JPH07173166A - Tan-1607a derivative, its production and use - Google Patents

Abstract

PURPOSE:To obtain a new TAN-1607A derivative having strong squalene synthetase inhibiting action and low toxicity, effective as a cholesterol-lowering agent and, accordingly, useful as an agent for the prevention and treatment of hyperlipemia. CONSTITUTION:This TAN-1607A derivative is expressed by formula I (X is ethylene or vinylene ; R1, R2, R6 and R7 each is H or an acyl; R3 to R5 each is OH, an alkoxy or amino; when R1 is 11-phenyl-10-undecenoyl, at least one of R3 to R5 is other than OH). The compound of formula I can be produced by deprotecting a compound of formula II (R8 to R10 each is carboxyl; when R1 is 11-phenyl-10-undecenoyl, at least one of R8 to R10 is a protected carboxyl) optionally after acylation. The starting compound of formula II is produced by esterifying TAN-1607A of formula III produced by a microbial strain which belongs to the genus Cladosporium e.g. with an alkyl halide and optionally selectively eliminating the produced side-chain acyl group.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel derivative of TAN-1607A, which is useful as a therapeutic agent for hyperlipidemia, a method for producing the same, and uses thereof.

[0002]

BACKGROUND ART Hyperlipidemia is known as three major risk factors for ischemic heart disease as well as hypertension and smoking. Proper control of blood cholesterol level is to prevent ischemic heart disease and coronary atherosclerosis. Very important for treatment. Although various drugs have been developed as drugs for lowering blood cholesterol level, recently, cholesterol biosynthesis inhibitors of microbial origin, particularly 3-hydroxy-3-, have been developed.
Lovastatin (Lovastatin, US Pat. No. 4,231,938), which inhibits methylglutaryl coenzyme A (HMG-CoA) reductase, simvastatin (Simvast)
atin, US Pat. No. 4,444,784) and pravastatin (Pravastatin, US Pat. No. 4,346,227).
No.) was developed and is marketed as a drug. Further, various compounds have been reported as squalene synthase inhibitors [JP-A-4-217986 (EP-A).
-448,393), JP-A-4-36089 (US Pat. No. 5,026,554) and JP-A-4-2795.
89 (US Pat. No. 5,053,425)].

[0003]

Inhibition of HMG-CoA reductase inhibits not only cholesterol biosynthesis but also biosynthesis of other biorequisite components such as ubiquinone, dolichol and heme A. , Side effects caused by them are concerned. It is known that these components are biosynthesized from farnesyl pyrophosphate on the cholesterol biosynthetic pathway. Therefore, in order to eliminate the side effects due to these defects, in the cholesterol biosynthetic pathway, the enzyme after farnesyl pyrophosphate is used. It is desirable to inhibit the system. Examples of such an enzyme include squalene synthase. However, the action of known squalene synthase inhibitors is not yet fully satisfactory.

[0004]

Means for Solving the Problems In view of the above situation, the present inventors have conducted research from a new perspective, and as a result, cultivated microorganisms belonging to the genus Cladosporium among many microorganisms separated from soil. Knowing that the liquid contained an active compound that strongly inhibits the biosynthesis of squalene, the active compound was successfully isolated and was named TAN-1607A. The compound is an acidic fat-soluble substance containing a carboxyl group, and the present inventors have found that the structures of these compounds are
The physicochemical and biological properties were examined in detail, and it was confirmed that the substance is a novel substance which is clearly different from known compounds. As a result of further research, the present inventors found that TAN-
Certain novel derivatives of 1607A are TAN-1607A
The inventors have found that they have an activity similar to or higher than that, and completed the present invention.

That is, the present invention provides (1) the general formula (I):

[0006]

[Chemical 5]

(Wherein X is an ethylene group or a vinylene group, R ₁ , R ₂ , R ₆ and R ₇ are each hydrogen or an optionally substituted acyl group, and R ₃ , R ₄ and R ₅ are Each represents a hydroxyl group, an alkoxy group or an optionally substituted amino group, provided that when R ₁ is an 11-phenyl-10-undecenoyl group, at least one of R ₃ , R ₄ and R ₅ is a group other than a hydroxyl group. Or a salt thereof, particularly (2) a compound represented by the general formula (I) in which X is a vinylene group, (3) R ₁ , R ₂ , R ₆ and R ₇ The compound represented by the general formula (I), in which the acyl group represented is an acyl group derived from an organic carboxylic acid, (4)
A compound represented by the general formula (I), wherein the acyl group represented by R ₁ , R ₂ , R ₆ and R ₇ is an acyl group having 1 to 30 carbon atoms, (5) R ₁ , R ₂ , R ₆ And a compound represented by the general formula (I) in which the acyl group represented by R ₇ is an acyl group having 1 to 6 unsaturated bonds, (6) represented by R ₁ , R ₂ , R ₆ and R ₇ . The acyl group which may be substituted with one or more groups selected from an alkyl group, an alkoxy group, a mono- or dialkylamino group, a halogen, a carboxyl group, a hydroxyl group, an acyloxy group, an amino group and a heterocyclic group. A compound represented by the general formula (I):
(7) Alkyl group having 1 to 6 carbon atoms, alkoxy group having 1 to 6 carbon atoms, mono- or dialkylamino group having mono- or dialkylamino group having 1 to 6 carbon atoms, acyloxy A compound represented by the formula (I) in which the group is an acyloxy group having 1 to 6 carbon atoms, the heterocyclic group is a heterocyclic group having 2 to 10 carbon atoms, and (8) R ₆ is hydrogen or acetyl. Compound,
(9) The alkoxy group represented by R ₃ , R ₄ and R ₅ is
The compound represented by the general formula (I), which is an alkoxy group having 1 to 6 carbon atoms, and (10) the optionally substituted amino group represented by R ₃ , R ₄ and R ₅ is an alkyl group, General formula (I) which is an amino group which may be disubstituted
A compound represented by: (11) an alkyl group having 1 to 6 carbon atoms
(12) which is an alkyl group of (12) R ₁ is hydrogen, an optionally substituted alkanoyl group or an optionally substituted alkenoyl group, R ₃ , R ₄ and R ₅
Are each a hydroxyl group or an alkoxy group, R ₇ is hydrogen,
R ₁ is octanoyl, decanoyl, 11-phenyl-1
When it is a 0-undecenoyl group or an 11-phenylundecanoyl group, a compound represented by the general formula (I) in which at least one of R ₃ , R ₄ and R ₅ is an alkoxy group,
(13) The compound of (12), wherein the alkanoyl group is an alkanoyl group having 1 to 7 carbon atoms, and (14) the alkenoyl group is an alkenoyl group having 3 to 20 carbon atoms (12).
And a compound of formula (II):

[0008]

[Chemical 6]

(In the formula, R ₁ , R ₂ , R ₆ and R ₇ are the same as in the general formula (I), and R ₈ , R ₉ and R ₁₀ are each an optionally protected carboxyl group. R ₁ is 11-
When it is a phenyl-10-undecenoyl group, at least one of R ₈ , R ₉ and R ₁₀ is a protected carboxyl group. ) Is optionally acylated and then subjected to a deprotection reaction, a process for producing a compound represented by the general formula (I) or a salt thereof,
And (16) an antihyperlipidemic agent comprising a compound represented by the general formula (I) or a salt thereof.

In each formula, examples of the acyl group in the optionally substituted acyl group represented by R ₁ , R ₂ , R ₆ or R ₇ include an acyl group derived from an organic carboxylic acid. . As a preferred example, an alkanoyl group,
Examples thereof include an alkenoyl group, an arylcarbonyl group, an aralkylcarbonyl group, an alkyloxycarbonyl group and a heterocyclic carbonyl group.

The alkanoyl group is preferably an alkanoyl group having 1 to 30 carbon atoms, such as formyl, acetyl, propionyl, butyryl, cyclopropanecarbonyl, isobutyryl, valeryl, isovaleryl, cyclobutanecarbonyl, hexanoyl, cyclopentanecarbonyl, heptanoyl. , Cyclohexanecarbonyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, nocosanoyl, tetracosanoyl, hexacosanoyl, ethyldodecanoyl, methyltridecanoyl, ethyltridecanoyl, ethyltridecanoyl, ethyltridecanoyl Methyl tetradecanoyl,
Ethyl tetradecanoyl, methyl pentadecanoyl, ethyl pentadecanoyl, methyl hexadecanoyl, ethyl hexadecanoyl, methylheptadecanoyl, ethylheptadecanoyl, methyloctadecanoyl, ethyloctadecanoyl, octacosanoyl, triacontanoyl Etc., more preferably a saturated alkanoyl group having 1 to 20 carbon atoms, for example, formyl, acetyl, propionyl,
Butyryl, cyclopropanecarbonyl, isobutyryl,
Valeryl, isovaleryl, cyclobutanecarbonyl, hexanoyl, cyclopentanecarbonyl, heptanoyl, cyclohexanecarbonyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, ethyldodecanoyl, methyltridecanoyl. Decanoyl, ethyltridecanoyl, methyltetradecanoyl, ethyltetradecanoyl, methylpentadecanoyl, ethylpentadecanoyl, methylhexadecanoyl, ethylhexadecanoyl, methylheptadecanoyl, ethylheptadecanoyl, methyloctadecyl Decanoyl, ethyl octadecanoyl and the like, particularly preferably alkanoyl group having 1 to 7 carbon atoms, for example, formyl, acetyl, propyl Cycloalkenyl, butyryl, cyclopropanecarbonyl, isobutyryl, valeryl, isovaleryl, cyclobutanecarbonyl, hexanoyl, cyclopentanecarbonyl, heptanoyl, cyclohexanecarbonyl, and the like.

The alkenoyl group is preferably
Alkenoyl groups having 3 to 24 carbon atoms, for example, propenoyl, butenoyl, 2-methylpropenoyl, 3-methyl-2-butenoyl, hexenoyl, hexadienoyl,
Heptenoyl, octenoyl, octadienoyl, decenoyl, decadienoyl, undecenoyl, dodecenoyl, (cis, cis) -9,12-octadecadienoyl, 9,12,15-octadecatrienoyl, 9,11,
13-octadecatrienoyl, 5,8,11,14-icosatetraenoyl, cis-15-tetracosaenoyl, etc., more preferably an alkenoyl group having 3 to 20 carbon atoms, for example, propenoyl, butenoyl, 2- Methyl propenoyl, 3-methyl-2-butenoyl, hexenoyl, hexadienoyl, heptenoyl, octenoyl,
Octadienoyl, decenoyl, decadienoyl, undecenoyl, dodecenoyl, (cis, cis) -9,12
-Octadecadienoyl, 9,12,15-octadecatrienoyl, 9,11,13-octadecatrienoyl,
Examples include 5,8,11,14-icosatetraenoyl and the like. The alkenoyl group is preferably an alkenoyl group having 1 to 6 unsaturated bonds.

The aryl group in the arylcarbonyl group is preferably an aryl group having 6 to 12 carbon atoms,
Examples include phenyl, naphthyl, biphenylyl and the like. The aralkyl group in the aralkylcarbonyl group is preferably an aralkyl group having 7 to 19 carbon atoms,
For example, benzyl, phenethyl, naphthylethyl, benzhydryl, trityl and the like can be mentioned. The alkyl group in the alkyloxycarbonyl group has 1 carbon atom.
Alkyl groups of 10 are preferred, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se
c-butyl, tert-butyl, pentyl, isopentyl,
Neopentyl, tert-pentyl, 1-ethylpropyl,
Hexyl, isohexyl, 1,1-dimethylbutyl, 2,
2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like can be mentioned. More preferably, an alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like can be mentioned.

Examples of the heterocyclic group in the heterocyclic carbonyl group include a 5- or 6-membered heterocyclic group containing 1 to 4 nitrogen atoms, oxygen atoms and / or sulfur atoms. Specific examples thereof include , Pyrrolidino, 2-oxopyrrolidino, pyrrolidinyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, piperidino, piperidinyl, pyridyl, pyridazinyl, pyrazinyl, piperazinyl, pyrimidinyl, indolyl, 1,2,3-yl. 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,3-dioxolanyl, morpholino, morpholinyl and the like can be mentioned. Further, the heterocyclic group has a 5- or 6-membered ring (eg, benzene, pyridine,
Bicyclic condensed ring group (eg, 8
-Quinolyl, 8-purinyl, etc.) may be formed.

The acyl groups are preferably alkanoyl, alkenoyl, arylcarbonyl and alkyloxycarbonyl. The acyl group is 1 to 7 appropriate substituents, for example, hydroxyl group, carboxyl group, halogen, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, aralkyl group, alkoxy group, alkyl group, or mono or It may be substituted with an optionally di-substituted amino group, an acyloxy group, a heterocyclic group or the like. Examples of the halogen as the substituent include fluorine, chlorine, bromine, iodine and the like. The alkyl group as the substituent of the acyl group and the alkyl group of the amino group which may be mono- or di-substituted by the alkyl group are preferably an alkyl group having 1 to 10 carbon atoms, for example,
Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2- Dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like, more preferably, an alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and the like. To be

The alkenyl group as the above substituent is preferably an alkenyl group having 1 to 6 carbon atoms, for example, a methylene group, a cis- or trans-ethylidene group, a vinyl group, an allyl group, a cis- or trans-propylidene group and isopropylidene group. Ridene group, isopropenyl group, cis- or trans-1-
Propenyl group, cis- or trans-1-butenyl group, ci
s- or trans-2-butenyl group, 3-butenyl group,
1,3-butadienyl group, 3-methyl-2-butenyl group, cis- or trans-1-pentenyl group, cis- or trans-2-pentenyl group, cis- or trans-1-
Examples thereof include a hexenyl group. The alkynyl group as the above substituent is preferably an alkynyl group having 1 to 6 carbon atoms, and examples thereof include a methylidin group and acetylene (ethynyl).
Group, propargyl (2-propynyl) group, propynyl group, butynyl group, 2-butynyl group, 3-butynyl group, pentynyl group, 2-pentynyl group, 3-pentynyl group, 4
-Pentynyl group, 3-methylbutynyl group, 3-methylpentynyl group, hexynyl group and the like. The cycloalkyl group as the above substituent is preferably a cycloalkyl group having a carbon number of 3 to 8, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. More preferably, it is a cycloalkyl group having 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The aryl group as the above substituent is preferably an aryl group having 6 to 12 carbon atoms, for example,
Examples thereof include phenyl, naphthyl, biphenylyl and the like.
The aralkyl group as the above substituent is preferably an aralkyl group having a carbon number of 7 to 19, and examples thereof include benzyl, phenethyl, naphthylethyl, benzhydryl and trityl. The alkoxy group as the above substituent is preferably an alkoxy group having 1 to 6 carbon atoms, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-
Examples thereof include butoxy group, pentyloxy group, neopentyloxy group and the like. The acyloxy group as the above substituent is preferably an acyloxy group having 1 to 6 carbon atoms, and examples thereof include a formyloxy group, an acetoxy group, a propanoyloxy group, a butyroxy group, an isobutyroxy group, a valeroyloxy group, an isovaleroyloxy group. , Pivaloyloxy group and the like.

The heterocyclic group as the above substituent is 1
A 5- or 6-membered heterocyclic group containing 4 to 4 nitrogen atoms, oxygen atoms and / or sulfur atoms, and specific examples thereof include pyrrolidino, 2-oxopyrrolidino,
Pyrrolidinyl, pyrrolyl, pyrazolyl, imidazolyl,
Furyl, thienyl, oxazolyl, isoxazolyl,
Isothiazolyl, thiazolyl, piperidino, piperidinyl, pyridyl, pyridazinyl, pyrazinyl, piperazinyl, pyrimidinyl, indolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,3- Examples include dioxolanyl, morpholino, morpholinyl and the like. Further, the heterocyclic group may be condensed with a 5- or 6-membered ring (eg, benzene, pyridine, cyclohexane etc.) to form a bicyclic condensed ring group (eg, 8-quinolyl, 8-purinyl etc.). Good. Of these substituents, an alkyl group, an alkoxy group, a mono- or dialkylamino group, a halogen, a carboxyl group, a hydroxyl group, an acyloxy group, an amino group, or a heterocyclic group is preferable. More preferably, an alkyl group,
An alkoxy group, a carboxyl group, a hydroxyl group, and an amino group. The alkoxy group represented by R ₃ , R ₄ or R ₅ is preferably an alkoxy group having 1 to 6 carbon atoms, and examples thereof include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group and a sec-butoxy group. Base, t
An ert-butoxy group, a pentyloxy group, a neopentyloxy group and the like can be mentioned. Examples of the substituent of the optionally substituted amino group represented by R ₃ , R ₄ or R ₅ include an alkyl group, a cycloalkyl group, an aryl group, an aralkyl group, an acyl group and a heterocyclic group. . Examples of the alkyl group, cycloalkyl group, aryl group, aralkyl group, acyl group and heterocyclic group are the same as the above-mentioned substituents of the acyl group. The above alkyl group,
An alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, an aralkyl group, an alkoxy group, an acyloxy group, and a heterocyclic group may be further substituted with a suitable substituent (eg, a hydroxyl group, a carboxyl group, a C _1-6 alkyl group or a di-substituted group). 1 or 2 may be substituted with an optionally substituted amino group). The substituent in the optionally substituted amino group is preferably an alkyl group or an aralkyl group,
More preferably, it is an alkyl group. Of which C _1-6
An alkyl group or a C _7-12 aralkyl group is more preferable.
X is preferably a vinylene group.

The protective group for the protected carboxyl group represented by R ₈ , R ₉ or R ₁₀ is not particularly limited, and possible carboxyl group protecting groups can be used. Preferable examples of the protected carboxyl group include ester and the like. Examples of the alcohol that forms an ester with the carboxyl group include, for example, a lower alcohol that may be substituted (eg, methanol, ethanol,
Cyanomethyl alcohol, 2-tetrahydropyranyl alcohol, benzoylmethyl alcohol, tert-butanol, etc.), arylalkanol [eg, lower alkyl group, lower alkoxy group or benzyl alcohol or benzhydrol which may be substituted by a halogen atom] (Eg, benzhydrol, p-nitrobenzyl alcohol, p-methoxybenzyl alcohol, 2,
4,6-trimethylbenzyl alcohol, etc.)],
Phenols and thiophenols optionally substituted with electron-withdrawing substituents (eg thiophenol, thiocresol, p-nitrothiophenol, 2,4,5- and 2,4,6-trichlorophenol, p-cyano Phenol, p-methanesulfonylphenol, etc.), N-hydroxyimide (eg, N-hydroxysuccinimide,
N-hydroxyphthalimide, etc.), N-hydroxypiperidine, 8-hydroxyquinoline, silanol (eg,
Trimethylsilanol, triethylsilanol, triisopropylsilanol, tert-butyldimethylsilanol, tert-butyldiphenylsilanol, and other trialkylsilanols).

The compound represented by the general formula (I) or (II) (hereinafter sometimes abbreviated as compound (I) or (II)) is an acidic substance and forms a salt with a suitable base. Examples of preferable salts are pharmacologically acceptable salts, for example, alkali metals such as sodium and potassium, for example, salts with alkaline earth metals such as calcium and magnesium or inorganic bases such as ammonium,
For example, with an organic base such as methylamine, ethylamine, propylamine, isopropylamine, butylamine, tertiary butylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine, N, N′-dibenzylethylenediamine. Examples thereof include salts, for example, salts with amino acids such as lysine.

