JPH0379332B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the formula (In the formula, R ¹ is

[Formula] Also teeth

[Formula] is shown. R ² represents an alkyl group having 1 to 10 carbon atoms. However, s-butyl group is excluded. ), a pharmacologically acceptable salt thereof, an ester thereof or a closed ring lactone thereof, and a method for producing the same. The present inventors have now demonstrated that the carboxylic acid having the general formula (), its pharmacologically acceptable salt, its ester, or its ring-closed lactone form all exhibit cholesterol synthesis inhibitory effects and are highly stable. The present invention has been completed. In the general formula (), R ² represents a straight or branched alkyl group having 1 to 10 carbon atoms. However, s-butyl group is excluded. As R ² ,
For example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl,
Decyl, isopropyl, isobutyl, t-butyl, isopentyl, neopentyl, t-pentyl, isohexyl, 1-ethylpropyl, 1-methylpentyl, 1-ethyl-1-methylpropyl, 1,1-dimethylpentyl, 1,2- Dimethylpentyl, 1-methylhexyl, 1,1-dimethylhexyl, 1-methylheptyl, 1,1-dimethylheptyl, 1-methyloctyl, 1,1-
Indicates dimethyloctyl or 1-methylnonyl. The pharmacologically acceptable salts of the present invention include metal salts,
Mention may be made of ammonium salts or salts of organic amines or amino acids. The metal salt of the compound of the present invention is represented by the following formula (). (In the formula, R ¹ has the same meaning as above,
M represents a metal atom, and n represents the valence of the metal atom M). Examples of metal salts include alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium salts, magnesium salts, aluminum salts, iron salts, zinc salts, copper salts, nickel salts, and cobalt salts. Among these, alkali metal salts, alkaline earth metal salts, magnesium salts and aluminum salts are preferred, and sodium salts, potassium salts, calcium salts and aluminum salts are most preferred. The ammonium salt, organic amine salt and amino acid salt of the compound of the present invention are represented by the following formula (). (In the formula, R ¹ has the same meaning as above,
A represents ammonia, an amino acid or an organic amine, and m represents an integer). The integer represented by m is preferably 1. That is, when A represents an amine or an amino acid, the amine or amino acid is preferably a monoacid base. In the above formula (), examples of the amino acid represented by A include arginine, lysine, histidine, α,
Basic amino acids such as γ-diaminobutyric acid and ornithine are preferred. When A is an organic amine, aliphatic, aromatic,
Cycloaliphatic, heterocyclic or carbohydrate monoamines are preferred. 1 such as octylamine, t-octylamine, 2-ethylhexylamine.
class alkylamine; benzylamine, α-methylbenzylamine, phenethylamine, dibenzylamine, N-methylbenzylamine, N,N-dimethylbenzylamine, N,N-diethylbenzylamine, N-ethyl-N-methylbenzylamine , primary, secondary or tertiary aralkylamines having 7 or 8 carbon atoms such as tribenzylamine; cyclopentylamine, cyclohexylamine, cycloheptylamine, N-methylcyclopentylamine, N-ethylcyclohexylamine, N- 5 to 7 primary, secondary or tertiary carbon atoms such as ethylcycloheptylamine, dicyclohexylamine, N,N-dimethylcyclopentylamine, N,N-dimethylcyclohexylamine, N,N-diethylcycloheptylamine saturated alicyclic amines; 5- to 6-membered heterocyclic amines having one nitrogen atom as a heteroatom such as pyrrolidine, N-methylpyrrolidine, piperidine, and N-methylpiperidine; morpholine; leucine methyl ester, diethyl glutamate, C1-3 alkyl esters of aliphatic or aromatic amino acids such as phenylglycine ethyl ester, β-phenylalanine propyl ester, β-phenylalanine methyl ester; amine derivatives of carbohydrates such as glucosamine; I can give it to you. When the aforementioned amino acids and amines exist in the form of stereoisomers or optical isomers, they are used in any form of these isomers or mixtures. Suitable amines include t-octylamine, benzylamine, dibenzylamine, N,N-dimethylbenzylamine, cyclohexylamine, dicyclohexylamine, N,N-dimethylcyclohexylamine, N-methylpyrrolidine, morpholine, L-leucinealkyl ester, dialkyl L-glutamate, D-phenylglycine alkyl ester and D-glucosamine,
Most preferably t-octylamine, dibenzylamine, dicyclohexylamine, morpholin,
D-phenylglycine alkyl ester and D
- Glucosamine. Among these salts are especially the alkali metal salts, most preferably the sodium or potassium salts. The ester of the compound of the present invention is represented by the following formula (). (In the formula, R ¹ has the same meaning as above,
