The method according to claim 18, characterized in that that an acid anhydride or acid halide is used as the acylating agent and the acylation in the presence of a organic base at a temperature of -20 to 0 C, to make a monoester as the main product. 21. The method according to claim 20, characterized in that an acid halide is used as the acylating agent in an amount of about 1 equivalent per equivalent of the compound of formula I is used. 22. The method according to claim 18, characterized in that the acylating agent is an acid anhydride or acid halide used in an amount of not less than 2 equivalents per equivalent of the compound of formula I and the acylation is carried out in the presence of an organic base at a temperature above room temperature to as the main Product to get the diester. 23. The method according to claim 16, characterized in that the acylation with a carboxylic acid in the presence of one Carries out condensing agent. 24. The method according to claim 16, characterized in that ML-236A-8'-butyrate, ML-236A-8'-isobutyrate, ML-236A-8'-isovalerate, MB-53OB-8'-butyrate, MB-5 3OB-8'-isovalerate, ML-236A-8 '- (4-pentenoate), ML-236A-3,8'-diacetate, ML-236A-3,8'-dibutyrate or ML-236A-3,8'-di (4-pentenoate) manufactures. 25. Medicaments containing at least one compound of the formula I according to claim 1 and pharmaceutically acceptable ones Carriers, auxiliaries and / or diluents. 26. Medicament according to claim 25, characterized in that bLcj as active ingredient ML-236A-8'-butyrate, ML-236A-8'-isobutyrate, ML-236A-8'-isovalerate, MB-53OB-8'-butyrate, MB-53OB-8'-isovalerate ,. ML-236A-8 '- (4-pentenoate), ML-236A-3, 8' -diacetate, ' ML-236A-3,8'-dibutyrate and / or ML-236A-3, 8-di (4-pentenoate) contain.