Next, a method for producing the compound (I) or a salt thereof will be described. Compound (I) or a salt thereof of the present invention can be produced by subjecting the carboxyl group-protecting group of compound (II) to a deprotection reaction. Compound (I
When R ₁ , R ₂ and / or R _{7 in} I) is hydrogen, it is subjected to an acylation reaction prior to the deprotection reaction. The acylation reaction is carried out by a method known per se. As the acylating agent used in this reaction, for example, an organic carboxylic acid for deriving the acyl group represented by R ₁ , R ₂ or R ₇ ,
Alternatively, a reactive derivative thereof is used.

When an organic carboxylic acid is used, it can be acylated by reacting it with a suitable condensing agent.
As the condensing agent, dicyclohexylcarbodiimide, diisopropylcarbodiimide, diimides such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, or the above condensing agent and pentachlorophenol, 2,4,5-trichlorophenol, 2 , 4-Dinitolphenol, cyanomethyl alcohol, p-nitrophenol, N-hydroxy-5-norbornene-
A mixture with 2,3-dicarboximide, N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxybenzotriazole, or the like is used. Alternatively, a mixture of azodicarboxylic acid esters (eg, azodicarboxylic acid diethyl ester) and trialkylphosphine (eg, triphenylphosphine, tributylphosphine) is used. The condensation reaction can be performed in the presence of a solvent. The solvent can be appropriately selected from those known to be usable in the condensation reaction. For example, amides such as formamide, dimethylformamide and N-methylpyrrolidine, sulfoxides such as dimethyl sulfoxide (hereinafter abbreviated as DMSO), aromatic amines such as pyridine, chloroform,
Examples thereof include halogenated hydrocarbons such as dichloromethane, ethers such as tetrahydrofuran and dioxane, nitriles such as acetonitrile, esters such as ethyl acetate and ethyl formate, and a mixture thereof at an appropriate ratio.

The reaction temperature is appropriately selected from the range known to be applicable to the condensation reaction. In particular,
For example, usually, it is appropriately selected from the range of -20 ° C to 50 ° C. The reaction time is appropriately selected from the range known to be necessary for the condensation reaction. Specifically, for example, the reaction is performed for several minutes to about 7 days.

When a reactive derivative of an organic carboxylic acid is used, as the reactive derivative, for example, an acid halide, an acid anhydride, an active amide, an active ester, an active thioester or the like which can be produced by a conventional method is used. . Specific examples of such a reactive derivative are as follows. (1) Acid halide: For example, acid chloride, acid bromide or the like is used. (2) Acid anhydride: for example, symmetrical acid anhydride, mono C _1-6
Alkyl carbonate mixed anhydride, mixed acid anhydride consisting of aliphatic carboxylic acid (eg, acetic acid, pivalic acid, valeric acid, isovaleric acid, trichloroacetic acid, etc.), aromatic, aromatic carboxylic acid (eg, benzoic acid, etc.) A mixed acid anhydride consisting of is used. Examples of symmetrical acid anhydrides include C _2-30 alkylcarboxylic acid anhydrides such as acetic anhydride, propionic anhydride and butanoic anhydride. (3) Active amide: For example, an amide with pyrazole, imidazole, 4-substituted imidazole, dimethylpyrazole, benzotriazole or the like is used. (4) Active ester: for example, methoxymethyl ester, 1-hydroxybenzotriazole ester, N-
Hydroxy-5-norbornene-2,3-dicarboximide ester, 4-nitrophenyl ester, 2,4
-Dinitrophenyl ester, trichlorophenyl ester, propargyl ester, pentachlorophenyl ester, and other esters, as well as 1-hydroxy-1H-2
-Esters with pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide and the like are used. (5) Active thioester: For example, a thioester with a heterocyclic thiol such as 2-pyridylthiol or 2-benzothiazolylthiol is used. The various reactive derivatives as described above are appropriately selected depending on the type of carboxylic acid.

As the acylating agent, a reactive derivative of sulfonic acid which can introduce an acyl sulfonate, for example,
Acid halides such as methanesulfonyl chloride, benzylsulfonyl chloride, p-toluenesulfonyl chloride,
Symmetrical acid anhydrides such as anhydrous methanesulfonic acid and anhydrous p-toluenesulfonic acid may be used. An acylating agent such as a carboxylic acid, a reactive derivative thereof or a reactive derivative of sulfonic acid, and a condensing agent may be used, for example, in an amount of about 1 mol or more per 1 mol of the raw material compound, and about 1 to 30 mol. Is preferred.

This reaction is carried out in a solvent which does not inhibit the reaction or in the absence of solvent. Examples of the solvent that does not inhibit the reaction include ketones such as acetone, ethers such as diethyl ether, tetrahydrofuran and dioxane, carboxylic acids such as acetic acid and propionic acid, nitriles such as acetonitrile, carbonization such as benzene, toluene and xylene. Hydrogen, dichloromethane, chloroform, 1,2
-Halogenated hydrocarbons such as dichloroethane, esters such as ethyl acetate, amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethyl sulfoxide, triethylamine, tributylamine,
N-methylmorpholine, N-methylpiperidine, N, N
-Tertiary amines such as dimethylaniline, pyridines such as pyridine, picoline, lutidine and collidine are used. You may use these individually or in mixture of 2 or more types in a suitable ratio.

The present acylation reaction proceeds more advantageously by using a catalyst capable of promoting the acylation of the raw material compound. Examples of such a catalyst include a base catalyst,
An acid catalyst is used. Examples of the base catalyst include tertiary amines [eg, aliphatic tertiary amines such as triethylamine, pyridine, α-, β- or γ-picoline, 2,6
-Lutidine, 4-dimethylaminopyridine, 4- (1-
Aromatic tertiary amines such as pyrrolidinyl) pyridine, dimethylaniline, diethylaniline], alkali metal halides (eg, potassium fluoride, anhydrous lithium iodide, etc.), organic acid salts (eg, sodium acetate), etc. are used. . Examples of the acid catalyst include Lewis acid (eg, anhydrous zinc chloride, anhydrous aluminum chloride (AlCl ₃ ), titanium tetrachloride (TiCl ₄ ), tin tetrachloride (SnCl ₄ ), antimony pentachloride, cobalt chloride, cupric chloride). , Boron trifluoride etherate, etc., inorganic strong acid (eg, sulfuric acid, perchloric acid, hydrogen chloride, hydrogen bromide, etc.), organic strong acid (eg, benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, trichloroacetic acid) , Camphor sulfonic acid, etc.), acidic ion exchange resin (eg, polystyrene sulfonic acid), etc. are used. Among the above catalysts, camphorsulfonic acid, hydrochloric acid, sulfuric acid, perchloric acid, triethylamine, pyridine, 4
-Dimethylaminopyridine and the like are preferred.

The amount of the catalyst used may be a catalytic amount capable of promoting the acylation of the raw material compound with a carboxylic acid, and is usually about 0.001 to 10 moles per 1 mole of the raw material compound.
It is preferably about 0.01 to 1 mol. The reaction temperature is not particularly limited, but is usually about -30 to 100 ° C, preferably about 10 to 50 ° C. The reaction time is about several minutes to several days (for example, about 5 minutes to 7 days).

Thus, the deprotection group reaction of compound (II) or a salt thereof can be carried out by a method known per se. The deprotection reaction of the carboxyl group (such as ester hydrolysis reaction) is carried out by contacting with an acid without solvent or in a solvent that does not adversely influence the reaction. As the solvent, halogenated hydrocarbons (eg, dichloromethane,
Chloroform, 1,2-dichloroethane, etc.), alcohols (eg, methanol, ethanol, etc.), water and a mixture thereof in an appropriate ratio are used. This reaction is
It is carried out by bringing the compound (II) or a salt thereof into contact with an acid. Examples of the acid include haloacetic acid (eg, trifluoroacetic acid, etc.), hydrohalic acid (eg, hydrochloric acid, hydrobromic acid, etc.), Lewis acid (eg, zinc-acetic acid,
Boron trifluoride ether complex, iodomethylsilane, etc.) and the like are used. Alternatively, it is carried out by contacting with a base in the absence of solvent or a solvent that does not adversely influence the reaction. Examples of the solvent include alcohols (eg, methanol, ethanol etc.), ethers (eg, dioxane, tetrahydrofuran etc.), nitrites (eg, acetonitrile etc.), ketones (eg acetone, methyl ethyl ketone etc.), water and these. The mixture is used in an appropriate ratio. Examples of the base include inorganic bases (eg, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.), organic bases (eg, pyridine, 2,4,6-trimethylpyridine, picoline, 4-dimethylaminopyridine, 2,6-
Pyridines such as lutidine, tertiary amines such as triethylamine and dimethylaniline) and the like are used.

Among the carboxyl group-protecting groups, protecting groups such as benzyl esters (eg, benzyl ester, benzhydryl ester, etc.) include, for example, palladium catalyst,
For example, it is advantageous to remove by catalytic hydrogenation using a palladium / barium sulphate, palladium black or rhodium catalyst. In that case, a solvent known in the literature, for example, a cyclic ether (eg, tetrahydrofuran, etc.) is optionally mixed with another inert solvent [eg, lower aliphatic acid amide (eg, dimethylformamide etc.)] and used. .
In the case of a trialkylsilyl group, under neutral conditions,
For example, a salt of hydrofluoric acid, such as potassium fluoride,
In particular, it can also be eliminated by allowing a salt of a quaternary nitrogen base and hydrofluoric acid (eg, tetraethylammonium fluoride, etc.) to act in a suitable solvent. The reaction temperature is
It is appropriately selected from the range known to be used in the deprotection reaction. For example, it is usually appropriately selected from the range of about -20 ° C to 80 ° C. The reaction time is appropriately selected from the range known to be necessary for the deprotection reaction. Specifically, the reaction is performed for, for example, several minutes to 48 hours. As described above, the protecting group of the carboxyl group is deprotected to remove R ₃ ,
A compound (I) or a salt thereof in which R ₄ and R ₅ are each a hydroxyl group can be produced.

The compound (I) in which R ₃ , R ₄ and / or R ₅ is an optionally substituted amino group is, for example, the corresponding carboxylic acid compound or its reactive derivative (eg, as described above. Acid halides, acid anhydrides, active esters, active thioesters, etc.) according to a general formula:

[0031]

[Chemical 7]

(Wherein R ₁₁ and R ₁₂ are each hydrogen or a substituent of the optionally substituted amino group represented by the above R ₃ , R ₄ and R ₅ ). It can be produced by reacting. For example, when using a free carboxylic acid, it can be amidated by reacting with a suitable condensing agent. As the condensing agent, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl)
Diimides such as carbodiimide hydrochloride or the above condensing agent and pentachlorophenol, 2,4,5-trichlorophenol, 2,4-dinitolphenol, cyanomethyl alcohol, p-nitrophenol, N-hydroxy-5-norbornene -2,3-dicarboximide,
A mixture with N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxybenzotriazole and the like are used. This reaction may be carried out in the presence of a base. Examples of the base used include aliphatic tertiary amines such as trimethylamine, triethylamine, tripropylamine, and tri-n-butylamine,
Diisopropylethylamine, N-methylpiperidine,
Tertiary amines such as N-methylpyrrolidine, cyclohexyldimethylamine and N-methylmorpholine, di-n-
Dialkylamines such as butylamine, diisobutylamine, dicyclohexylamine, dicyclohexylamine, aromatic amines such as pyridine, lutidine and γ-collidine, alkali metals such as lithium, sodium and potassium, water such as alkaline earth metals such as calcium and magnesium. Examples thereof include oxides and carbonates. Also,
Of the above, the liquid one can also be used as a solvent.

In this reaction, the amines are usually used in an amount of about 1 to 100 mol per mol of the starting compound, but they may be used in excess unless the reaction is hindered. When a base is used, the amount of the base used varies depending on the starting compound used or a salt thereof, the type of the reactive derivative of carboxylic acid, and other reaction conditions, but is usually about 1 to 30 equivalents relative to the starting compound. It is preferably about 1 equivalent to 10 equivalents.
This reaction is usually performed in a solvent that does not inhibit the reaction. Examples of the solvent include ethers such as dioxane, tetrahydrofuran, diethyl ether and diisopropyl ether, esters such as ethyl acetate and ethyl formate, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,1-trichloroethane and the like. Halogenated hydrocarbons, benzene, toluene, hydrocarbons such as n-hexane, N, N-dimethylformamide, N, N
Ordinary organic solvents such as amides such as dimethylacetamide and nitriles such as acetonitrile are used alone or in combination. The reaction temperature is not particularly limited as long as the reaction proceeds, but is usually about -50 ° C to 150 ° C, preferably about -30 ° C to 50 ° C. The reaction time is
The reaction is usually completed in several tens of minutes to several tens of hours, though it varies depending on the raw material used, base, reaction temperature, type of solvent, etc.
Sometimes it takes several days.

The compound (II), which is the starting compound for the production of the object compound (I) of the present invention, has the formula:

[0035]

[Chemical 8]

It can be produced by preparing a carboxyl group-protected derivative of TAN-1607A represented by the formula (1), and then, if necessary, selectively eliminating the side chain acyl group formed. As the carboxyl group-protected derivative of TAN-1607A, an ester form is preferable. The esterification reaction is carried out by a method known per se. For example, compound T
A method of reacting AN-1607A or a salt thereof with a halide can be mentioned. The halide used is an alkyl halide (eg, methyl iodide, ethyl iodide,
Propyl iodide, allyl bromide, benzyl bromide, tert-bromide
-Butyl, triphenylmethyl bromide, methoxymethyl chloride, methylthiomethyl chloride, tetrahydropyranyl chloride, etc.), silyl halides (eg, trimethylsilyl chloride, triethylsilyl chloride, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride, chloride) tert-butyldiphenylsilyl and the like).

This reaction is usually carried out in the presence of a base. Examples of the base used include tertiary amines such as trimethylamine, triethylamine, tripropylamine, tri-n-butylamine, diisopropylethylamine, N-methylpiperidine, N-methylpyrrolidine, cyclohexyldimethylamine and N-methylmorpholine, di-
Dialkylamines such as n-butylamine, diisobutylamine, dicyclohexylamine and dicyclohexylamine, aromatic amines such as imidazole, pyridine, 4-dimethylaminopyridine, lutidine, diazabicyclononane, diazabicycloundecene and γ-collidine,
Examples thereof include alkali metals such as lithium, sodium and potassium, and hydroxides and carbonates of alkaline earth metals such as calcium and magnesium. Further, among the above, the liquid one can be used also as a solvent.

In this reaction, a halide is usually used in an amount of about 1 to 100 mol per mol of the raw material compound.
It may be used in excess unless it interferes with the reaction. When a base is used, the amount of the base used varies depending on the kind of halide and other reaction conditions, but is usually about 1 to 30 equivalents, preferably about 3 to 1 equivalent to the starting compound.
It is 0 equivalent. Alternatively, a lower alcohol which may be substituted with the compound TAN-1607A or a salt thereof (eg, methanol, ethanol, isopropanol, te
rt-butanol, cyanomethyl alcohol, benzoylmethyl alcohol, etc.), arylalkanol [eg,
Benzyl alcohol or benzhydrols optionally substituted by a lower alkyl group, a lower alkoxy group or a halogen atom (eg, benzhydrol, p-nitrobenzyl alcohol, p-methoxybenzyl alcohol, 2,4,6-trimethyl) Benzyl alcohol) and the like] can be esterified by reacting with a suitable condensing agent. As the condensing agent, dicyclohexylcarbodiimide, diisopropylcarbodiimide,
Diimides such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, or the above condensing agent and pentachlorophenol, 2,4,5-trichlorophenol, 2,4-dinitrophenol, cyanomethyl alcohol, p-nitrophenol, N-hydroxy-5-norbornene-2,3-dicarboximide, N
-Hydroxysuccinimide, N-hydroxyphthalimide, a mixture with N-hydroxybenzotriazole and the like are used. Or azodicarboxylic acid esters (eg, azodicarboxylic acid diethyl ester)
And a trialkylphosphine (eg, triphenylphosphine, tributylphosphine, etc.) are used. Alternatively, the compound TAN-1607A or a salt thereof can be esterified by reacting with the above alcohols or the like under a suitable acid catalyst. You may use these alcohols as a solvent. Alternatively, compound T
The esterification can be carried out by reacting AN-1607A or a salt thereof with a lower carboxylic acid ester of the above alcohols, for example, a formic acid ester, an acetic acid ester, a propionic acid ester, or the like, under a suitable acid catalyst. These lower carboxylic acid esters may be used as a solvent. Alternatively, the compound TAN-1607A or a salt thereof may be substituted with ethylene under a suitable acid catalyst, for example, 2-methylpropene, 2-methylbutene, 2
It can be esterified by reacting with -ethylbutene, 2,3-dimethylbutene, 2-phenylpropene, 2-phenylstyrene and the like. When these ethylenes are gases at room temperature, the reaction is usually carried out under a closed condition.

Alternatively, the compound TAN-1607A or a salt thereof is described in the literature as an isourea derivative such as the above alcohols or an N, N-dialkylformamide acetal derivative [eg, Synthesis, 561 (19).
79) etc.] and the like can be used for esterification. The above esterification reaction is usually carried out in a solvent that does not inhibit the reaction. As the solvent,
For example, ethers such as dioxane, tetrahydrofuran, diethyl ether and diisopropyl ether, for example, esters such as ethyl acetate and ethyl formate, such as chloroform, dichloromethane, 1,2-dichloroethane, 1,1,1-trichloroethane and the like. Halogenated hydrocarbons, for example, benzene, toluene, hydrocarbons such as n-hexane, for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, for example, nitriles such as acetonitrile, for example Ordinary organic solvents such as sulfoxides such as dimethyl sulfoxide may be used alone or as a mixture. The reaction temperature is not particularly limited as long as the reaction proceeds, but usually,
About -50 ° C to 150 ° C, preferably about -30 ° C to 50 ° C
Done in. The reaction time will differ depending on the starting materials used, the base, the reaction temperature, the type of solvent, etc., but the reaction is usually completed in several tens of minutes to several tens of hours, but sometimes it may take several tens of days.

The selective deacylation reaction (ester hydrolysis reaction) can be carried out by a method known per se. It is carried out by contacting with a base in a solvent that does not adversely influence the reaction. As the solvent, alcohols (eg, methanol, ethanol, etc.), ethers (eg, dioxane, tetrahydrofuran, etc.), nitrites (eg, acetonitrile, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), water and these The mixture is used in an appropriate ratio. Examples of the base used in this reaction include inorganic bases (eg, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.), organic bases (eg, pyridine, 2,4,6-trimethyl). Pyridine, picoline, 4-dimethylaminopyridine, 2,
Pyridines such as 6-lutidine, and tertiary amines such as triethylamine and dimethylaniline) are used.
The reaction temperature is appropriately selected from the range known to be applicable to ester hydrolysis reaction. For example, usually about -30 ° C to 120 ° C, preferably about -10 ° C to 4
It is appropriately selected from the range of 0 ° C. The reaction time is appropriately selected from the range known to be necessary for the deprotection reaction. Specifically, for example, the reaction is performed for about several minutes to about 48 hours, preferably about 30 minutes to 4 hours. Compound (II) can be produced by removing the acyl group as described above.