R represents an ester residue, and p represents the valence of R). When p is 1, R is preferably an alkyl group,
Substituted benzyl group having at least one substituent selected from unsubstituted benzyl group, alkyl, alkoxy, and halogen, unsubstituted phenacyl group, having at least one substituent selected from alkyl, alkoxy, and halogen It is a substituted phenacyl group. When R represents an alkyl group, it is linear or branched and preferably has 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, and the like. When R represents a benzyl group, it may be unsubstituted or substituted, and the substituent is preferably alkyl, alkoxy or halogen having 1 or 2 carbon atoms. There is one or more substituents, preferably one, and when there is more than one, they may be the same or different. For example, benzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-ethylbenzyl, 3-ethylbenzyl,
4-ethylbenzyl, 2-methoxybenzyl, 3
-methoxybenzyl, 4-methoxybenzyl, 2
-ethoxybenzyl, 3-ethoxybenzyl, 4
-ethoxybenzyl, 2-chlorobenzyl, 3-
These include chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, and the like. When R represents an unsubstituted or substituted phenacyl group, the substituent is preferably alkyl having 1 or 2 carbon atoms, alkoxy or halogen.
One or more substitutions, preferably one,
If there are more than one, they may be the same or different. For example, phenacyl, 2-methylphenacyl, 3-methylphenacyl, 4-methylphenacyl, 2-ethylphenacyl, 3-ethylphenacyl, 4-ethylphenacyl, 2-methoxyphenacyl, 3-methoxyphenacyl, 4-methoxyphenacyl, 2-ethoxyphenacyl , 3-ethoxyphenacyl, 4-ethoxyphenacyl, 2-
Chlorophenacyl, 3-chlorophenacyl, 4-
Chlorophenacyl, 2-bromophenacyl, 3-
Bromophenacyl, 4-bromophenacyl, and the like. When p is 2, R represents a divalent alcohol residue, preferably an alkylene group or alkylidene group having 2 to 6 carbon atoms. For example, ethylene, ethylidene, propylene, propylidene,
Trimethylene, tetramethylene, butylidene, pentamethylene, pentylidene, etc., including those having one or more substituents, such as hydroxy, halogen, trifluoromethyl. When p is 3, R represents a trivalent alcohol residue, preferably a saturated aliphatic hydrocarbon group having 2 to 6 carbon atoms and having one or more substituents such as hydroxy, halogen, and trifluoromethyl. It is. Preferably p is 1 and R is an alkyl group (optimally methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, hexyl, etc.), optionally substituted benzyl groups (optimally benzyl, 4-methylbenzyl, 4-methoxybenzyl, 4-chlorobenzyl, etc.), optionally substituted phenacyl groups ( Most suitable is fenacil,
4-methylphenacyl, 4-methoxyphenacyl, 4-bromophenacyl, etc.). The most preferred radicals R are methyl, ethyl, propyl, isopropyl, butyl, isobutyl. The ring-closed lactone of the compound having the general formula () above refers to a compound in which the formula () is represented by the following ring-closed structural formula. In the general formula () of the present invention, the following geometric isomers exist depending on the arrangement of substituents. Furthermore, various optical isomers also exist due to the presence of asymmetric carbon atoms. In the general formula (),
All of these isomers and mixtures of these isomers are shown in a single formula. Therefore, in the present invention, the carboxylic acid having the general formula (), its pharmacologically acceptable salt, its ester or its ring-closed lactone, includes the carboxylic acid having the general formula () to (), its It includes not only pharmacologically acceptable salts, esters thereof, or ring-closed lactones thereof, but also mixtures of these isomers. The object compound of the present invention has an effect of lowering blood lipids by inhibiting cholesterol synthesis, and can be used in medicine, for example, as a therapeutic agent for hyperlipidemia or a preventive agent for arteriosclerosis. These compounds of the invention are administered in conventional manner, for example parenterally (subcutaneous, intravenous or intramuscular injection) or orally (tablets, capsules, powders or granules). The dosage for adults varies depending on age, body weight, symptoms, etc., but usually about 0.2 to 200 mg per day is administered to adults once or in 3 to 4 divided doses. The object compound of the present invention has the formula (In the formula, R ² has the same meaning as above.)
