GB2073193A - Inhibitors of Cholesterol Biosynthesis, their Preparation and Use - Google Patents

Inhibitors of Cholesterol Biosynthesis, their Preparation and Use Download PDF

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GB2073193A
GB2073193A GB8110075A GB8110075A GB2073193A GB 2073193 A GB2073193 A GB 2073193A GB 8110075 A GB8110075 A GB 8110075A GB 8110075 A GB8110075 A GB 8110075A GB 2073193 A GB2073193 A GB 2073193A
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Sankyo Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/02—Oxygen as only ring hetero atoms
    • C12P17/06—Oxygen as only ring hetero atoms containing a six-membered hetero ring, e.g. fluorescein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/30—Oxygen atoms, e.g. delta-lactones

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

SPECIFICATION Inhibitors of Cholesterol Biosynthesis, their Preparation and Use The present invention relates to a series of new compounds having inhibitory activity against the biosynthesis of cholesterol and which are derivatives of certain compounds designated ML-236A and MB-530A. The invention also provides a process for preparing these compounds.
Hyperlipaemia, especially hypercholesteraemia, is known to be one of the main causes of cardiopathy, such as cardiac infarction or arteriosclerosis. As a result, considerable research has been carried out in an effort to discover compounds capable of reducing lipid, and especially cholesterol, levels in the blood. A group of compounds of this type is disclosed in U.S. Patent Specification No.
3983,140 and is isolated from microorganisms of the genus Penicillium: this group of compounds is collectively designated ML-236.
In US Patent Applications Serial No. 121,515, filed 14 February, 1980, and No. 137,821,filed4 April, 1980, another such compound, which has been designated Monacolin K or MB-530B, is disclosed and this may be prepared by cultivating microorganisms of the genus Monascus, especially strains of Monascus ruber.
We have now discovered a series of compounds related to ML-236 and MB-5303 which have better development of activity as a result of their improved absorption on oral administration and easier availability as a pro-drug (i.e. a drug which is converted to an active or more active form after administration by chemical or bio-chemical reactions in the body).
ML-236A and ML-236B (two of the compounds in the ML-236 complex disclosed in US Patent No.3,983,140) have the formulae (II) and (III), respectively:
whilst MB-530B (or Monacolin K) has the formula (IV):
The new compounds of the invention are those compounds of formula (I):
wherein R1 and R2 are the same or different and each represents a hydrogen atom or an acyl group; and R3 represents a hydrogen atom or a methyl group; provided that, where R' represents a hydrogen atom, R2 and R3 do not simultaneously represent hydrogen atoms, and R2 does not represent an amethylbutyryl group.
The compound of the invention in which R1 and R2 both represent hydrogen atoms and R3 represents a methyl group, i.e. the compound of formula (V):
which has been designated MB-530A, can be prepared by cultivating an MB-530A-producing microorganism of the genus Monascus in a culture medium therefor and separating the produced MB530A from the resulting culture medium.
The other compounds of the invention, which may be regarded as 3- and/or 8'-acylated derivatives of ML-236A or MB-530A may be prepared by acylating ML-236A, ML-236B, MB-530A or MB-530B. For clarity these acylated derivatives are referred to herein as esters of the compound (ML236A, ML-236B, MB-530A or MB-530B) from which they were derived by acylation.
For the avoidance of doubt, the numbering system employed in defining the compounds of the invention is shown as follows:
Where one or both of R1 and R2 represents an acyl 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 having from 2 to 20 carbon atoms, preferably from 2 to 6 carbon atoms; and straight or branched chain alkenoyl groups having from 3 to 20 carbon atoms, more preferably from 2 to 6 carbon atoms.
Preferred saturated aliphatic acyl groups are the formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, hexanoyl, 2-methylvaleryl, 3-methylvaleryl, 4-methylvaleryl, 2-ethylbutyryl, heptanoyl, octanoyl, 2-ethylhexanoyl, nonanoyl, isononanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, palmitoyl, stearoyl, isostearoyl, nonadecanoyl, eicosanoyl or pivaloyl groups.
Examples of suitable unsaturated aliphatic acyl groups include the acryloyl, 3-butenoyl, methacryloyl, 2-pentenoyl, 4-pentenoyl, 2-undecenoyl, 4-undecenoyl, 2-tridecenoyl, 2-tetradecenoyl, 2-hexadecenoyl, linolenoyl, linoleyl, arachidonoyl, propioloyl crotonoyl, tigloyl, angeloyl, senecioyl, 2- heptenoyl, 2-octenoyl and 2-nonenoyl groups.
Where R1 and/or R2 represents an aromatic acyl group, this is preferably a benzoyl group optionally having one or more substituents in its phenyl moiety. Such substituents are preferably C1- C4 alkyl groups, C1-C4 alkoxy groups, hydroxy groups, methylenedioxy groups, halogen atoms or trifluoromethyl groups. Such substituents may be in any of the ortho, meta or para positions and, where there are two or more substituents, these may be the same or different.
Examples of such benzoyl groups having a single substituent include the methylbenzoyl, ethylbenzoyl, propylbenzoyl, butylbenzoyl, methoxybenzoyl, ethoxybenzoyl, propoxybenzoyl, butoxybenzoyl, hydroxybenzoyl, chlorobenzoyl, bromobenzoyl and fluorobenzoyl groups, in which the substituents may be at any of the ortho, meta or para positions. Examples of such groups having two or more substituents include the 2,3-dimethoxybenzoyl, 2,4-dimethoxybenzoyl, 2,5-dimethoxybenzoyl, 2.6-dimethoxybenzoyl, 2,4,6-trimethoxybenzoyl, 3,4,5-trimethoxybenzoyl, 3,4-methylenedioxybenzoyl and 2,3-methylenedioxybenzoyl.
Where R1 and/or R2 represents an araliphatic acyl group, this is preferably a phenylalkanoyl group optionally having one or more substituents in the phenyl moiety. The alkanoyl group of this phenylalkanoyl group is preferably a C2-C4 alkanoyl group (preferably an acetyl, propionyl or butyryl group) and the substituents are preferably C1-C4 alkyl groups, C1-C4 alkoxy groups, hydroxy groups, methylenedioxy groups, halogen atoms or trifluoromethyl groups. These substituents may be at any of the ortho, meta or para positions and, where there are two or more substituents, these may be the same or different.
Examples of such araliphatic acyl groups include the cinnamoyl, chlorocinnamoyl, bromocinnamoyl, methoxycinnamoyl, methylcinnamoyl, phenylacetyl, phenoxyacetyl and phenylpropionyl groups, the substituents on said cinnamoyl groups being in any of the ortho, meta or para positions.
Alternatively, although less preferred, R' and/or R2 may represent a heterocyclic acyl group (e.g.
2-furoyl, 2-thenoyl, 3-thenoyl, nicotinoyl or isonicotinoyl) or a heterocyclic-substituted aliphatic acyl group (e.g. 2-thienyiacetyl, 3-thienylacetyl, 2-furylacetyl, 3-furylacetyl, 2-thienylacryloyl, 3- thienylacryloyl, 2-furylacryloyl or 3-furylacryloyl), or an alicyclic acyl group; this is preferably a cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, cyclooctanecarbonyl, cyclohexaneacetyl, 3-cyclohexanepropionyl, 4- cyclohexanebutyryl or 1 -adamantanecarbonyl group.