TAN-1607A belongs to the genus Cladosporium, and its physiologically active substance TAN-
It can be obtained by culturing a bacterium producing 1607A by a method known per se. Examples of the producing bacterium include, for example, Cladosporium cladospo isolated from Indian soil.
rioides FL-21431) strain. This strain has been deposited with the Fermentation Research Institute under the deposit number IFO-32443 since April 21, 1992.
Deposit No. FERM B from April 27, 1992 to the Institute of Biotechnology, Ministry of International Trade and Industry, based on the Budapest Treaty.
Deposited as P-3844.

The medium used for culture may be liquid or solid as long as it contains a nutrient source that can be utilized by the strain, but when treating a large amount, it is more suitable to use a liquid medium. An assimilable carbon source, a digestible nitrogen source, an inorganic substance, and a micronutrient are appropriately mixed in the medium. As a carbon source,
For example, glucose, lactose, sucrose, maltose, dextrin, starch, glycerin, mannitol, sorbitol,
Fats and oils (eg, soybean oil, olive oil, bran oil, sesame oil, lard oil, chicken oil, etc.) and nitrogen sources include, for example, meat extract, yeast extract, dry yeast, soybean powder, corn steep liquor, peptone, Cottonseed flour, urea, ammonium salts (eg ammonium sulfate, ammonium acetate, etc.)
Others can be used. In addition, salts containing sodium, potassium, calcium, magnesium, etc.,
Metal salts such as iron, manganese, zinc, cobalt and nickel, salts such as phosphoric acid and boric acid, and salts of organic acids such as acetic acid and propionic acid can be appropriately used. Other,
Amino acids (eg, glutamic acid, aspartic acid, alanine, lysine, valine, methionine, proline, etc.), peptides (eg, dipeptide, tripeptide, etc.), vitamins (eg, vitamin B ₁ , vitamin B ₂ , nicotinic acid, Vitamin B ₁₂ , vitamin C, etc.), nucleic acids (eg, purine, pyridine and derivatives thereof) and the like may be contained. Of course, inorganic or organic acids, alkalis, buffers and the like may be added for the purpose of adjusting the pH of the medium, or fats and oils, surfactants and the like may be added in appropriate amounts for the purpose of defoaming.

The means for culturing may be static culture, shaking culture, aeration and stirring culture, or the like. For large-scale treatment, so-called deep aeration stirring culture is desirable. Cultivation conditions vary depending on the condition of the medium, composition, type of strain, and culture means, but it is usually preferable to select a temperature of about 12 ° C to 44 ° C and an initial pH of about 5-9. Especially, the temperature in the middle stage of culture is about 20 to 30 ° C, and the initial pH is
Is preferably about 6-8. Although the culture time is not constant under the above conditions, it is preferable to culture until the concentration of the physiologically active substance becomes maximum. The time required for this is usually about 1 in the case of shaking culture using a liquid medium or aeration stirring culture.
It is about 10 days. Compound T of interest from culture
To collect AN-1607A, since the compound is acidic and fat-soluble, a general means utilizing this property may be adopted. First, after adjusting the pH of the culture solution to about 1.5 to 6, preferably about 2 to 4, an organic solvent immiscible with water,
For example, by adding dichloromethane, ethyl acetate, methyl isobutyl ketone, butanol, etc., TAN-16
07A is extracted. After washing the extract with water and concentrating,
A crude material containing AN-1607A is obtained. Also,
The organic solvent layer is extracted with diluted alkaline water, TAN-1607
It is also possible to transfer A into the aqueous layer. When the transferred water layer is adjusted to be acidic again and extracted with the above organic solvent, TAN-
1607A is extracted in the organic solvent layer.

The crude material was further purified to give pure TAN-1
Various chromatographic methods are advantageously used to obtain 607A. As the carrier, silica gel, crystalline cellulose, adsorptive resin such as Diaion HP-20 (manufactured by Mitsubishi Kasei), Sephadex LH-20 (manufactured by Pharmacia, Sweden), anion exchange resin such as Amberlite IRA-402 ( Amberlite Co., USA), Dowex-1 (Dow and Chemical Co., USA) and the like can be used, and these are usually carried out by a column chromatography method. To elute the active substance from the carrier, depending on the kind of the carrier, a suitable organic solvent such as dichloroethane, toluene, ethyl acetate,
Alone or mixed solvent such as acetone, methanol,
Alternatively, water-miscible organic solvents and aqueous solutions, such as water,
A mixed solvent of dilute alkaline water, dilute acidic water, salt, an aqueous solution of an inorganic salt such as ammonium chloride, and a buffer solution is used. The organic solvent eluate containing the active substance is concentrated, or if it contains an aqueous solution, it is extracted with a suitable organic solvent immiscible with water and concentrated, and the residue is pulverized.

To further purify the crude powder to obtain the pure product, preparative high performance liquid chromatography (HPLC)
Can be purified by. As the carrier, octadecylsilane (ODS) type and silica gel type carriers are advantageously used. For example, in the case of ODS, a mixed solution of methanol or acetonitrile and a salt-containing aqueous solution is advantageously used as the mobile phase. The eluate containing the desired product is extracted with a suitable organic solvent immiscible with water, the extract is concentrated, and the residue is crystallized or powdered from the aforementioned suitable organic solvent to obtain the desired TAN-1607A.

The object compound (I) of the present invention obtained as described above can be obtained by a method known per se, for example, concentration, liquid conversion,
It can be isolated and purified by phase transfer, solvent extraction, freeze-drying, crystallization, recrystallization, fractional distillation, chromatography and the like. The compound (I) of the present invention can be converted into a salt with a base, particularly a salt with a pharmaceutically acceptable base described above by a method known per se. Examples of the base include alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, and organic bases such as triethylamine, pyridine and piperidine. Compound
Since (I) has two or more asymmetric carbons in the basic skeleton, theoretically there are four or more types of stereoisomers, but each isomer and a mixture thereof are also included in the present invention. Similarly, when the substituent has an asymmetric carbon, stereoisomers are similarly produced, and each isomer and a mixture thereof are also included in the present invention. When the unsaturated bond is contained, the geometric isomer produced thereby is also included in the present invention.

Next, the biological activity of the compound (I) of the present invention will be explained. The squalene synthase inhibitory activity of compound (I) can be measured as follows. (1) Preparation of rat liver-derived enzyme SD male rats (6 weeks old) were exsanguinated and killed, and then the liver was excised. After washing approximately 10 g of liver with ice-cold saline,
5 ml ice-cold buffer [100 mM potassium phosphate (pH 7.
4), homogenize in 15 mM nicotinamide, 2 mM MgCl ₂ ], and centrifuge at 10,000 × g for 20 minutes (4 ° C.). The supernatant obtained is further added at 90,000 xg for 90
Centrifuge for minutes (4 ° C), suspend the precipitate in ice-cold 100 mM potassium phosphate buffer (pH 7.4), and then resuspend at 105,0 again.
Centrifuge at 00 × g for 90 minutes (4 ° C.). The precipitate (microsome fraction) thus obtained was suspended in ice-cold 100 mM potassium phosphate buffer (pH 7.4) (protein concentration about 40 mg).
/ Ml, measured with BCA protein assay kit from Pierce), and use this as the enzyme solution.

(2) Preparation of Human Cell-Derived Enzymes Human hepatoma cells HepG2 (about 1 × 10 6) obtained by culturing in Dulbecco's modified Eagle medium containing 10% fetal bovine serum (37 ° C., in the presence of 5% CO ₂ ). ⁹ cells) in 10 ml ice-cold buffer
Ultrasonic treatment after suspension in [100 mM potassium phosphate (pH 7.4), 30 mM nicotinamide, 2.5 mM MgCl ₂ ].
Crush the cells by (twice for 30 seconds). A microsome fraction is obtained from the obtained sonicate by the same operation as in Experimental Example 1. This is suspended in ice-cold 100 mM potassium phosphate buffer (pH 7.4) (protein concentration of about 4 mg / ml) to obtain an enzyme solution.

(3) Method for measuring squalene synthase inhibitory activity The squalene synthase inhibitory activity is determined by the above (1) and (2).
Using the enzyme solution obtained by the above method, the measurement is performed as follows. 5 μM [1- ³ H] farnesyl pyrophosphate (specific activity 25 μCi / μmole), 1 mMNADPH, 5 mM MgCl
₂ , 6 mM glutathione, 100 mM potassium phosphate buffer (pH 7.4) and test compound (aqueous solution or DMSO
Solution (added as a solution) (total volume 50 μl) to the enzyme solution (protein amount 0.8) prepared in (1) or (2) above.
μg) was added, and the mixture was reacted at 37 ° C. for 45 minutes.
The reaction was stopped by adding a mixed solution of chloroform / methanol (1: 2) (150 μl), and then chloroform (50 μl).
l) and 3N aqueous sodium hydroxide solution (50 μl) are added. A chloroform layer (lower layer, 50 μl) containing a reaction purified product containing squalene as a main component is mixed with 3 ml of a toluene liquid scintillator, and its radioactivity is measured by a liquid scintillation counter. The measurement result of the squalene synthase inhibitory activity is expressed as the concentration [IC ₅₀ (μg / ml)] at which the radioactivity incorporated into the chloroform layer is inhibited by 50%. For example, R ₁ is myristoyl, R ₂ is hydrogen, R ₃ ,
The compound (I) in which R ₄ and R ₅ are hydroxyl groups, R ₆ is an acetyl group, and R ₇ is hydrogen (the compound of Example 21 below) had an IC ₅₀ value of 0.00029 μg / ml for human enzyme.
Thus, the compound (I) of the present invention inhibits the action of squalene synthase derived from human cells and rat liver at a very low concentration.

The compounds of the present invention are effective as cholesterol lowering agents, have low toxicity, and are effective for humans and mammals (eg dogs,
It is useful as a preventive and therapeutic drug for hyperlipidemia in cats, cattle, rats, monkeys, etc.). Further, the compound is provided as a parenteral or oral preparation in an appropriate dosage form as a medicine by mixing with a pharmaceutically acceptable carrier. Parenteral agents include, for example, injections, drops, solutions, suspensions, suppositories, etc., and oral agents include capsules, tablets, syrups, powders, granules and the like. These are produced by a method known per se. Parenteral agents, for example, an isotonicity agent (eg,
Glucose, sorbitol, mannitol, sodium chloride, etc., preservatives (eg, benzyl alcohol, chlorobutanol, methyl parahydroxybenzoate, etc.), anticoagulants (eg, dextran sulfate, heparin, etc.), solubilizers (eg, cyclo Dextrins, Tween, etc.), stabilizers (eg, polyethylene glycol, polylactic acid, etc.) and the like may be contained. For administration, these compounds are dissolved in a conventional aqueous diluent and used as a solution. Diluents include aqueous glucose solution, physiological saline, Ringer's solution, nutritional supplement solution, and the like. In addition, usual additives for oral agents, such as excipients, binders, disintegrants, lubricants,
Coloring agents, flavoring agents, stabilizers and the like may be included.

These preparations are orally or parenterally administered, and when used in humans, the dose may vary depending on the administration route, the type and extent of the target disease, the age of the patient, etc. ), Based on the amount of
kg) about 0.2 mg to 100 mg per person, especially about 2 mg
It is preferable to administer -50 mg once or in 2 to 4 divided doses to prevent or treat diseases.

[0052]

The present invention will be described in more detail with reference to reference examples and examples, but the present invention is not limited thereto. The composition percentages of the medium in the following reference examples are weight / volume percentages. Further, abbreviations in ¹³ C-NMR are as follows: Q = quaternary carbon, CH
= Methine carbon, CH ₂ = methylene carbon, CH ₃ = methyl carbon, and the number preceding the abbreviation indicates the number of overlapping carbons. Abbreviations in ¹ H-NMR indicate s = 1 doublet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, and J represents a coupling constant.

Reference Example 1 Cladosporium cladsporioides (Clados) preliminarily and sufficiently grown on a slant medium composed of Bacto potato dextrose agar (Difco, USA).
5 platinum loops of porium cladosporioides) FL-21431, glucose 2.0%, maltose 3.0%, raw soybean flour 1.5%, corn steep liquor 1.0%, polypeptone 0.5%, and yeast Extract 0.3%, salt 0.3
The seed culture medium (500 ml, pH 6.0) was inoculated into a 2-liter volume Sakaguchi flask that had been sterilized by dispensing, and the mixture was cultured at 28 ° C. for 2 days on a reciprocal shaker. 1 liter of this culture solution was added with glucose 1.0%, dextrin 4.0%, raw soybean powder 0.5%, malt extract 0.5%, polypeptone 0.5.
%, Yeast extract 0.2%, iron sulfate heptahydrate 0.05%, magnesium sulfate heptahydrate 0.05%, manganese sulfate heptahydrate 0.05%.
120 liters of the main culture medium consisting of 05%, potassium phosphate 0.1%, and precipitated calcium carbonate 0.5% and pH 7.5 was transplanted to a 200-liter fermentation layer sterilized by injection. This main fermentation is 28 ℃, aeration (120 l / min),
The mixture was cultivated with stirring (140 rpm) for 114 hours under an internal pressure of 1.0 kg / cm ² , and TAN-1607A was produced and accumulated.

Reference Example 2 The culture solution (100 liters) obtained in Reference Example 1 was adjusted to pH 2.8.
After adjusting to, ethyl acetate (80 liters) was added, the mixture was stirred for 30 minutes, and filtered with a filter aid, Radiolite 600 (manufactured by Showa Chemical Industry Co., Ltd.). Separated ethyl acetate layer (59 liters)
Was extracted twice with 2% aqueous sodium carbonate solution (25 liters). The sodium carbonate layer was adjusted to pH 3.0 and then reextracted twice with ethyl acetate (20 liters). Ethyl acetate layer (4
(0 liter) was washed with water (13 liter), concentrated to 3 liter, and redissolved again with 2% aqueous sodium carbonate solution (1.5 liter). After correcting the sodium carbonate layer to pH 6.5, it was chromatographed on Diaion HP-20 (300 ml, manufactured by Mitsubishi Kasei Kogyo Co., Ltd.) to obtain 60% methanol /
The active ingredient was eluted with 0.02 M aqueous ammonia (1.8 liter). After the eluate was concentrated, it was washed with ethyl acetate (3
(00 ml) twice, the extract was washed with water and then dried over anhydrous sodium sulfate. Crude substance obtained by concentrating the extract to dryness
Silica gel column chromatography (40 g)
0 ml, Kieselgel 60, 70-230 mesh, A
The product was washed with dichloroethane (1.6 liters) and eluted with a 5% methanol / dichloroethane solution (2.4 liters). The eluate was concentrated and crystallized from methanol to obtain TAN-1607A (2.81 g) as white crystals.

Example 1 Preparation of tetrahydro form of TAN-1607A TAN-1607A (0.22 g, purity 86%) was dissolved in methanol (7.5 ml) and 10% palladium carbon (22 mg) was dissolved.
In the presence of hydrogen, the mixture was stirred at room temperature under a hydrogen atmosphere for 1.5 hours. The reaction mixture was filtered through a membrane filter (0.5 μm, Millipore) and concentrated to dryness to give an oil (213 mg). This was subjected to reverse phase preparative HPLC [column; ODS, YMC-Pack (manufactured by YMC, Japan), SH-343, mobile phase: 45% acetonitrile / 0.01 M phosphate buffer, pH 6.3]. The fraction with an elution volume of 530-800 ml was concentrated to about 30 ml. Correct this to pH 2.0 and ethyl acetate (20 ml)
Extracted twice with water, washed with water and saturated saline, dried over sodium sulfate and concentrated to dryness to give a white powder of tetrahydro form.
(152 mg) was obtained. Elemental _{analysis: C 43 H 58 O 14 ·} 1.5H calcd _{2 O, C, 62.53; H} , 7.44 Found, C, 62.26; H, 7.45 13 C-NMR ( 75 MHz, in deuterated methanol, δ ppm) 173.7 (Q), 173.1 (Q), 172.5 (Q), 170.
2 (Q), 168.5 (Q), 143.9 (Q), 143.7 (Q),
129.4 (CH), 129.4 (CH), 129.4 (CH), 1
29.4 (CH), 129.3 (CH), 129.3 (CH), 12
9.2 (CH), 129.2 (CH), 126.7 (CH), 12
6.6 (CH), 107.2 (Q), 91.0 (Q), 82.2 (C
H), 81.0 (CH), 78.1 (CH), 76.6 (CH), 7
5.6 (Q), 37.3 (CH), 37.0 (CH ₂ ), 36.9 (C
H ₂ ), 36.3 (CH ₂ ), 35.0 (CH ₂ ), 33.6 (CH ₂ ),
32.7 (CH ₂ ), 32.5 (CH ₂ ), 30.7 (CH ₂ ), 30.
6 (CH ₂ ), 30.5 (CH ₂ ), 30.3 (CH ₂ ), 30.3 (C
H ₂ ), 30.2 (CH ₂ ), 30.1 (CH ₂ ), 25.8 (C
H ₂ ), 21.1 (CH ₃ ), 20.1 (CH ₂ ), 14.8 (C
H ₃ ).

Example 2 4-O- of TAN-1607A
Production of acetyl compound TAN-1607A (376 mg, purity 96%) was added to acetic acid (4 m
l) and acetic anhydride (2 ml), and stirred at room temperature for 17 hours. The reaction solution was concentrated to dryness, and reverse phase preparative HPLC (carrier;
ODS, YMC-Pack, S-363, mobile phase; 42% acetonitrile / 0.01 M phosphate buffer, pH 6.3). Fractions with an elution volume of 720-810 ml were concentrated to approximately 20 ml. This was corrected to pH 2.0 and ethyl acetate (10 m
It was extracted twice with l), washed with water and saturated brine, dried over sodium sulfate and concentrated to dryness to give a white powder of 4-O-acetyl compound (129 mg). Elemental analysis value: calculated as C ₄₅ H ₅₆ O ₁₅ .H ₂ O, C, 63.22; H, 6.84 actual value, C, 63.20; H, 6.83 ¹³ C-NMR (75 MHz, Δppm in deuterated methanol) 173.3 (Q), 172.9 (Q), 170.0 (Q), 169.
6 (Q), 168.3 (Q), 168.2 (Q), 139.2 (Q),
139.0 (Q), 132.8 (CH), 131.7 (CH), 13
1.1 (CH), 129.6 (CH), 129.4 (CH), 12
9.4 (CH), 129.4 (CH), 129.4 (CH), 12
7.9 (CH), 127.8 (CH), 127.0 (CH), 12
7.0 (CH), 126.9 (CH), 126.9 (CH), 10
8.2 (Q), 89.1 (Q), 82.1 (Q), 81.8 (CH), 8
1.7 (CH), 78.0 (CH), 75.5 (CH), 38.1 (C
H), 37.9 (CH ₂ ), 35.5 (CH ₂ ), 35.0 (CH ₂ ),
34.0 (CH ₂ ), 32.6 (CH ₂ ), 30.5 (CH ₂ ), 30.
4 (CH ₂ ), 30.3 (CH ₂ ), 30.3 (CH ₂ ), 30.1 (C
H ₂ ), 25.7 (CH ₂ ), 21.3 (CH ₃ ), 21.2 (CH ₃ ),
_{20.2 (CH 2), 14.7 (} CH 3).