a pharmacologically acceptable salt thereof,
The ester or its ring-closed lactone (raw material compound) is enzymatically hydroxylated by contacting it with a 3-hydroxylated or 6-hydroxylated converting bacterium or its cell-free extract, and then the resulting converted reaction product is converted into the desired reaction product. It can be obtained by subjecting it to a hydrolysis reaction, salt formation reaction, esterification reaction, or lactonization reaction and collecting it from the reaction solution. Microorganisms that can convert the raw material compound into a carboxylic acid having the general formula (), a pharmacologically acceptable salt thereof, an ester thereof, or a closed ring lactone thereof include the genus Mucor belonging to the Zygomycete. Among these microorganisms, Mucor hyimaris and Forma hyimaris are particularly popular.
hiemalis f. hiemalis) IFO 5834 IFO 5303 IFO 8567 IFO 8449 IFO 8448 IFO 8565 Mucor circinelloides f.
circinelloides) IFO 4554 Same IFO 5775 Mucor hiemalis f.corticolus SANK 34572 (F.K.F. corticolus No. 5913) Mucor dimorp
−hosporus) IFO4556 Mucor genevensis IFO 4585 Mucor globosus
SANK 35472 (Fiber Science and Technology Research Institute No. 5915) Mucor circinelloides f.grise-
ocyanus) IFO 4563 is preferred. All of the microorganisms suitably used in the present invention have been deposited with the Institute of Fine Technology, or are available from public archives (IFO). In order to convert the carboxylic acid having the general formula (), its pharmacologically acceptable salt, its ester or its ring-closed lactone (raw material compound) into the compound of the present invention, complete cells in culture or in a resting bacterial system are used. This is achieved by contacting with microorganisms or, as the case may be, with cell-free extracts of these microorganisms. The type of compound obtained varies depending on the culture conditions, the type of microorganism used, and the properties of the raw material compound. For example, when whole-cell microorganisms are cultured in the presence of starting compounds, the resulting compounds may vary depending on the culture conditions, especially
Depending on the pH value, they are carboxylic acids, lactones, esters (especially alkyl esters), or salts (especially alkali metal salts). On the other hand, if the starting compound is simply brought into contact with a resting bacterial system or a cell-free extract;
The compounds obtained are mostly in the form of alkali metal salts. Usually, it is obtained as a mixture of 3-hydroxy form and 6-hydroxy form. The progress of the conversion reaction is determined by measuring samples of the reaction mixture during the reaction to determine the rate of conversion. When culturing microorganisms in the presence of starting compounds to obtain the compounds of the present invention, the culture conditions and the culture medium used are selected depending on the requirements of the particular microorganism being cultured. In the method of the present invention, all the microorganisms used are known, and therefore the culture conditions for these microorganisms and the culture medium used are all known. The compounds of the invention are separated from the reaction mixture by conventional methods. For example, it can be obtained by removing the microbial cells if necessary and then subjecting the residual mixture to a combination of thin layer chromatography, column chromatography and high performance liquid chromatography. The two isomeric compounds of the present invention can be separated from each other during their chromatographic purification, if desired. Alternatively, they can be separated as a mixture. In the enzymatic hydroxylation process according to the invention, the carboxylic acids or lactones are obtained in the form of carboxylic acids or lactones, which can be converted into the corresponding salts or esters by conventional methods of chemical reactions. For example, metal salts [formula ()] and amino acid salts [in formula (), A is an amino acid]
If so, it can be produced according to the method for producing ML-236B carboxylate described in British Patent No. 1555831. Amine salts are prepared by reacting the alkali metal carboxylate salt of the compound with ammonia or a mineral salt of an organic amine (eg, hydrochloric acid) in a suitable solvent. The nature of the solvent is not particularly limited as long as it does not affect the reaction, and is preferably an aqueous solvent.
