NL8101592A - CHOLESTEROL BIOSYNTHESIS BRAKES, THEIR PREPARATION AND USE. - Google Patents

Abstract

Compounds of formula (I): <IMAGE> (in which R<1> and R<2>, which may be the same or different, each represents a hydrogen atom or an acyl group and R<3> represents a hydrogen atom or a methyl group, provided that, where R<1> represents a hydrogen atom, R<2> and R<3> cannot simultaneously be hydrogen atoms and R<2> cannot be a a- methylbutyryl group) inhibit the biosynthesis of cholesterol and hence can be used for the treatment of disorders resulting from high cholesterol levels. The compounds of the invention can be prepared by acylation of corresponding compounds where one or both of R<1> and R<2> represents a hydrogen atom and these may, in turn, be prepared by cultivation of microoorganisms of the genus Monascus.

Description

813087 / vdv / mk

Short designation: Cholesterol biosynthesis inhibitors, their preparation and use.

The invention relates to a series of new compounds which inhibit cholesterol biosynthesis and which are derivatives of certain compounds designated ML-263A and MB-53QA. The invention also relates to a process for the preparation of these compounds.

Hyperlipaemia, in particular hypercholesteraemia, is known as one of the main causes of heart disease such as myocardial infarction or arteriosclerosis. As a result, much research has been conducted in an effort to find compounds capable of lowering lipid levels, and in particular blood cholesterol levels. A group of compounds of this type is described in U.S. Pat.

15 3 · 983 · 140 and isolated from microorganisms of the genus Penicillium. this group in its entirety being designated ML-236.

In U.S. patent application no. 121,515 February 14, 1980 and No. 137,821, dated April 4, 1980, another similar compound, designated Monacoline K or MB-530B, has been described and can be prepared by cultivating microorganisms of the genus Monascus, in particular strains of Monascus ruber.

A series of compounds related to ML-236 and MB-530B have now been found which show better development of activity due to their improved absorption upon oral administration and easier availability as a drug precursor (ie a drug which is converted into an active or more active form after administration by chemical or biochemical reactions in the body).

ML-236A and ML-236B (two compounds from the NL-236 complex described in U.S. Patent No. 3,983,140) have formulas 2 and 3 of the formula sheet, respectively, while MB-530B (or Monacoline K) has formula 4.

The new compounds of the invention are compounds of the formula 1 of the formula sheet wherein: 1 2 R and R are the same or different and each represents a hydrogen atom or an acyl group; and R 1 represents a hydrogen atom or a methyl group, provided that when R represents a hydrogen atom, R and R do not simultaneously represent 2 hydrogen atoms and R does not represent an o (-methylbutyryl group).

1 2

The compounds of the invention wherein R and R 40 both represent hydrogen atoms and R 2 represents a methyl group, i.e., the 8101592 r * t 2 compound of formula 5 of the formula sheet, designated MB-530A, may be prepared by culturing an MB-530A-yielding microorganism of the genus Monascus in a culture medium therefor and separating from the resulting culture medium of the MB-53OA formed.

The other compounds of the invention which may be considered as 3- and / or 8'-acylated derivatives of ML-236A or MB-53OA can be prepared by acylating ML-236A, ML-236B, MB-530A or MB- 530B. For the sake of clarity, these acylated derivatives are referred to herein as esters of the compound (ML-236A, ML-236B, MB-530A or MB-10 530B) from which they are obtained by acylation.

For the avoidance of doubt, the following numbering system is used to describe the compounds of the invention »(see formula 6 of the formula sheet).

When one or both of the substituents R and R represent an acyl-15 group, this acyl group is preferably a saturated or unsaturated acyl group, an aromatic acyl group or an araliphatic acyl group.

Preferred aliphatic acyl groups include: the formyl group, straight or branched chain alkanoyl groups of 2 to 20 carbon atoms, preferably 2 to 6 carbon atoms, and straight or branched chain alkenoyl groups of 20 to 3 carbon atoms, more preferably 2 to 6 carbon atoms.

Preferred saturated aliphatic acyl groups are the formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, hexa-noyl, 2-methylvaleryl, 3-methylvaleryl, 4-methylvaleryl, 2-ethylbutyryl, heptanoyl, octanoyl, 2-ethylheoyl , decanoyl, unde-25 canoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, palmitoyl, stearoyl, isostearoyl, nonadecanoyl, eicosanoyl or pivaloyl groups.

Examples of suitable unsaturated aliphatic groups include the acryloyl, 3-butenoyl, methacryloyl, 2-pentenoyl, 4-pentenoyl, 2-undecenoyl, * t-undecenoyl, 2-trideceneoyl, 2-tetradeooyloyl, 2-hexadecenoyl, linoloyloyl arachidonoyl, propioloyl, crotonoyl, tigloyl, angeloyl, senecioyl (2-heptenoyl, 2-octenoyl and 2-nonenoyl groups.

1 2

When R and / or R represent an aromatic acyl group, it is preferably a benzoyl group if desired with one or more substituents in the phenyl moiety. Such substituents are preferably G 1 -G 2 alkyl-35 groups, G 1 -C 2 alkoxy groups, hydroxy groups, methylenedioxy groups, halogen atoms or trifluoromethyl groups. Such substituents may exist in the ortho, meta or para positions, and if two or more substituents exist they may or may not be the same.

Examples of such benzoyl groups with a single bO substituent are the methylbenzoyl, ethylbenzoyl, propylbenzpyl, butylbenzoyl, 8101592-β-methoxybenzoyl, ethoxybenzoyl, propoxybenzoyl, butoxybenzoyl, and chlorobenzoyl, chlorobenzoyl, chlorobenzoyl, chlorobenzoyl, ortho, meta or para positions. Examples of such groups with two or more substituents are the 2,3-dimethoxybenzoyl, 2,4-diraethoxybenzoyl, 2,5-dimethoxybenzoyl, 2,6-dimethoxybenzoyl, 2,4,6-trimethoxybenzoyl, 3-5. trimethoxybenzoyl, 3,4-methylenedioxybenzoyl and 2,3-ethylenedioxybenzoyl · 1/2

When B and / or β / araliphatic represent acyl group, this is preferably a phenylalkanoyl group optionally with one or more substituents in the phenyl moiety. The alkanoyl group of this phenylalkanoyl group is preferably a C 1 -C 6 alkanoyl group (preferably an acetyl, propionyl or butyryl group) and the substituents are preferably C 1 -C 2 alkyl groups, C 1 -C 1 alkoxy groups, hydroxy groups, methylenedioxy groups, halogen atoms or trifluoromethyl groups. These substituents can exist in the ortho, 13 meta or para positions and when two or more substituents are present they may or may not be the same.

Examples of such araliphatic acyl groups include the cinnamoyl, chlorocinnamoyl, bromocinnamoyl, methoxycinnamoyl, methylcinnamoyl, phenylacetyl, phenoxyacetyl and phenylpropionyl groups, where the substituents of these cinnamoyl groups may exist in any of the ortho, meta or para-standings.

If desired, although less preferred, 1 2 B and / or fi may represent a heterocyclic acyl group (eg 2-furo-yl, 2-thenoyl, 3-thenoyl, micotinoyl or isonicotinoyl) or a heterocyclic substituted aliphatic acyl group ( for example, 2-thienylacetyl, 3-thienylacetyl, 2-furylacetyl, 3-furylacetyl, 2-thienylacryloyl, 3-thienylacryloyl, 2-furylacryloyl or 3-furylacryloyl) or an alicyclic acyl group, cyclopropanylcarbonobylcarbonylcarbonylcarbonyl pentane carbonyl, cyclohexane carbonyl, cycloheptane carbonyl, cyclooctane-carbonyl, cyclohexane acetyl, 3-cyclohexane propionyl, 4-, cyclohexane butyryl or 1-adaneane carbonyl group.