Example 3 TAN-1607A 4,7-
Preparation of di-O-acetyl compound TAN-1607A (105 mg, purity 86%) was added to acetic acid (2 m
l) and acetic anhydride (1 ml), 10-camphor
The mixture was stirred at room temperature for 62 hours in the presence of rufonic acid (2.6 mg).
Dilute reaction mixture with ether-hexane (3: 1, 20 ml)
And extracted 3 times with 2% aqueous sodium carbonate (12 ml). water
The layers were combined and corrected to pH 2.5 and with ethyl acetate (20 ml)
Extract twice and wash the organic phase with water and saturated saline solution, respectively.
Dry with sodium acidate and concentrate to dryness to give a crude powder (116 mg).
Obtained. Reversed phase preparative HPLC (carrier; ODS, YMC
-Pack, SH-343, mobile phase; 46% acetonitrile
/0.01 M phosphate buffer, pH 6.3). Elution volume
Concentrate the 280-345 ml fraction to about 20 ml.
Was adjusted to pH 2.0 and extracted twice with ethyl acetate (10 ml).
It was The organic phase is washed with water and saturated saline, and then washed with sodium sulfate.
Dried with sodium and concentrated to dryness to give 4,7-di-O-acetyl derivative
A white powder (58 mg) of was obtained. Elemental analysis value: C₄₇H₅₈O₁₆・ 1.5H₂Calculated as O, C, 62.31; H, 6.79 Measured value, C, 62.10; H, 6.73¹³ C-NMR (75 MHz, in deuterated methanol, δ ppm) 173.0 (Q), 172.9 (Q), 171.0 (Q), 169.
1 (Q), 168.1 (Q), 167.7 (Q), 139.3 (Q),
139.1 (Q), 132.9 (CH), 131.8 (CH), 13
1.1 (CH), 129.5 (CH), 129.5 (CH), 12
9.5 (CH), 129.5 (CH), 129.5 (CH), 12
7.9 (CH), 127.8 (CH), 127.0 (CH), 12
7.0 (CH), 126.9 (CH), 126.9 (CH), 10
7.4 (Q), 89.1 (Q), 81.7 (Q), 80.7 (CH), 7
8.8 (Q), 77.8 (CH), 75.5 (CH), 38.2 (C
H), 37.9 (CH₂), 35.6 (CH₂), 34.9 (CH₂),
34.1 (CH₂), 32.5 (CH₂), 30.5 (CH₂), 30.
4 (CH₂), 30.2 (CH₂), 30.2 (CH ₂), 30.0 (C
H₂), 25.7 (CH₂), 21.3 (CH₃), 21.1 (CH₃),
20.6 (CH₃), 20.1 (CH₂), 14.8 (CH₃).

Example 4 Triethylamide Form of TAN-1607A TAN-1607A (100 mg) was added to dichloromethane (4 m).
l) and then 1-hydroxybenzotriazole
(68 mg), ethylamine hydrochloride (42 mg), triethylamine (139 μl), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (97 mg) were added, and 0
After stirring at 0 ° C for 1 hour, the mixture was stirred at 20 ° C for 15 hours. The reaction mixture was concentrated, 2% aqueous sodium hydrogen carbonate solution (50 ml) was added, and the mixture was extracted with ethyl acetate (100 ml). The obtained organic solvent layer was washed with water, dried over sodium sulfate, and concentrated to dryness to obtain a white powder (112 mg). This powder was subjected to column chromatography on silica gel (10 ml) filled with chloroform. After washing with chloroform (60 ml), the mixture was eluted with chloroform-methanol (97: 3) and fractionated in 4 ml portions. Fractions 7-10 were collected and concentrated to dryness, TAN-1607
A triethylamide (48 mg) was obtained. Elemental analysis value: calculated as C ₄₉ H ₆₉ N ₃ O ₁₁ ; C, 67.18; H, 7.94; N, 4.80 measured value; C, 66.68; H, 7.95; N, 4.78 Red external absorption (IR) spectrum: major absorption in KBr tablets (wavenumber, cm ⁻¹ ) 3410, 2930, 1730, 1670, 1540, 12
50,960,740 ¹³ C NMR (75 MHz, in deuterated chloroform, δ ppm) 173.7 (Q), 173.0 (Q), 170.6 (Q), 168.
8 (Q), 167.0 (Q), 139.2 (Q), 139.0 (Q),
133.0 (CH), 131.7 (CH), 131.2 (CH), 1
29.5 (CH), 129.5 (CH), 129.4 (CH), 12
9.4 (CH), 129.3 (CH), 128.0 (CH), 12
7.8 (CH), 127.0 (CH), 127.0 (2CH), 12
6.9 (CH), 126.9 (CH), 107.4 (Q), 91.0
(Q), 82.4 (CH), 80.9 (CH), 77.6 (CH), 7
7.5 (CH), 74.8 (Q), 38.2 (CH), 38.1 (CH
₂ ), 36.4 (CH ₂ ), 35.2 (CH ₂ ), 35.0 (CH ₂ ), 3
4.9 (CH ₂ ), 34.8 (CH ₂ ), 34.1 (CH ₂ ), 32.7
(CH ₂ ), 30.5 (CH ₂ ), 30.4 (CH ₂ ), 30.3 (CH
₂ ), 30.3 (CH ₂ ), 30.1 (CH ₂ ), 25.8 (CH ₂ ), 2
1.2 (CH ₃ ), 20.2 (CH ₂ ), 15.2 (CH ₃ ), 15.0
_{(CH 3), 14.6 (CH} 3), 14.4 (CH 3).

Example 5 TAN-1607A (purity 69%, 2.09 g) was dissolved in acetonitrile (hereinafter sometimes abbreviated as MeCN, 104 ml) to prepare 1,8-diazabicycloundecene (hereinafter DB).
Abbreviated as U, 5.6 ml) in the presence of methyl iodide (hereinafter referred to as MeI).
(2.26 ml) and stirred at room temperature for 4 hours. DBU (2.8 ml) and MeI (1.1 ml) were added to the reaction solution, and DBU (0.3 ml) and MeI were further added twice every 1 hour.
(0.3 ml) was added, and the mixture was further stirred at room temperature for 1 hr. After evaporating MeCN from the reaction solution, it was diluted with ethyl acetate-hexane (2: 1, 200 ml), and 0.4 M aqueous citric acid solution was added.
0% ammonium chloride water, 2% sodium hydrogen carbonate water,
The extract was washed with water and saturated saline (100 ml each), dried over sodium sulfate and concentrated to dryness to give a crude powder (2.5 g). After column chromatography on silica gel (80 ml), the fractions eluted with ethyl acetate-hexane (1: 1) were collected and concentrated to dryness. R ₁ was 11-phenyl-10-undecenoyl group and R ₂ was hydrogen. , R ₃ , R ₄ and R ₅ are each a methoxy group,
White powder of compound (I) in which R ₆ is an acetyl group and R ₇ is hydrogen
(1.01 g) was obtained. Elemental _{analysis: C 46 H 60 O 14 ·} H 2 O Calculated: C, 64.62; H, 7.31 Found: C, 64.34; H, 7.17 13 C-NMR (75MHz, Δppm in deuterated methanol) 173.4 (Q), 173.0 (Q), 171.1 (Q), 168.
7 (Q), 167.3 (Q), 139.3 (Q), 139.1 (Q),
132.9 (CH), 131.8 (CH), 131.2 (CH), 1
29.6 (CH), 129.5 (4CH), 128.0 (CH), 1
27.8 (CH), 127.0 (2CH), 126.9 (2CH),
107.5 (Q), 91.1 (Q), 81.8 (CH), 81.0 (C
H), 77.9 (CH), 76.8 (CH), 76.2 (Q), 53.
6 (CH ₃ ), 53.0 (CH ₃ ), 52.8 (CH ₃ ), 38.0 (C
H), 38.0 (CH ₂ ), 36.1 (CH ₂ ), 34.9 (CH ₂ ),
34.1 (CH ₂ ), 32.6 (CH ₂ ), 30.5 (CH ₂ ), 30.
4 (CH ₂ ), 30.3 (CH ₂ ), 30.2 (CH ₂ ), 30.1 (C
H ₂ ), 25.9 (CH ₂ ), 21.2 (CH ₃ ), 20.1 (CH ₂ ),
14.7 (CH _3).

Example 6 TAN-1607A (100 mg) was dissolved in ether (3 ml) and stirred with excess diazomethane at room temperature for 1 hour. The reaction solution was concentrated to dryness to obtain a crude powder (110 mg). It was subjected to column chromatography on silica gel (6 ml), and the fractions eluted with chloroform were collected and concentrated to dryness to obtain a white powder (100 mg) of the compound described in Example 5 above.

Example 7 TAN-1607A (purity 89%, 294 mg) was added to dimethylformamide-dimethylsulfoxide (5: 1, 12 m).
l), dissolved in the presence of potassium carbonate (151 mg), methyl iodide (MeI, 0.20 ml) was added, and the mixture was stirred at room temperature for 2 hours. After distilling off dimethylformamide from the reaction solution, it was diluted with ether-ethyl acetate-hexane (2: 1: 1, 40 ml), water, 2% aqueous sodium hydrogen carbonate solution, water, saturated saline solution.
(20 ml each), dried over sodium sulfate and concentrated to dryness to obtain a crude powder. This was subjected to column chromatography on silica gel (20 ml), ethyl acetate-hexane.
Fractions eluted at (1: 1) were collected and concentrated to dryness to obtain a white powder (229 mg) of the compound described in Example 5 above.

Example 8 TAN-1607A (purity 64%, 6.9 g) was dissolved in dichloromethane (100 ml), and the mixture was allowed to stand at room temperature for 6 days with isobutene (40 ml) in the presence of concentrated sulfuric acid (0.50 ml). . After isobutene was distilled off from the reaction solution, it was diluted with ethyl acetate-hexane (1: 4, 250 ml), washed with 2% aqueous sodium hydrogen carbonate solution, water and saturated saline solution (200 ml each), dried over sodium sulfate and concentrated. Drying gave a crude powder. This was subjected to column chromatography on silica gel (240 ml), and the fractions eluted with ethyl acetate-hexane (1: 4) were collected and concentrated to dryness. R ₁ was 11-phenyl-10-undecenoyl group, R ₂ Is hydrogen and R ₃ , R ₄ and R ₅ are each t-
A compound in which butoxy group, R ₆ is acetyl group, and R ₇ is hydrogen
A white powder (2.8 g) of (I) was obtained. Elemental analysis value: C ₅₅ H ₇₈ O ₁₄ · 0.5H ₂ O Calculated value: C, 67.95; H, 8.19 Actual value: C, 68.07; H, 8.19 ¹³ C-NMR ( 75 MHz, in deuterated chloroform, δ ppm) 174.2 (Q), 171.0 (Q), 168.6 (Q), 165.
6 (Q), 164.3 (Q), 137.9 (Q), 137.7 (Q),
131.4 (CH), 131.0 (CH), 129.8 (CH), 1
28.8 (CH), 128.5 (4CH), 126.9 (CH), 1
26.8 (CH), 126.0 (2CH), 125.9 (2CH),
104.7 (Q), 88.8 (Q), 85.5 (Q), 83.7 (Q),
83.1 (Q), 82.1 (CH), 81.4 (CH), 76.8 (C
H), 75.2 (CH), 74.3 (Q), 36.8 (CH ₂ ), 36.
4 (CH), 35.7 (CH ₂ ), 34.0 (CH ₂ ), 33.0 (C
H ₂ ), 31.1 (CH ₂ ), 29.3 (CH ₂ ), 29.3 (CH ₂ ),
29.2 (CH ₂ ), 29.1 (CH ₂ ), 29.0 (CH ₂ ), 28.
1 (3CH ₃ ), 28.1 (3CH ₃ ), 28.0 (3CH ₃ ), 2
4.8 (CH ₂ ), 21.2 (CH ₃ ), 18.9 (CH ₂ ), 14.1
(CH _3).

Example 9 TAN-1607A (purity 85%, 1.37 g) was dissolved in toluene (28 ml) and stirred at 80 ° C. with N, N-dimethylformamide di-tert-butylacetal (purity 80%, (4.4 ml) was added dropwise over 45 minutes, and the mixture was further stirred for 16 hours. The reaction mixture is concentrated to dryness, and the residue is silica gel.
The mixture was subjected to column chromatography (80 ml), and the fractions eluted with ethyl acetate-hexane (1: 4) were collected and concentrated to dryness to give a white powder (926 mg) of compound (I) of Example 8 above. It was

Example 10 TAN-1607A (purity 79%, 336 mg) was dissolved in methanol (17 ml), and the mixture was stirred at room temperature for 17 hours in the presence of concentrated hydrochloric acid (0.14 ml). The reaction mixture was added with 2% aqueous sodium hydrogen carbonate (27.5 ml), concentrated to 20 ml, and washed with ether-hexane (2: 1, 30 ml). The organic layer was extracted with 2% aqueous sodium carbonate (30 ml). Combine the aqueous layers to pH
Correct to 3.0, extract three times with ethyl acetate (12 ml), combine the organic layers, wash with water and saturated saline respectively, dry over sodium sulfate and concentrate to dryness to obtain a crude powder (233 mg). It was
This was subjected to reverse phase preparative HPLC (carrier; ODS, YMC-Pac
k, SH-343, mobile phase; 48% acetonitrile / 0.
01M phosphate buffer, pH 6.3). Elution volume 7
0-130 ml, 223-280 ml and 337-413
Each ml fraction was collected and concentrated to about 20 ml. These were adjusted to pH 2.0, extracted three times with ethyl acetate (10 ml), washed with water and saturated brine respectively, dried over sodium sulfate and concentrated to dryness to give a mixture, R ₁ was 11-phenyl-10.
Undecenoyl group, R ₂ is hydrogen, R ₃ and R ₄ are each a hydroxyl group, R ₅ is a methoxy group, and R ₆ and R ₇ are each a hydrogen compound (I) (51 mg) and the corresponding R ₆ is an acetyl group. A white powder of (I) (76 mg) was obtained. The mixture was again subjected to reverse phase preparative HPLC (mobile phase; 31% acetonitrile / 0.01 M phosphate buffer, pH 3.0).
Fractions with an elution volume of 70-125 ml and 450-580 ml were collected and concentrated to about 20 ml. These are pH 2.
Correct to 0, add saturated sodium chloride, and add ethyl acetate (10 m
l) three times, washed with saturated saline each, dried over sodium sulfate and concentrated to dryness, and the corresponding compound (I) (25 mg) in which R ₁ and R ₆ are each hydrogen, and R ₁ is hydrogen , R ₆
A white powder of compound (I) (34 mg) having an acetyl group was obtained.

Elemental analysis value: C ₄₄ H ₅₆ O ₁₄ · 0.5H ₂ O (R ₁ = 11-phenyl-10-undecenoyl group, R ₆ = acetyl group) Calculated value: C, 64.61; H, 7.02 found: C, 64.78; H, 7.02 ¹³ C-NMR (75 MHz, in deuterated methanol, δ ppm) 173.6 (Q), 173.0 (Q), 172.4 (Q). , 169.
0 (Q), 168.4 (Q), 139.3 (Q), 139.1 (Q),
132.9 (CH), 131.8 (CH), 131.2 (CH), 1
29.6 (CH), 129.5 (2CH), 129.5 (2CH),
128.0 (CH), 127.8 (CH), 127.0 (2CH),
126.9 (2CH), 107.2 (Q), 91.0 (Q), 82.
2 (CH), 81.0 (CH), 78.0 (CH), 77.0 (C
H), 75.7 (Q), 52.5 (CH 3), 38.0 (CH 2), 38.
0 (CH), 36.3 (CH ₂ ), 35.0 (CH ₂ ), 34.1 (C
H ₂ ), 32.6 (CH ₂ ), 30.5 (CH ₂ ), 30.4 (CH ₂ ),
30.3 (2CH ₂ ), 30.1 (CH ₂ ), 25.8 (CH ₂ ), 2
_{1.2 (CH 3), 20.1 (} CH 2), 14.7 (CH 3).

Elemental analysis value: C ₄₂ H ₅₄ O ₁₃ .H ₂ O (R ₁ = 11-phenyl-10-undecenoyl group, R ₆
= Hydrogen) Calculated value: C, 64.27; H, 7.19 Measured value: C, 64.23; H, 7.19 ¹³ C-NMR (75 MHz, in deuterated methanol, δ ppm) 173.6 (Q) , 172.4 (Q), 169.1 (Q), 168.
5 (Q), 139.2 (2Q), 132.5 (CH), 131.8
(CH), 131.2 (CH), 130.6 (CH), 129.5
(4CH), 127.8 (CH), 127.8 (CH), 127.0
(2CH), 126.9 (2CH), 107.4 (Q), 91.0
(Q), 82.0 (CH), 80.7 (CH), 77.0 (CH), 7
5.8 (Q), 75.0 (CH), 52.6 (CH ₃ ), 40.1 (C
H), 38.3 (CH ₂ ), 36.4 (CH ₂ ), 35.5 (CH ₂ ),
35.0 (CH ₂ ), 34.1 (CH ₂ ), 30.5 (CH ₂ ), 30.
4 (CH ₂ ), 30.3 (2CH ₂ ), 30.2 (CH ₂ ), 25.8
_{(CH 2), 20.7 (CH} 2), 14.2 (CH 3).

Elemental analysis value: C ₂₇ H ₃₄ O ₁₃ · 1.5H ₂ O (R ₁ = hydrogen, R ₆ = acetyl group) Calculated value: C, 54.63; H, 6.28 Measured value: C ^{, 54.64; H, 6.21 13 C} -NMR (75MHz, in heavy methanol, δppm) 173.1 (Q), 172.9 (Q), 169.5 (Q), 169.
3 (Q), 139.1 (Q), 132.8 (CH), 129.6 (C
H), 129.5 (2CH), 128.0 (CH), 127.0 (2
CH), 107.0 (Q), 93.1 (Q), 83.9 (CH), 7
9.4 (CH), 78.1 (CH), 76.9 (CH), 75.9
(Q), 52.5 (CH ₃ ), 38.0 (CH ₂ ), 37.9 (CH),
36.4 (CH ₂ ), 32.7 (CH ₂ ), 21.2 (CH ₃ ), 20.
1 (CH ₂ ), 14.7 (CH ₃ ).

¹³ C-NMR (75 MHz, δ ppm in deuterated methanol) (R ₁ and R ₆ = hydrogen) 170.4 (Q), 139.3 (Q), 132.5 (CH), 13
0.6 (CH), 129.5 (2CH), 127.8 (CH), 12
7.0 (2CH), 106.6 (Q), 93.9 (Q), 83.6 (C
H), 79.2 (CH), 77.0 (CH), 76.4 (Q), 75.
1 (CH), 52.6 (CH ₃ ), 40.1 (CH), 38.3 (CH
₂ ), 36.7 (CH ₂ ), 35.6 (CH ₂ ), 20.8 (CH ₂ ), 1
4.3 (CH _3).