Examples of such solvents are water and mixed solvents of water and organic solvents such as alcohols (eg methanol, ethanol) or ketones (eg acetone). The amount of the amine salt is preferably an equivalent to a slightly excess molar amount relative to the carboxylic acid metal salt. For example, the molar ratio of amine salt to carboxylic acid metal salt is 1:1 to 1.2:1. The reaction is preferably between 7.0 and 8.5
The pH value is below room temperature, for example from 0°C to 10°C, preferably from 5°C to 10°C. After the reaction is complete,
The resulting salt is separated from the reaction mixture by extraction with a suitable solvent such as ethyl acetate. The ester [formula ()] can be produced using a lactone, a carboxylic acid, or a corresponding salt (preferably an alkali metal salt), for example, according to the method described in British Patent No. 1,555,831. For example, in the production of ML-236B carboxylic acid ester, it can be produced according to a method in which a starting compound is reacted with an alcohol or a diazo compound, preferably diazomethane or C-substituted diazomethane, in the presence of a suitable catalyst. In addition, by appropriately adjusting the pH conditions,
converting a carboxylic acid into the corresponding lactone;
You can also do the opposite. Furthermore, esters can also be converted into salts by appropriately combining the appropriate chemical reactions described above. The above-mentioned conversion reaction is performed after separating and purifying the raw material compound from the culture or reaction mixture, or before or during the separation step. The raw material compound is produced by subjecting the corresponding MB-530 compound to an acyl substitution reaction, or preferably by using MB-530A (Japanese Unexamined Patent Publication No. 56-138181) as described in British Patent No. 2073193. For example, it can be manufactured by the following method. Method 1 MB-530A is reacted with a suitable acid chloride or acid anhydride of the group R ² COO- introduced in the 1-position. The reaction is preferably carried out with a base (acting as an acid binder), such as pyridine, triethylamine, N,
It is carried out in the presence of an organic amine such as N-dimethylaminopyridine, N-methylpyrrolidine or N-methylmorpholine. The reaction is preferably carried out in the presence of a solvent, and the solvent is not particularly limited as long as it does not affect the reaction. Chloroform, methylene chloride, and diethyl ether are suitable as the solvent. Excess reagents or bases can also be used as solvents in the reaction. Although the reaction may be carried out over a wide temperature range, relatively low temperatures are usually preferred to carry out the reaction properly, for example -20°C to room temperature, preferably -20°C to 0°C. However, it can be carried out at higher temperatures if desired. Method 2 Produced by treating a carboxylic acid with a chlorocarbonate ester or sulfonic acid chloride in the presence of a base such as the organic amines described above to give a mixed acid anhydride and then reacting with MB-530A. . The reaction is preferably carried out in the presence of a solvent, and there is no particular limitation as long as it does not affect the reaction. Examples of the solvent include diethyl ether, benzene, chloroform, and methylene chloride. The reaction is carried out over a wide temperature range, but from -20°C to room temperature, preferably from -20°C to 0°C. Method 3 Prepared by reacting MB-530A with a carboxylic acid and a diazoalkyl dicarboxylate in the presence of, for example, dicyclohexylcarbodiimide, triphenylphosphine, dimethylphosphite amide. The reaction is preferably carried out in the presence of a solvent, and the solvent is not particularly limited as long as it does not affect the reaction. Examples of solvents include chloroform, methylene chloride, benzene, and diethyl ether, and the reaction is carried out over a wide temperature range. Each of the above reactions is usually completed in 30 minutes to 5 hours, but the exact time depends on the reagents and reaction temperature. After the reaction is completed, the desired compound is collected from the reaction mixture in a conventional manner. For example, the solvent is distilled off from a solution (reaction mixture or extraction solvent from the reaction mixture) containing the desired compound, washed and dried as appropriate, and then column chromatography, thin layer chromatography, recrystallization, or a combination thereof. It can be obtained by subjecting it to purification. Next, examples will be shown. Example 1 1-(2,2-dimethylbutyryloxy)-6-
Hydroxy-isoMB-530B lactone Twenty 500 mg Erlenmeyer flasks containing 100 mg of the medium with the following composition were inoculated with Mucor hyimaris IFO 5834 at 26°C and 220 rpm.