Examples of compounds of the invention include the following: ML-236A and MB-530A 3,8'-diformate ML-236A and MB-530A 3,8'-diacetate ML-236A and MB-530A 3,8'-dipropionate ML-236A and MB-530A 3,8'-dibutyrate ML-236A and MB-530A 3,8'-diisobutyrate ML-236A and MB-530A 3,8'-divalerate ML-236A and MB-530A 3,8'-diisovalerate ML-236A and MB-530A 3,8'-dipivalate ML-236A and MB-530A 3,8'-dihexanoate ML-236A and MB-530A 3,8'-diheptanoate ML-236A and MB-530A 3,8'-bis(2-methylvalerate) ML-236A and MB-530A 3,8'-bis(3-methylvalerate) ML-236A and MB-530A 3,8'-bis(2-ethylbutyrate) ML-236A and MB-530A 3,8'-dioctanoate ML-236A and MB-530A 3,8'-bis(2-ethylhexanoate) ML-236A and MB-530A 3,8'-dinonanoate ML-236A and MB-530A 3,8'-diisononanoate ML-236A and MB-530A 3,8'-diundecanoate ML-236A and MB-530A 3,8'-ditetradecanoate ML-236A and MB-530A 3,8'-dipentadecanoate ML-236A and MB-530A 3,8'-dipaimitate ML-236A and MB-530A 3,8'-distearate ML-236A and MB-530A 3,8'-diisostearate ML-236A and MB-530A 3,8'-dinonadecanoate ML-236A and MB-530A 3,8'-dieicosanoate ML-236A and MB-530A 3,8'-bis(1-adamantanecarboxylate) ML-236A and MB-530A 3,8'-dicyclopropanecarboxylate ML-236A and MB-530A 3,8'-dicyclobutanecarboxylate ML-236A and MB-530A 3,8'-dicyclopentanecarboxylate ML-236A and MB-530A 3,8'-dicyclohexanecarboxylate ML-236A and MB-530A 3,8'-dicycloheptanecarboxylate ML-236A and MB-530A 3,8'-dicyclooctanecarboxylate ML-236A and MB-530A 3,8'bis(cyclohexaneacetate) ML-236A and MB-530A 3,8'-bis(3-cyclohexanepropionate) ML-236A and MB-530A 3,8'-bist4-cyclohexanebutyrate) ML-236A and MB-530A 3,8'-diacrylate ML-236A and MB-530A 3,8'-dipropiolate ML-236A and MB-530A 3,8'-dicrotonate ML-236A and MB-530A 3,8'-bis(3-butenoate) ML-236A and MB-530A 3,8'-dimethacrylate ML-236A and MS-530A 3,8'-bis(2-pentenoate) ML-236A and MB-530A 3,8'-bis(4-pentenoate) ML-236A and MB-530A 3,8'-ditiglate ML-236A and M8-530A 3,8'-diangelate M L-236A and MB-530A 3,8'-disenecioate ML-236A and MB-530A 3,8'-bis(2-heptenoate) ML-236A and MB-530A 3,8'-bis(2-octenoate) ML-236A and MB-530A 3,8'-bis(2-nonenoate) ML-236A and MB-530A 3,8'-dilinoleate ML-236A and MB-530A 3,8'-dioleate ML 236A and MB-530A 3,8'-dilinolenate ML-236A and MB-530A 3,8'-dicinnamate ML-236A and MB-530A 3,8'-bis(o-chlorocinnamate) ML-236A and MB-530A 3,8'-bis(m-chlorocinnamate) ML-236A and MB-530A 3,8'-bis(p-chlorocinnamate) ML-236A and MB-530A 3,8'-bis(o-bromocinnamate) ML-236A and MB-530A 3,8'-bis(m-bromocinnamate) ML-236A and MB-530A 3,8'-bis(p-bromocinnamate) ML-236A and MB-530A 3,8'-bis(o-methoxycinnamate) ML-236A and MB-530A 3,8'-bis(m-methoxycinnamate) ML-236A and MB-530A 3,8'-bis(p-methoxycinnamate) ML-236A and MB-530A 3,8'-bis(o-methylcinnamate) ML-236A and MB-530A 3,8'-bis(m-methylcinnamate) ML-236A and MB-530A 3,8'-bis(p-methylcinnamate) ML-236A and MB-530A 3,8'-bis(phenylacetate) ML-236A and MB-530A 3,8'-bis(phenoxyacetate) ML-236A and MB-530A 3,8'-bis(3-phenylpropionate) ML-236A and M8-530A 3,8'-bis(2-thienylacetate) ML-23 6A and M B-530A 3,8'-bis(2-furylacetate) ML-236A and MB-530A 3,8'-bis(2-thiophenecarboxylate) ML-236A and MB-530A 3,8'-bis(2-furoate) ML-236A and MB-530A 3,8'-bis(2-thienylacrylate) ML-236A and MB-530A 3,8'-bis(2-furylacrylate) ML-236A and MB-530A 3,8'-bis(3-furoate) ML-236A and MB-530A 3,8'-dinicotinate ML-236A and MB-530A 3,8'-diisonicotinate ML-236A and MB-530A 3,8'-dibenzoate ML-236A and MB-530A 3,8'-bis(o-methylbenzoate) M L-23 6A and MB-530A 3,8'-bis(m-methylbenzoate) ML-236A and MB-530A 3,8'-bis(p-methylbenzoate) ML-236A and MB-530A 3,8'-bis(o-ethylbenzoate) ML-236A and MB-530A 3,8'-bis(m-ethylbenzoate) ML-236A and MB-530A 3,8'-bis(p-ethylbenzoate) ML-236A and MB-530A 3,8'-bis(o-propylbenzoate) ML-236A and M B-530A 3,8'-bis(m-propylbenzoate) ML-236A and MB-530A 3,8'-bis(p-propylbenzoate) ML-236A and MB-530A 3,8'-bis(o-butylbenzoate) ML-236A and MB-530A 3,8'-bis(m-butylbenzoate) ML-236A and MB-530A 3,8'-bis(p-butylbenzoate) ML-236A and MB-530A 3,8'-bis(o-methoxybenzoate) ML-236A and MB-530A 3,8'-bis(m-methoxybenzoate) ML-236A and MB-530A 3,8'-bis(p-methoxybenzoate) ML-236A and MB-530A 3,8'-bis(o-ethoxybenzoate) ML-236A and MB-530A 3,8'-bis(m-ethoxybenzoate) ML-236A and M B-530A 3,8'-bis(p-ethoxybenzoate) ML-236A and MB-530A 3,8'-bis(o-propoxybenzoate) ML-236A and MB-530A 3,8'-bis(m-propoxybenzoate) ML-236A and MB-530A 3,8'-bis(p-propoxybenzoate) M L-236A and MB-530A 3,8'-bis(o-butoxybenzoate) ML-236A and MB-530A 3,8'-bis(m-butoxybenzoate) ML-236A and MB-530A 3,8'-bis(p-butoxybenzoate) ML-236A and MB-530A 3,8'-bis(o-hydroxybenzoate) ML-236A and MB-530A 3,8'-bis(m-hydroxybenzoate) ML-236A and MB-530A 3,8'-bis(p-hydroxybenzoate) ML-236A and MB-530A 3,8'-bis(2,3-dimethoxybenzoate) M L-23 6A and M B-530A 3,8'-bis(2,4-dimethoxybenzoate) 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 M8-530A 3,8'-bis(2,4,6-trimethoxybenzoate) ML-236A and MB-530A 3,8'-bis(3,4, 5-trimethoxybenzoate) ML-236A and M8-530A 3,8'-bis(3,4-methylenedioxybenzoate) ML-236A and MB-530A 3,8'-bis(2,3-methylenedioxybenzoate) ML-236A and MB-530A 3,8'-bis(o-chlorobenzoate) ML-236A and M B-530A 3,8'-bis(m-chlorobenzoate) ML-236A and MB-530A 3,8'-bis(p-chlorobenzoate) M L-23 6A and MB-530A 3,8'-bis(o-bromobenzoate) ML-236A and MB-530A 3,8'-bis(m-bromobenzoate) M L-236A and MB-530A 3,8'-bis(p-bromobenzoate) M L-236A and MB-530A 3,8'-bis(o-fluorobenzoate) ML-236A and MB-530A 3,8'-bis(m-fluorobenzoate) ML-236A and MB-530A 3,8'-bis(p-fluorobenzoate) ML-2368 and MB-530B acetate ML-2368 and MB-530B propionate ML-236B and MB-530B butyrate ML-236B and M8-530B isobutyrate ML-236B and MB-530B valerate ML-236B and MB-5308 isovalerate ML-236B and MB-530B pivalate ML-236B and MB-530B hexanoate ML-236B and MB-530B heptanoate ML-236B and MB-530B (2-methylvalerate) M L-236B and MB-530B (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 ML-2368 and MB-530B isononanoate ML-236B and MB-530B undecanoate ML-236B and MB-5308 tetradecanoate ML-236B and M B-5308 pentadecanoate ML-236B and MB-5308 palmitate ML-236B and MB-530B stearate ML-236B and MB-530B isostearate ML-236B and MB-530B nondecanoate ML-236B and MB-530B eicosanoate ML-236B and MB-530B (1-adamantanecarboxylate) ML-23 6B and MB-530B cyclopropanecarboxylate ML-236B and MB-530B cyclobutanecarboxylate ML-236B and MB-5308 cyclopentanecarboxylate ML-236B and MB-530B cyclohexanecarboxylate ML-2368 and MB-530B cycloheptanecarboxylate M L-236B and MB-530B cyclooctanecarboxylate ML-236B and MB-S3OB cyclohexaneacetate ML-236B and MB-530B (3-cyclohexanepropionate) ML-236B and MB-530B acrylate ML-236B and MB-530B propiolate 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 senecioate ML-236B and MB-5306 (3-butenoate) M L-236B and MB-530B (2-pentenoate) ML-236B and MB-53OB linoleate ML-236B and MB-530B oleate ML-236B and MB-530B linolenate ML-236B and MB-530B cinnamate ML-236B and MB-530B (o-chlorocinnamate) ML-236B and MB-5308 (m-chlorocinnamate) ML-236B and MB-530S (p-chlorocinnamate) ML-236B and MB-530B (o-bromocinnamate) ML-23 6B and MB-530B (m-bromocinnamate) ML-236B and MB-530B (p-bromocinnamate) ML-236B and MB-530B (o-methoxycinnamate) ML-236B and MB-530B (m-methoxycinnamate) M L-236B and MB-530B (p-methoxycinnamate) ML-2368 and MB-530B (o-methylcinnamate) ML-236B and MB-530B (m-methylcinnamate) ML-236B and M8-530B (p-methylcinnamate) ML-236B and MB-530B phenylacetate ML-2368 and MB-530B phenoxyacetate ML-236B and MB-530B (3-phenylpropionate) ML-236B and MB-530B (2-thienylacetate) ML-236B and MB-530B (2-furylacetate) ML-236B and MB-530B (2-thiophenecarboxylate) ML-236B and MB-530B (2-furoate) ML-236B and MB-530B (2-thienylacrylate) ML-236B and MB-530B (2-furylacrylate) ML-2368 and MB-530B (3-furoate) ML-236B and MB-530B nicotinate ML-236B and MB-530B isonicotinate ML-236B and MB-530B benzoate ML-236B and MB-530B (o-methylbenzoate) ML-236B and MB-530B (m-methylbenzoate) ML-236B and MB-530B (p-methylbenzoate) ML-236B and MB-530B (o-ethylbenzoate) ML-236B and MB-530B (m-ethylbenzoate) ML-236B and MB-530B (p-ethylbenzoate) ML-236B and MB-530B (o-propylbenzoate) ML-236B and MB-530B (m-propylbenzoate) ML-236B and MB-530B (p-propylbenzoate) ML-236B and MB-530B (o-butylbenzoate) ML-236B and MB-530B (m-butylbenzoate) ML-236B and MB-530B (p-butylbenzoate) ML-236B and MB-530B (o-methoxybenzoate) ML-2368 and MB-5308 (m-methoxybenzoate) ML-236B and MB-5308 (p-methoxybenzoate) ML-236B and MB-530B (o-ethoxybenzoate) ML-2368 and MB-530B (m-ethoxybenzoate) ML-236B and MB-530B (p-ethoxybenzoate) ML-236B and MB-530B (o-propoxybenzoate) ML-236B and MB-530B (m-propoxybenzoate) ML-236B and MB-530B (p-propoxybenzoate) ML-236B and MB-530B (o-butoxybenzoate) ML-236B and MB-530B (m-butoxybenzoate) ML-236B and MB-530B (p-butoxybenzoate).