Example 11 R ₁ obtained in Example 10 above was 11-phenyl-10
A compound (I) in which undecenoyl group, R ₂ is hydrogen, R ₃ and R ₄ are hydroxyl groups, R ₆ is acetyl group, and R ₇ is hydrogen
(225 mg) was dissolved in toluene (4.5 ml), and N, N-dimethylformamide di-tert-butylacetal (purity 80%, 0.39 ml) was added dropwise over 15 minutes while stirring at 80 ° C. Stir for 4 hours. Reaction solution is ethyl acetate
The mixture was diluted with (15 ml), washed with 2% aqueous sodium hydrogen carbonate solution, water and saturated brine (10 ml each), dried over sodium sulfate and concentrated to dryness to give a crude powder (259 mg). This was subjected to column chromatography on silica gel (20 ml), and the fractions eluted with ethyl acetate-hexane (1: 2) were collected and concentrated to dryness. R ₁ was 11-phenyl-10-undecenoyl group, R ₂ Is hydrogen, R ₃ and R ₄ are t-butoxy groups, R ₅
Is a methoxy group, R ₆ is an acetyl group, and R ₇ is hydrogen
A colorless oil (131 mg) of (I) was obtained. ¹³ C-NMR (75 MHz, in deuterated chloroform, δ ppm) 174.2 (Q), 171.1 (Q), 168.1 (Q), 167.
2 (Q), 164.0 (Q), 137.9 (Q), 137.7 (Q),
131.5 (CH), 131.1 (CH), 129.8 (CH), 1
28.8 (CH), 128.5 (4CH), 126.9 (CH), 1
26.8 (CH), 126.0 (2CH), 125.9 (2CH),
105.1 (Q), 88.5 (Q), 85.3 (Q), 84.0 (Q),
82.0 (CH), 81.3 (CH), 76.7 (CH), 75.7
(CH), 74.3 (Q), 52.1 (CH ₃ ), 36.7 (CH ₂ ),
36.6 (CH), 35.5 (CH ₂ ), 34.0 (CH ₂ ), 33.
0 (CH ₂ ), 31.1 (CH ₂ ), 29.3 (CH ₂ ), 29.3 (C
H ₂ ), 29.2 (CH ₂ ), 29.1 (CH ₂ ), 29.0 (CH ₂ ),
28.0 (3CH ₃ ), 27.9 (3CH ₃ ), 24.8 (CH ₂ ),
_{21.2 (CH 3), 18.9 (} CH 2), 14.2 (CH 3).

Example 12 R ₁ and R ₂ are hydrogen, R ₃ , R ₄ and R ₅ are hydroxyl groups, R ₆
Is an acetyl group and R ₇ is hydrogen, and the compound (I) (83 mg) is dissolved in acetonitrile (4.2 ml) and methyl iodide (0.2 mg) is added in the presence of 1,8-diazabicycloundecene (0.23 ml). 0
94 ml) and stirred at room temperature for 8 hours. The reaction mixture was diluted with ethyl acetate-hexane (2: 1, 20 ml), washed with 0.4 M aqueous citric acid solution, 2% aqueous sodium hydrogen carbonate solution, water and saturated saline solution (10 ml each), and dried over sodium sulfate. After concentration to dryness, white powder (31 mg) of the corresponding compound (I) in which all of R ₃ , R ₄ and R ₅ were methoxy groups was obtained.

Example 13 R ₁ and R ₂ are hydrogen, R ₃ , R ₄ and R ₅ are hydroxyl groups, R ₆
Is an acetyl group and R ₇ is hydrogen (I) (purity 87%,
2.70 g) was dissolved in toluene (90 ml), N, N′-diisopropyl-O-tert-butylisourea (purity 60%, 3.72 ml) was added dropwise with stirring at 60 ° C., and the mixture was stirred for 2 hours. . After that, the isourea (1.
0 ml) was added and the mixture was further stirred for 13 hours. The reaction solution was filtered, and the filtrate was concentrated to dryness to obtain a crude powder. This was subjected to column chromatography on silica gel (210 ml), and the fractions eluted with ethyl acetate-hexane (1: 1) were collected and concentrated to dryness. The corresponding R ₃ , R ₄ and R ₅ were all t-
A white powder (776 mg) of the compound (I) having a butoxy group was obtained.

Example 14 Compound (I) in which R ₁ is 11-phenyl-10-undecenoyl group, R ₂ is hydrogen, R ₃ , R ₄ and R ₅ are methoxy groups, R ₆ is acetyl group, and R ₇ is hydrogen (94 mg) was dissolved in dimethylformamide (3.0 ml), and the mixture was stirred at room temperature for 3 hr in the presence of potassium carbonate (31 mg). Potassium tert-butoxide (90%, 21 mg) was added to the reaction solution, and the mixture was further stirred for 1 hour. The reaction mixture was neutralized by adding water (10 ml) and 1N hydrochloric acid (0.39 ml), and extracted twice with ethyl acetate (12 ml). The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated to dryness to give a crude powder (92 mg). This was subjected to silica gel column chromatography (7 ml), first eluted with an appropriate amount of ethyl acetate, and then the fractions eluted with methanol-ethyl acetate (1: 4) were collected and concentrated to dryness to give the corresponding R ₅ A white powder (78 mg) of hydroxyl group compound (I) was obtained. Elemental _{analysis: C 45 H 58 O 14 ·} 2H 2 O Calculated: C, 62.92; H, 7.27 Found: C, 62.65; H, 6.72 13 C-NMR (75MHz, Δppm in deuterated methanol) 173.4 (Q), 173.0 (Q), 171.2 (Q), 169.
9 (Q), 167.4 (Q), 139.3 (Q), 139.1 (Q),
132.9 (CH), 131.8 (CH), 131.2 (CH), 1
29.6 (CH), 129.5 (4CH), 128.0 (CH), 1
27.8 (CH), 127.0 (2CH), 126.9 (2CH),
107.5 (Q), 91.2 (Q), 81.8 (CH), 81.0 (C
H), 78.0 (CH), 76.4 (CH), 76.1 (Q), 53.
6 (CH ₃ ), 53.0 (CH ₃ ), 38.0 (CH), 38.0 (C
H ₂ ), 36.0 (CH ₂ ), 34.9 (CH ₂ ), 34.1 (CH ₂ ),
32.6 (CH ₂ ), 30.5 (CH ₂ ), 30.4 (CH ₂ ), 30.
3 (CH ₂ ), 30.2 (CH ₂ ), 30.1 (CH ₂ ), 25.9 (C
H ₂ ), 21.2 (CH ₃ ), 20.1 (CH ₂ ), 14.7 (C
H ₃ ).

Example 15 Compound (I) in which R ₁ is 11-phenyl-10-undecenoyl group, R ₂ is hydrogen, R ₃ , R ₄ and R ₅ are methoxy groups, R ₆ is acetyl group, and R ₇ is hydrogen (426 mg) in methanol
(8.5 ml), the mixture was stirred in the presence of sodium carbonate (32.4 mg) at 0 ° C. for 90 minutes. Ammonium chloride (136 mg) was added to the reaction solution, diluted with ethyl acetate (25 ml), and the mixture was diluted to 10
% Washed with ammonium chloride (20 ml), water and saturated saline, dried over sodium sulfate and concentrated to dryness to give a crude powder.
(0.43 g) was obtained. This was subjected to column chromatography on silica gel (25 ml), and ethyl acetate-hexane (2:
The fractions eluted at 1-5: 2) were collected and concentrated to dryness to obtain the corresponding white powder (284 mg) of compound (I) in which R ₁ was hydrogen. Elemental _{analysis: C 29 H 38 O 13 ·} 0.5H 2 O Calculated: C, 57.70; H6.51 ^{Found: C, 57.62; H6.45 13 C} -NMR (75MHz, deuterated methanol Medium, δppm) 173.1 (Q), 171.6 (Q), 169.1 (Q), 168.
3 (Q), 139.1 (Q), 132.9 (CH), 129.6 (C
H), 129.5 (2CH), 128.0 (CH), 127.0 (2
CH), 107.3 (Q), 93.3 (Q), 83.7 (CH), 7
9.7 (CH), 78.1 (CH), 76.8 (CH), 76.3
_{(Q), 53.4 (CH 3} ), 52.7 (CH 3), 52.6 (CH 3),
38.0 (CH ₂ ), 37.9 (CH), 36.3 (CH ₂ ), 32.
7 (CH ₂ ), 21.2 (CH ₃ ), 20.1 (CH ₂ ), 14.7 (C
H ₃ ).

Example 16 A compound in which R ₁ is 11-phenyl-10-undecenoyl group, R ₂ is hydrogen, R ₃ , R ₄ and R ₅ are t-butoxy groups, R ₆ is acetyl group, and R ₇ is hydrogen ( I) (4.54 g) was dissolved in methanol (90 ml), and the mixture was stirred at room temperature for 90 min in the presence of potassium carbonate (651 mg). 10% Ammonium chloride (5 ml) was added to the reaction mixture and concentrated, and ethyl acetate-hexane was added.
The mixture was diluted with (2: 1, 300 ml), washed with water and saturated brine, dried over sodium sulfate and concentrated to dryness to give a crude powder. This was subjected to column chromatography on silica gel (160 ml), and the fractions eluted with ethyl acetate-hexane (1: 2) were collected and concentrated to dryness, and the corresponding R ₁ was a hydrogen compound (I) white. A powder (2.83 g) was obtained. Elemental analysis value: C ₃₈ H ₅₆ O ₁₃ · 0.5H ₂ O calculated value: C, 62.53; H, 7.87 Measured value: C, 62.60; H, 7.84 ¹³ C-NMR ( 75 MHz, in deuterated chloroform, δ ppm) 171.3 (Q), 168.6 (Q), 166.4 (Q), 165.
9 (Q), 137.7 (Q), 131.5 (CH), 128.7 (C
H), 128.5 (2CH), 126.9 (CH), 126.0 (2
CH), 104.9 (Q), 91.2 (Q), 85.0 (Q), 84.
2 (Q), 83.2 (Q), 82.5 (CH), 78.9 (CH), 7
6.9 (CH), 75.2 (CH), 74.3 (Q), 36.8 (CH
₂ ), 36.5 (CH), 35.3 (CH ₂ ), 31.1 (CH ₂ ), 2
8.2 (3CH ₃ ), 28.1 (3CH ₃ ), 28.0 (3CH ₃ ),
_{21.3 (CH 3), 19.1 (} CH 2), 14.1 (CH 3).

Example 17 TAN-1607A (purity 69%, 580 mg) was dissolved in dioxane-2% aqueous sodium carbonate solution (1: 4, 50 ml), and the mixture was stirred at 80 ° C. for 4 hours while adjusting the pH to 11.0. The reaction mixture was filtered, the filtrate was adjusted to pH 2.0, saturated with sodium chloride, and then ethyl acetate-isopropanol (5: 1, 2
It was extracted 3 times with 0 ml). The organic layers were combined, washed with saturated brine, dried over sodium sulfate, and concentrated to dryness to give a crude powder.
(246 mg) was obtained. Reversed phase preparative HPLC (carrier; O
DS, YMC-Pack, SH-343, mobile phase; 30% acetonitrile / 0.01 M phosphate buffer, pH 3.0). Elution volumes 168-236 ml and 457-593
Each ml fraction was collected and concentrated to about 20 ml. Each of these was adjusted to pH 2.0, saturated with sodium chloride, extracted three times with ethyl acetate-isopropanol (5: 1, 20 ml), washed with saturated saline each time, and dried over sodium sulfate.
After concentration to dryness, R ₁ and R ₂ are hydrogen, R ₃ , R ₄ and R ₅
Is a hydroxyl group and R ₆ and R ₇ are hydrogen (I) (42 mg)
And the corresponding compound (I) in which R ₆ is an acetyl group (83 m
White powders of g) were obtained respectively.

Elemental analysis value: C ₂₄ H ₃₀ O ₁₂ · 2H ₂ O (R ₁ and R ₆ = hydrogen) Calculated value: C, 52.74; H, 6.27 Found value: C, 53.07; ^{H, 6.46 13 C-NMR (} 75MHz, in heavy methanol, δppm) 173.2 (Q), 170.7 (Q), 169.7 (Q), 139.
3 (Q), 132.4 (CH), 130.6 (CH), 129.5
(2CH), 127.8 (CH), 127.0 (2CH), 107.
1 (Q), 93.2 (Q), 83.8 (CH), 79.4 (CH), 7
6.6 (CH), 75.9 (Q), 75.0 (CH), 40.0 (C
H), 38.3 (CH ₂ ), 36.5 (CH ₂ ), 35.6 (CH ₂ ),
_{20.6 (CH 2), 14.2 (} CH 3).

Elemental analysis value: C ₂₆ H ₃₂ O ₁₃ .H ₂ O (R ₁ = hydrogen, R ₆ = acetyl group) Calculated value: C, 54.73; H, 6.01 Measured value: C, 54 .78; H, 6.19 ¹³ C-NMR (75 MHz, in deuterated methanol, δ ppm) 173.2 (Q), 173.1 (Q), 170.6 (Q), 169.
6 (Q), 139.1 (Q), 132.9 (CH), 129.7 (C
H), 129.5 (2CH), 128.0 (CH), 127.1 (2
CH), 107.0 (Q), 93.2 (Q), 83.9 (CH), 7
9.4 (CH), 78.2 (CH), 76.6 (CH), 75.9
(Q), 38.0 (CH ₂ ), 37.9 (CH), 36.5 (CH ₂ ),
32.7 (CH ₂ ), 21.2 (CH ₃ ), 20.1 (CH ₂ ), 14.
7 (CH _3).

Example 18 A compound in which R ₁ is 11-phenyl-10-undecenoyl group, R ₂ is hydrogen, R ₃ and R ₄ are hydroxyl groups, R ₅ is methoxy group, R ₆ is acetyl group, and R ₇ is hydrogen ( I) (89 mg) was dissolved in acetone-2% aqueous sodium carbonate solution (1: 1, 10 ml), potassium carbonate (200 mg) was added, the pH was adjusted to 12.0, and the mixture was stirred at room temperature for 2 hr. Acetone was distilled off from the reaction solution and filtered, the filtrate was adjusted to pH 2.0, and ethyl acetate (1
It was extracted twice with 0 ml). The organic layers were combined, washed with saturated brine, dried over sodium sulfate, and concentrated to dryness to give a crude powder. Reversed phase preparative HPLC (carrier; ODS, YMC
-Pack, SH-343, mobile phase; 43% acetonitrile / 0.01 M phosphate buffer, pH 6.3). Fractions with an elution volume of 220 to 290 ml were collected and concentrated to about 20 ml. Correct this to pH 2.0 and triturate with ethyl acetate (10 ml).
It was extracted twice, washed with saturated brine, dried over sodium sulfate, and concentrated to dryness to obtain a white powder (39 mg) of the corresponding compound (I) in which R ₅ was a hydroxyl group and R ₆ was hydrogen. Elemental analysis value: C ₄₁ H ₅₂ O ₁₃ · 1.5H ₂ O calculated value: C, 63.14; H, 7.11 Actual value: C, 63.40; H, 7.01 ¹³ C-NMR ( 75 MHz, in deuterated methanol, δ ppm) 173.7 (Q), 172.6 (Q), 170.4 (Q), 168.
6 (Q), 139.3 (2Q), 132.5 (CH), 131.8
(CH), 131.2 (CH), 130.6 (CH), 129.5
(4CH), 127.8 (CH), 127.8 (CH), 127.0
(2CH), 126.9 (2CH), 107.4 (Q), 91.1 (Q),
82.1 (CH), 81.0 (CH), 76.6 (CH), 75.7
(Q), 75.0 (CH) , 40.1 (CH), 38.3 (CH 2), 3
6.4 (CH ₂ ), 35.5 (CH ₂ ), 35.0 (CH ₂ ), 34.1
(CH ₂ ), 30.5 (CH ₂ ), 30.4 (CH ₂ ), 30.3 (2C
H ₂ ), 30.2 (CH ₂ ), 25.8 (CH ₂ ), 20.7 (CH ₂ ),
14.2 (CH _3).

Example 19 Compound (I) (1) in which R ₁ and R ₂ are hydrogen, R ₃ , R ₄ and R ₅ are t-butoxy groups, R ₆ is an acetyl group, and R ₇ is hydrogen.
(05 mg) was dissolved in dichloromethane (3.5 ml), and hexanoic acid (20 μl), 1-hydroxybenzotriazole (hereinafter abbreviated as HOBT, 20 mg), 1-ethyl-3- (3-
Dimethylaminopropyl) carbodiimide hydrochloride (hereinafter,
WSC (abbreviated as WSC, 28 mg) was sequentially added, and the mixture was stirred at room temperature for 2 hours. Triethylamine (20 μl) was added to the reaction solution, and the mixture was further stirred at room temperature for 38 hours. The reaction solution was diluted with ethyl acetate-hexane (1: 1, 20 ml), 10% aqueous ammonium chloride solution, 2% aqueous sodium hydrogen carbonate solution, water, saturated saline solution.
(20 ml each), dried over sodium sulfate and concentrated to dryness to obtain a crude powder (117 mg). This was subjected to silica gel thin layer chromatography (200 × 200 × 2 mm, Kieselgel 60, F ₂₅₄ , manufactured by A Merck, Germany), developed with ethyl acetate-hexane (1: 2), and Rf 0.3.
The portions having a UV absorption of 1 to 0.47 were collected, eluted with ethyl acetate and concentrated to dryness. R ₁ was hexanoyl group, R ₂ was hydrogen, R ₃ , R ₄ and R ₅ were each t-butoxy group, A compound (I) (48 mg) having R ₆ as an acetyl group and R ₇ as hydrogen was obtained. This is trifluoroacetic acid (hereinafter abbreviated as TFA, 0.3 ml)
, And left for 70 minutes at room temperature. The reaction mixture was concentrated to dryness, diluted with methanol (2.5 ml), 1N aqueous sodium hydroxide solution (0.18 ml) was added, and the precipitate was collected by filtration to give R ₃ ,
A trisodium salt (19 mg) of compound (I) having R ₄ and R ₅ each being a hydroxyl group was obtained. The filtrate was diluted with 2% aqueous sodium hydrogencarbonate (5 ml) and diluted with ethyl acetate-hexane (1: 1, 6 m).
After washing twice with l), the pH was adjusted to pH 2, sodium chloride (1 g) was added, and the mixture was extracted twice with ethyl acetate (6 ml). The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated to dryness to give a free hexanoyl compound powder (24 mg). Elemental _{analysis: C 32 H 40 O 14 ·} 0.5H 2 O Calculated: C, 58.44; H, 6.28 Found: C, 58.56; H, 7.05 13 C-NMR ( 75 MHz, in deuterated methanol, δ ppm) 173.6 (Q), 173.1 (Q), 172.5 (Q), 170.
1 (Q), 168.4 (Q), 139.1 (Q), 132.9 (C
H), 129.6 (CH), 129.5 (2CH), 127.9 (C
H), 127.0 (2CH), 107.2 (Q), 91.0 (Q), 8
2.2 (CH), 81.0 (CH), 78.0 (CH), 76.6 (C
H), 75.6 (Q), 38.0 (CH ₂ ), 37.9 (CH), 36.
3 (CH ₂ ), 35.0 (CH ₂ ), 32.7 (CH ₂ ), 32.3 (C
H ₂ ), 25.5 (CH ₂ ), 23.3 (CH ₂ ), 21.2 (CH ₃ ),
_{20.1 (CH 2), 14.7 (} CH 3), 14.3 (CH 3).