After 4 days, 1-(2,2-dimethylbutyryloxy)-MB-530B lactone was added to a final concentration of 0.05%, and cultured for another 6 days.
Cultured at 220 rpm. Medium composition Glucose 1.0% Peptone 0.2 Meat extract 0.1 Yeast extract 0.1 Corn steep liquor 0.3 Tap water Remaining (pH uncorrected) After completion of the culture, a converted reverse liquid of 1.9 was obtained. The resulting conversion reaction solution was adjusted to pH 3.0 with trifluoroacetic acid. It was then extracted three times with 1 portion of ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and then a catalytic amount of trifluoroacetic acid was added for lactonization. After lactonization, the extract was washed with 5% sodium bicarbonate, dried over sodium sulfate, and then dried under reduced pressure. The resulting residue was purified with ethyl acetate using a Roper column (manufactured by Merck & Co., si60 size A) to obtain the desired target compound. 1 NMR spectrum Measured at 90MHz in deuterated chloroform using TMS as an internal standard. (CDC ₃ , δ: ppm) 0.82 (3H, t) 0.85 (3H, d) 1.12 (6H, s) 1.70 (3H, s) 3.92 (1H, d) 4.32 (1H, m) 4.63 (1H, m) 5.45 (1H, m) 5.58 (1H, d) 5.90 (1H, broad) Example 2 1-pivaloyloxy-6-hydroxy-iso
MB-530 Lactone In Example 1, the raw material compound 1-(2,2-
1-pivaloyloxy-MB-530B instead of dimethylbutyryloxy)-MB-530B lactone
Similar treatment with lactone gave the title compound. 1 NMR spectrum Measurement conditions were the same as in Example 1. 0.87 (3H, d) 1.22 (9H, s) 1.70 (3H, s) 3.91 (1H, d) 4.32 (1H, m) 4.61 (1H, m) 5.42 (1H, m) 5.55 (1H, d) 5.87 ( 1H, broad m) Example 3 1-isobutyryloxy-6-hydroxy-isoMB-530B lactone In Example 1, the starting compound 1-(2,2-
1-isobutyryloxy-MB- instead of dimethylbutyryloxy)-MB-530B lactone
Similar treatment with 530B lactone gave the title compound. 1 NMR spectrum Measurement conditions were the same as in Example 1. 0.87 (3H, d) 1.11 (6H, d) 1.71 (3H, s) 3.93 (1H, d) 4.32 (1H, m) 4.60 (1H, m) 5.44 (1H, m) 5.57 (1H, d) 5.85 ( 1H, broad s) Example 4 1-acetoxy-6-hydroxy-isoMB-
530B Lactone In Example 1, the starting compound 1-(2,2-
When 1-acetoxy-MB-530B lactone was used instead of dimethylbutyryloxy)-MB-530B lactone, the title compound was obtained. 1 NMR spectrum Measurement conditions were the same as in Example 1. 0.84 (3H, d) 1.71 (3H, s) 2.06 (3H, s) 3.90 (1H, d) 4.30 (1H, m) 4.66 (1H, m) 5.46 (1H, m) 5.53 (1H, m) 5.88 ( 1H, broad s) Example 5 1-Butyryloxy-6-hydroxy-iso