ML-236B and MB-236B (o-hydroxybenzoate) ML-236B and MB-530B (m-hydroxybenzoate) ML-236B and MB-530B (p-hydroxybenzoate) ML-236B and MB-530B (2,3-dimethoxybenzoate) ML-236B and MB-530B (2,4-dimethoxybenzoate) ML-236B and MB-530B (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 (3,4,5-trimethoxybenzoate) ML-236B and MB-530B (3,4-methylenedioxybenzoate) ML-236B and MB-530B (2,3-methylenedioxybenzoate) ML-236B and MB-530B (o-chlorobenzoate) ML-236B and M8-53OB (m-chiorobenzoate) ML-236B and MB-530B (p-chlorobenzoate) ML-236B and MB-530B (o-bromobenzoate) ML-236B and MB-530B (m-bromobenzoate) ML-236B and MB-530B (p-bromobenzoate) ML-236B and MB-530B (o-fluorobenzoate) ML-236B and MB-530B (m-fluorobenzoate) ML-236B and MB-530B (p-fluorobenzoate) For brevity, there are listed above only the diesters of ML-236A and MB-530A, however, it will be appreciated that each of the corresponding 3-monoesters and 8'-monoesters is also possible.Of these compounds, the following are particularly preferred: ML-236A 8'-butyrate ML-236A 8'-isobutyrate ML-236A 8'-isovalerate MB-530A 8'-butyrate MB-530A 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).
MB-530A, which is one of the compounds of the invention, may be prepared by cultivating an MB-530A producing microorganism of the genus Monascus, preferably a strain of Monascus ruber and most preferably Monascus ruber SANK 1 5177. This strain was deposited on 27 April, 1979, under the Accession No. FERM 4956 with The Fermentation Research Institute, Agency of Industrial Science and Technology, Ministry of International Trade and Industry, Japan, and on 25 January 1980 under the Accession No. NRRL 1 2081 with the Agricultural Research Service Culture Collection, Northern Regional Research Laboratory, Peoria, Illinois, U.S.A..The morphology and physiology of this strain are described in more detail in US Patent Application Serial No. 137,821,filed filed 4 1980.
The desired MB-530A may be produced by cultivating the chosen microorganism in a culture broth under aerobic conditions, using the same techniques as are well-known in the art for the cultivation of fungi and other microorganisms. For example, the chosen strain of Monascus may first be cultivated on a suitable medium and then the produced microorganisms may be collected and inoculated into and cultivated on another culture medium to produce the desired MB-530A; the culture medium used for the multiplication of the microorganism and the culture medium used for the production of MB-530A may be the same or different.
Any culture medium well-known in the art for the cultivation of fungi may be employed, provided that it contains, as is well-known, the necessary nutrient materials, especially an assimilable carbon source and an assimilable nitrogen source. Examples of suitable sources of assimilable carbon include glucose, maltose, dextrin, starch, lactose, sucrose and glycerine. Of these sources, glucose, glycerine and starch are particularly preferred for the production of MB-530A. Examples of suitable sources of assimilable nitrogen are peptone, meat extract, yeast, yeast extract, soybean meal, peanut meal, corn steep liquor, rice bran and inorganic nitrogen sources. Of these nitrogen sources, corn steep liquor and peptone are particularly preferred. When producing MB-530A, an inorganic salt and/or a metal salt may, if necessary, be added to the culture medium. Furthermore, if necessary, a minor amount of a heavy metal may also be added.
The microorganism is preferably cultivated under aerobic conditions using cultivation methods well-known in the art, for example solid culture, shaken culture or culture under aeration and agitation.
The microorganism will grow over a wide temperature range, e.g. from 7 to 400C, but, especially for the production of MB-530A, the more preferred cultivation temperature is within the range from 20 to 300C.
During the cultivation of the microorganism, the production of MB-530A may be monitored by sampling the culture medium and measuring the physiological activity of the medium by well-known tests. Cultivation may then be continued until a substantial accumulation of MB-530A has been achieved in the culture medium, at which time the MB-530A may then be isolated and recovered from the culture medium and the tissues of the microorganism by any suitable combination of isolation techniques, chosen having regard to its physical and chemical properties.For example, any or all of the following isolation techniques may be employed: extraction of the liquor from the culture broth with a hydrophiiic 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, e.g. by evaporating off some or part of the solvent under reduced pressure; dissolution into a more polar solvent (such as acetone or an alcohol); removal of impurities with a less polar solvent (such as petroleum ether or hexane); gel filtration through a column of a material such as Sephadex (a trade name for a material available from Pharmacia Co. Limited, U.S.A.); absorptive chromatography with active carbon or silica gel; and other similar methods.By using a suitable combination of these techniques, the desired MB530A can be isolated from the culture broth as a pure substance.
Similarly, the other known starting materials for the acylation process of the invention, that is to say ML-236A, ML-236B and MB-530B can be produced from culture media containing the appropriate microorganism using techniques as outlined above or as described in U.S. Patent Specification No.
3983,140, or U.S. Applications Serial No. 121,515 filed 14 February, 1980 or No. 137,821,filed 4 April, 1980.
The acylated derivatives of the present invention may be prepared from ML-236A, ML-236B, MB-530A or MB-530B by any of the following Methods: Method 1 ML-236A, ML-236B, MB-530A or ML-530B is reacted with an acid chloride or acid anhydride appropriate to the acyl derivative which it is intended to produce. The reaction is preferably carried out in the presence of a base (which acts as an acid-binding agent" preferably an organic amine, such as pyridine, triethylamine, N,N-dimethylaminopyridine, 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 include chloroform, methylene chloride and diethyl ether.In some cases, it is possible to carry out the reaction using as solvent an excess of one of the reagents or of the base. The reaction will take place over a wide range of temperatures, although, in order to control the reaction properly, a relatively low temperature is normally preferred, for example from -200C to room temperature, more preferably from -200C to OOC. However, higher temperatures may also be employed, if desired.
Method 2 A carboxylic acid is treated with a chlorocarbonate ester or with a sulphonic acid chloride in the presence of a base, for example one of the organic amines rnentioned above, to prepare a mixed acid anhydride and this is, in turn, reacted with ML-236A, ML-236B, MB-530A or MB-530B. The reaction is preferably effected n presence of a solvent, the nature of which is not critical, provided that it has no adverse effect upon the reaction. Suitable solvents include, for example, diethyl ether, benzene, chloroform and methylene chloride. The reaction will take place over a wide range of temperatures, for example from --200C to room temperature, preferably from -200C to OOC.
