JPH0141130B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the formula a pharmacologically acceptable salt thereof,
The present invention relates to novel 6β-hydroxy-iso ML-236B derivatives, which are lower alkyl esters or lactones thereof.

Japanese Patent Application Laid-Open No. 155690/1983 and Journal of Antibiotics
Antibiotics, Vol. 29, pp. 1346-1348 (1976), the formula Carboxylic acids and their ring-closed lactones inhibit cholesterol biosynthesis by competing with its rate-limiting enzyme, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and have a strong serum cholesterol-lowering effect. known to show. Also, JP-A-53-84954
The alkyl ester of carboxylic acid of the above formula () is disclosed in JP-A-53-56314, JP-A-54
Metal salts, amino acid salts, and amine salts of the carboxylic acid of the above formula () are known from Publication No. 28828 and Japanese Patent Application Laid-open No. 123140/1982.
ML-236B also exhibits cholesterol synthesis inhibitory activity.

The present inventors have researched derivatives of ML-236B, and have published Japanese Patent Application Laid-open Nos. 57-2240 and 57-50894,
In the specifications of JP-A-57-67575, JP-A-57-155995 and JP-A-58-10572, the formula (In the formula, R~ represents 〓OH or...OH.), a salt thereof, an alkyl ester thereof, or a lactone thereof, 3-hydroxy-
ML-236B derivatives were further developed in JP-A-57-
108039, JP-A-57-50894 and JP-A-57-
In the specification of No. 155995, the formula It has been found that 6α-hydroxy-iso ML-236B derivatives, which are carboxylic acids, their salts, their lower alkyl esters, or their lactones, all exhibit cholesterol synthesis inhibitory effects.

This time, the present inventors have discovered a 6β-hydroxy-iso ML-236B derivative, which is a carboxylic acid having the formula (), a pharmacologically acceptable salt thereof, an alkyl ester thereof, or a lactone thereof, and which inhibits cholesterol synthesis. The present invention was completed by discovering that the present invention exhibits an effect.

The 6β-hydroxy-iso ML-236B derivatives of the present invention have the effect of lowering blood lipids by inhibiting cholesterol synthesis, and are used as medicines, for example, as antihyperlipidemia agents and arteriosclerosis preventive agents. can be used.

These compounds can be administered orally or parenterally, for example, in the form of capsules, tablets, injections, and the like. The dosage varies depending on age, symptoms, body weight, etc., but it is usually about 0.5 to 500 mg per day for adults.
is administered in 3 to 4 divided doses. However, larger amounts can be used if desired.

The object compound of the present invention can be obtained, for example, by subjecting the above-mentioned 3-hydroxy-ML-236B derivatives or 6α-hydroxy-isoML-236B derivatives to a contact reaction with a strong acid, and then optionally performing a salt formation reaction, an esterification reaction, or Obtained by subjecting it to a lactonization reaction.

In the following description of this specification, 6β-hydroxy-iso-ML- of the target compound in formula ()
236B derivatives include isoM-4, isoM-4 salt,
They are called isoM-4 alkyl ester and isoM-4 lactone.

Also, in the formula () of the raw material compound, ~R is
3β-Hydroxy-ML-236B derivatives which are OH are called M-4, M-4 salts, M-4 alkyl esters and M-4 lactones, and 3α-hydroxy-ML- where ~R is...OH. 236B derivatives are M
-4', M-4' salt, M-4' alkyl ester and M-4' lactone.

Furthermore, the 6α-hydroxy-isoML-236B derivatives in formula () are isoM-4′, isoM-
4' salts, isoM-4' alkyl esters and isoM
-It is called the 4′ lactone form.

The salts of the isoM-4 salt of the target compound and the M-4 salt, M-4' salt, and isoM-4' salt of the raw material compound include pharmacologically acceptable salts, such as metal salts, amino acid salts, or amine salts. It is. Examples of metal salts include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, aluminum salts, iron salts, zinc salts, copper salts, nickel salts, and cobalt salts. Of these, alkali metal salts, alkaline earth metal salts and aluminum salts are preferred;
Furthermore, the sodium, potassium, calcium and aluminum salts are most preferred. Preferred amino acid salts include basic amino acids such as arginine, lysine, histidine, α,γ-diaminobutyric acid, and ornithine. Examples of amine salts include t-octylamine, dibenzylamine,
Dicyclohexylamine, morpholine, D-phenylglycine alkyl ester, D-glucosamine, and the like are suitable.

Similarly, isoM-4 alkyl ester, M-4
Examples of the alkyl ester, M-4' alkyl ester and isoM-4' alkyl ester include alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and pentyl. Methyl is preferred.