MB-530 Lactone In Example 1, the raw material compound 1-(2,2-
When 1-butyryloxy-MB-530B lactone was used instead of dimethylbutyryloxy-MB-530B lactone, the title compound was obtained. 1 NMR spectrum Measurement conditions were the same as in Example 1. 0.83 (3H, d) 0.98 (3H, t) 1.72 (3H, s) 3.87 (1H, d) 4.34 (1H, m) 4.64 (1H, m) 5.43 (1H, d) 5.54 (1H, d) 5.91 ( 1H, broad s) Example 6 1-isovaleryloxy-6-hydroxy-isoMB-530 lactone In Example 1, the starting compound 1-(2,2-
1-isovaleryloxy-MB- instead of dimethylbutyryloxy)-MB-530B lactone
Similar treatment with 530B lactone gave the title compound. 0.82 (6H, d) 0.88 (3H, d) 1.73 (3H, s) 3.91 (1H, d) 4.30 (1H, m) 4.65 (1H, m) 5.44 (1H, m) 5.54 (1H, d) 5.90 ( 1H, broad s) Example 7 1-(2,2-dimethylbutyryloxy)-3-
Hydroxy-MB-530B carboxylic acid methyl ester Twenty 500 ml Erlenmeyer flasks containing 100 ml of the medium with the following composition were inoculated with Mucor hyimaris IFO 5834 at 26°C, 220 rpm.
After 4 days, 1-(2,2-dimethylbutyryloxy)-MB-530B lactone was added to a final concentration of 0.05%, and cultured for another 6 days.
Cultured at 220 rpm. Medium composition Glucose 1.0% Peptone 0.2 Meat extract 0.1 Yeast extract 0.1 Corn steep liquor 0.3 Tap water remaining (pH uncorrected) After culturing, filter the conversion reaction solution and transfer the solution to Diaion HP-20 (Mitsubishi Chemical Industries, Ltd.) product) was adsorbed onto a column using the product. Next, elution was performed with 70% methanol, and the eluate was distilled off. Then, the pH was adjusted to 3.0 with trifluoroacetic acid. Then ethyl acetate 1
1-(2,2-dimethylbutyryloxy)-3-hydroxy-MB-
530B carboxylic acid and 1-(2,2-dimethylbutyryloxy)-6-hydroxy-isoMB-
A segment containing 530B carboxylic acid was obtained. An ether solution of diazomethane was immediately added to the obtained extract, and the mixture was left to stand for 30 minutes. The extract was then washed with saturated brine and dried under reduced pressure. The obtained residue was applied to Micro Bondabac C ₁₈ (manufactured by Waters), extracted with 53% methanol, and 1-(2,2-
dimethylbutyryloxy)-3-hydroxy-
When the part containing MB-530B carboxylic acid methyl ester is separated, collected, and purified, it becomes 1-(2,2-dimethylbutyryloxy)-3-hydroxy-MB.