Examples of compounds of the invention include the following compounds: ML-236A and MB-530A 3 "8'-diformate 35 ML-236A and MB-530A 3" 8'-diacetate ML-236A and MB-530A 3 i 8'- dipropionate ML-23ÊA and MB-530A 3j8 * -dibutylate MI1-236A and MB-530A 3j 81-diisobutyrate ML-236A and MB-530A 3 * 8 * -divalerate 40 ML-236A and MB-530A 3.8'- diisovalerate 8101592 * »-h- ML-236A and MB-530A 3» 8 'dipivalate ML-236A and MB-53OA 3,8 * di-exanoate ML-236A and MB-530A 3,8'-diheptanoate ML- 236A and MB-530A 3 * 8'-bis (2-methylvalerate) 5 MI-236A and MB-530A 3'8'-bis (3-phlethylvalerate) ML-236A and MB-530A 3i8'-bis (2-ethylbutyrate ) ML-23éA and MB-330A 318'-dioctanoate ML-236A and MB-530A 3,8'-bis (2-ethylhexanoate) ML-236A and MB-53OA 3,8'-dinonanoate 10 ML-236A and MB- 53OA 3,8'-diisononanoate ML-236A and MB-530A 3i8'-diundecanoate ML-236A and MB-530A 3 ♦ 81-ditetradecanoate ML-236A and MB-330A 3,8'-dipentadecanoate ML-236A and MB-53OA 3i8'-dipalmitate 15 ML-236A and MB-330A 3 »8 -distearate ML-236A and MB-530A 318'-diisos tearate ML-236A and MB-530A 3181-dinone decanoate ML-236A and MB-530A 3 5 8'-deicosanoate ML-236A and MB-530A 3,8'-bis (1-adamantane carboxylate) 20 ML-23ÖA and MB-530A 3,8'-dicyclopropane carboxylate ML-236A and MB-53OA 3,8, dicyclobutane carboxylate ML-236A and MB-530A 3) 8, dicyclopentane carboxylate ML-236A and MB-530A 3,8, dicyclohexane carboxylate ML-236A and MB -530A 3,8'-dicycloheptane carboxylate 25 ML-236A and MB-530A 3 »8, dicyclooctane carboxylate ML-236A and MB-530A 3i8, bis (cyclohexane acetate) ML-236A and MB-530A 3,8'-bis ( 3-cyclohexane propionate) ML-236A and MB-530A 318'-bis (A-cyclohexane butyrate) ML-236A and MB-530A 3i8'-diacrylate 30 ML-23ÊA and MB-53OA 3,8'-dipropiolate ML-236A and MB -530A 3.8 * dicrotonate ML-236A and MB-530A 3i8'-bis (3-butenoate) ML-236A and MB-530A 3,8'-dimethacrylate ML-236A and MB-530A 318'-bis (2 pentenoate) 35 ML-236A and MB-530A 3,8'-bis (4-pentenoate) ML-236A and MB-530A 3,8'-ditigate ML-236A and MB-530A 3i8 'diangelate ML-236A and MB-530A 3,8'-disenecicate ML-236A and MB-530A 3,8'-bis (2-heptenoate) kO ML-236A and MB-53OA 318'bis (2-octenoate) 81015 9 2 ƒ * -5- ML-236A and MB-530A 3i8'-bis (2-nonenoate ) HL-236A and MB-530A 318'-Dilinoleate ML-236A and MB-530A 3.8, Dioleate ML-236A and MB-530A 3 »81-Dilinolenate 5 ML-236A and MB-530A 3.8 ' dicinnamate ML-236A and MB-53OA 3,8'-bis (_-chlorocinnamate) ML-236A and MB-530A 3181-bis (jn-chlorocinate) ML-23éA and MB-530A 318'-bis (j3- chlorocinnamate) ML-236A and MB-530A 3,8'-bis (o-bromo cinnamate) 10 ML-236A and MB-530A 3 f 8'-bisCm boracinnamate) HL-236A and MB-530A 3,8 * bis (j> -bromocinnamate) ML-23ÖA and MB-530A 3 »8'-bis (o-methoxycinnamate) ML-236A and HB-530A 3» 8-bis (o-methoxycinnainate) ML-236A and MB-530A 3 , 8'-bis (1-methoxycinnamate) 15 ML-236A and MB-33OA 3,8'-bis (10-methyicinnainate) ML-236A and MB-330A 3? 8 'bis (n-ethyl cinnamate) ML-236A and MB-530A 3 * 8 * bis (γ-methyl cinnamate) ML-236A and MB-530A 3'8'-bis (phenyl acetate) ML-236A and MB-530A 3, 8'-bis (phenoxyacetate) 20 ML-236A and MB-530A 3i8'-bis (3-phenylpropionate) ML-236A and MB-530A 3i8, bis (2-thienyl acetate) ML-236A and MB-53OA 3 »81 bis (2-furyl acetate) ML-236A and MB-530A 3181-bis (2-thiophene carboxylate) ML-236A and MB-530A 3,8'-bis (2-furoate) 25 ML-236A and MB-530A 3, 8'-bis (2-thienyl acrylate) ML236A and MB-530A 3f8'-bis (2-fury acrylate) ML-236A and MB-530A 318'-bis (3-furoate) ML-236A and MB-530A 318'-dinicotinate ML-236A and MB-530A 3 »8'-diisonicotinate 30 ML-236A and MB-530A 3» 8'-dibenzoate ML-236A and MB-530A 3 »81-bis (o-methyl benzoate) ML-236A and MB- 530A 3,8'-bis (m-methylbenzoate) ML-236A and MB-530A 3i8'-bis (p-methylbenzoate) ML-236A and MB-530A 3i8'-bis (o-ethylbenzoate) 35 ML-236A and MB -530A 3 »8-bis (m-ethyl benzoate) ML-236A and MB-530A 3,8 * bis-ethyl benzoate) HL-236A and MB-530A 3« 8 'bis (o-propyl benzoate) ML-236A and MB-530A 3,8'-bis (mp ropyl benzoate) ML-236A and MB-530A 3 5 8 'bis (j> propyl benzoate) kO ML-236A and MB-530A 3 »8'-bis (o-butyl benzoate) 8101592 # w -6-ML-236A and MB-53OA 3,8'-bis (m-butyl benzoate) HL-236A and MB-530A 3,8'-bis (j-butyl benzoate) ML-236A and MB-530A 3,8 'bis (_-methoxybenzoate ) ML-236A and MB-530A 3 »8, bis (m-methoxybenzoate) 5 ML-236A and MB-530A 3,8 'bis (j> -raethoxybenzoate) ML-236A and MB-530A 3» 8' bis (_-ethoxybenzoate) ML-236A and MB-53OA 318 'bis (--ethoxybenzoate) ML-236A and MB-530A 3 8 8'-bis (8-ethoxybenzoate) ML-236A and MB-530A 3i8 bis (o-propoxybenzoate) 10 ML-236A and MB-530A 3.8 * bis (m-propoxybenzoate) ML-236A and MB-530A 318'-bis (<-propoxybenzoate) ML-236A and MB- 530A 3- »8 'bis (o-butoxybenzoate) ML-236A and MB-530A 3,8'-bis (m-butoxybenzoate) ML-236A and MB-53OA 318'-bis (j-butoxybenzoate) 15 ML -236A and MB-530A 3 »8'-bis (o-hydroxybenzoate) ML-23ÖA and MB-530A 318'-bis (m-hydroxybenzoate) ML-236A and MB-530A 318 'bis (j3-hydroxybenzoate) ML -236A and MB-330A 3> 8'-bi s (2,3-dimethoxybenzoate) ML-236A and MB-530A 318'-bis (2,4-dimethoxybenzoate) 20 ML-236A and MB-530A 3 '8'-bis (2,5-dimethoxybenzoate) ML-236A and MB-530A 3,8, bis (2,6-dimethoxybenzoate) ML-236A and MB-530A 3,8'-bis (2,4,6-trimethoxybenzoate) ML-236A and MB-53OA 318'-bis (3,5,5-trimethoxybenzoate ) ML-236A and MB-530A 3i 8'-bis (3, 1 - methylenedioxybenzoate) 25 ML-236A and MB-530A 3,8 'bis (2,3-methylenedioxybenzoate) ML-236A and MB-530A 3, 8, bis (io-chlorobenzoate) ML-236A and MB-330A 3,8, bis (m-chlorobenzoate) ML-236A and MB-53OA 3,8 'bis (j-chlorobenzoate) ML- 236A and MB-530A 3,8 'bis (_-bromobenzoate) 30 ML-23ÖA and MB-530A 3' 8'-bisim bromobenzoate) ML-236A and MB-530A 3) 8'-bis (j> * bromobenzoate) ML-236A and MB-530A 3,8'-bis (_-fluorobenzoate) ML-236A and MB-530A 3,8, bis (jn-fluorobenzoate) ML-23ÖA and MB-530A 3 »8'- bis (_-fluorobenzoate) 35 ML-236B and MB-530B acetate ML-236B and MB-530B propionate ML-236B and MB-530B butyrate ML-236B and MB-530B isobutyrate ML-236B and MB-530B valerate ML- 23ÖB and MB-530B isovalerate 8101592 * t -7- »m ML-236B and MB-530B pivalate ML-236B and MB-530B hexanoate ML-23ÖB and MB-530B heptanoate HL-236B and MB-530B (2-raethylvalerate) 5 ML-23ÊB and MB-330B (3-methylvalerate) ML -236B and MB-530B (2-ethylbutyrate) ML-236B and MB-530B octanoate ML-236B and MB-530B (2-ethylhexanoate) ML-236B and MB-530B nonanoate 10 ML-236B and MB-330B isononanoate ML- 236B and MB-530B undecanoate ML-236B and MB-530B tetradecanoate ML-236B and MB-530B pentadecanoate ML-236B and MB-530B palmitate 15 ML-236B and MB-530B stearate ML-236B and MB-530B isostearate ML-236B and MB-530B non-decanoate ML-23ÊB and MB-530B Eicosanoate ML-236B and MB-530B (1-adamantane carboxylate) 20 ML-236B and MB-530B cyclopropane carboxylate ML-236B and MB-530B cyclobutane carboxylate ML-236B and MB-53OB cyclopentane carboxylate ML-236B and MB-530B Cyclohexane Carboxylate ML-236B and MB-530B Cycloheptane Carboxylate 25 ML-236B and MB-53OB Cyclooctane Carboxylate ML-236B and MB-530B Cyclohexane Acetate ML-236B and MB-530B (3-Cyclohexane Propionate) ML-236B -530B acr ylate HL-236B and MB-530B propiolate 30 ML-236B and MB-530B crotonate ML-236B and MB-530B methacrylate ML-236B and MB-530B tigLate ML-236B and MB-530B angelate ML-236B and MB-530B senecio .ate 35 ML-236B and MB-530B (3-butenoate) ML-236B and MB-530B (2-pentenoate).