Iso M-4 lactone, M-4 lactone, M
-4' lactone body and isoM-4' lactone body are
This is a compound in which the substituent at position 8 of the hexahydronaphthalene ring in formulas (), (), and () has the following partial structural formula.

In these, among M-4s, M-4's and isoM-4's used as raw material compounds,
In particular, alkali metal salts, most preferably sodium or potassium salts, are preferably used.

Examples of the carboxylic acid having the general formula (), its pharmacologically acceptable salt, its lower alkyl ester, or its lactone form obtained by the present invention include the compounds described below.

1 IsoM-4 carboxylic acid 2 IsoM-4 sodium salt 3 IsoM-4 potassium salt 4 IsoM-4 calcium salt 5 IsoM-4 aluminum salt 6 IsoM-4 arginine salt 7 IsoM-4 lysine salt 8 IsoM-4t-octylamine salt 9 IsoM-4D-phenylglycine ethyl ester salt 10 IsoM-4 methyl ester 11 IsoM-4 lactone The method for producing the target compound of the present invention will be described below.

The carboxylic acid having the formula () is M-4 class, M
It can be obtained by subjecting -4' or isoM-4' to a catalytic reaction with a strong acid. Suitable acids to be used include, for example, inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid. The reaction is PH
It is preferable to carry out the reaction in the range of PH 1 to 3, particularly around PH 1.5. The reaction is usually carried out in the presence of a solvent. The solvent to be used is not particularly limited as long as it does not participate in the reaction; for example, water; polar organic solvents such as nitrites such as acetonitrile, alcohols such as propanol and butanol; or combinations of these organic solvents. A mixed solvent with water is preferred. The reaction temperature is not particularly limited and depends on the relationship with the reaction time, but is usually room temperature to 50°C, preferably
The temperature is 30 to 40°C.

Alternatively, it can also be obtained by subjecting a carboxylate salt or lactone body described below to acidic conditions.

The carboxylic acid having the formula () obtained in this way is extracted, washed, dehydrated, etc., and then
It can be used in the following reactions.

A metal salt of a carboxylic acid having the formula () can be obtained by contacting a hydroxide, carbonate, etc. of the metal with the above carboxylic acid or a lactone described below in an aqueous solvent. Suitable examples of the aqueous solvent used include water; a mixed solvent of water and alcohols such as methanol and ethanol, and organic solvents such as acetone, n-hexane and ethyl acetate.
Particularly suitable is a mixed solvent of a hydrophilic organic solvent and water. The reaction is usually suitably carried out around room temperature,
The heating may be carried out if necessary.

The amine salt of a carboxylic acid having the formula () can be obtained by contacting an amine with the above carboxylic acid or a lactone described below in an aqueous solvent.
Examples of the aqueous solvent used include water; alcohols such as methanol and ethanol; ethers such as tetrahydrofuran; and mixed solvents of water and nitriles such as acetonitrile; preferred is aqueous acetone. The reaction is usually suitably carried out at a pH of 7 to 8.5 and below room temperature, particularly at 5 to 10°C. The reaction is completed instantly. Alternatively, the carboxylic acid metal salt obtained above can be dissolved in an aqueous solvent, and then a mineral acid salt (eg, hydrochloride) of the desired amine can be added under the above conditions to obtain the salt exchange reaction.

Amino acid salts of carboxylic acids having the formula () are:
It can be obtained by contacting an amino acid with the above carboxylic acid or a lactone described below in an aqueous solvent. Examples of the aqueous solvent used include water; a mixed solvent of water and alcohols such as methanol and ethanol; and ethers such as tetrahydrofuran. The reaction is usually carried out under heating, preferably around 50 to 60°C.

The lower alkyl ester of a carboxylic acid having the formula () can be obtained by contacting the carboxylic acid obtained above or the lactone described below with an alcohol. In this case, a mineral acid such as hydrochloric acid or sulfuric acid, boron fluoride, an acidic ion exchange resin, or the like is used as a catalyst, and as a solvent, the same alcohol or one that does not participate in the reaction, such as benzene, chloroform, or ether, is used. or,
It is obtained by contacting the carboxylic acid obtained above with a diazoalkane. The reaction is usually carried out by contacting with an ethereal solution of the diazoalkane. Alternatively, it can be obtained by contacting the metal salt of carboxylic acid obtained above with an alkyl halide. Suitable solvents to be used include, for example, dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and acetone. All reactions are preferably carried out at around room temperature, but depending on the type of reaction system, they may be carried out under heating if necessary.

The lactone form of carboxylic acid having the formula () is
It is obtained by contacting the carboxylic acid obtained above with a catalytic amount of acid. Suitable acids used include, for example, inorganic acids such as hydrochloric acid, and organic acids such as p-toluenesulfonic acid and trifluoroacetic acid. The reaction is usually carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not participate in the reaction, and suitable examples include aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran, and ethyl acetate. The reaction temperature is not particularly limited and depends on the relationship with the reaction time, but is usually carried out at room temperature to around 60°C.