-530B carboxylic acid methyl ester was obtained. 1 NMR spectrum Measured at 90MHz in deuterated chloroform using TMS as an internal standard. 0.83 (3H, t) 0.91 (3H, d) 1.12 (6H, s) 1.34 (3H, s) 3.73 (3H, s) 3.81 (1H, m) 4.26 (1H, q) 5.45 (2H, m) 5.91 ( 1H, dd) 6.01 (1H, d) Example 8 1-pivaloyloxy-3-hydroxy-MB
-530B carboxylic acid methyl ester In Example 7, the starting compound 1-(2,2-
1-pivaloyloxy-MB-530B instead of dimethylbutyryloxy)-MB-530B lactone
Similar treatment with lactone gave the title compound. 1 NMR spectrum Measurement conditions were the same as in Example 7. 0.90 (3H, d) 1.23 (9H, s) 1.33 (3H, s) 3.74 (3H, s) 3.82 (1H, m) 4.25 (1H, q) 5.44 (2H, m) 5.92 (1H, d-d) 6.01(1H,d) Example 9 1-isobutyryloxy-3-hydroxy-MB
-530B carboxylic acid methyl ester In Example 7, the starting compound 1-(2,2-
1-isobutyryloxy-MB- instead of dimethylbutyryloxy)-MB-530B lactone
Similar treatment with 530B lactone gave the title compound. 1 NMR spectrum Measurement conditions were the same as in Example 7. 0.92 (3H, d) 1.10 (6H, d) 1.36 (3H, s) 3.73 (3H, s) 3.83 (1H, m) 4.24 (1H, q) 5.43 (2H, m) 5.91 (1H, d-d) 6.00 (1H, d) Example 10 1-acetoxy-3-hydroxy-MB-
530B carboxylic acid methyl ester In Example 7, the starting compound 1-(2,2-
When 1-acetoxy-MB-530B lactone was used instead of dimethylbutyryloxy)-MB-530B lactone, the title compound was obtained. 1 NMR spectrum Measurement conditions were the same as in Example 7. 0.92 (3H, d) 1.38 (3H, s) 2.07 (3H, s) 3.74 (3H, s) 3.84 (1H, m) 4.26 (1H, q) 5.45 (2H, m) 5.91 (1H, d-d) 6.03(1H,d) Example 11 1-Butyryloxy-3-hydroxy-MB-
530B carboxylic acid methyl ester In Example 7, the starting compound 1-(2,2-
When 1-butyryloxy-MB-530B lactone was used instead of dimethylbutyryloxy-MB-530B lactone, the title compound was obtained. 1 NMR spectrum Measurement conditions were the same as in Example 7. 0.90 (3H, d) 1.00 (3H, t) 1.36 (3H, s) 3.73 (3H, s) 3.85 (1H, m) 4.26 (1H, q) 5.42 (2H, m) 5.91 (1H, d-d) 6.03(1H,d) Example 12 1-isovaleryloxy-3-hydroxy-
MB-530B carboxylic acid methyl ester In Example 7, the starting compound 1-(2,2-
1-isovaleryloxy-MB- instead of dimethylbutyryloxy)-MB-530B lactone
Similar treatment with 530B lactone gave the title compound. 1 NMR spectrum Measurement conditions were the same as in Example 7. 0.82 (6H, d) 0.92 (3H, d) 1.37 (3H, s) 3.73 (3H, s) 3.86 (1H, m) 4.25 (1H, q) 5.43 (2H, m) 5.92 (1H, d-d) 6.02 (1H, d)

Claims (1)

[Claims] 1 formula (In the formula, R ¹ represents [Formula] or [Formula]. R ² represents an alkyl group having 1 to 10 carbon atoms. However, s-butyl group is excluded.) MB-530B derivatives consisting of acceptable salts, esters thereof, or ring-closed lactones thereof. 2 formulas (In the formula, R ¹ represents [Formula] or [Formula]. R ² represents an alkyl group having 1 to 10 carbon atoms. However, s-butyl group is excluded.) MB- consisting of an acceptable salt, its ester or its ring-closed lactone
In the production of 530B derivatives, 3-hydroxylated or 6-hydroxylated bacteria belonging to the genus Mucor or their cell-free extracts are used as formula (In the formula, R ² has the same meaning as above.)
a pharmacologically acceptable salt thereof,
It is enzymatically hydroxylated by contacting with a raw material compound consisting of the ester or its ring-closed lactone, and then the resulting conversion reaction product is subjected to a hydrolysis reaction, a salt formation reaction, an esterification reaction, or a lactonization reaction, as desired. A method for producing an MB-530B derivative, which comprises collecting the MB-530B derivative from the reaction solution.