ML-236B and HB-530B linoleate ML-236B and MB-530B oleate ML-236B and MB-530B linolenate 40 ML-236B and HB-530B cinnamate 81 01 592 * -8- ML-236B and MB-530B (o_ chlorocinnamate) ML-236B and MB-53OB (m-chlorocinnamate) ML-236B and MB-530B (jg-chlorocinnamate) ML-236B and MB-530B (jo-bromo cinnamate) 5 ML-236B and MB-330B (jn- bromine cinnamate) ML-236B and MB-530B (jo-bromine cinnamate) ML-236B and MB-53OB (o-methoxycinnamate) ML-236B and MB-530B (m-methoxycinnamate) ML-236B and MB-330B (_-methoxycinnamate ) 10 ML-236B and MB-530B (ethyl methyl cinnamate) ML-236B and MB-530B (m-methyl cinnamate) ML-23ÖB and MB-530B (yom methyl cinnamate) ML-23ÖB and MB-530B phenyl acetate ML-236B and MB- 530B Phenoxy Acetate 15 ML-23ÖB and MB-530B (3-Phenylpropionate) ML-236B and MB-530B (2-Thienyl Acetate) ML-236B and MB-530B (2-Furylacetate) ML-236B and MB-330B (2-Thiophene Carboxylate ) ML-236B and MB-530B (2-furoate) 20 ML-23ÖB and MB-330B (2-thienyl acrylate) ML-236B and MB-53OB (2-furyl acrylate) ML-236B and MB-53OB (3-furoate) ML-236B and MB-330B nicotinate ML-236B and MB-530B isonicotinate 25 ML-236B and MB-530B benzoate ML-236B and MB-530B (_-ethyl ethyl benzoate) ML-23ÖB and MB-530B (m-methyl benzoate) ML-236B and MB-53OB Og methyl benzoate) ML-236B and MB-530B (ethyl ethyl benzoate) 30 ML-236B and MB-53OB GN ethyl benzoate) ML-236B and MB-530B Cg ethyl benzoate) ML-236B and MB-530B (_-propyl benzoate) ML-236B and MB-330B (ra-propyl benzoate) ML-236B and MB-53OB (jg-propyl benzoate) ML-236B and MB-53OB (o-butyl benzoate) ML-236B and MB-530B (m-butyl benzoate) ML -236B and MB-530B (g-butylbenzoate) ML-236B and MB-530B (o-methoxybenzoate) HL-236B and MB-530B (m-methoxybenzoate) kO ML-236B and MB-530B (j) -methoxybenzoate) 8101592 * f -9- ML-236B and MB-530B (o-ethoxybenzoate) ML-236B and MB-530B (m-ethoxybenzoate) HL-236B and MB-530B (y-ethoxybenzoate) ML-236B and MB-530B (o propoxybenzoate) 5 ML-236B and MB-530B (m -propoxybenzoate) ML-236B and MB-530B Cg -propoxybenzoate) ML-236B and MB-530B (oi-butoxybenzoate) ML-236B and MB-530B (m-butoxy benzoate) ML-236B and MB -530B (jH-butoxybenzoate) ML-236B and MB-530B (o-hydroxybenzoate) ML-236B and HB-530B (m-hydroxybenzoate) ML-236B and MB-530B (g-hydroxybenzoate) ML-236B and MB-530B (2 , 3-dimethoxybenzoate) ML-236B and MB-530B (2, Jf-dimethoxybenzoate) ML-236B and MB-330B (2,5-dimethoxybenzoate) ML-236B and MB-530B (2,6-dimethoxybenzoate) ML-236B and MB-530B (2,4,6-trimethoxybenzoate) ML-236B and MB-530B (3, 5-trimethoxybenzoate) ML-236B and MB-530B (3, 5-methylenedioxybenzoate) 20 ML-236B and MB -530B (2,3-methylenedioxybenzoate) ML-236B and MB-530B (o-chlorobenzoate) ML-236B and MB-530B (jn-chlorobenzoate) ML-236B and MB-530B (j-chlorobenzoate) ML-2363 and MB-530B (o-bromobenzoate) 25 ML-236B and MB-530B (m-bromobenzoate) MI1-236B and MB-530B (j> * bromobenzoate) ML-236B and MB-530B (o-fluorobenzoate) ML-236B and MB-530B (m-fluorobenzoate) ML-236B and MB-330B (g-fluorobenzoate) For brevity, only the diesters of ML-236A and MB-53OA have been mentioned above, but it will be appreciated that each of the corresponding 3 monoesters and 8 '»monoesters is possible. Of these compounds, the following compounds are particularly preferred: ML-236A 8'-butyrate 35 ML-236A 8'-isobutyrate ML-236A 8'-isovalerate MB-530A 8'-butyrate MB-530A 8'- isovalerate ML-236A 8 '- (^ f-pentenoate) ifO ML-236A 3,8'-diacetate 8101592 I, * • 10 · * ML-236A 3,8'-dibutyrate, and ML-236A 3 ϊ δf -di (* - pentenoate) MB-530A, one of the compounds of the invention, can be prepared by cultivating an MB-530A-forming microorganism of the genus Monascus, preferably a strain of Monascus ruber and most preferred earning Monascus ruber SANK 15177 · This strain was deposited on April 27, 1979 under the designation No. FERM ^ 956 at the Fermentation Research Institute, Commissioner for Industrial Science and Technology, Ministry of International Trade and Industry, Japan and on January 10, 1980 under No. NRRL 12081 with Agriculture Research Service Culture Collection, Northern Regional Research Laboratory, Peoria, Illinois, I.S.A. The morphology and physiology of this strain are more particularly described in U.S. Patent Application No. 137-821 issued April 9, 1980.

The desired MB-530A can be formed by culturing the selected microorganism in a culture broth under aerobic conditions, using the well known techniques of culturing fungi and other microorganisms. For example, the selected Monascus strain may first be grown on a suitable medium and then the microorganisms formed may be collected and seeded and grown on another culture medium to form the desired MB-530A; the culture medium used to propagate the microorganisms and the culture medium used to form MB-530A may or may not be the same.

Any culture medium well known for fungal cultivation can be used, provided it contains, as is well known, the necessary nutritional components, in particular an assimilable carbon source and an assimilable nitrogen source. Examples of suitable sources of assimilable carbon include glucose, maltose, dextrin, starch, lactose, sucrose-lycerol. Of these sources, particular preference is given to glucose, glycerol and starch for the preparation of MB-530A. Examples of suitable sources of assimilable nitrogen are peptone, meat extract, yeast, yeast extract, soybean meal, groundnut meal, corn steep liquor, rice bran and inorganic nitrogen sources. Of these nitrogen sources, corn liquor and peptone are particularly preferred. In the formation of MB-53OA, an inorganic salt and / or a metal salt can be added to the culture medium, if desired. In addition, a small amount of a heavy metal can optionally also be added.

The microorganisms are preferably grown under aerobic conditions using culture methods which are well known, for example, solid culture methods, shake culture methods, or culture under aeration and stirring. The microorganisms grow within wide temperature limits, for example from 7 to 40 ° C, but in particular for the preparation of MB-53OA the preferred culture temperature is between 20 and 30 ° C.

While culturing the microorganisms, the formation of MB-530A can be checked by taking samples from the culture medium and measuring the physiological activity of the medium using well known assay methods. Culturing can then be continued until a significant build-up of MB-530A in culture medium 10 has occurred, at which time the MB-530A can be isolated and recovered from the culture medium and the microorganism tissue by an appropriate combination of isolation techniques , which has been chosen taking into account its physical and chemical properties. For example, any or all of the following isolation techniques can be used: Extraction of the liquid from the culture medium, a hydrophilic solvent (such as diethyl ether, ethyl acetate, chloroform or benzene), extraction of the organism with a hydrophilic solvent (such as acetone or an alcohol ), concentration, for example by evaporating part of the solvent under reduced pressure, dissolving in 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 through a column of a material such as Sephadex (a trade name for a material available from Pharmacia Co. Limited, USA), absorption chromatography with active carbon or silica gel and other similar methods. When using a suitable combination of these techniques, the desired MB-53OA can be isolated from the culture medium as a pure substance.

Similarly, the other known starting materials for the acylation process of the invention, i.e., ML-236A, ML-236B and MB-530B, can be prepared from culture media containing suitable microorganisms using the techniques mentioned above or described in more detail in U.S. Patent Application No. 3,983,44 or U.S. Patent Application 121,515, February 14, 1980, or No. 137,821 dated April 4, 1980.

Ce acylated derivatives of the invention can be prepared from ML-236A, ML-236B, MB-530A or MB-530B by any of the following methods.