Example 20 Dodecanoic acid (61 mg) was dissolved in dichloromethane (6.0 ml), HOBT (45 mg) and WSC (63 mg) were sequentially added, and the mixture was stirred at room temperature for 3 hours. In the reaction solution, R ₁ and R ₂ are hydrogen,
Compound (I) (216 mg) in which R ₃ , R ₄ and R ₅ were t-butoxy groups, R ₆ was acetyl group and R ₇ was hydrogen, and triethylamine (50 μl) were added, and the mixture was further stirred at room temperature for 60 hours. The reaction mixture was diluted with ethyl acetate-hexane (1: 1, 20 ml), washed with 10% aqueous ammonium chloride solution, 2% aqueous sodium hydrogen carbonate solution, water and saturated saline solution (20 ml each), dried over sodium sulfate and concentrated. Drying gave a crude powder. This was subjected to silica gel thin layer chromatography, developed with ethyl acetate-hexane (1: 2), and Rf 0.39 to 0.55 U.
The portions having V absorption were collected, eluted with ethyl acetate and concentrated to dryness. The corresponding R ₁ was dodecanoyl group, R ₃ , R ₄ and R ₅
To give compound (I) (165 mg) in which each is a t-butoxy group. This was dissolved in TFA (0.5 ml) and left at room temperature for 70 minutes. The reaction mixture was concentrated to dryness, diluted with methanol (5.0 ml), 1N aqueous sodium hydroxide (0.72 ml) was added, the precipitate was collected by filtration, and the corresponding R ₃ , R ₄ and R ₅ were each a hydroxyl group. A trisodium salt of the compound of (60 mg) was obtained. The filtrate was diluted with water (10 ml), adjusted to pH 2 and extracted with ethyl acetate (10 ml).
ml) and extracted twice. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated to dryness to give the corresponding free dodecanoyl compound powder (22 mg). Elemental _{analysis: C 38 H 54 O 14 ·} 3.5H 2 O Calculated: C, 57.20; H, 7.70 Found: C, 57.05; H, 7.09 13 C-NMR ( 75 MHz, in deuterated methanol, δ ppm) 173.6 (Q), 173.0 (Q), 172.5 (Q), 170.
2 (Q), 168.4 (Q), 139.1 (Q), 132.9 (C
H), 129.6 (CH), 129.5 (2CH), 128.0 (C
H), 127.0 (2CH), 107.2 (Q), 91.0 (Q), 8
2.2 (CH), 81.0 (CH), 78.0 (CH), 76.6 (C
H), 75.6 (Q), 38.0 (CH ₂ ), 38.0 (CH), 36.
3 (CH ₂ ), 35.0 (CH ₂ ), 33.1 (CH ₂ ), 32.7 (C
H ₂ ), 30.8 (CH ₂ ), 30.7 (CH ₂ ), 30.6 (CH ₂ ),
30.5 (CH ₂ ), 30.4 (CH ₂ ), 30.2 (CH ₂ ), 25.
9 (CH ₂ ), 23.7 (CH ₂ ), 21.2 (CH ₃ ), 20.1 (C
_{H 2), 14.7 (CH 3} ), 14.5 (CH 3).

Example 21 Myristic acid (475 mg) was dissolved in dichloromethane (15 ml).
Then, add HOBT (328 mg) and WSC (465 mg) sequentially.
And stirred at room temperature for 5 hours. R in the reaction solution₁And R₂But water
Elementary, R₃, R_FourAnd R_FiveIs a t-butoxy group, R₆Acechi
Lu group, R₇Dichloro of compound (I) (1.00 g) in which is hydrogen
Add methane solution (5 ml) and triethylamine (0.58 ml).
Then, the mixture was further stirred at room temperature for 65 hours. About 5 ml of reaction solution
After concentrating with, dilute with ethyl acetate-hexane (3: 2, 50 ml).
10% ammonium chloride water, 2% sodium hydrogen carbonate
Wash with sodium chloride water, water, and saturated saline (40 ml each), then wash with sodium sulfate.
It was dried with thorium and concentrated to dryness to obtain a crude powder. This
Subject to lica gel column chromatography (60 ml) and add vinegar.
Fractions eluted with ethyl acetate-hexane (1: 5 to 1: 4)
Collect and concentrate to dryness, then use the corresponding R₁Is a myristoyl group,
R₃, R_FourAnd R_FiveIs a compound (I) in which each is a t-butoxy group.
(949 mg) was obtained. Dichloromethane-TFA (3:
1, 10 ml) and stirred at room temperature for 14 hours. reaction
The liquid was concentrated to dryness, and column chromatography of LH-20
-(MeOH, 500 ml), elution volume 305-380
Concentration of the ml fractions to dryness gives the corresponding free myristoylation
Compound (R ₃, R_FourAnd R_FiveIs a compound of hydroxyl group (I)) white
A colored powder (531 mg) was obtained. Elemental analysis value: C₄₀H₅₈O₁₄・ H₂Calculated as O: C, 61.52; H, 7.74 Measured value: C, 61.42; H, 8.00¹³ C-NMR (75 MHz, δ ppm in deuterated methanol) 173.6 (Q), 173.0 (Q), 172.4 (Q), 170.
1 (Q), 168.4 (Q), 139.0 (Q), 132.8 (C
H), 129.5 (CH), 129.4 (2CH), 127.9 (C
H), 127.0 (2CH), 107.2 (Q), 91.0 (Q), 8
2.1 (CH), 80.9 (CH), 78.0 (CH), 76.6 (C
H), 75.6 (Q), 38.0 (CH₂), 37.9 (CH), 36.
2 (CH₂), 35.0 (CH₂), 33.0 (CH₂), 32.6 (C
H₂), 30.7 (4CH₂), 30.6 (CH₂), 30.4 (C
H₂), 30.3 (CH₂), 30.1 (CH₂), 25.8 (CH₂),
23.7 (CH₂), 21.2 (CH₃), 20.0 (CH₂), 14.
6 (CH₃), 14.5 (CH₃).

Example 22 Compound (I) wherein R ₁ and R ₂ are hydrogen, R ₃ , R ₄ and R ₅ are t-butoxy groups, R ₆ is acetyl group and R ₇ is hydrogen
(896 mg) was dissolved in dichloromethane (18 ml), and in the presence of p-toluenesulfonic acid pyridine salt (15.6 mg), 2
-Methoxypropene (0.245 ml) was stirred at 0 ° C for 40 minutes. The reaction solution was ethyl acetate-hexane (1: 1, 20m).
l) and diluted with 2% aqueous sodium hydrogen carbonate (10 ml),
The organic layer was 2% aqueous sodium hydrogen carbonate, water, and saturated saline.
(20 ml each), dried over sodium sulfate and concentrated to dryness to obtain a crude powder. This was subjected to silica gel column chromatography (90 ml), and ethyl acetate-hexane (1:
Fractions eluted at 4: 1 to 2) were collected and concentrated to dryness to obtain a white powder (652 mg). Dichloromethane (13 ml)
And dissolved in acetic anhydride (0.39 ml) and triethylamine (1.41 ml) in the presence of dimethylaminopyridine (hereinafter, abbreviated as DMAP, 20 mg) at room temperature for 14 hours.
After distilling off the solvent from the reaction solution, ethyl acetate-hexane (1:
The organic layer was washed with saturated and 2% aqueous sodium hydrogencarbonate, water and saturated saline (30 ml each), dried over sodium sulfate and concentrated to dryness to give a crude powder (70
5 mg) was obtained. This was subjected to silica gel column chromatography (40 ml), and ethyl acetate-hexane (1: 6 ~
Elution fractionation at 1: 4) yielded 6-acetyl body fraction, 7-acetyl body fraction and mixture fraction, respectively. The mixture fraction was again subjected to silica gel column chromatography (40 ml) and similarly fractionated into 3 fractions. The mixture fraction was again subjected to silica gel thin layer chromatography, developed with ethyl acetate-hexane (1: 2), and the 6- and 7-acetyl derivative fractions were collected and eluted with ethyl acetate. Obtained 6
The-and 7-acetyl fractions were combined and concentrated to dryness to give a white powder (456 mg and 154 mg). These were each dissolved in dichloromethane-TFA (2: 1, 4.5 ml and 1.5 ml) and stirred at room temperature for 12 hours. The reaction solutions were concentrated to dryness and subjected to LH-20 column chromatography (MeOH, 500 ml and 190 ml), respectively, and the elution volumes of 350 to 385 ml and 125 to 155 ml were concentrated to dryness to obtain R ₁ Acetyl group, R ₂ is hydrogen,
Compounds (I) wherein R ₃ , R ₄ and R ₅ are hydroxyl groups, R ₆ is an acetyl group, R ₇ is hydrogen, R ₁ is hydrogen, R ₂ is an acetyl group, R ₃ , R ₄ and R ₅ are hydroxyl groups, R White powders (187 mg and 88 mg) of compound (I) in which ₆ was an acetyl group and R ₇ was hydrogen were obtained, respectively.

Elemental analysis value: C ₂₈ H ₃₄ O ₁₄ · 0.5H ₂ O (R ₁ = acetyl group, R ₂ = hydrogen) Calculated value: C, 55.72; H, 5.84 Measured value: C , 55.89; H, 5.88 ¹³ C-NMR (75 MHz, in deuterated methanol, δ ppm) 173.1 (Q), 172.4 (Q), 171.0 (Q), 170.
1 (Q), 168.5 (Q), 139.1 (Q), 132.8 (C
H), 129.6 (CH), 129.5 (2CH), 128.0 (C
H), 127.0 (2CH), 107.2 (Q), 91.0 (Q), 8
2.1 (CH), 81.2 (CH), 78.1 (CH), 76.6 (C
H), 75.6 (Q), 38.0 (CH ₂ ), 37.9 (CH), 36.
3 (CH ₂ ), 32.7 (CH ₂ ), 21.2 (CH ₃ ), 20.8 (C
_{H 3), 20.1 (CH 2} ), 14.7 (CH 3).

Elemental analysis value: C ₂₈ H ₃₄ O ₁₄ · 0.5H ₂ O (R ₁ = hydrogen, R ₂ = acetyl group) Calculated value: C, 55.72; H, 5.84 Measured value: C , 55.81; H, 5.84 ¹³ C-NMR (75 MHz, in deuterated methanol, δ ppm) 173.1 (Q), 172.9 (Q), 171.4 (Q), 170.
0 (Q), 168.8 (Q), 139.1 (Q), 132.9 (C
H), 129.6 (CH), 129.5 (2CH), 128.0 (C
H), 127.1 (2CH), 106.3 (Q), 93.2 (Q), 8
3.4 (CH), 78.0 (CH), 77.1 (CH), 76.7 (C
H), 75.5 (Q), 38.0 (CH ₂ ), 38.0 (CH), 36.
5 (CH ₂ ), 32.6 (CH ₂ ), 21.2 (CH ₃ ), 20.7 (C
_{H 3), 20.0 (CH 2} ), 14.7 (CH 3).

Example 23 Compound (I) (2) in which R ₁ and R ₂ are hydrogen, R ₃ , R ₄ and R ₅ are t-butoxy groups, R ₆ is an acetyl group, and R ₇ is hydrogen.
89 mg) was dissolved in dichloromethane (6.0 ml), and DMAP was added.
In the presence of (1.0 mg), the mixture was stirred with acetic anhydride (0.115 ml) and triethylamine (0.195 ml) at room temperature for 2.5 hours.
Methanol (0.10 ml) was added to the reaction mixture, and the mixture was stirred at -20 ° C for 1 hour.
It was left for 2 hours. The reaction solution was mixed with ethyl acetate-hexane (1:
1, 20 ml), and the organic layer was washed with saturated and 10% aqueous ammonium chloride, water and saturated saline (15 ml each), dried over sodium sulfate and condensed to dryness to obtain a crude powder (32
0 mg) was obtained. This was subjected to silica gel column chromatography (20 ml), and elution fractionation was performed with ethyl acetate-hexane. Collect and concentrate to a white powder (160mg
And 134 mg) were obtained. Each of these is TFA (0.5 ml)
And was left at room temperature for 40 minutes. The reaction solutions were concentrated to dryness, and R ₁ and R ₂ were acetyl groups, R ₃ , R ₄ and R 2.
Compounds in which ₅ is a hydroxyl group, R ₆ is an acetyl group, and R ₇ is hydrogen
(I) and R ₁ and R ₂ are acetyl groups, R ₃ and R ₄ are hydroxyl groups, R ₅ is a methoxy group, R ₆ is an acetyl group, R ₇
A white powder of compound (I) having a hydroxyl group (119 mg and 11
2 mg) respectively.

Elemental analysis value: C ₃₀ H ₃₆ O ₁₅ · 0.5H ₂ O (R ₃ , R ₄ and R ₅ = hydroxyl group) Calculated value: C, 55.81; H, 5.78 Measured value: C , 55.81; H, 6.12 ¹³ C-NMR (75 MHz, in deuterated methanol, δ ppm) 173.1 (Q), 172.3 (Q), 171.0 (Q), 170.
5 (Q), 169.6 (Q), 167.8 (Q), 139.1 (Q),
132.9 (CH), 129.6 (CH), 129.5 (2CH),
128.0 (CH), 127.0 (2CH), 106.3 (Q), 9
1.0 (Q), 80.8 (CH), 78.1 (CH), 77.8 (C
H), 76.6 (CH), 75.4 (Q), 38.1 (CH ₂ ), 38.
0 (CH), 36.2 (CH ₂ ), 32.5 (CH ₂ ), 21.2 (C
_{H 3), 20.6 (CH 3} ), 20.6 (CH 3), 20.0 (CH 2),
14.7 (CH _3).

Elemental analysis value: C ₃₁ H ₃₈ O ₁₅ .H ₂ O (R ₃ and R ₄ = hydroxy group, R ₅ = methoxy group) Calculated value: C, 55.68; H, 6.03 Measured value: C, 56.04; H, 6.11 173.0 (Q), 172.2 (Q), 171.0 (Q), 170.
5 (Q), 168.5 (Q), 167.7 (Q), 139.1 (Q),
132.9 (CH), 129.6 (CH), 129.5 (2CH),
128.0 (CH), 127.1 (2CH), 106.4 (Q), 9
0.9 (Q), 80.9 (CH), 78.1 (CH), 77.8 (C
H), 77.0 (CH), 75.5 (Q), 52.7 (CH ₃ ), 38.
1 (CH ₂ ), 37.9 (CH), 36.3 (CH ₂ ), 32.5 (C
H ₂ ), 21.1 (CH ₃ ), 20.6 (CH ₃ ), 20.6 (CH ₃ ),
_{20.0 (CH 2), 14.7 (} CH 3).

Example 24 Compound (I) (2) in which R ₁ and R ₂ are hydrogen, R ₃ , R ₄ and R ₅ are t-butoxy groups, R ₆ is an acetyl group, and R ₇ is hydrogen.
81 mg) was dissolved in dichloromethane (6.0 ml), and DMAP was added.
(1.0 mg) in the presence of isobutyric anhydride (0.08 ml) and diisopropylethylamine (0.103 ml) at room temperature for 100
After stirring for 1 minute, methanol (0.10 ml) was added to the reaction solution. The reaction solution was ethyl acetate-hexane (1: 1, 20 ml).
The organic layer was diluted with and washed with saturated and 10% aqueous ammonium chloride, water and saturated saline (15 ml each), dried over sodium sulfate and concentrated to dryness to give a crude powder (318 mg). This was subjected to silica gel column chromatography (20 ml), and eluted and fractionated with ethyl acetate-hexane to give (1: 5-1 :).
4) The elution fraction and the (1: 3 to 1: 2) elution fraction were collected and concentrated and coagulated to obtain white powders (146 mg and 70 mg). Each of these was dissolved in TFA (0.5 ml) and left at room temperature for 40 minutes. The reaction solution each and concentrated to dryness to R ₁ is hydrogen, R ₂ is an isobutyryl group, R _3, R ₄ and R ₅ is hydroxyl, R ₆ is acetyl group, the compound of R ₇ is hydrogen (I) and R ₁ is White powders (117 mg and 56 mg) of Compound (I) in which hydrogen, R ₂ is an isobutyryl group, R ₃ and R ₄ are hydroxyl groups, R ₅ is a methoxy group, R ₆ is an acetyl group, and R ₇ is hydrogen are obtained.

Elemental analysis value: C ₃₀ H ₃₈ O ₁₄ · 0.5H ₂ O (R ₃ , R ₄ and R ₅ = hydroxyl group) Calculated value: C, 57.05; H, 6.22 Measured value: C , 56.80; H, 6.57 ¹³ C-NMR (75 MHz, in deuterated methanol, δ ppm) 177.1 (Q), 173.0 (2Q), 170.2 (Q), 16
9.1 (Q), 139.1 (Q), 132.9 (CH), 129.5
(CH), 129.5 (2CH), 127.9 (CH), 127.0
(2CH), 106.2 (Q), 93.3 (Q), 83.2 (CH),
77.8 (CH), 77.2 (CH), 76.7 (CH), 75.5
_{(Q), 37.9 (CH 2} ), 37.9 (CH), 36.6 (CH 2),
35.0 (CH), 32.5 (CH ₂ ), 21.2 (CH ₃ ), 19.
9 (CH ₂ ), 19.3 (CH ₃ ), 19.1 (CH ₃ ), 14.6 (C
H ₃ ).

Elemental analysis value: C ₃₁ H ₄₀ O ₁₄ .H ₂ O
(R ₃ and R ₄ = hydroxyl group, R ₅ = methoxy group) Calculated value: C, 56.88; H, 6.47 Measured value: C, 56.65; H, 6.38 ¹³ C-NMR (75 MHz, Δppm in deuterated methanol) 177.1 (Q), 173.2 (Q), 173.0 (Q), 169.
4 (Q), 169.2 (Q), 139.1 (Q), 132.9 (C
H), 129.5 (CH), 129.5 (2CH), 127.9 (C
H), 127.0 (2CH), 106.0 (Q), 93.4 (Q), 8
3.3 (CH), 77.8 (CH), 77.1 (CH), 77.1 (C
H), 75.7 (Q), 52.6 (CH ₃ ), 38.0 (CH), 38.0
(CH ₂ ), 36.6 (CH ₂ ), 35.0 (CH), 32.5 (C
H ₂ ), 21.2 (CH ₃ ), 19.9 (CH ₂ ), 19.3 (CH ₃ ),
_{19.1 (CH 3), 14.7 (} CH 3).