Method 3 ML-236A, ML-236B, MB-530A or MB-530B is reacted with a carboxylic acid and a diazoalkyl dicarboxylate in the presence of, for example, dicyclohexylcarbodiimide, triphenylphosphine or dimethylphosphorous amide. The reaction is preferably effected in the presence of a solvent, the nature of which is not critical, provided that it has no adverse effect upon the reaction. Suitable solvents include 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 upon the reagents and the reaction temperature. After completion of the reaction, the desired product may be separated from the reaction mixture by conventional means, e.g. by evaporating the solvent from a solution containing the desired product (which solution may be simply the reaction mixture or may be a solution obtained by extracting the reaction mixture with an organic solvent), optionally after washing and drying the solution, after which the product may be purified by conventional means, for example by column chromatography, thin layer chromatography or recrystallization or by any combination thereof.
Where the starting material for the acylation reaction contains two hydroxyl groups, i.e. where it is ML-236A or MB-530A, the reactions described above are capable of producing the 3-monoester, the 3,8'-diester or the 8'-monoester or a mixture thereof. The nature of the product obtained can be influenced by varying the quantities of reagents, the reaction temperature and other reaction conditions and, although the reasons are not understood, it is believed that the 3-monoester is preferentially formed, followed by the 3,8'-diester and the 8'-monoester. However, in the case of any particular reaction, the skilled man can easily determine which are the optimum conditions for producing the particular product desired.In general, the following will be achieved: The 3-monoester and/or 8-monoester will be produced predominantly by carrying out the reaction using, as acylating agent, an acid anhydride or halide in the presence of an organic base at a temperature from 20at to OOC. The amount of acylating agent, preferably the acid halide, is preferably about 1 equivalent per equivalent of ML-236A, ML-236B, MB-530A or MB-530B.
The 3,8'-diester is predominantly produced where the acylating agent employed is an acid anhydride or halide in an amount of at least 2 equivalents per equivalent of ML-236A, ML-236B, MB530A or MB-530B, and the acylation is effected in the presence of an organic base at a temperature above room temperature.
The compounds of the invention have been found to have a specific inhibitor activity against 3hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), which is the rate-controlling enzyme in the biosynthesis of cholesterol. The inhibitory activities of certain of the compounds of the invention against the biosynthesis of cholesterol are shown in the following Table in terms of their 150 values (that is to say, the concentration in yg/ml which results in a 50% inhibition of cholesterol biosynthesis), as measured by the method of Knaus et al., J. Biol. Chem. 234, 2835 (1959).
Table
R1 R2 R3 /50 ( g/ml) Acetyl H H 0.21 Butyryl H H 0.10 Isobutyryl H H 0.29 Butyryl H CH3 0.39 4-Pentenoyl H H 0.17 H Butyryl H 0.017 H Butyryl CH3 0.021 H Isobutyryl H 0.061 H Isovaleryl H 0.039 H Isovaleryl CH3 0.026 H 4-Pentenoyl H 0.096 H Hexanoyl H 0.13 H Octanoyl H 0.34 H Palmityl H 0.24 H Linolyl H 0.16 Acetyl Acetyl H 0.12 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 (Monacolin K), which is used as a starting material in some of these Examples, are described in more detail in US Patent Applications Serial No.
121,515 filed 14 February, 1980 and No. 137,821 filed 4April, 1980. Similarly, the preparation and properties of ML-236A and ML-236B are described in more detail in US Patent Specification No.
3,983,140.
Example 1 Preparation of MB-530A 300 litres of a culture medium having a pH of 5.5 before sterilization and containing 5% w/v glucose, 0.5% w/v corn steep liquor, 2% w/v peptone (kyokuto brand, available from Kyokuto Seiyaku KK, Japan) and 0.5% ammonium chloride were charged into a 600 litre fermenter and inoculated with a culture of Monascus ruber SANK 15177 (FERM 4956, NRRL 12081). Cultivation of the microorganism was continued for 120 hours at 270C with an aeration rate of 300 litres/minutes and agitation at 1 90 revolutions per minute.
At the end of this time, the culture broth was filtered in a filter press to give a filtrate and a filter cake comprising wet cells of the microorganism.
The filtrate was adjusted to a pH of 3.0 by the addition of 6N hydrochloric acid and then extracted with 400 litres of ethyl acetate. The extract (about 400 litres) was concentrated by evaporation under reduced pressure and then dehydrated over anhydrous sodium sulphate, after which it was evaporated to dryness, to give about 60 g of an oily product. This oily product was washed with ethylcyclohexane and with hexane and the residue (20 g) was separated by chromatography using a liquid chromatography device for large volume sampling (System 500 liquid chromatography, produced by Waters Co., U.S.A.), eluted with 60% v/v aqueous methanol. Fractions having a chromatographic retention time of 6 minutes were collected and concentrated by evaporation under reduced pressure to give 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 give 57 mg of the desired product in the form of colourless needles having the following properties: 1. Melting Point: 92-930C.
2. Elemental Analysis: Calculated for C19H28O :C, 69.76% H, 8.68%.
Found:C, 71.22%; H, 8.81%.
3. Molecular weight: 320 (by mass analysis).
4. Molecular formula: C19H2804.
5. Ultraviolet Absorption Spectrum: As shown in Figure 1 of the accompanying drawings.
6. infrared Absorption Spectrum: As shown in Figure 2 of the accompanying drawings.
7. Nuclear Magnetic Resonance Spectrum: As shown in Figure 3 of the accompanying drawings.
8. Solubility: readily soluble in methanol, ethanol, acetone and ethyl acetate, soluble in benzene, insoluble in hexane and petroleum ether.
9. Colouration reaction: a pink colour is seen when a thin layer chromatogram on silica gel of the compound is developed with 50% v/v sulphuric acid.
10. Inhibitory activity against the biosynthesis of cholesterol: a 50% inhibition of the synthesis of cholesterol in a rat liver is observed at a concentration of 0.04 ,ug/ml.
Example 2 ML-236A 3-acetate ML-236A (918 mg) and pyridine (0.36 ml) were dissolved in methylene chloride (10 ml), and acetic anhydride (1.0 ml) was added dropwise, while maintaining the temperature at -20 to--10 C.
After completion of the reaction, water was added to the reaction mixture and the methylene chloride layer was separated and washed with water, after which it was dried over anhydrous sodium sulphate.
The residue obtained by evaporation of methylene chloride was subjected to separation by column chromatography using silica gel (10 g), followed by recrystallization from diethyl ether, to give 780 mg of the desired product, melting at 138-1390C.
Elemental analysis: Calculated for C20H25O : C, 68.97%; H, 8.05% Found: C, 68.99%; H, 8.01% Nuclear Magnetic Resonance Spectrum (CDCl3) Us ppm: 1.98 (3H, sing!et); 5.10 (1H, multiplet).
Infrared Absorption Spectrum (Nujol-trade mark) VmaX cm~1: 3400, 1740.
Example 3 ML-236A 3-butyrate ML-236A (918 mg) was dissolved in pyridine (5 ml) and butyric anhydride (1 ml) was added dropwise to the resultant solution. After the mixture had been ieft to stand at room temperature overnight, water was added to the reaction mixture, which was then extracted with diethyl ether. The ether layer was washed with a saturated aqueous solution of sodium bicarbonate, a 1 N HCI solution and water, and then dried over anhydrous sodium sulphate. The residue obtained by evaporation of the diethyl ether was subjected to separation by silica gel chromatography, to give 930 mg of the desired product.
Elemental analysis: Calculated for C22H3205: C, 70.21%; H, 8.51% Found: C,69.96%; H, 8.69% Nuclear Magnetic Resonance Spectrum (CDCl3) 8 ppm: 0.95 (3H, triplet); 4.27 (1H, multiplet); 5.32 (1 H, multiplet).
Infrared Absorption Spectrum (liquid film) VmaX cm~1: 3460,1740.
Example 4 ML-236A 3-butyrate Following the same procedure as described in Example 2, there were prepared 853 mg of the desired product (having the same properties as the product of Example 3) from ML-236A (918 mg) and butyryl chloride (0.32 ml).
Example 5 ML-236A 3-isobutyrate Following the same procedure as described in Example 2, there were prepared 841 mg of the desired product from ML-236A (91 8 mg) and isobutyryl chloride (0.32 ml).
Elemental analysis: Calculated for C22H32O5: C, 70.21%; H, 8.51% Found: C, 69.84%; H, 8.32% Nuclear Magnetic Resonance Spectrum (CDCl3) 8 ppm: 1.17 (6H, doublet); 4.27 (1H, multiplet); 5.25 (1H, multiplet).
Infrared Absorption Spectrum (liquid film) VmaX cm~1: 3440, 1730, 1720.