METHOD I

ML-236A, ML-236B, MB-530A or MB-530B are reacted 40 with an appropriate acid chloride or anhydride to form the acyl derivatives which it is desired to prepare. The reaction is preferably carried out in the presence of a base (which acts as an acid binder), preferably an organic amine, such as pyridine, triethylamine, Ν, Ν-dimethylamino-pyridine, N-methylpyrrolidine or N-methylmorpholine. The reaction is preferably carried out in the presence of a solvent and the nature of this solvent is not critical, provided that it does not adversely affect the reaction. Suitable solvents are chloroform, methylene chloride and diethyl ether. In certain 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 can take place over a wide range of temperatures, although to control the reaction efficiently, a relatively low temperature is generally preferred, for example from -20 ° C to room temperature and more particularly from -20 ° C to 0 ° C. If desired, however, higher temperatures can also be used.

15 METHOD II

A carboxylic acid is treated with a chlorocarbonate ester or with a sulfonic acid chloride in the presence of a base, for example one of the above-mentioned organic amines, to prepare a mixed acid anhydride, and this in turn is reacted with 20 ML-236A, ML -236B, MB-530A or MB-530B. The reaction is preferably conducted in the presence of a solvent, the nature of which is not critical, provided it does not adversely affect the reaction. Suitable solvents are, for example, diethyl ether, benzene, chloroform and methylene chloride. The reaction can take place within a wide temperature range, for example from -20 ° C to room temperature, preferably from -20 ° C to 0 ° C. METHOD III

ML-236A, ML-236B, MB-530A or MB-530B are reacted with a carboxylic acid and a diazoalkyl dicarboxylate in the presence of, for example, dicyclohexylcarbodiimide, triphenylphosphine or dimethylphosphoramide. The reaction is preferably conducted in the presence of a solvent, the nature of which is not critical, provided that it does not adversely affect the reaction. Suitable solvents are chloroform, methylene chloride, benzene and diethyl ether.

Each of the above reactions will normally be complete within a period of from 30 minutes to 5 hours, although the precise time required for the reaction will depend on the reactants and the reaction temperature. After the completion of the reaction, the desired product can be separated from the reaction mixture in a manner known per se, for example, by evaporation of the solvent from a solution containing the desired product (which solution can simply be the reaction mixture or other). solution obtained by extracting the reaction mixture with an organic solvent), if desired after washing and drying the solution, after which the product can be purified in a manner known per se, for example by column chromatography, thin layer chromatography or recrystallization or by a combination of these methods.

When the starting material for the acylation reaction contains two hydroxy groups, i.e., when it is ML-236A or MB-53OA, the above reactions may include the 3-monoester, the 3,8'-diester or the 8'-monoester or a mixture thereof. The nature of the product obtained 10 can be influenced by changing the amounts of reactants, the reaction temperature and other reaction conditions, and although the reasons for this are not clear, it is believed that preferably the 3-monoester is formed, followed by the 3, 8 'diester and the 8f monoester. However, in the case of any particular reaction, one skilled in the art can easily determine which optimal conditions to maintain to obtain the desired particular product. In general, the following will be achieved.

The 3-monoester and / or 8-monoester will mainly be formed by carrying out the reaction using an alkylating agent, an acid anhydride or halide in the presence of an organic base at a temperature of -20 ° C to 0 ° C. The amount of acylating agent, for example the acid halide, is preferably 1 equivalent per equivalent of ML-236A, ML-236B, MB-53OA or MB-530B

The 3,8'-diester is mainly formed when the acylating agent used is an acid anhydride or halide in an amount of at least 2 equivalents per equivalent of ML-236A, ML-236B, MB-53OA or MB-530B, and the acylation is carried out in the presence of an organic base at a temperature above room temperature.

The compounds of the invention appear to have a specific inhibitory activity against 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMG-CoA reductase) which is the rate-controlling enzyme in cholesterol biosynthesis. The inhibitory effects of certain compounds of the invention in the bio-synthesis of cholesterol are shown in the following table expressed in their Iq values (ie the concentration in µg / ml which leads to a 5% inhibition of the cholesterol biosynthesis), as determined by the method of Knaus et al., J. Biol. Ghem. 23, 2835, (1959).

40 8101592 -14- ______ TABLE______ ^ 50 ^ / S / nil)

Acetyl Η H 0.21 5 Butyryl Η H 0.10

Isobutyryl Η H 0.29

Butyryl H CH ^ 0.39 4-Pentenoyl Η H 0.17 H Butyryl H 0.017 10 H Butyryl CH ^ 0.021 H Isobutyryl H 0.061 H Isovaleryl H 0.039 H Isovaleryl CH ^ 0.026 H 4-Pentenoyl H 0.096 15 H Hexanoyl H 0, 13 H Octanoyl H 0.34 H Palmityl H 0.24 H Linolyl H 0.16

Acetyl Acetyl Η 0.12 20 Butyryl Butyryl H 0.065 4-Pentenoyl 4-Pentenoyl H 0.12

The preparation of the compounds of the invention is further illustrated by the following examples. The preparation and properties of MB-530B (Monacoline K) used as starting compound in some examples are more particularly described in U.S. Patent Application No. 121,515 February 14, 1980 and No. 137 * 821 of April 4, 1980. Likewise, the preparation and properties of ML-236A and ML-236B are more particularly described in U.S. Patent No. 5,318,395. 3 * 983,140.

EXAMPLE I Preparation of MB-530A

300 liters of a culture medium with a pH of 5 »5 for 35 sterilization containing 5 $ w / v glucose, 0.5 $ w / v corn steep liquor, 2 $ w / v peptone (kyokuto brand, from Kyokuto Seiyaku KK, Japan) and 0.5% ammonium chloride were placed in a 600 liter fermentation tank and seeded with a culture of Monascus ruber SANK 15177 (FERM 4956, NERL 12081). Culturing of the microorganism was carried out at 27 ° C for 120 hours at an aeration rate of 300 liters per minute and stirring at a rate of 190 revolutions per 8101592-15 minutes

At the end of this period, the culture broth was filtered in a filter press to obtain a filtrate and a filter cake containing moist microorganism cells.5 The filtrate was adjusted to a pH of 3.0 by adding 6N hydrochloric acid and then extracted with ^ 00 liters of ethyl acetate · The extract (about 400 liters) was concentrated by evaporation under reduced pressure and then dehydrated over anhydrous sodium sulfate, after which it was evaporated to dryness to obtain about 60 g of an oily product. was washed with ethylcyclohexane and with hexane and the residue (20 g) was separated by chromatography using a liquid chromatograph for processing large volume samples (System 500 liquid chromatography from Waters Co. USA) and eluting with 60% s / v aqueous Methanol · Fractions with a chromatographic retention time of 6 minutes were collected and concentrated by evaporation under reduced pressure to obtain 100 mg of the desired MB-530A as an oily product. This oily MB-530A was recrystallized from a mixture of acetone and diethyl ether to obtain 57 mg of the desired product in the form of colorless needles with the following properties;

1. Melting point: 92-93 ° C

2. Basic analysis:

Calculated for C 69.76 $; H 8.68 $

Found C 71.22 $; H 8.81 $ 25 3 Molecular weight: 520 (according to mass analysis) h. Molecular Formula: C ^^ H ^ s ^ ij. · 5 · Ultraviolet Absorption Spectrum: as shown in Fig. 1 of the accompanying drawing · 6. Infrared Absorption Spectrum: As shown in Fig. 2 of the accompanying drawing 50 · 7 · Nuclear magnetic resonance spectrum: As shown in Fig 3 of the accompanying drawing · 8. Solubility: Easily soluble in methanol, ethanol, acetone, ethyl acetate, soluble in benzene; insoluble in hexane and petroleum ether · 9 · Color reaction: a pink color develops when a thin layer chromatography on silica gel of the compound is developed with 50 $ v / v sulfuric acid · 40 "JOt Inhibition of cholesterol biosynthesis: 50 $ inhibition of the 8101592 -16- cholesterol synthesis in the rat liver is observed at a concentration of 0.04 µg / inl.

EXAMPLE II ML-236A 5-acetate 5 ML-236A (918 rag) and pyridine (0.36 ml) were dissolved in methylene chloride (10 ral), and acetic anhydride (1.0 ml) was added dropwise keeping the temperature at -20 to -10 ° C. After the completion of the reaction, water was added to the reaction mixture, the methylene chloride layer was separated and washed with water, after which it was dried over anhydrous sodium sulfate. The residue obtained by evaporation of the methylene chloride was subjected to column chromatography using silica gel (10 g) followed by recrystallization with diethyl ether to obtain 780 mg of the desired product, mp 138-139 ° C. Elemental analysis:

Calculated for C20H28 ° 5: C'68.97 $; H, 8.05 $;

Found C, $ 68.99; H, 8.01 $.