Example 25 2-Octenoic acid (0.49 ml) was added to dichloromethane (20 ml).
, HOBT (433 mg) and WSC (614 mg) were sequentially added, and the mixture was stirred at room temperature for 7 hours. R ₁ and R _{2 in the} reaction solution
Is hydrogen, R ₃ , R ₄ and R ₅ are t-butoxy groups, R ₆ is an acetyl group and R ₇ is hydrogen, a solution of compound (I) (1.32 g) in dichloromethane (6 ml), triethylamine (0.76).
ml) was added, and the mixture was further stirred at room temperature for 88 hours. The reaction mixture was diluted with ethyl acetate-hexane (1: 1, 50 ml) and diluted to 10
% Ammonium chloride water, 2% sodium hydrogen carbonate water,
The extract was washed with water and saturated saline (50 ml each), dried over sodium sulfate and concentrated to dryness to give a crude powder. This was subjected to silica gel column chromatography (80 ml), and the fractions eluted with ethyl acetate-hexane (1: 5 to 1: 3) were collected and concentrated to dryness. The corresponding R ₁ was a 2-octenoyl group, R ₃ , R
Compounds (I) (7) in which ₄ and R ₅ are both t-butoxy groups
10 mg) was obtained. This was dissolved in TFA (1.0 ml) and stirred at room temperature for 1.5 hours. The reaction mixture is concentrated to dryness and LH-2
Column chromatography of 0 (MeOH, 500 ml) and fractions with an elution volume of 300-410 ml were concentrated to dryness to give a powder (540 mg). This is dichloromethane-TFA
It was dissolved in (3: 1, 8 ml) and stirred at room temperature for 22 hours. The reaction solution was concentrated to dryness and subjected to reverse phase preparative HPLC (carrier; ODS,
YMC-Pack, SH-363, mobile phase; 31% acetonitrile / 0.02M phosphate buffer, pH 6.3).
Fractions with an elution volume of 1.1 to 1.6 liters were collected, concentrated to about 40 ml, adjusted to pH 2.0, and then adjusted to 3 with ethyl acetate (20 ml).
After extraction twice, the organic layer was washed with water and saturated saline respectively, dried over sodium sulfate and concentrated to dryness, and white powder (214 mg) of the corresponding compound (I) having R ₃ , R ₄ and R ₅ as hydroxyl groups. Got Elemental _{analysis: C 34 H 44 O 14 ·} H 2 O Calculated: C, 58.78; H, 6.67 Found: C, 58.60; H, 6.64 13 C-NMR (75MHz, Δppm in deuterated methanol) 173.1 (Q), 172.4 (Q), 172.0 (Q), 170.1
(Q), 168.4 (Q), 139.1 (Q), 136.1 (CH),
132.8 (CH), 129.6 (CH), 129.5 (2CH),
127.9 (CH), 127.0 (2CH), 122.3 (CH),
107.2 (Q), 91.0 (Q), 82.1 (CH), 81.2 (C
H), 78.0 (CH), 76.6 (CH), 75.6 (Q), 38.
6 (CH ₂ ), 38.0 (CH ₂ ), 37.9 (CH), 36.3 (C
H ₂ ), 33.2 (CH ₂ ), 32.6 (CH ₂ ), 32.5 (CH ₂ ),
23.2 (CH ₂ ), 21.2 (CH ₃ ), 20.1 (CH ₂ ), 14.
_{6 (CH 3), 14.3 (} CH 3).

Example 26 2-decenoic acid (0.19 ml) was dissolved in dichloromethane (5.0 ml), HOBT (101 mg) and WSC (144 mg) were sequentially added, and the mixture was stirred at room temperature for 6.5 hr. R ₁ and R in the reaction solution
₂ is hydrogen, R ₃ , R ₄ and R ₅ are t-butoxy groups, R ₆ is acetyl group, and R ₇ is hydrogen. A solution of compound (I) (0.30 g) in dichloromethane (1.0 ml), triethylamine (0 .1
7 ml) was added, and the mixture was further stirred at room temperature for 87 hours. The reaction solution was diluted with ethyl acetate-hexane (1: 1, 25 ml) to give 1
0% ammonium chloride water, 2% sodium hydrogen carbonate water,
The extract was washed with water and saturated saline (20 ml each), dried over sodium sulfate and concentrated to dryness to give a crude powder. This was subjected to silica gel column chromatography (20 ml), and the fractions eluted with ethyl acetate-hexane (1: 5 to 1: 4) were collected and concentrated to dryness. The corresponding R ₁ was a 2-decenoyl group, R ₃ and R ₄
Compounds (I) (2) in which R and R ₅ are both t-butoxy groups
03 mg) was obtained. This was dissolved in TFA (0.5 ml) and left at room temperature for 2.0 hours. The reaction mixture was concentrated to dryness, dissolved in ethyl acetate (20 ml), washed with saturated brine (20 ml), dried over sodium sulfate and concentrated to dryness to give a crude powder (173 mg). Reversed phase preparative HPLC (carrier; ODS, YMC
-Pack, SH-343, mobile phase; 37% acetonitrile / 0.01 M phosphate buffer, pH 6.3). Fractions with an elution volume of 310 to 410 ml were collected and concentrated to about 10 ml,
After adjusting to pH 2.0, add salt (1.0 g) to dissolve,
Extract twice with ethyl acetate (10 ml). The organic layer was washed with saturated brine, dried over sodium sulfate, concentrated to dryness, and LH
-20 column chromatography (MeOH, 70 ml) and subjected to elution volume 44-56ml in the fractions concentrated to dryness has solidified the corresponding free 2-decenoyl compound (R _3, R ₄ and R ₅
A white powder (50 mg) of the compound (I) having a hydroxyl group was obtained. Elemental analysis value: Calculated as C ₃₆ H ₄₈ O ₁₄ .H ₂ O: C, 59.82; H, 6.97 Actual value: C, 59.81; H, 7.13 ¹³ C-NMR (75 MHz, 75 MHz, Δppm in deuterated methanol) 173.0 (Q), 172.5 (Q), 172.1 (Q), 170.
2 (Q), 168.4 (Q), 139.1 (Q), 136.2 (C
H), 132.9 (CH), 129.6 (CH), 129.5 (2C
H), 127.9 (CH), 127.0 (2CH), 122.3 (C
H), 107.2 (Q), 91.0 (Q), 82.1 (CH), 81.
2 (CH), 78.0 (CH), 76.6 (CH), 75.6 (Q),
38.6 (CH ₂ ), 38.0 (CH ₂ ), 37.9 (CH), 36.
3 (CH ₂ ), 33.5 (CH ₂ ), 32.9 (CH ₂ ), 32.7 (C
H ₂ ), 30.3 (CH ₂ ), 30.0 (CH ₂ ), 23.7 (CH ₂ ),
_{21.2 (CH 3), 20.1 (} CH 2), 14.7 (CH 3), 14.
5 (CH _3).

Example 27 Sorbic acid (50.5 mg) was dissolved in dichloromethane (10 ml), HOBT (67 mg) and WSC (95 mg) were sequentially added,
Stir at room temperature for 5 hours. R ₁ and R ₂ are hydrogen in the reaction solution,
A dichloromethane solution (1.0 ml) of compound (I) (276 mg) in which R ₃ , R ₄ and R ₅ are t-butoxy groups, R ₆ is an acetyl group and R ₇ is hydrogen, and triethylamine (0.075 ml) are added, Furthermore, it stirred at room temperature for 41 hours. DMA in the reaction solution
P (2 mg) and triethylamine (0.025 ml) were added, and the mixture was further stirred at room temperature for 70 hours. The reaction solution was diluted with ethyl acetate-hexane (1: 1, 30 ml), 10% aqueous ammonium chloride solution, 2% aqueous sodium hydrogen carbonate solution, water, saturated saline solution.
(20 ml each), dried over sodium sulfate and concentrated to dryness to obtain a crude powder. This was subjected to silica gel column chromatography (20 ml), and ethyl acetate-hexane (1:
The fractions eluted at 4-1: 3) were collected, concentrated to dryness, and powdered.
(77 mg) was obtained. This was dissolved in TFA (0.5 ml) and left at room temperature for 40 minutes. The reaction mixture was concentrated to dryness, 2% aqueous sodium carbonate solution (15 ml) was added and dissolved, and ether (10 m
It was washed twice with l). The aqueous layer was adjusted to pH 2.0 and salt (1.
0 g) was added and dissolved, and the mixture was extracted twice with ethyl acetate (10 ml). The organic layers were combined, washed with saturated brine, dried over sodium sulfate, and concentrated to dryness to give a crude powder (68 mg). This was subjected to reverse phase preparative HPLC (carrier; ODS, YMC-Pack,
D-ODS-5, mobile phase; 31% acetonitrile / 0.0
2M phosphate buffer, pH 6.3). Elution volume 20
Fractions of 0 to 260 ml and 280 to 380 ml were collected and concentrated to about 10 ml. These were adjusted to pH 2.0, saturated with sodium chloride, extracted twice with ethyl acetate (10 ml), and the organic layer was washed with saturated brine, dried over sodium sulfate and concentrated to dryness to give the corresponding product. R ₁ is a sorbyl group,
Compounds (I) (2) in which R ₃ , R ₄ and R ₅ are all hydroxyl groups
1 mg) and the corresponding R ₂ were sorbyl groups, and R ₃ , R ₄ and R ₅ were all hydroxyl groups to obtain a white powder of compound (I) (9 mg).

[0094] Elemental analysis: as _{C 32 H 38 O 14 · 2H} 2 O (R 1 = sorbyl group) Calculated: C, 56.30; H, 6.20 Found: C, 56.34; H, 5.93 ¹³ C-NMR (75 MHz, δ ppm in deuterated methanol) 173.1 (Q), 172.6 (Q), 170.2 (Q), 168.
6 (Q), 167.1 (Q), 147.7 (CH), 141.7 (C
H), 139.1 (Q), 132.9 (CH), 130.9 (CH),
129.6 (CH), 129.5 (2CH), 128.0 (CH),
127.0 (2CH), 119.0 (CH), 107.3 (Q), 9
1.1 (Q), 82.3 (CH), 81.1 (CH), 78.1 (C
H), 76.7 (CH), 75.7 (Q), 38.0 (CH ₂ ), 38.
0 (CH), 36.4 (CH ₂ ), 32.7 (CH ₂ ), 21.2 (C
H ₃ ), 20.1 (CH ₂ ), 18.8 (CH ₃ ), 14.7 (C
H ₃ ).

¹³ C-NMR (75 MHz, δ ppm in deuterated methanol) (R ₂ = sorbyl group) 173.1 (Q), 173.0 (Q), 170.1 (Q), 168.
9 (Q), 167.4 (Q), 148.3 (CH), 142.1 (C
H), 139.2 (Q), 132.9 (CH), 131.0 (CH),
129.7 (CH), 129.5 (2CH), 128.0 (CH),
127.1 (2CH), 118.6 (CH), 106.4 (Q), 9
3.3 (Q), 83.3 (CH), 78.0 (CH), 77.3 (C
H), 76.8 (CH), 75.6 (Q), 38.0 (CH ₂ ), 37.
9 (CH), 36.6 (CH ₂ ), 32.5 (CH ₂ ), 21.2 (C
_{H 3), 19.9 (CH 2} ), 18.8 (CH 3), 14.7 (C
H ₃ ).

Example 28 Compound (I) (1) in which R ₁ and R ₂ are hydrogen, R ₃ , R ₄ and R ₅ are t-butoxy groups, R ₆ is an acetyl group, and R ₇ is hydrogen.
26 mg) was dissolved in dichloromethane (4.2 ml) and trans-
Cinnamic acid (52 mg), HOBT (47 mg), WSC (67 mg)
Were sequentially added, and the mixture was stirred at room temperature for 3 hours. Triethylamine (61 μl) was added to the reaction solution, and the mixture was further stirred at room temperature for 66 hours. DMAP (2.2 mg) was added to the reaction solution, and the mixture was further stirred at room temperature for 44 hours. The reaction solution is ethyl acetate-hexane
Dilute with 1: 1 (20 ml), wash with 10% aqueous ammonium chloride, 2% aqueous sodium hydrogencarbonate, water and saturated saline (20 ml each), dry over sodium sulfate and concentrate to dryness to give a crude powder. Obtained. This was subjected to silica gel thin layer chromatography, developed twice with ethyl acetate-hexane (1: 2), and the portions having UV absorption of Rf 0.43 to 0.55 and Rf 0.57 to 0.64 were collected, respectively. eluting with ethyl acetate Te, concentrated to dryness, the corresponding R ₁ or R ₂ is a cinnamoyl group, R _3, R ₄ and powder (96 mg) and R ₁ also R ₅ are all compounds of t- butoxy group (I) A powder (20 mg) of compound (I) in which R ₂ and R ₂ are cinnamoyl groups and R ₃ , R ₄ and R ₅ are all t-butoxy groups was obtained. These were each dissolved in TFA (0.5 ml) and left at room temperature for 60 minutes. The reaction solutions were each concentrated to dryness. The former is a reverse phase preparative HPLC (carrier; ODS, YMC-Pack, D-ODS-
5, mobile phase; 33% acetonitrile / 0.01 M phosphate buffer, pH 6.3). Elution volume 120-135 ml
And collect the fractions of 140-205 ml respectively and about 10 ml
Concentrated to. Correcting these to pH 2.0, ethyl acetate
It was extracted twice with (10 ml), and the organic layer was washed with saturated saline solution, dried over sodium sulfate and concentrated to dryness to obtain a compound in which R ₁ is a cinnamoyl group and R ₃ , R ₄ and R ₅ are all hydroxyl groups. (I) (19 mg) and R ₁ is hydrogen, R ₂ is a cinnamoyl group, and R ₃ , R ₄ and R ₅ are all hydroxyl groups (I)
(12 mg) of white powder was obtained.

¹³ C-NMR (75 MHz, δ ppm in deuterated methanol) (R ₁ = cinnamoyl group) 173.1 (Q), 172.6 (Q), 170.2 (Q), 168.
6 (Q), 166.7 (Q), 147.2 (CH), 139.1
(Q), 135.6 (Q), 132.9 (CH), 131.8 (C
H), 130.1 (2CH), 129.6 (CH), 129.5 (2
CH), 129.4 (2CH), 128.0 (CH), 127.0
(2CH), 118.2 (CH), 107.3 (Q), 91.2
(Q), 82.3 (CH), 81.4 (CH), 78.1 (CH), 7
6.7 (CH), 75.7 (Q), 38.0 (CH ₂ ), 38.0 (C
H), 36.4 (CH ₂ ), 32.7 (CH ₂ ), 21.2 (CH ₃ ),
_{20.2 (CH 2), 14.7 (} CH 3).

Elemental analysis value: C ₃₅ H ₃₈ O ₁₄ · 1.5H ₂ O (R ₁ = hydrogen, R ₂ = cinnamoyl group) Calculated value: C, 59.23; H, 5.82 Measured value: C , 59.42; H, 5.94 ¹³ C-NMR (75 MHz, in deuterated methanol, δ ppm) 173.1 (Q), 173.0 (Q), 170.2 (Q), 168.
9 (Q), 167.2 (Q), 147.9 (CH), 139.1
(Q), 135.5 (Q), 132.9 (CH), 131.9 (C
H), 130.1 (2CH), 129.6 (CH), 129.6 (2
CH), 129.5 (2CH), 127.9 (CH), 127.0
(2CH), 117.8 (CH), 106.4 (Q), 93.3
(Q), 83.6 (CH), 78.0 (CH), 77.3 (CH), 7
6.8 (CH), 75.8 (Q), 38.0 (CH ₂ ), 37.9 (C
H), 36.6 (CH ₂ ), 32.5 (CH ₂ ), 21.1 (CH ₃ ),
_{20.0 (CH 2), 14.7 (} CH 3). The latter is methanol
(0.5 ml), diluted with 1N aqueous sodium hydroxide (0.10 m
l) is added and the precipitate is collected by filtration to obtain a compound (I) in which R ₁ and R ₂ are cinnamoyl groups, and R ₃ , R ₄ and R ₅ are all hydroxyl groups.
The trisodium salt of (12 mg) was obtained.

¹³ C-NMR (75 MHz, in deuterated chloroform, δ ppm) (R ₁ and R ₂ = cinnamoyl group, tri-te
rt-butyl ester) 170.9 (Q), 168.6 (Q), 165.7 (Q), 165.
6 (Q), 164.6 (Q), 163.7 (Q), 146.8 (C
H), 146.4 (CH), 137.7 (Q), 134.1 (Q), 1
34.0 (Q), 131.4 (CH), 130.8 (2CH), 13
0.6 (2CH), 129.0 (2CH), 129.0 (2CH),
128.9 (CH), 128.4 (2CH), 128.3 (2C
H), 128.2 (2CH), 126.9 (CH), 126.0 (2
CH), 116.8 (CH), 116.4 (CH), 104.3
(Q), 90.1 (Q), 86.3 (Q), 84.4 (Q), 83.6
(Q), 81.2 (CH), 76.6 (CH), 76.1 (CH), 7
5.5 (CH), 73.9 (Q ), 36.6 (CH 2), 36.3 (C
H), 36.0 (CH ₂ ), 30.9 (CH ₂ ), 28.1 (3C
_{H 3), 28.0 (3CH 3} ), 28.0 (3CH 3), 21.2 (C
_{H 3), 19.0 (CH 2} ), 14.2 (CH 3).

Example 29 Linolenic acid (0.21 ml) was dissolved in dichloromethane (6.0 ml), HOBT (104 mg) and WSC (148 mg) were sequentially added, and the mixture was stirred at room temperature for 6 hours. In the reaction solution, R ₁ and R ₂ are hydrogen, R ₃ , R ₄ and R ₅ are t-butoxy groups, R ₆ is an acetyl group, R ₇ is hydrogen (I) (348 mg), triethylamine (0.134 ml) Was added, and the mixture was further stirred at room temperature for 40 hours. The reaction solution was diluted with ethyl acetate-hexane (1: 1, 25
ml), washed with 10% aqueous ammonium chloride solution, 2% aqueous sodium hydrogen carbonate solution, water and saturated saline solution (20 ml each), dried over sodium sulfate and concentrated to dryness to give a crude powder. Silica gel column chromatography (25 m
l), and the fractions eluted with ethyl acetate-hexane (1: 5 to 1: 4) were collected and concentrated to dryness to give a powder (252 mg). This was dissolved in TFA (0.5 ml) and left at room temperature for 70 minutes. The reaction mixture was concentrated to dryness, diluted with ethyl acetate (30 ml), washed with saturated brine, dried over sodium sulfate, concentrated to dryness and the corresponding R ₁ was linolenoyl group, R ₃ , R ₄ and R _5. Powder of compound (I) having hydroxyl groups (216 m
g) was obtained. Elemental _{analysis: C 44 H 60 O 14 ·} 1.5H 2 O Calculated: C, 62.92; H, 7.56 Found: C, 62.93; H, 7.77 13 C-NMR ( 75 MHz, δppm in deuterated methanol) 173.6 (Q), 173.0 (Q), 172.4 (Q), 170.
1 (Q), 168.4 (Q), 139.1 (Q), 132.9 (C
H), 132.7 (CH), 131.1 (CH), 129.6 (C
H), 129.5 (2CH), 129.2 (CH), 129.2 (C
H), 128.8 (CH), 128.2 (CH), 127.9 (CH),
127.0 (2CH), 107.2 (Q), 91.0 (Q), 82.
2 (CH), 81.0 (CH), 78.0 (CH), 76.6 (C
H), 75.6 (Q), 38.0 (CH ₂ ), 38.0 (CH), 36.
3 (CH ₂ ), 35.0 (CH ₂ ), 34.9 (CH ₂ ), 34.9 (C
H ₂ ), 32.7 (CH ₂ ), 30.7 (CH ₂ ), 30.2 (CH ₂ ),
30.2 (CH ₂ ), 26.5 (CH ₂ ), 26.4 (CH ₂ ), 25.
8 (CH ₂ ), 21.5 (CH ₂ ), 21.2 (CH ₃ ), 20.1 (C
_{H 2), 14.7 (2CH 3} ).