Example 6 ML-236A 3-(4-pentenoate) Following the same procedure as described in Example 2, there were prepared 834 mg of the desired product from ML-236A (918 mg) and 4-pentenoyl chloride (0.39 ml).
Elemental Analysis: Calculated for C23H3205: C, 71 .13%; H, 8.25% Found: C, 71.43%; H, 8.00% Nuclear Magnetic Resonance Spectrum (CDCI3) 8 ppm: 4.27 (1 H, multiplet); 4.8-6.2 (7H, multiplet).
Infrared Absorption Spectrum (liquid film) PmaX cm~1: 3400, 1730, 1 640.
Example 7 ML-236A 3-isovalerate Following the same procedure as described in Example 2, there were prepared 894 mg of the desired product from ML-236A (918 mg) and isovaleryl chloride (0.40 ml).
Elemental Analysis: Calculated for C23H34O5: C, 70.77% H, 8.72% Found: C, 70.61% H, 8.80% Nuc!ear Magnetic Resonance Spectrum; (CDCl3) 8 ppm: 0.95 (6H, doublet); 4.23 (1H, multiplet); 5.27 (1H, multiplet).
Infrared Absorption Spectrum (liquid film) Vmax cam : 3460, 1740.
Example 8 ML-236A 3-hexanoate Following the same procedure as described in Example 2, there were prepared 2.90 g of the desired product (melting at 70--72 C) from ML-236A (2.70 g) and hexanoyl chloride (1.36 ml).
Elemental Analysis: Calculated for C24H3605: C, 71.29%; H, 8.91% Found: C, 71.04%; H, 8.79% Example 9 ML-236A 3-octanoate Following the same procedure as described in Example 2, there were prepared 690 mg of the desired product from ML-236A (612 mg) and octanoyl chloride (0.64 ml).
Elemental Analysis: Calculated for C26H4005: C, 72.22%; H, 9.26% Found: C, 72.45%; H, 9.12% Nuclear Magnetic Resonance Spectrum (CDCl3) 8 ppm: 0.88 (3H, broad triplet); 4.28 (1H, multiplet); 5.33 (1 H, multiplet).
Infrared Absorption Spectrum (liquid film) Vmax cm :3450,1735.
Example 10 ML-236A 3-palmitate Following the same procedure as described in Example 2, there were prepared 749 mg of the desired product from ML-236A (827 mg) and palmitoyl chloride (0.82 9).
Elemental Analysis: Calculated for C34H58O5: C,75.00%; H,10.29% Found: C,74.89%; H, 10.35% Nuclear Magnetic Resonance Spectrum (CDCl3) 8 ppm: 0.90 (3H. broad triplet); 1.27 (24H, broad singlet); 4.27 (1 H, multiplet); 5.32 (1H, multiplet).
Infrared Absorption Spectrum (liquid film) vmax cm-1: 3460, 1735.
Example 11 ML-236A 3-linoleate Following the same procedure as described in Example 2, there were prepared 897 mg of the desired product from ML-236A (918 mg) and linoleyl chloride (1.03 g).
Elemental analysis: Calculated for C38H56O5: C,76.06%; H, 9.86% Found: C,76.24%; H,9.96% Nuclear Magnetic Resonance Spectrum (CDCI3) 8 ppm: 0.90 (3H, broad triplet); 1.32 (18H, broad singlet); 4.27 (1H, multiplet).
Infrared Absorption Spectrum (liquid film) VmaX cm-1: 3460, 1 740.
Example 12 MB-530A 3-butyrate Following the same procedure as described in Example 2, there were prepared 250 mg of the desired product from MB-530A (300 mg) and butyryl chloride (0.47 ml).
Elemental analysis: Calculated for C23H3405: C,70.77%; H,8.72% Found: C,70.60%; H,8.89% Nuclear Magnetic Resonance Spectrum (CDCl3) 8 ppm: 0.90 (3H, triplet); 4.17 (1H, multiplet): 5.22 (1H, multiplet).
Infrared Absorption Spectrum (liquid film) Vmax cm~1: 3450, 1 730.
Example 13 MB-530A 3-isovaierate Following the same procedure as described in Example 2, there were prepared 235 mg of the desired product from MB-530A (320 mg) and isovaleryl chloride (0.47 ml).
Elemental analysis: Calculated for C24H3BO5: C,71.29%; H, 8.91% Found: C,71.20%; H,8.87% Nuclear Magnetic Resonance Spectrum (CDCI3) 8 ppm: 0.89 (6H, doublet); 4.16 (1H, multiplet); 5.22 (1H, multiplet).
Infrared Absorption Spectrum (Nujol) vrn8xcm1:3510, 1730,1710.
Example 14 MB-530A 3-hexanoate Following the same procedure as described in Example 2, there were prepared 410 mg of the desired product from MB-530A (420 mg) and hexanoyl chloride (0.21 ml).
Elemental analysis: Calculated for C25H38O5: C, 71.77%; H, 9.09% Found: C, 71.55%; H, 9.19% Nuclear Magnetic Resonance Spectrum (CDCl3) X ppm: 0.88 (3H, broad triplet); 4.19 (1H, multiplet); 5.25 (1H, multiplet).
Infrared Absorption Spectrum (liquid film) Vmax cm~l: 3400, 1730.
Example 15 MB-530A 3-octanoate Following the same procedure as described in Example 2, there were prepared 340 mg of the desired product from MB-530A (322 mg) and octanoyl chloride (0.28 ml).
Elemental analysis: Calculated for C27H4205: C, 72.65%; H, 9.42%; Found: C, 72.44%; H, 9.34% Nuclear Magnetic Resonance Spectrum (CDCl3) 8 ppm: 0.84 (3H, broad triplet); 1.21 (12H, broad singlet); 4.18 (1 H, multiplet); 5.23 (iH, multiplet).
Infrared Absorption Spectrum (liquid film) Vmax cm~': 3400, 1730.
Example 16 ML-236A 8'-butyrate ML-236A (918 mg) and pyridine (0.36 ml) were dissolved in methylene chloride (10 ml). The resultant solution was cooled to 0 C and butyryl chloride (0.35 ml) was added dropwise thereto. After completion of the reaction, water was added to the reaction mixture and the methylene chloride layer separated was washed with water, and then dried over an hydros sodium sulphate. The residue obtained by evaporation of methylene chloride was subjected to separation by column chromatography using silica gel (lOg), followed by recrystallization from diethyl ether, to give 395 mg of the desired product, melting at 124-1250C.
Elemental analysis: Calculated for C22H3205: C, 70.21%; H, 8.51% Found: C, 70.25%; H, 8.50% Nuclear Magnetic Resonance Spectrum (CDCl3) 8 ppm: 0.95 (3H, triplet); 4.42 (1 H, multiplet); 5.43 (1H, multiplet).
Infrared Absorption Spectrum (Nujol) Vmax cm-1: 3400, 1730, 1710.
Example 17 ML-236A 8'-isobutyrate Following the same procedure as described in Example 16, there were prepared 100 mg of the desired product from ML-236A (285 mg) and isobutyryl chloride (0.1 1 ml).
Elemental analysis: Calculated for C22H3205: C, 70.21%; H, 8.51% Found: C, 70.05%; H, 8.67% Nuclear Magnetic Resonance Spectrum (CDCl3) 8 ppm: 1.14 (6H, doublet); 4.35 (1H, multiplet); 5.32 (1H, multiplet).
Infrared Absorption Spectrum (liquid film) PmaX cm-1:3400, 1730, 1700.
Example 18 ML-236A 8'-(4-pentenoate) Following the same procedure as described in Example 1 6, there were prepared 370 mg of the desired product from ML-236A (918 mg) and 4-pentenoyl chloride (0.39 ml).
Elemental analysis: Calculated for C23H32O5: C, 71.13%; H, 8.25% Found: C, 70.82%; H, 8.33% Nuclear Magnetic Resonance Spectrum (CDCl3) a ppm: 4.14 (1H, multiplet); 4.8-6.2 (8H, multiplet).
Infrared Absorption Spectrum (liquid film) Vmax cm-1: 3400, 1730.
Example 19 ML-236A 8'-isovalerate Following the same procedure as described in Example 16, there were prepared 365 mg of the desired product from ML-236A (918 mg) and isovaleryl chloride (0.47 ml).
Elemental analysis: Calculated for C23H34O5: C, 70.77%; H, 8.72% Found: C, 70.59%; H, 8.90% Nuclear Magnetic Resonance Spectrum (CDCl3) S ppm: 0.93 (6H, doublet); 4.35 (1 H, multiplet); 5.35 (1 H, multiplet).
Infrared Absorption Spectrum (liquid film) Vmax cm-1: 3430, 1730, 1710.
Example 20 ML-236A 8'-hexanoate Following the same procedure as described in Example 1 6, there were prepared 408 mg of the desired product from ML-236A (918 mg) and hexanoyl chloride (0.46 ml).