Nuclear Magnetic Resonance Spectrum (CDCl ^) S ppm: 1.98 (3H, singlet) 20 5.10 (1H, multiplet) •• 1

Infrared Absorption Spectrum (Nujol trademark) λ} cm "max 3 ^ 00, 17to EXAMPLE III ML-236A 3-butyrate 25 ML-236A (918 mg) was dissolved in pyridine (5 ml) and acid anhydride (1 ml) ) was added dropwise to the resulting solution After standing the mixture overnight at room temperature, water was added as the reaction mixture, which was then extracted with diethyl ether The ether layer was washed with a saturated aqueous solution of sodium bicarbonate, a 1N hydrochloric acid solution and water and then dried over anhydrous sodium sulfate The residue obtained by evaporation of the diethyl ether was subjected to a separation by silica gel chromatography to obtain 930 mg of the desired product.

35 Elemental analysis:

Calculated for C 3 H 20 O: C 70.21 $; H, 8.51 $.

Found C, 69.96 $; H, $ 8.69

Nuclear Magnetic Resonance Spectrum (CDCl ^) £> ppm: 0.95 (3H, triplet) kO k, 2? (1H, multiplet) 81015 92-17 5.32 (1H, multiplet).

Infrared Absorption Spectrum (liquid film) * 9 cm: 3460.1740 EXAMPLE IV ML-256A-3-butrate 5 Proceeding in the same manner as described in Example II, 853 mg of the desired product were prepared (having the same properties as the product of Example III) from ML-236A (918 mg) and butyryl chloride (0.32 ml).

EXAMPLE V

10 ML-256A 3 isobutyrate

Proceeding in the same manner as described in Example II, 841 mg of the desired product were prepared from ML-236A (918 mg (and isobutyryl chloride), 032 mL).

Elemental Analysis: Calculated for C 3 H 3 O 3: C, 70.21 #; H, 8.51 #

Found C, 69.84 #; H, 8.32 #.

Nuclear Magnetic Hesonance Spectrum (CDCl 3) PP®: 1.17 (6H, doublet); 4.27 (1H, multiplet); 20 5 »25 (1H, multiplet)

Infrared Absorption Spectrum (liquid film) ^ cm 3440, 1730, 1720.

EXAMPLE VI

ML-236A 3- (4-nentenoate) Proceeding in the same manner as described in Example II, 834 mg of the desired product were prepared from ML-236A (918 mg) and 4-pentenoyl chloride (0.39 ml).

Elemental analysis:

Calculated for: C, 71.13 #; H, 8.25 # 30 Found C, 71.43 #; H, 8.00 #

Nuclear Magnetic Resonance Spectrum (CDCl 3) S ppm: 4.27 (1H, multiplet) 4.8-6.2 (7H, multiplet).

Infrared Absorption Spectrum (liquid film ^ cm- "".

3400, 1730, 1640 EXAMPLE VII ML-256A 3 Isovalerate

Proceeding in the same manner as described in Example II, 894 mg of the desired product were prepared from ML-236A (918 mg) and isovaleryl chloride 40 ride (0.40 ml).

8101592 i, t; -18-

Elemental analysis:

Calculated for GZ3E3 ^ ° 5 * C '7 ° '77 ^; H "8" 72 ^

Found C, 70.61 $; H, 8.80 $

Nuclear Magnetic Resonance Spectrum (CDGl 4) S ppm: 0.95 (6H, doublet); ^ .23 (1H, multiplet); 5 »27 (1H, multiplet).

»—1

Infrared Absorption Spectrum (liquid film) * v cm: 1 max 3 ^ 60, Wk)

EXAMPLE VIII

ML-236A 3-hexanoate

Proceeding in the same manner as described in Example II, 2.90 g of the desired product were prepared (melting point 70-72 ° C) from ML-236A (2.70 g) and hexanoyl chloride (1.36 ml).

15 Basic analysis:

Calculated for C24S36 ° 5: C'71'29 ^ Hl 8.91%

Found C, 71.0 * $; H, 8.79 $.

EXAMPLE IX ML-236A 3-Octanoate 20 Proceeding in the same manner as described in Example II, 690 mg of the desired product were prepared from ML-236A (612 mg) - and octanoyl chloride (0.5 * 1 ml).

. Elemental analysis:

Calculated for C 25 H 25 q C, 72.22 $; H, 9.26 $; 25 Found C, 72, *! ·! $; H, 9.12 $.

Nuclear Magnetic Resonance Spectrum (CDCl 3) & ppm: 0.88 (3H, wide triplet); * f, 28 (1H, multiplet); 5.33 (1H, multiplet).

30 Infrared Absorption Spectrum (liquid film) ^ cm: 3 ^ 50, 1735.

EXAMPLE X ML-236A 3 Palmitate

Proceeding in the same manner as in Example II, 7 * f9 mg of the desired product were prepared from ML-236A (827 mg) and palmitoyl chloride (0.82 g).

Elemental analysis:

Calculated for C 7 H 15 g C: 75.00 $; H, 10.29 $

Found: C, 7 **, 89 $; H, 10.35 $ kO Nuclear Magnetic Resonance Spectrum (CDCl 3) & ppm: 8101592-19 0.90 (3H, wide triplet); 1.27 (24H, broad singlet); 4.27 (1H, multiplet); 5.32 (1H, multiplet).

5 Infrared Absorption Spectrum (liquid film) ^ may cm: 3460, 1735.

EXAMPLE XI ML-236A 3-linoleate

Proceeding in the same manner as described in Example 10, 897 mg of the desired product were prepared from ML-236A (918 mg) and linoleyl chloride (1.03 g) ·

Elemental analysis:

Calcd for C 19 H 10 g O: C, 76.06 $; H, 9.86 $.

Found: C, 76.24 $; H, 9.96 $.

15 Nuclear Magnetic Resonance Spectrum (CDCl 3) & ppm: 0.90 (3H, wide triplet); 1.32 (18H, broad singlet); 4.27 (1H, multiplet).

• “1

Infrared Absorption Spectrum (liquid film) *>) cm: max 20 3460, 1740.

EXAMPLE XII MB-530A 3-butyrate

Proceeding in the same manner as described in Example II, 250 mg of the desired product were prepared from MB-530A (300 mg) and butyryl chloride (0.47 ml).

Elemental analysis:

Calculated for: C, 70.77 $; ïï, 8.72 $

Found: C, 70.60 $; H, 8.89 $.

Nuclear Magnetic Resonance Spectrum (CDGl ^) & ppm: 0.90 (3H, triplet); 4.17 (1H, multipLet); 5.22 (1H, multiplet).

Infrared Absorption Spectrum (liquid film) cm ”1: max 3450, 1730.

EXAMPLE XIII

MB-530A 3 Isovalerate

Proceeding in the same manner as described in Example II, 235 mg of the desired product were prepared from MB-530A (320 mg) and isovaleryl chloride (0.47 ml).

4θ Elemental analysis: 8101592 • v -20-

Calculated for CaH3605: C, 71.29 $; H, 8.91 #

Found: C, 71.20 #; H, 8.87 #

Nuclear Magnetic Resonance Spectrum (CDCl 3) S ppm: 0.89 (HH, doublet); 4.16 (1H, multiplet); 5.22 (1H, multiplet).

a

Infrared Absorption Spectrum (Nujol) $ may cm: 3510, 1730, 1710.

EXAMPLE XIV 10 MB-550A 5-Hexanoate

Proceeding in the same manner as described in Example II, 410 mg of the desired product were prepared from MB-530A (420 mg) and hexanoyl chloride (0.21 ml).

Elemental Analysis: Calculated for C 25 H 38 ° 5: c 771.77 #; H, 9.09 #.

Found: C, 71.55 #; H, 9.19 #.

Nuclear Magnetic Resonance Spectrum (CDC1_)% ppm: 3 0.88 (3H, broad triplet); 4.19 (1H, multiplet); 5.25 (1H, multiplet).

Infrared Absorption Spectrum (liquid film) O cm ”1: max 3400, 1730.

EXAMPLE XV MB-530A 3-Octanoate Proceeding in the same manner as described in Example II, 340 mg of the desired product were prepared from MB-530A (322 mg) and octanoyl chloride (0.28 ml).

Elemental analysis:

Calculated for C27 H42 ° 5: C »72.65 #; H, 9.42 # 30 Found: C, 72.44 #; H, 9.34 #

Nuclear Magnetic Resonance Spectrum (GDCl2) ppmppm: 0.84 (3H, broad triplet); 1.21 (12H, broad singlet); 4.18 (1H, multiplet); 5.23 (1H, multiplet).

Infrared Absorption Spectrum (liquid film) ^ fflax cm ”1: 3400, 1730.

EXAMPLE XVI ML-236A 8'-butyrate ^ ML-236A (918 mg) and pyridine (0.36 ml) were dissolved in 8101592 1 -21-methylene chloride (10 ml). The resulting solution was cooled to 0 ° C and was added dropwise to this butyryl chloride / After addition of the reaction, water was added to the reaction mixture and the separated methylene chloride layer was washed with water and then dried over anhydrous sodium sulfate. The residue obtained by evaporation of methylene chloride was subjected to column chromatography using silica gel (10 g) followed by recrystallization from diethyl ether to obtain 395 mg of the desired product, m.p. 124-125 ° C. 10 Basic analysis:

Calculated for ^ 22 ^ 32 ^ 5: G »70.21 #; H, 8.51 #

Found: C, 70.2 ^ £; H, 8.50 #

Nuclear Magnetic Resonance Spectrum (CDCl 3) 1 ppm: 0.95 (3H, triplet); 4.42 (1H, multiplet); 5.43 (1H, multiplet).