Example 30 (2Z, 4E) -10-Methyldodecadienoic acid (118 mg)
Was dissolved in dichloromethane (6.5 ml) and HOBT (81 m
g), WSC (115 mg) and R ₁ and R ₂ are hydrogen,
Compounds (I) (0.31 g) in which R ₃ , R ₄ and R ₅ are t-butoxy groups, R ₆ is an acetyl group, and R ₇ is hydrogen are sequentially added,
It was stirred at room temperature for 1 hour. Triethylamine (0.
095 ml) was added, and the mixture was further stirred at room temperature for 7 days. The reaction solution was diluted with ethyl acetate-hexane (1: 1, 25 ml),
The extract was washed with 10% aqueous ammonium chloride solution, 2% aqueous sodium hydrogen carbonate solution, water and saturated saline solution (20 ml each), dried over sodium sulfate and concentrated to dryness to give a crude powder. This was subjected to silica gel column chromatography (20 ml), and the fractions eluted with ethyl acetate-hexane (1: 5 to 1: 4) were collected and concentrated to dryness to give a powder (82 mg). This is TFA (0.
5 ml) and left at room temperature for 40 minutes. The reaction mixture was concentrated to dryness, diluted with ethyl acetate (30 ml), washed with saturated brine, dried over sodium sulfate, and concentrated to dryness. The residue was subjected to reverse phase preparative HPLC (carrier; ODS, YMC-Pack, D-O).
DS-5, mobile phase; 45% acetonitrile / 0.02M phosphate buffer, pH 6.3). Elution volume 260 to 3
Fractions of 00 ml were collected and concentrated to about 10 ml. This is pH
After adjusting to 2.0, salt was added to saturate, and ethyl acetate (10 m
l) twice, the organic layer was washed with saturated brine, dried over sodium sulfate and concentrated to dryness to obtain R ₁ of the formula (a):

[0102]

[Chemical 9]

A powder (9 mg) of compound (I) in which all of the groups represented by R ₃ , R ₄ and R ₅ were hydroxyl groups was obtained. ¹³ C-NMR (75 MHz, in deuterated methanol, δ ppm) 173.1 (Q), 172.6 (Q), 170.3 (Q), 168.
6 (Q), 166.2 (Q), 148.0 (CH), 147.9 (C
H), 139.1 (Q), 132.9 (CH), 129.6 (CH),
129.5 (2CH), 128.3 (CH), 128.0 (CH),
127.1 (2CH), 115.2 (CH), 107.2 (Q), 9
1.2 (Q), 82.4 (CH), 80.9 (CH), 78.1 (C
H), 76.7 (CH), 75.7 (Q), 38.0 (CH ₂ ), 38.
0 (CH), 37.6 (CH ₂ ), 36.4 (CH ₂ ), 35.7 (C
H), 34.1 (CH ₂ ), 32.7 (CH ₂ ), 30.6 (CH ₂ ),
30.3 (CH ₂ ), 27.9 (CH ₂ ), 21.2 (CH ₃ ), 20.
1 (CH ₂ ), 19.6 (CH ₃ ), 14.7 (CH ₃ ), 11.8 (C
H ₃ ).

Example 31 (2E, 4E) -10-methyldodecadienoic acid and (2E, 4E)
E) -10-Methyl undecadienoic acid mixture (1: 1;
150 mg) and R ₁ and R ₂ are hydrogen, R ₃ , R ₄ and R ₅ are t-butoxy groups, R ₆ is an acetyl group, and R ₇ is hydrogen. Compound (I) (408 mg) is added to dichloromethane (8.0 ml). , WSC (163 mg) and DMAP (7.1 mg) were sequentially added, and the mixture was stirred at room temperature for 69 hours. The reaction mixture was diluted with ethyl acetate-hexane (1: 1, 25 ml), washed with 10% aqueous ammonium chloride, 2% aqueous sodium hydrogencarbonate, water and saturated brine (20 ml each), dried over sodium sulfate and concentrated. Coagulation gave a coarse powder. This was subjected to silica gel column chromatography (25 ml), ethyl acetate-hexane.
Fractions eluted at (1: 5 to 1: 4) were collected and concentrated to dryness.
A powder (102 mg) was obtained. This was dissolved in TFA (0.5 ml) and left at room temperature for 40 minutes. The reaction solution was concentrated to dryness and then reverse phase preparative HPLC (carrier; ODS, YMC-Pack, D-OD
S-5, mobile phase; 42% acetonitrile / 0.02M phosphate buffer, pH 6.3). Elution volume 320-44
Fractions of 0 ml and 540-670 ml respectively were collected and about 1
Concentrated to 0 ml. These were adjusted to pH 2.0, saturated with sodium chloride, extracted twice with ethyl acetate (10 ml), the organic layer was washed with saturated brine, dried over sodium sulfate and concentrated to dryness to obtain R ₂ of the formula (B):

[0105]

[Chemical 10]

Compound (I) (3.7 mg) in which R ₃ , R ₄ and R ₅ are all hydroxyl groups and R ₂ is represented by the formula (c):

[0107]

[Chemical 11]

A white powder of compound (I) (6.5 mg) in which all of the groups represented by R ₃ , R ₄ and R ₅ are hydroxyl groups was obtained.

¹ H-NMR (300 MHz, δ ppm in deuterated methanol) [R ₂ = group of formula (b)] 7.33 (1 H, brd, J = 8 Hz), 7.32 (1 H, dd, J = 1
5.4, 10.0 Hz), 7.26 (1 H, t, J = 7.3 Hz), 7.
16 (1H, t, J = 7.1Hz), 6.38 (1H, d, J = 15.
8Hz), 6.24 (2H, m), 6.22 (1H, m), 5.92 (1
H, d, J = 15.4Hz), 5.27 (1H, d, J = 0.8Hz),
5.27 (1H, d, J = 0.8Hz), 5.04 (1H, s), 4.9
3 (1H, m), 2.29 (1H, m), 2.18 (2H, q, J = 6.
2Hz), 2.05 (1H, m), 2.04 (3H, s), 1.93 (2
H, m), 1.89 (1H, m), 1.67 (2H, brs), 1.62 (2
H, br), 1.40 (1H, m), 1.34 (2H, m), 1.32 (4
H, brs), 1.13 (2H, m), 0.96 (3H, d, J = 6.8H
z), 0.87 (3H, t, J = 6.8Hz), 0.86 (3H, d, J
= 7.2 Hz).

¹³ C-NMR (75 MHz, δ ppm in deuterated methanol) [R ₂ = group of formula (c)] 173.1 (Q), 173.0 (Q), 170.2 (Q), 169.
0 (Q), 167.4 (Q), 148.4 (CH), 147.4 (C
H), 139.1 (Q), 132.8 (CH), 129.7 (CH),
129.5 (2CH), 129.0 (CH), 127.9 (CH),
127.1 (2CH), 118.8 (CH), 106.4 (Q), 9
3.3 (Q), 83.4 (CH), 78.0 (CH), 77.3 (C
H), 76.8 (CH), 75.6 (Q), 40.0 (CH), 38.
0 (CH ₂ ), 38.0 (CH), 37.8 (CH ₂ ), 36.6 (C
H ₂ ), 34.1 (CH ₂ ), 32.4 (CH ₂ ), 30.1 (CH ₂ ),
29.1 (CH ₂ ), 28.1 (CH ₂ ), 23.0 (2CH ₃ ), 2
_{1.2 (CH 3), 20.0 (} CH 2), 14.7 (CH 3).

Example 32 Cholic acid tritetrahydropyranyl ether compound (275 m
g) was dissolved in dichloromethane (5.0 ml) and HOBT (67
mg) and WSC (96 mg) were sequentially added, and the mixture was stirred at room temperature for 4.5 hours. In the reaction solution, R ₁ and R ₂ are hydrogen, R ₃ , R ₄ and R
₅ is t-butoxy group, R ₆ is acetyl group, R ₇ is hydrogen compound (I) (200 mg) and triethylamine (0.11).
5 ml) was added, and the mixture was further stirred at room temperature for 41 hours. The reaction mixture was diluted with ethyl acetate-hexane (1: 1, 20 ml) and diluted to 1
0% ammonium chloride water, 2% sodium hydrogen carbonate water,
The extract was washed with water and saturated saline (20 ml each), dried over sodium sulfate and concentrated to dryness to give a crude powder. This was subjected to silica gel column chromatography (20 ml), and the fractions eluted with ethyl acetate-hexane (1: 3) were collected and concentrated to dryness to give a powder (231 mg). This was dissolved in TFA (0.5 ml) and left at room temperature for 1.5 hours. The reaction mixture was concentrated to dryness, 2% aqueous sodium hydrogencarbonate (15 ml) was added and mixed. The mixture was adjusted to pH 7.4 and extracted twice with ethyl acetate (10 ml). 2% aqueous sodium hydrogencarbonate solution,
The extract was washed with water and saturated saline (10 ml each), dried over sodium sulfate and concentrated to dryness to give a crude powder. This was subjected to reverse phase preparative HPLC (carrier; ODS-YMC-Pack, SH-34
3, mobile phase: 35% acetonitrile / 0.01 M phosphate buffer, pH 6.3). Elution volume 250-450 ml
Were collected, concentrated to about 10 ml, adjusted to pH 2.0, dissolved by adding sodium chloride (1.0 g), and extracted twice with ethyl acetate (10 ml). The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated to dryness, and R ₁ was represented by the formula (d):

[0112]

[Chemical 12]

A choryl group represented by R ₃ , R ₄ and R ₅
A white powder (38 mg) of compound (I) having a hydroxyl group was obtained. Elemental analysis value: Calculated value as C ₅₀ H ₇₀ O ₁₇ · 2.5H ₂ O; C, 60.78; H, 7.65 Measured value; C, 60.72; H, 7.59

¹³ C-NMR (75 MHz, δ ppm in deuterated methanol) 174.3 (Q), 173.1 (Q), 172.4 (Q), 170.
2 (Q), 168.4 (Q), 139.0 (Q), 132.8 (C
H), 129.6 (CH), 129.5 (2CH), 127.9 (C
H), 127.0 (2CH), 107.2 (Q), 91.0 (Q), 8
2.2 (CH), 81.0 (CH), 78.1 (CH), 76.6 (C
H), 75.6 (Q), 74.3 (CH), 72.8 (CH), 69.
1 (CH), 47.8 (Q), 47.4 (CH), 43.1 (CH),
43.0 (CH), 40.9 (CH), 40.4 (CH), 38.0
(CH ₂ ), 37.9 (CH), 36.6 (CH), 36.4 (C
H ₂ ), 36.3 (CH ₂ ), 35.9 (Q), 35.8 (CH ₂ ), 3
2.6 (CH ₂ ) 32.0 (CH ₂ ), 31.9 (CH ₂ ), 31.0 (C
H ₂ ), 29.5 (CH ₂ ), 28.6 (CH ₂ ), 27.8 (CH),
24.2 (CH ₂ ), 23.2 (CH ₃ ), 21.2 (CH ₃ ), 20.
1 (CH ₂ ), 17.6 (CH ₃ ), 14.7 (CH ₃ ), 13.0 (C
H ₃ ).

Example 33 Compound (I) (699 mg) wherein R ₁ is a 2-octenoyl group, R ₂ is hydrogen, R ₃ , R ₄ and R ₅ are hydroxyl groups, R ₆ is an acetyl group, and R ₇ is hydrogen is ethanol. It was dissolved in (35 ml) and stirred at room temperature for 47 hours in the presence of camphorsulfonic acid (240 mg). 2% aqueous sodium hydrogen carbonate solution (5.
1 ml) was added, the mixture was concentrated to 10 ml, and diluted with water (40 ml). Sodium chloride (10 g) was added to the aqueous layer to dissolve it, the pH was adjusted to 2.5, and the mixture was extracted twice with ethyl acetate (35 ml). The organic layers were combined, washed with saturated brine, dried over sodium sulfate, and concentrated to dryness to give a crude powder (686 mg). Reversed phase preparative HPLC (carrier; ODS, YMC
-Pack, SH-363, mobile phase; 35% acetonitrile / 0.01 M phosphate buffer, pH 6.3). Fractions with an elution volume of 610-850 ml were collected and collected to about 50
The mixture was concentrated to ml, dissolved with sodium chloride (2 g), adjusted to pH 2.4, and extracted twice with ethyl acetate (40 ml). The organic layers were combined, washed with saturated brine, dried over sodium sulfate, and concentrated to dryness to obtain a white powder (375 mg) of the corresponding compound (I) having R ₅ as an ethoxy group. Elemental analysis value: Calculated as C ₃₆ H ₄₈ O ₁₄ · 0.5H ₂ O; C, 60.58; H, 6.92 actual value; C, 60.42; H, 6.89

¹³ C-NMR (75 MHz, in deuterated chloroform, δ ppm) 173.0 (Q), 172.3 (Q), 172.0 (Q), 168.
4 (Q), 168.3 (Q), 139.0 (Q), 136.1 (C
H), 132.8 (CH), 129.5 (CH), 129.4 (2C
H), 127.9 (CH), 127.0 (2CH), 122.2
(CH), 107.1 (Q), 90.9 (Q), 82.1 (CH), 8
1.1 (CH), 77.9 (CH), 76.7 (CH), 75.7
(Q), 62.6 (CH ₂ ), 38.6 (CH ₂ ), 38.0 (CH ₂ ),
37.9 (CH), 36.3 (CH ₂ ), 33.2 (CH ₂ ), 32.
6 (CH ₂ ), 32.4 (CH ₂ ), 23.2 (CH ₂ ), 21.2 (C
_{H 3), 20.0 (CH 2} ), 14.6 (CH 3), 14.3 (CH 3),
14.2 (CH _3).

Formulation Example 1 R ₁ obtained in Example 21 is myristoyl, R ₂ is hydrogen,
Using a compound (I) in which R ₃ , R ₄ and R ₅ are hydroxyl groups, R ₆ is an acetyl group, and R ₇ is hydrogen, all the ingredients of the formulation shown below are mixed and filled into a gelatin capsule to give 1 capsule. A capsule containing 50 mg of the above compound was prepared. Compound obtained in Example 21 50 mg Lactose 100 mg Corn starch 40 mg Magnesium stearate 10 mg Total 200 mg

Formulation Example 2 R ₁ obtained in Example 21 is myristoyl, R ₂ is hydrogen,
A compound (I) in which R ₃ , R ₄ and R ₅ are hydroxyl groups, R ₆ is an acetyl group and R ₇ is hydrogen and magnesium stearate are granulated with an aqueous solution of soluble starch according to a method known per se, dried, and then lactose and Mixed with corn starch. The mixture was compression-molded to produce tablets having the formulations shown below. Compound obtained in Example 21 50 mg Lactose 65 mg Corn starch 30 mg Soluble starch 35 mg Magnesium stearate 20 mg Total 200 mg

[0119]

INDUSTRIAL APPLICABILITY The compound of the present invention is a novel compound having a squalene synthase inhibitory activity, has low toxicity, and is effective as a cholesterol lowering agent, and is therefore useful as a preventive and therapeutic drug for antihyperlipidemia.

Claims (16)

[Claims] 1. A compound represented by the general formula (I): (In the formula, X represents an ethylene group or a vinylene group, R ₁ ,
R ₂ , R ₆ and R ₇ each represent hydrogen or an optionally substituted acyl group, and R ₃ , R ₄ and R ₅ each represent a hydroxyl group, an alkoxy group or an optionally substituted amino group. However, when R ₁ is an 11-phenyl-10-undecenoyl group, at least one of R ₃ , R ₄ and R ₅ is a group other than a hydroxyl group. ) The compound or its salt represented by this. 2. The compound according to claim 1, wherein X is a vinylene group. 3. The acyl group represented by R ₁ , R ₂ , R ₆ and R ₇ is an acyl group derived from an organic carboxylic acid.
The described compound. 4. The compound according to claim 1, wherein the acyl group represented by R ₁ , R ₂ , R ₆ and R ₇ is an acyl group having 1 to 30 carbon atoms. 5. The compound according to claim 1, wherein the acyl group represented by R ₁ , R ₂ , R ₆ and R ₇ is an acyl group having 1 to 6 unsaturated bonds. 6. The acyl group represented by R ₁ , R ₂ , R ₆ and R ₇ is an alkyl group, an alkoxy group, a mono- or dialkylamino group, a halogen, a carboxyl group, a hydroxyl group, an acyloxy group, an amino group and a heterocycle. 1 selected from the group
The compound according to claim 1, which is an acyl group which may be substituted with one or more groups. 7. A mono- or dialkylamino group in which an alkyl group has a C1-6 alkyl group, an alkoxy group has a C1-6 alkoxy group, and a mono- or dialkylamino group has a C1-6 alkyl group. The compound according to claim 6, wherein the acyloxy group is an acyloxy group having 1 to 6 carbon atoms, and the heterocyclic group is a heterocyclic group having 2 to 10 carbon atoms. 8. The compound according to claim 1, wherein R ₆ is hydrogen or acetyl. 9. The compound according to claim 1, wherein the alkoxy group represented by R ₃ , R ₄ and R ₅ is an alkoxy group having 1 to 6 carbon atoms. 10. The compound according to claim 1, wherein the optionally substituted amino group represented by R ₃ , R ₄ and R ₅ is an amino group optionally mono- or di-substituted with an alkyl group. 11. The compound according to claim 10, wherein the alkyl group is an alkyl group having 1 to 6 carbon atoms. 12. R ₁ is hydrogen, an optionally substituted alkanoyl group or an optionally substituted alkenoyl group, R ₃ , R ₄ and R ₅ are each a hydroxyl group or an alkoxy group, and R ₇ is hydrogen, R ₁ is an octanoyl, decanoyl, 11-phenyl-10-undecenoyl group or 1
The compound according to claim 1, wherein in the case of a 1-phenylundecanoyl group, at least one of R ₃ , R ₄ and R ₅ is an alkoxy group. 13. The compound according to claim 12, wherein the alkanoyl group is an alkanoyl group having 1 to 7 carbon atoms. 14. The compound according to claim 12, wherein the alkenoyl group is an alkenoyl group having 3 to 20 carbon atoms. 15. A compound represented by the general formula (II): (Wherein R ₁ , R ₂ , R ₆ and R ₇ are represented by the following general formula (I)
And R ₈ , R ₉ and R ₁₀ each represent an optionally protected carboxyl group. Provided that when R ₁ is an 11-phenyl-10-undecenoyl group, R ₈ , R ₉ and R
_At least one of the _ten is a protected carboxyl group. A compound represented by the formula (1) or a salt thereof is optionally acylated and then subjected to a deprotection reaction, represented by the general formula (I): (In the formula, X represents an ethylene group or a vinylene group, R ₁ ,
R ₂ , R ₆ and R ₇ each represent hydrogen or an optionally substituted acyl group, and R ₃ , R ₄ and R ₅ each represent a hydroxyl group, an alkoxy group or an optionally substituted amino group. However, when R ₁ is an 11-phenyl-10-undecenoyl group, at least one of R ₃ , R ₄ and R ₅ is a group other than a hydroxyl group. The manufacturing method of the compound or its salt represented by these. 16. A compound represented by the general formula (I): (In the formula, X represents an ethylene group or a vinylene group, R ₁ ,
R ₂ , R ₆ and R ₇ each represent hydrogen or an optionally substituted acyl group, and R ₃ , R ₄ and R ₅ each represent a hydroxyl group, an alkoxy group or an optionally substituted amino group. However, when R ₁ is an 11-phenyl-10-undecenoyl group, at least one of R ₃ , R ₄ and R ₅ is a group other than a hydroxyl group. ) An antihyperlipidemic agent containing a compound represented by the formula (1) or a salt thereof.