Elemental analysis: Calculated forC24H36O5: C, 71.29%; H, 8.91% Found: C, 71.07%; H, 9.01% Nuclear Magnetic Resonance Spectrum (CDCl3) a ppm: 0.87 (3H, triplet); 4.32 (1H, multiplet); 5.32 (1H, multiplet).
Infrared Absorption Spectrum (liquid film) Vmax cm-1: 3400, 1720, 171 0.
Example 21 ML-236A 8'-octanoate Following the same procedure as described in Example 16, there were prepared 462 mg of the desired product from ML-236A (918 mg) and octanoyl chloride (0.54 ml).
Elemental analysis: Calculated for C2aH4005: C, 72.22%; H, 9.26% Found: C, 72.04%; H, 9.10% Nuclear Magnetic Resonance Spectrum (CDCl3) S ppm: 0.88 (3H, broad triplet); 1.28 (12H, broad singlet); 4.42 (1 H, multiplet); 5.42 (1H, multiplet).
Infrared Absorption Spectrum (liquid film) PmaX cm-1: 3470, 1735.
Example 22 ML-236A 8'-palmitate Following the same procedure as described in Example 16, there were prepared 490 mg of the desired product from ML-236A (918 mg) and palmitoyl chloride (640 mg).
Elemental analysis: Calculated for C34H58O5: C, 74.73%; H, 10.62% Found: C, 74.56%; H, 10.78% Nuclear Magnetic Resonance Spectrum (CDCI3) S ppm: 0.88 (3H, broad triplet); 1.28 (24H, broad singlet); 4.38 (1H, multiplet); 5.40 ( 1 H, multiplet).
Infrared Absorption Spectrum (liquid film) PmaX cm-': 3450, 1735.
Example 23 ML-236A 8'-linoleate Following the same procedure as described in Example 16, there were prepared 41 5 mg of the desired product from ML-236A (918 mg) and linoleyl chloride (1.0 g).
Elemental analysis: Calculated for C3SH5605: C, 76.06%; H, 9.86% Found: C, 76.23%; H, 10.03% Nuclear Magnetic Resonance Spectrum (CDCl3) 8 ppm: 0.90 (3H, broad triplet); 1.32 (18H, broad singlet); 4.40 (1 H, multiplet); 5.2-5.5 (5H, multiplet).
Infrared Absorption Spectrum (liquid film) Vmax cm-': 3440, 1 735.
Example 24 MB-530A 8'-butyrate Following the same procedure as described in Example 1 6, there were prepared 1 54 mg of the desired product from MB-530A (309 mg) and butyryl chloride (0.16 ml).
Elemental analysis: Calculated for C23H3405: C, 70.77%; H, 8.72% Found: C, 70.58%; H, 8.61% Nuclear Magnetic Resonance Spectrum (CDCl3) 8 ppm: 0.90 (3H, triplet); 4.17 (1H, multiplet); 5.22 (1H, multiplet).
Infrared Absorption Spectrum (liquid film) Vmax cm-1: 3450, 1 730.
Example 25 MB-530A 8'-isovalerate Following the same procedure as described in Example 1 6, there were prepared 109 mg of the desired product from MB-530A (308 mg), and isovaleryl chloride (0.12 ml).
Elemental analysis: Calculated for C24H38O5: C,71.29%; H, 8.91% Found: C, 71.17%; H, 8.69% Nuclear Magnetic Resonance Spectrum (CDCl3) 8 ppm: 0.88 (6H, doublet); 4.15 (1 H, multiplet); 5.22 (1H, multiplet.
Infrared Absorption Spectrum (liquid film) Vmax cm-1 3420, 1 730.
Example 26 MB-530A 8'-hexanoate Following the same procedure as described in Example 1 6, there were prepared 87 mg of the desired product from MB-530A (308 mg) and hexanoyl chloride (0.15 ml).
Elemental analysis: Calculated for C25H3805: C,71.77%; H, 9.09% Found: C,71.95%; H, 9.17% Nuclear Magnetic Resonance Spectrum (CDCl3) 8 ppm: 0.90 (3H, triplet); 4.33 (1H, multiplet); 5.33 ( 1 H, multiplet).
Infrared Absorption Spectrum (liquid film) Vmax cm-1: 3440, 1735.
Example 27 MB-530A 8'-octanoate Following the same procedure as described in Example 16, there were prepared 96 mg of the desired product from MB-530A (304 mg) and octanoyl chloride (0.11 ml).
Elemental analysis: Calculated for C27H4205: C,72.65%: H, 9.42% Found: C,72.52%; H, 9.50% Nuclear Magnetic Resonance Spectrum (CDCl3) a ppm: 0.85 (3H, broad triplet); 1.22 (12H, broad singlet); 4.19 (1H, multiplet); 5.23 (1H, multiplet).
Infrared Absorption Spectrum (liquid film) vmax cam : 3400,1735.
Example 28 ML-236A 3,8'-diacetate Following the same procedure as described in Example 3. there were prepared 914 mg of the desired product from ML-236A (918 mg), pyridine (5 ml) and acetic anhydride (1 ml).
Elemental analysis: Calculated for C22H2006: C,67.69%; H, 7.69% Found: C, 67.44%; H, 7.79% Nuclear Magnetic Resonance Spectrum (CDCl3) a ppm: 1.89 (6H, singlet); 5.10 (2H, multiplet).
Infrared Absorption Spectrum (liquid film) Vmax cm~1: 1735, 1250, 1170.
Example 29 ML-236A 3,8'-dibutyrate ML-236A (306 mg) and pyridine (0.5 ml) were dissolved in methylene chloride (3 ml), and to the resultant solution was added butyryl chloride (0.5 ml), with ice-cooling. The mixture was stirred at room temperature for 1 hour. The reaction mixture was then treated similarly to that in Example 2. The residue obtained was subjected to separation by chromatography, to give 384 mg of the desired product.
Elemental analysis: Calculated for C26H3806: C, 69.96%; H,8.52% Found: C,70.14%; H,8.31% Nuclear Magnetic Resonance Spectrum (CDCl3) S ppm: 0.93 (6H, triplet); 5.2-5.5 (2H, multiplet).
Infrared Absorption Spectrum (liquid film) z'max 1735,1250,1175.
Example 30 ML-236A 3,8'-bis(4-pentenoate) Following the same procedure as described in Example 29, there were prepared 405 mg of the desired product from ML-236A (306 mg), pyridine (0.5 ml) and 4-pentenoyl chloride (0.4 ml).
Elemental analysis: Calculated for C2BH3806: C,71.48%; H,8.09% Found: C,71.25%; H,8.30% Nuclear Magnetic Resonance Spectrum (CDCl3) a ppm: 4.8-6.2 (11 H, multiplet).
Infrared Absorption Spectrum (liquid film) L'max cm-1:1735, 1640, 1460, 1240, 11 70.
Example 31 ML-236A 3,8'-dioctanoate Following the same procedure as described in Example 29, there were prepared 1.7 g of the desired product from ML-236A (918 mg) and octanoyl chloride (1.4 ml).
Elemental analysis: Calculated for C34H54O8: C,73.12%; H, 9.68% Found: C, 72.95%; H, 9.79% Nuclear Magnetic Resonance Spectrum (CDCl3) 8 ppm: 0.88 (6H, broad triplet); 1.32 (24H, broad singlet); 5.2-5.5 (2H, multiplet).
Infrared Absorption Spectrum (liquid film) PmaX cm-1: 1735, 1460, 1250, 1 165.
Example 32 ML-236A 3,8'-dipalmitate Following the same procedure as described in Example 29, there were prepared 1.0 g of the desired product from ML-236A (41 5 mg) and palmitoyl chloride (0.71 ml).
Elemental analysis: Calculated for C50H8fO5: C, 76.73%; H, 1 1.00% Found: C, 76.99%; H, 10.81% Nuclear Magnetic Resonance Spectrum (CDCl3) s ppm: 0.87 (6H, broad triplet); 1.25 (52H, broad singlet); 5.2-5.5 (2H, multiplet).
Infrared Absorption Spectrum (liquid film) Vmax cm-1: 1735, 1460.
Example 33 ML-236A 3,8'-dilinoleate Following the same procedure as described in Example 29, there were prepared 804 mg of the desired product from ML-236A (306 mg) and linoleyl chloride (0.6 ml).
Elemental Analysis: Calculated for C54H86O6: C, 78.07%; H, 10.36% Found: C, 78.30%; H, 10.19% Nuclear Magnetic Resonance Spectrum (CDCl3) s ppm: 0.90 (6H, broad triplet); 1.30 (36H, broad singlet); 5.1-6.2 (13H, multiplet).
Infrared Absorption Spectrum (liquid film) Vmax cm-1: 1740, 1460, 1240, 1170.