Infrared Absorption Spectrum (Nujol) ^ cm: 3400, 1730, 1710.

EXAMPLE XVII 20 ML-236A S4 Isobutyrate

Proceeding in the same manner as described in Example XVI, 100 mg of the desired product were prepared from ML-236A (285 mg) and isobutyryl chloride (0.11 ml).

Elemental analysis: 25 Calculated for c22 ^ 32 ^ 3: G 7 ° 21 # i E, 8.51 #.

Found: C, 70.05 #; H, 8.67 #

Nuclear Magnetic Resonance Spectrum (CDCl 3)% ppm: 1.14 (6H, doublet); 4.35 (1H, multiplet); 5.52 (1H, multiplet).

Infrared Absorption Spectrum (liquid film) * \) cm ”: max 3400, 1730, 1700.

EXAMPLE XVIII ML-236A 8 * - (4-Ientenoate) Proceeding in the same manner as described in Example XVI, 370 mg of the desired product were prepared from ML-236A (918 mg) and 4-pentenoyl chloride (0.39 ml) .

Elemental analysis:

Calcd for C 7 H 15 O: C 71.13 #; H, 8.25 # 40 Found: C, 70.82 #; H, 8.33 # 8101592 «; 5 »-22-

Nuclear Magnetic Resonance Spectrum (CDCl 3)% ppm: 4.14 (1H, multiplet) 4.8 - 6.2 (8H, multiplet).

a

Infrared Absorption Spectrum (liquid film) O cm: v max 5 3400, 1730.

EXAMPLE XIX ML-236A 81 Isovalerate

Proceeding in the same manner as described in Example XVI, 3Φ? mg of the desired product prepared from ML-236A (918 10 mg) and isovaleryl chloride (0.4-7 ml)

Elemental analysis:

Calculated for 023Η ^ 05: 0, 70.7Τ # ί Η, 8.72 *.

Found: C, 70.59 $; H, 8.90 $.

Nuclear Magnetic Resonance Spectrum (CDCl 3) & ppm: 0.93 (6H, doublet); 4.55 (1H, multiplet); 535 (1H, multiplet).

—1

Infrared Absorption Spectrum (liquid film) V cm: max 3430, 1730, 1710

20 EXAMPLE XX

ML-256A 8 * hexanoate

Proceeding in the same manner as described in Example XVI, 4-8 mg of the desired product were prepared from ML-236A (918 mg) and hexanoyl chloride (0.4-6 ml).

25 Basic analysis:

Calculated for: C2 ^ H56 ° 5: C'71'29 ^; H 8.91 $ ..

Found: C, 71.77 $; H, 9 * 01 $.

Nuclear Magnetic Resonance Spectrum (CDCl 3)% ppm: 0.87 (3H, triplet); 4.32 (1H, multiplet); 5.32 (1H, multiplet).

«1

Infrared Absorption Spectrum (liquid film) -y> max cm ": 3400, 1720, 1710 EXAMPLE XXI 35 ML-236A S-octanoate

Proceeding in the same manner as described in Example XVI, 462 rag of the desired product were prepared from ML-236A (918 mg) and octanoyl chloride (0.54 ml).

Elemental Analysis: 40 Calc'd for C 12 H 10 O: c, 72.22 $; H, 926 $.

8101592 -23-

Found: C, 72.04 $; 9, 9.10 $

Nuclear magnetic. Resonance Spectrum (CDCl ^) δ pp® · 0.88 (3H, wide triplet); 1.28 (12H, broad singlet); 4.42 (1H, multiplet); 5.42 (1H, multiplet).

Infrared Absorption Spectrum (liquid film) '^ max cm' ^: 3470, 1735.

EXAMPLE XXII 10 ML-256A S-nalmitate. Proceeding in the same manner as described in Example XVI, 490 mg of the desired product were prepared from ML-236A (918 mg) and palmitoyl chloride (640 mg).

Elemental Analysis Calculated for C 7 H 10 g C: C, 74.73 $, 3, 10.62 $.

Found: C, 74.56 $; H, $ 10.78

Nuclear Magnetic Resonance Spectrum (CDCl 3) S PP®: 0.88 (3H, wide triplet); 1.28 (24H, broad singlet); 4.38 (1H, multiplet); 5.40 (1H, multiplet).

Infrared Absorption Spectrum (liquid film) o? cm% 3450, 1735.

EXAMPLE XXIII 25 ML-236A S'-linoleate

Proceeding in the same manner as described in Example XVI, 415 mg of the desired product were prepared from ML-236A (918 mg) and linoleyl chloride (1.0 g).

Elemental Analysis: Calculated for C 18 H 16 gO 3 - C, 76.06 $; H, 9.86 $

Found: C, 76.23 $; H, $ 10.03.

Nuclear Magnetic Resonance Spectrum (CDCl 3) ppm: 0.90 (3H, wide triplet); 1.32 (18H, broad singlet); 4.40 (1H, multiplet); 5.2 - 5.5 - (53, multiplet).

Infrared Absorption Spectrum (liquid film) cm: 3440, 1735.

EXAMPLE XXIV 40 MB-530A 8 * Butyrate 8101592 A '1 -2k-

Proceeding in the same manner as described in Example XVI, 15 ** mg of the desired product were prepared from MB-530A (309 mg) and butyryl chloride (0.16 ml).

Elemental analysis: 5 Calculated for C? 3H3 ** ° 5: 7 ° "77 ^ H" 8 "72 ^ *

Found: C, 70.58 $; H, 8.61 $.

Nuclear Magnetic Resonance Spectrum (CDCl 3) b ppm: 0.90 (3H, triplet); **, 17 (1H, multiplet); 5.22 (1H, multiplet).

Infrared Absorption Spectrum (liquid film) "w cm": max 3 ** 50, 1730.

EXAMPLE XXV MB-530A 8 * Isovalerate 15 Proceeding in the same manner as described in Example XVI, 109 mg of the desired product were prepared from MB-530A (308 mg) and isovaleryl chloride (0.12 ml).

Elemental analysis:

Calculated for C 2 ** 36 ° 5: C 71 2 ^ H 8 91 ^ * 20 Found: C 71.1756; H, 8.69 #

Nuclear Magnetic Resonance Spectrum (CDCl 3) ppm: 0.88 (6H, doublet); **, 15 (1H, triplet -); 5.22 (1H, multiplet).

25 Infrared Absorption Spectrum (liquid film) A cm: max 3 ** 20, 1730.

EXAMPLE XXVI MB-530A 81-hexanoate

Proceeding in the same manner as described in Example 30 XVI, 87 mg of the desired product were prepared from MB-530A (308 mg) and hexanoyl chloride (0.15 ml).

Elemental analysis:

Calculated for Cg ^ H ^ gO ^: C, 71 »77 $ 5 H, 9.09 $.

Found: C, 71H, 9.17 # · 35 Nuclear Magnetic Resonance Spectrum (CDCl 3) & ppm: 0.90 (3H, triplet); **, 33 (1H, multiplet); 5 * 33 (1H, multiplet).

Infrared Absorption Spectrum (liquid film) "0 cm" "*: max ko 3 **** 0, 1735.

81 01 592 -25- PREVIEWED.P XXVII MB-55QA 8t Octanoate

Proceeding in the same manner as described in Example XVI, 96 mg of the desired product were prepared from MB-530A (304 mg) 5 and octanoyl chloride (0.11 ml).

Elemental analysis:

Calculated for ^ 7¾ ^: 72.65 #; H, 9.42 #

Found: C, 72.52 #; H, 9.50 #.

Nuclear Magnetic Resonance Spectrum (CDCl 3) ^ ppm: 0.85 (3H, wide triplet); 1.22 (12H, broad singlet); 4.19 (1H, multiplet); 5.23 (1H, multiplet).

Infrared Absorption Spectrum (liquid film) may cm ”1; 3400, 1735 EXAMPLE XXVIII ML-236A 5.8 diacetate

Proceeding in the same manner as described in Example III, 914 mg of the desired product were prepared from ML-236A (918 20 mg), pyridine (5ml) and acetic anhydride (1ml).

Elemental analysis:

Calculated for ^ 22 ^ 30 ^ 6: 67.69 #; H, 7.69 #.

Found: C, 67.44 #; H, 7.79 #

Nuclear Magnetic Resonance Spectrum (CDCl 3)% ppm: 1.89 (6H, singlet); 5.10 (2H, multiplet).

Infrared Absorption Spectrum (liquid film) o) cm ”: 1735, 1250, 1170.

EXAMPLE XXIX 30 ML-256A 3.8 * dibutyrate ML-236A (306 mg) and pyridine (0.5 ml) were dissolved in methylene chloride (3 ml) and the resulting solution was cooled with butyryl chloride (0.5 with ice) ml). The mixture was stirred at room temperature for 1 hour. The reaction mixture was then treated in the same manner as in Example II. The resulting residue was subjected to chromatography to give 384 mg of the desired product.

Elemental analysis:

Calculated for C 25 g H gg 69.96 #; H, 8.52 #.

Found: C, 70.14 #; H, 8.31 · 8101592 -26-

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

Infrared Absorption Spectrum (liquid film) ν 'may cm: 5 1735, 1250, 1175.

EXAMPLE XXX

ML-236A 3.8t-bis (4-pentenoate).

Proceeding in the same manner as described in Example XXIX, 405 mg of the desired product were prepared from ML-236A (306 10 mg), pyridine (0.5 ml) and 4-pentenoyl chloride (0.4 ml).

Elemental analysis:

Calculated for ^ 28 ^ 38 ^ 6: ^ "71.48 $; H, 8.09 #;

Found: C, 71.25 #; H, 8.30 #.

Nuclear Magnetic Resonance Spectrum (CDCl 3) ppm: 4.8 - 6.2 (11H, multiplet).

Infrared Absorption Spectrum (liquid film) ^ cm ”1: max 1735, ι64ο, 146ο, 1240, 1170.

EXAMPLE XXXI ML-256A 3, 8, Dioctanoate 20 Proceeding in the same manner as described in Example XXIX, 1.7 g of the desired product were prepared from ML-236A-X918 mg) and octanoyl chloride (1.4 ml).

Elemental analysis:

Calculated for C34H54 ° 6: C'73'12 ^; H 9 <68 ^ 25 Found: C, 72.95 #; H, 9.79 #.

Nuclear Magnetic Resonance Spectrum (CDCl 3) b ppm: 0.88 (6H, wide triplet); 1.32 (24H, broad singlet); 5.2 - 5.5 (2H, multiplet).

30 Infrared Absorption Spectrum (liquid film) cm ”max 1735, 1460, 1250, 1165.

EXAMPLE XXXII ML-236A 3 · 81-dipalmitate

Proceeding in the same manner as described in Example 35, 1.0 g of the desired product were prepared from ML-236A (415 mg) and palmitoyl chloride (0.71 ml).

Elemental analysis:

Calculated for C 14 Hg 50 C, 76.73 $; H, 11.00 #

Found: C, 76.99 #; H, 10.81 #.

40 Nuclear Magnetic Resonance Spectrum (CDCl 3) ppm: 8101592 <-27- 0.87 (6H, broad triplet); 1.25 (52H, broad singlet); 5.2-5.5 (2i, multiplet).

_ «» 1

Infrared Absorption Spectrum Liquid Film) V cm: 5 1735, 1460.

EXAMPLE XXXIII ML-236A 3,8'-dilinoleate

Proceeding in the same manner as described in Example XXIX, 804 mg of the desired product were prepared from ML-236A (306 10 mg) and linoleyl chloride (0.6 ml).

Elemental analysis:

Calculated for C 14 HggOg: C, 78.0? H, 10.36 #;

Found: C, 78.30 #; H, 10.19¾.

Nuclear Magnetic Resonance Spectrum (CDCl 3) & ppm: 0.90 (6H, wide triplet); 1.30 (36H, broad singlet); 5.1-6.2 (13H, multiplet).

Infrared Absorption Spectrum (liquid film) -p cm: 1740, 1460, 1240, 1170.

EXAMPLE XXXIV

MB-530 A 3.8 * dihexanoate

Proceeding in the same manner as described in Example XXIX, 440 mg of the desired product were prepared from M3-530A (330 mg) and hexanoyl chloride (0.5 ml).

25 Basic analysis:

Calculated for: C, 71.43 #; H, 9.52 #;

Found: C, 71.58 #; H, 9.30 #

Nuclear Magnetic Resonance Spectrum (CDCl 3) ^ ppm: 0.86 (3H, wide triplet); 0.91 (3H, broad triplet); 5.0-6.1 (5H, multiplet).

Infrared Absorption Spectrum (liquid film) ν cm: * max 1730.

EXAMPLE XXXV

35 MB-530 A 3.8 dioctanoate

Proceeding in the same manner as described in Example XXIX, 498 mg of the desired product were prepared from MB-53OA (330 mg), pyridine (0.5 µl) and octanoyl chloride (0.5 ml).

Elemental Analysis: 40 Calc'd for C 4 H 15 gO: C, 72.85 #; H, 10.00 #; 8101592 -28-

Found: C, 72.58 $; H, 10.18 $.

Nuclear magnetic. Resonance Spectrum (CDCl 3) S ppm; 0.82 (3H, broad triplet); 0.91 (3H, broad multiplet); 5 5.0 - 6.1 (5H, multiplet)

Infrared Absorption Spectrum (liquid film) -O cm: max 1730 EXAMPLE XXXVI ML-236B acetate NL-236B (7.8 g) was dissolved in dry pyridine (10 ral) and distilled acetic anhydride (4.5 ml) to the resulting solution. ) added · The reaction mixture was heated at 40-45 ° C for 1 hour with stirring. The reaction mixture was then poured into ice water, acidified with hydrochloric acid and extracted with benzene. The benzene layer was washed with water and dried over sodium-free sodium sulfate. The oily product obtained by evaporation of the solvent was subjected to silica gel chromatography using a mixture of benzene and ethyl acetate as eluent, using ML-236B acetate (7.3 g) obtained as an oily product.

This oily product was recrystallized from aqueous ethanol to yield ML-236B acetate (6.6 g) as white crystals melting at 48-51 ° C.

Elemental analysis:

Calculated for C ^ H ^ gOg: ^^^^ »^ 3 $ 25 Found: C, 69.35 $ i H, 8.50 $.

Nuclear Magnetic Resonance Spectrum (CDCl 3) $ ppm: 6.05 (1H, doublet); 5.80 (1H, doubled doublet); 2.8 (2H, doublet); 2.1 (3H, singlet).

Infrared Absorption Spectrum (KBr) Ϋ cm: 1740, 1710 EXAMPLE XXXVII ML-236B benzoate 35 ML-236B (7.8 g) was dissolved in dry pyridine (20 ml) and the resulting solution was cooled with ice with benzoyl chloride (4 1.2 g) added · The mixture was stirred at room temperature for 15 hours and then poured into ice water acidified with hydrochloric acid. The reaction product was then extracted with benzene, washed with water and dried over anhydrous sodium sulfate and the resulting solution concentrated by evaporation under reduced pressure. The concentrated oily product was separated and purified by silica gel chromatography. mixture of benzene and ethyl acetate as eluent

The purified product was recrystallized from a mixture of diethyl ether and hexane to obtain ML-23OB benzoate (9.1 g) as white crystals melting at 102-104 ° C.

Elemental analysis:

Calculated for C15 H15: C, 73.00 $; H, 7.70 $;

Found: C, 72.81 $; H, 7.75 $ · 10 Nuclear Magnetic Resonance Spectrum (CDCl 3) 5 PP®; 7.2 (5H, multiplet); 6.10 (1H, doublet); 5.82 (1H, doubled doublet); 2.82 (2H, doublet).

Cnujol is one. N% -1 15 Infrared Absorption Spectrum Bloomable Paraffin) V max cm: 1745, 1708 EXAMPLE XXXVIII ML-236B pivaloate ML-236B (7.8 g) was dissolved in dry pyridine (20 ml) and the resulting solution was pivaloyl chloride (3.6 g) added under ice-cooling · The mixture was stirred at room temperature for 1 hour and then poured into ice water acidified with hydrochloric acid · The reaction product was then extracted with benzene, the benzene extract was washed with water and dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The concentrated oily product was purified by silica gel chromatography. The purified product was recrystallized from aqueous ethanol to obtain ML-236B pivaloate (4.9 g) as white crystals which melt at 104-105 ° C30 Elemental analysis:

Calculated for ^ £ 8 ^ 42 ^ 6: 8.92 $

Found: C, 70.53 $; H, 8.86 $

Nuclear Magnetic Resonance Spectrum (CDCl 3) ppmppm: 6.00 (1H, doublet); 5.93 (1H double doublet); 5.52 (1H, multiplet); 5.22 (2H, multiplet); 4.38 (1H, multiplet); 2.63 (2H, doublet); 40 1.14 (9H, singlet), 8101592 -30- (nujol is a <Λ _1

Infrared Absorption Spectrum / liquid paraffin; y may cm: 1735, 1720.

EXAMPLE XXXIX ML-256B Phenoxy Acetate 5 ML-236B (7.8 g) was dissolved in dry pyridine (20 ml) and to the resulting solution was added phenoxyacetyl chloride (5.1 g) under ice-cooling. The mixture was stirred at room temperature for 1 hour and then poured into ice water acidified with hydrochloric acid. The reaction product was then extracted with ethyl acetate and the extract washed with water and dried over anhydrous sodium sulfate, then concentrated by evaporation under reduced pressure. The concentrated oily product was separated and purified by silica gel chromatography using a solvent system containing hexane, diethyl ether and ethyl acetate. The purified product was recrystallized from aqueous ethanol to give / ML-236B phenoxyacetate (2.5 g) as white crystals melting at b2-bk ° C.