Example 34 MB-530A 3,8'-dihexanoate Following the same procedure as described in Example 29, there were prepared 440 mg of the desired product from MB-530A (330 mg) and hexanoyl chloride (0.5 ml).
Elemental analysis: Calculated for C30H48O6: C, 71.43%; H, 9.52% Found: C,71.58%; H, 9.30% Nuclear Magnetic Resonance Spectrum (CDCl3) 8 ppm: 0.86 (3H, broad triplet); 0.91 (3H, broad triplet); 5.0-6.1 (5H, multiplet).
Infrared Absorption Spectrum (liquid film) Vmax cm~': 1730.
Example 35 MB-530A 3,8'-dioctanoate Following the same procedure as described in Example 29, there were prepared 498 mg of the desired product from MB-530A (330 mg), pyridine (0.5 ml) and octanoyl chloride (0.5 ml).
Elemental analysis: Calculated for C34H56O6: C, 72.85%; H, 10.00% Found: C, 72.58%; H, 10.18% Nuclear Magnetic Resonance Spectrum (CDCl3) 3 ppm: 0.82 (3H, broad triplet); 0.91 (3H, broad triplet); 5.0-6.1 (5H, multiplet).
Infrared Absorption Spectrum (liquid film) PmaX cam : 1730.
Example 36 ML-236B Acetate ML-236B (7.8 g) was dissolved in dry pyridine (10 ml) and to the resultant solution was added distilled acetic anhydride (4.5 ml). The reaction mixture was heated, with stirring, at 40--45 C for 1 hour. 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 anhydrous sodium sulphate. The oily product obtained by evaporation of the solvent was subjected to separation by silica gel chromatography using a mixture of benzene and ethyl acetate as eluant, to give ML-236B acetate (7.3 g) as oily product.
This oily product was recrystailized from aqueous ethanol, to give ML-236B acetate (6.6 g) as white crystals, melting at 48-51 OC.
Elemental analysis: Calculated for C25H3806: C, 69.44%; H, 8.33% Found: C,69.35%; H, 8.50% Nuclear Magnetic Resonance Spectrum (CDCI3) a ppm: 6.05 (1 H, doublet); 5.80 (1 H, double doublet); 2.8 (2H, doublet); 2.1 (3H, singlet).
Infrared Absorption Spectrum (KBr) Vmax cm~': :1740,1710.
Example 37 ML-236B Benzoate ML-236B (7.8 g) was dissolved in dry pyridine (20 ml) and to the resultant solution was added benzoyl chloride (4.2 g), with ice-cooling. 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 sulphate, and the resulting solution was concentrated by evaporation under reduced pressure. The concentrated oily product was separated and purified by silica gel chromatography using a mixture of benzene and ethyl acetate as eluant. The purified product was recrystallized from a mixture of diethyl ether and hexane, to give ML-236B benzoate (9.1 g) as white crystals, melting at 102-1 040C.
Elemental analysis: Calculated for C30H3BOf,: C,73.00%; H, 7.70% Found: C,72.81%; H, 7.75% Nuclear Magnetic Resonance Spectrum (CDCl3) a ppm: 7.2 (5H, multiplet); 6.10 (1H, doublet); 5.82 (1 H, double doublet); 2.82 (2H, doublet).
Infrared Absorption Spectrum (Nujol-trade mark) may cm-': 1745,1708.
Example 38 ML-236B Pivaloate ML-236B (7.8 g) was dissolved in dry pyridine (20 ml), and to the resultant solution was added pivaloyl chloride (3.6 g), with 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 and the benzene extract was washed with water and dried over anhydrous sodium sulphate 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 give ML-236B pivaloate (4.9 g) as white crystals, melting at 104-1 050C.
Elemental analysis: Calculated for C28H4206: C,70.55%; H, 8.92% Found: C,70.53%; H, 8.86% Nuclear Magnetic Resonance Spectrum (CDCl3) 8 ppm: 6.00 (1 H, doublet); 5.93 (1 H, double doublet); 5.52 (1H, multiplet); 5.22 (2H, multiplet): 4.38 (1H, multiplet); 2.63 (2H, doublet); 1.14 (9H, singlet).
Infrared Absorption Spectrum (Nujol) Vmax cam : 1735, 1720.
Example 39 ML-236B Phenoxyacetate ML-236B (7.8 g) was dissolved in dry pyridine (20 ml), and to the resultant solution was added phenoxyacetyl chloride (5.1 g), with 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 was washed with water and dried over anhydrous sodium sulphate, after which it was concentrated by evaporation under reduced pressure. The concentrated oily product was separated and purified by silica gel chromatography using a solvent system comprising 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 42-440C.
Elemental analysis: Calculated for C3,H4007: C,70.97%; H, 7.69% Found: C, 70.8%; H, 7.68% Nuclear Magnetic Resonance Spectrum (CDCl3) 8 ppm: 6.6-7.4 (5H, multiplet); 5.86 (1H, doublet); 5.65 (1 H, double doublet); 4.51 (2H, singlet); 4.15 (1H, multiplet).
Infrared Absorption Spectrum (Nujol) Vmax cm-1: 1740 (shoulder), 1725.
Example 40 MB-530B Acetate MB-530B (0.081 g) was dissolved in dry pyridine (0.2 ml), and to the resultant solution was added acetic anhydride (0.05 ml). The mixture was stirred at room temperature for 2 hours and then poured into ice-water acidified wtih hydrochloric acid. The reaction product was then extracted with benzene, and the benzene extract was washed with water and dried over anhydrous sodium sulphate, after which it was concentrated by evaporation under reduced pressure. The concentrated oily product was separated and purified through silica gel column (Lobar column; produced by Merck Co., U.S.A.).
The purified product was recrystallized from a mixture of diethyl ether and hexane, to give MB-530B acetate (0.076 g) as white needles, melting at 92-930C.
Elemental analysis: Calculated for C2ssH3808: C,69.93%; H, 8.58% Found: C, 69.71%; H, 8.60% Nuclear Magnetic Resonance Spectrum (CDCl3) 8 ppm: 6.06 (1H, doublet); 5.88 (1 H, double doublet); 2.73 (2H, doublet); 2.10 (3H, singlet).
Infrared Absorption Spectrum (Nujol) Vmax cm~1: 1736,1720.
Example 41 MB-530B Benzoate Following substantially the same procedure as described in Example 40, there was prepared MB 530B benzoate (0.09 g) from MB-530B (0.081 g) and benzoyl chloride (0.044 g).
Nuclear Magnetic Resonance Spectrum (CDCl3) 8 ppm: 8.1 (2H, multiplet); 7.6 (3H, multiplet); 6.01(1H,doublet); 5.85 (1 H, double doublet); 2.78 (2H, doublet).
Infrared Absorption Spectrum (liquid film) PmnX cm~': 1750-1720,1600,1580.

Claims (34)

Claims
1. Compounds of formula (I):
wherein R1 and R2 are the same or different and each represents a hydrogen atom or an acyl group; and R3 represents a hydrogen atom or a methyl group; provided that, when R1 represents a hydrogen atom, R2 and R3 do not both represent hydrogen atoms, and R2 does not represent an a-methylbutyryl group.
2. The compound claimed in Claim 1, wherein both R' and R2 represent hydrogen atoms.
3. Compounds as claimed in Claim 1, wherein at least one of R' and R2 represents a saturated or unsaturated aliphatic acyl group, an aromatic acyl group or an araliphatic acyl group.
4. Compounds as claimed in Claim 1, wherein at least one of R1 and R2 represents a formyl group, a straight or branched chain C2-C20 alkanoyl group, a straight or branched chain C3-C20 alkenoyl group, a benzoyl group, a benzoyl group having one or more substituents in the phenyl moiety, a phenylalkanoyl group, a 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, said substituents being selected from C1-C4 alkyl groups, C1-C4 alkoxy groups, hydroxy groups, methylenedioxy groups, halogen atoms and trifluoromethyl groups.
5. Compounds as claimed in Claim 1, wherein: R1 represents a hydrogen atom; and R2 represents a straight or branched chain C2-C20 alkanoyl group, a straight or branched chain C3-C20 alkenoyl group or an unsubstituted benzoyl group.
6. Compounds as claimed in Claim 1, wherein: R1 represents a hydrogen atom; and R2 represents a straight or branched chain C2-C6 alkanoyl group or a straight or branched chain C3-C8 aikenoyl group.
7. Compounds as claimed in Claim 1, wherein: R1 represents a hydrogen atom; and R2 represents a butyryl, isobutyryl, 4-propenoyl or isovaleryl group.
8. Compounds as claimed in Claim 1, wherein: R1 represents a straight or branched chain C2-C20 alkanoyl group, a straight or branched chain C3-C20 alkenoyl group or an unsubstituted benzoyl group; and R2 represents a hydrogen atom or an a-methylbutyryl group.