Elemental analysis:

Calculated for C 1 H 30 O: C 70.97 $; H, $ 7.69;

Found: C, 70.89 $; H, 7.68 $.

20 Nuclear Magnetic Resonance Spectrum (CDCl 3) & ppm: 6.6 - 7Λ (5H, multiplet); 5.86 (1H, doublet); 5.65 (1H, doubled doublet); ^, 51 (2H, singlet); 25 M5 (1H, multiplet).

Infrared Absorption Spectrum / ^ i ^ i ^ ar4S paraffin-cm 2: ^: 17 ^ 0 (shoulder), 1725 * EXAMPLE XL MB-530B acetate 30 MB-530B (0.081 g) was dissolved in dry pyridine (0, 2 ml) and acetic anhydride (0.05 nil) was added to the resulting solution The mixture was stirred at room temperature for 2 hours and then poured into ice water acidified with hydrochloric acid The reaction product was then extracted with benzene and the benzene extract was washed with water and -35 dried over anhydrous sodium sulfate, then concentrated by evaporation under reduced pressure The concentrated oily product was separated and purified through a silica gel column (Lobar column; from Merck Co., USA). The purified product was recrystallized from a mixture of diethyl ether and hexane to obtain MB-530B acetate (0.076 g) 40 as white needles melting at 92-93 ° C.

8101592 -31-

Elemental analysis:

Calcd for C 7 H 15 g C, 69.93 $; H, 8.58 #;

Found: C, 69.71 $; H, 8.60 #

Nuclear Magnetic Resonance Spectrum (CDCl 3) S ppm: 6.06 (1H, doublet); 5 »88 (1H, doubled doublet); 2.73 (2H, doublet); 2.10 (3H, singlet).

Infrared Absorption Spectrum (liquid paraffin) "5? Y cm" "*: 10 1736, 1720.

EXAMPLE XLI MB-530B benzoate

Acting essentially in the same manner as described in Example XL, MB-530B benzoate (0.09 g) was prepared from MB-530B (0.081 g) and benzoyl chloride (0.0Mf g).

Nuclear Magnetic Resonance Spectrum (CDCl 3) & ppm: 8.1 (2H, multiplet); 7.6 (3H, multiplet); 6.01 (1H, doublet); 20 δ5 (1H, doubled doublet); 2.78 (2H, doublet).

Infrared Absorption Spectrum (liquid film) ^ cm: 1750 - 1720, 1600, 1380.

25 8101592

Claims (26)

1. Compounds suitable as medicaments and as chemical intermediates, characterized in that they have the formula 1 of the formula sheet wherein: 1 2 R and R are the same or different and each represents a hydrogen atom or an acyl group, and R 1 a hydrogen atom or a methyl group; 1 2 3 provided that when R represents a hydrogen atom, R and R both do not represent hydrogen atoms and R does not pre-form a c * -methylbutyryl group. Compounds according to claim 1, characterized in that at least one of the substituents R and R represents a saturated or unsaturated aliphatic acyl group, an aromatic acyl group or an araliphatic acyl group. 3 * Compounds according to claim 1, characterized in that at least one of the substituents R and R is a formyl group, a straight or branched C 1 -C 6 q alkanoyl group, a straight or branched C 1 -C 6 q alkenoyl group, one benzoyl group, a benzoyl group with one or more substitute! # grafting in the phenyl moiety represents a phenylalkanoyl group, / phenylalkanoyl group having one or more substituents in the phenyl moiety, a phenylalkenoyl group, or a phenylalkenoyl group having one or more substituents in the phenyl moiety, these substituents being selected from C 1 -C 6 alkyl groups C 1 -C 6 alkoxy groups, hydroxy groups, methylenedioxy groups, halogen atoms and trifluoromethyl groups. Compounds according to claim 1, characterized in that R 1 represents a hydrogen atom; and R is a straight or branched chain, alkane, straight chain or branched chain C 1 -C 6 q alkenoyl group or an unsubstituted benzoyl group. Compounds according to claim 4, characterized in that R represents a straight or branched chain C 1 -C 8 alkanoyl group or a straight or branched chain C 1 -C 8 alkenoyl group. 6. Compounds according to claim 5, characterized in that R represents a butyryl, isobutyryl, 4-propenoyl or isovaleryl group. Compounds according to claim 1, characterized in that: Λ R represents a straight or branched chain ^ 20 ^ anoyl group een a straight or branched chain C 1 -C 2 q alkenoyl group or an unsubstituted benzoyl group; and 2 40. a hydrogen atom or a m-methylbutyryl group. 8101592 -33- Compounds according to claim 7, characterized in that R represents a straight or branched C 1 -C 6 alkanoyl group, a straight or branched chain C 1 -C 8 alkenoyl group or an unsubstituted benzoyl group. 9- Compounds according to claim 7, characterized in that R represents an acetyl, butyryl, isobutyryl, 4-propenoyl, isovaleryl, hexanoyl or benzoyl group; and 2 R is an Or-methylbutyryl group. Compounds according to claim 1, characterized in that R and R are the same or different and each has a straight or branched chain C 1 -C 8 alkanoyl group, a straight or branched chain C 1 -C 8 alkenoyl group or represent an unsubstituted benzoyl group. Compounds according to claim 10, characterized in that 15. represent an acetyl, butyryl, isobutyryl, 4-propenoyl, isova leryl, hexanoyl or benzoyl group; and 2 R a butyryl, isobutyryl, -propenoyl or isovaleryl group. Compounds according to claim 1, characterized in that they are: 20 MB-530A ML-236A 8'-butyrate ML-236A 8'-isobutyrate ML-236A 8'-isovalerate MB-530A 8f-butyrate 25 MB-530A 8'-Isovalerate ML-236A 8 '- (if pentenoate) ML-236A 3, S, Diacetate ML-236A 3.8 * Dibutyrate and ML-236A 3.8' Di (^ f -pentenoate). Process for preparing MB-530A, characterized in that an MB-530A-forming microorganism of the genus Monascus is grown in a culture medium therefor and separated from the resulting culture liquid MB-530A · 1 * 1 ·. Method according to claim 13, characterized in that the microorganism of the strain is Monascus ruber. Method according to claim 1 * 1, characterized in that the microorganism is Monascus ruber SANK 15177 (FERM ^ 95 ^, NRRL 12081). 16 · Process for the preparation of a compound of formula 1 1 2 kO of the formula sheet in which one of the substituents R and R is a hydrogen 3101592 -34-> | atom and the other represents an acyl group (provided that H does not represent hydrogen atom 2 if R is an (X-methylbutyryl group); or 1 2 R and R both represent acyl groups; and 3 R represents a hydrogen atom or a methyl group, characterized in that a compound of formula 1 wherein one 1 or both of the substituents R and R represent hydrogen atoms are acylated with an acylating agent The process according to claim 16, characterized in that the acylation is carried out with a reactive carboxylic acid derivative or with a carboxylic acid in the presence of a condensing agent. 18. Process according to claim 17j, characterized in that the acylating agent is an acid anhydride or acid halide and the acylation is carried out in the presence of an organic base. Process according to claim 18, characterized in that the organic base is pyridine. 20. Process according to claim 18, characterized in that the acylating agent is an acid anhydride or halide and the acylation is carried out in the presence of an organic base 20 at a temperature of -20 to 0 ° C to form a monoester as the main product . A method according to claim 20, characterized in that the acylating agent is an acid halide in an amount of about 1 equivalent per equivalent of the compound of formula 1. A method according to claim 18, characterized in that the acylating agent is an acid anhydride or acid halide in an amount of not less than 2 equivalents per equivalent of the compound of formula 1 and the acylation is carried out in the presence of an organic base at a temperature above room temperature to form the diester as the main product. The method according to claim 16, characterized in that the acylation is carried out with a carboxylic acid in the presence of a condensing agent. The process according to claim 16, characterized in that the following compounds are prepared: ML-236A 8'-butyrate ML-236A 8'-isobutyrate ML-236A 8'-isovalerate MB-530B 8'-butyrate 40 MB-530B 8'-Isovalerate 8101592 ί V -35- ML-236A 8 '- (^ f-pent enoate) ML-236A 3,8'-Diacetate ML-236A 3181-dibutyrate or ML-236A 3 »8' -di (4-pentenoate) Pharmaceutical composition containing a pharmaceutically portable carrier or diluent and an active ingredient, characterized in that the active ingredient is one or more of the compounds of formula 1, wherein 1 2 R and R are the same or different and each a hydrogen-10 atom or an acyl group, and R 1 represents a hydrogen atom or a methyl group; 1 2 3 provided that when R represents a hydrogen atom, R and R do not both represent hydrogen atoms and R does not represent ü (-methylbutyryl group). 26. Pharmaceutical preparation according to claim 25, characterized in that the active ingredient consists of: ML-236A 8'-butyrate ML-236A 8'-isobutyrate ML-236A 8 * isovalerate MB-530A 8'-butyrate 20 MB-530 ^ 8'-Isovalerate ML-236A 8 * - (Jf Pentenoate) ML-236A 3,8'-Diacetate ML-236A 3,8'-Dibutyrate or 25 ML-236A 3T 8-di (4-pentenoate) 8101592