9. Compounds as claimed in Claim 1, wherein: R' represents a straight or branched chain C2-C6 alkanoyl group, a straight or branched chain C3-C8 alkenoyl group or an unsubstituted benzoyl group; and R2 represents a hydrogen atom or an cr-methylbutyryl group.
10. Compounds as claimed in Claim 1, wherein: R' represents an acetyl, butyryl, isobutyryl, 4-propenoyl, isovaleryl, hexanoyl or benzoyl group; and R2 represents an a-methylbutyryl group.
11. Compounds as claimed in Claim 1, wherein: R' and R2 are the same or different and each represents a straight or branched chain C2-C6 alkanoyl group, a straight or branched chain C3-C6 alkenoyl group or an unsubstituted benzoyl group.
12. Compounds as claimed in Claim 1, wherein: R1 represents an acetyl, butyryl, isobutyryl, 4-propenoyl, isovaleryl, hexanoyl or benzoyl group; and R2 represents a butyryl, isobutyryl, 4-propionyl or isovaleryl group.
13. ML-236A 8'-butyrate.
14. ML-236A 8'-isobutyrate.
1 5. ML-236A 8'-isovalerate.
1 6. MB-530A 8'-butyrate.
1 7. MB-530A 8'-isovalerate.
1 8. ML-236A 8'-(4-pentenoate).
1 9. ML-236A 3,8'-diacetate.
20. ML-236A 3,8'-dibutyrate.
21. ML-236A 3,8'-di(4-pentenoate).
22. A process for producing MB-530A, which comprises cultivating an MB-530A producing microorganism of the genus Monascus in a culture medium therefor, and separating MB-530A from the resulting culture broth.
23. A process as claimed in Claim 22, wherein said microorganism is of the species Monascus ruber.
24. A process as claimed in Claim 23, wherein said microorganisms is Monascus ruber SANK 15177 (FERM 4956, NRRL 12081).
25. A process for preparing a compound of formula (I):
wherein one of R1 and R2 represents a hydrogen atom and the other represents an acyl group; or R' and R2 both represent acyl groups; and R3 represents a hydrogen atom or a methyl group which process comprises acylating a compound of said formula (I) wherein one or both of R1 and R2 represent hydrogen atoms with an acylating agent and separating the product from the reaction mixture.
26. A process as claimed in Claim 25, wherein said acylation is effected with a reactive derivative of a carboxylic acid or with a carboxylic acid in the presence of a condensing agent.
27. A process as claimed in Claim 26, wherein said acylating agent is an acid anhydride or halide and said acylation is effected in the presence of an organic base.
28. A process as claimed in Claim 27, wherein said organic base is pyridine.
29. A process as claimed in Claim 27, wherein said acylating agent is an acid anhydride or halide, and said acylation is effected in the presence of an organic base at a temperature from -200C to OOC to produce a monoester as the predominant product
30. A process as claimed in Claim 29, wherein said acylating agent is an acid halide in an amount of about 1 equivalent per equivalent of said compound of formula (I).
31. A process as claimed in Claim 27, wherein said acylating agent is an acid anhydride or halide in an amount not less than 2 equivalents per equivalent of said compound of formula (I), and said acylation is effected in the presence of an organic base at a temperature above room temperature, to produce the diester as the predominant product.
32. A process as claimed in Claim 25, wherein said acylation is effected with a carboxylic acid in the presence of a condensing agent.
33. A process as claimed in Claim 25, wherein there is produced: ML-236A 8'-butyrate ML-236A 8'-isobutyrate ML-236A 8'-isovalerate MB-530A 8'-butyrate MB-530A 8'-isovalerate ML-236A 8'-(4-pentenoate) ML-236A 3,8'-diacetate ML-236A 3,8'-butyrate or ML-236A 3,8'-di(4-pentenoate).
34. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient, one or more compounds as claimed in any one of Claims 1 to 21.
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Cited By (9)

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EP0113881A1 (en) * 1982-12-22 1984-07-25 Merck & Co. Inc. Antihypercholesterolemic compounds
EP0215665A2 (en) * 1985-09-13 1987-03-25 Sankyo Company Limited Hydroxy-ML-236B derivatives, their preparation and use
EP0314435A2 (en) 1987-10-27 1989-05-03 Sankyo Company Limited Octahydronaphthalene oxime derivatives for cholesterol synthesis inhibition, processes for their preparation and compositions containing them
US5021451A (en) * 1988-11-14 1991-06-04 Hoffman-La Roche Inc. Method for inhibiting hyperproliferative diseases
US5073568A (en) * 1988-11-14 1991-12-17 Hoffmann-La Roche Inc. Antipsoriatic agents
US5075327A (en) * 1988-08-10 1991-12-24 Hoffmann-La Roche Inc. Antipsoriatic agents
US5159104A (en) * 1991-05-01 1992-10-27 Merck & Co., Inc. Process to simvastatin ester
US5200549A (en) * 1988-11-14 1993-04-06 Hoffman-La Roche Inc. Antipsoriatic agents
FR2937537A1 (en) * 2008-10-29 2010-04-30 Centre Nat Rech Scient NANOPARTICLES OF STATIN

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KR101820099B1 (en) 2013-01-18 2018-01-18 에스프린팅솔루션 주식회사 resistive heat generating material, heating member and fusing device adopting the same
US11970482B2 (en) 2018-01-09 2024-04-30 Ligand Pharmaceuticals Inc. Acetal compounds and therapeutic uses thereof

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JPS5612114B2 (en) * 1974-06-07 1981-03-18
JPS5925599B2 (en) * 1979-02-20 1984-06-19 三共株式会社 New physiologically active substance monacolin K and its production method
US4231938A (en) * 1979-06-15 1980-11-04 Merck & Co., Inc. Hypocholesteremic fermentation products and process of preparation
IL60219A (en) * 1979-06-15 1985-05-31 Merck & Co Inc Hypocholesteremic fermentation products of the hmg-coa reductase inhibitor type,their preparation and pharmaceutical compositions containing them
AU548996B2 (en) * 1980-02-04 1986-01-09 Merck & Co., Inc. Tetrahydro-2h-pyran-2-one derivatives
US4282155A (en) * 1980-02-04 1981-08-04 Merck & Co., Inc. Antihypercholesterolemic compounds
PT72394B (en) * 1980-02-04 1982-09-06 Merck & Co Inc Process for preparing dihydro and tetrahydromevinoline hypocholesterolimics
ZA81703B (en) * 1980-02-04 1982-09-29 Merck & Co Inc New antihypercholesterolemic compounds,intermediates and processes

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0113881A1 (en) * 1982-12-22 1984-07-25 Merck & Co. Inc. Antihypercholesterolemic compounds
EP0215665A2 (en) * 1985-09-13 1987-03-25 Sankyo Company Limited Hydroxy-ML-236B derivatives, their preparation and use
EP0215665A3 (en) * 1985-09-13 1988-10-05 Sankyo Company Limited Hydroxy-ml-236b derivatives, their preparation and use
US5403860A (en) * 1987-10-27 1995-04-04 Sankyo Company, Limited Octahydronaphthalene oxime compounds for cholesterol synthesis inhibition
EP0314435A2 (en) 1987-10-27 1989-05-03 Sankyo Company Limited Octahydronaphthalene oxime derivatives for cholesterol synthesis inhibition, processes for their preparation and compositions containing them
US4997848A (en) * 1987-10-27 1991-03-05 Sankyo Company, Limited Octahydronaphthalene oxime derivatives for cholesterol synthesis inhibition
US5658942A (en) * 1987-10-27 1997-08-19 Sankyo Company, Limited Octahydronaphthalene oxime compounds for cholesterol synthesis inhibition
US5075327A (en) * 1988-08-10 1991-12-24 Hoffmann-La Roche Inc. Antipsoriatic agents
US5073568A (en) * 1988-11-14 1991-12-17 Hoffmann-La Roche Inc. Antipsoriatic agents
US5200549A (en) * 1988-11-14 1993-04-06 Hoffman-La Roche Inc. Antipsoriatic agents
US5021451A (en) * 1988-11-14 1991-06-04 Hoffman-La Roche Inc. Method for inhibiting hyperproliferative diseases
US5159104A (en) * 1991-05-01 1992-10-27 Merck & Co., Inc. Process to simvastatin ester
FR2937537A1 (en) * 2008-10-29 2010-04-30 Centre Nat Rech Scient NANOPARTICLES OF STATIN
WO2010049900A1 (en) * 2008-10-29 2010-05-06 Centre National De La Recherche Scientifique Statin nanoparticles
US8748414B2 (en) 2008-10-29 2014-06-10 Patrick Couvreur Statin nanoparticles

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DK32190D0 (en) 1990-02-07
NL8101592A (en) 1981-10-16
SE461590B (en) 1990-03-05
ATA150781A (en) 1983-03-15
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