The 6β-hydroxy-iso ML-236B derivatives thus obtained can be collected and purified by appropriately combining various methods.
For example, this can be carried out by adsorption using various carriers such as activated carbon or silica gel, ion exchange chromatography, high performance liquid chromatography, gel filtration using a Sephadex column, or extraction using an organic solvent such as ether, ethyl acetate, or chloroform.

Examples will be shown next, but the present invention is not limited to these examples.

Example 1 50 mg of M-4 sodium salt was dissolved in 10 ml of water, and then the pH was adjusted to 1.5 with 1N hydrochloric acid. This solution was heated at 37°C.
After stirring for 2 hours at
ml x 3) extracted. The obtained extract was concentrated to about 20 ml, and the concentrated solution was washed with water, dehydrated, and concentrated to dryness to obtain a residue containing isoM-4 carboxylic acid. The obtained residue was dissolved in 10 ml of benzene, a catalytic amount of p-toluenesulfonic acid was added, and the mixture was heated at 50°C.
The mixture was stirred for 15 minutes. After the reaction was completed, the reaction mixture was washed with water and concentrated to dryness. The resulting residue was dissolved in 1 ml of acetonitrile. 100μ of this solution was subjected to high performance liquid chromatography (column: manufactured by Waters,
Radial-pak C-8 5 mmi.d., solvent: 25% acetonitrile, flow rate: 2 ml/min), 14-16
The portion eluted within minutes was collected. This operation was repeated 10 times and each fraction was combined. Acetonitrile was distilled off from the eluate, the remaining aqueous layer was adjusted to pH 4 with 1N hydrochloric acid, and then diluted with 10 ml of ethyl acetate three times (10
ml x 3) extracted. The extract was washed with water, dehydrated, and then concentrated to dryness to obtain about 1 mg of the desired isoM-4 lactone.

Physical properties of isoM-4 lactone 1 Nuclear magnetic resonance spectrum (Fig. 1) Measured in deuterated chloroform at 200MHz (JNM/FX-200 model manufactured by JEOL Ltd.) using TMS as an internal standard. (CDCl ₃ , δ: ppm) 0.82 (3H, d, J = 7.1Hz) 0.86 (3H, t, J = 7.3 to 7.6Hz) 1.08 (3H, d, J = 6.8Hz) 2.00 (1H, dddd, J = 14, 4, 3, 1.5Hz) 2.10 (1H, m) 2.15 (1H, m) 2.33 (1H, sex, J = 7Hz) 2.42 (2H, m) 2.64 (1H, ddd, J = 17.3, 4, 1.5Hz) 2.72 (1H, dd, J = 17.5, 5Hz) 4.42 (1H, br.) 4.39 (1H, qu, J = 4~5Hz) 4.65 (1H, m) 5.43 (1H, br.) 5.61 (1H , a pair of m, J = 9Hz) 5.49 (1H, br.) 6.11 (1H, d, br.J = 9Hz) 2 Ultraviolet absorption spectrum (Figure 2) Measured with 25% acetonitrile solution (Hitachi, Ltd.) 124 type manufactured by Seisakusho).

λmax (nm): 232, 238, 245 3 Mass spectrum After silylation with N,O-bis(trimethylsilyl)trifluoroacetamide, JEOL D
- Measured using Model 300.

M/Z: 350 (M ⁺ ), 448, 358, 343, 272, 246,
233, 231 Example 2 22 mg of isoM-4 lactone in 50% ethanol water 2
ml, 0.5 ml of 0.1N sodium hydroxide was added, and the mixture was stirred at room temperature for 3 hours. After the reaction is complete, 3 ml of distilled water is added to the reaction mixture and freeze-dried to obtain isoM-
22 mg of the tetrasodium salt was obtained as a colorless powder.

1 Elemental analysis value (%) as C ₂₃ H ₃₅ O ₇ Na Calculated value C, 61.86H, 7.92 Actual value C, 61.57H, 7.86 2 Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 3400, 11725, 1590 3 Nucleus Magnetic resonance spectra in deuterated methanol using TMS as internal standard
Measured at 200MHz. (CD ₃ OD, δ: ppm) 3.70
(1H, m), 3.98 (1H, m), 4.25 (1H, m), 5.38
(1H, m), 5.45 (1H, br.s), 5.64 (1H, m),
6.00 (1H, m) Example 3 20 mg of isoM-4 sodium salt was dissolved in 2 ml of water, then 2 ml of 0.1N hydrochloric acid was added, and the mixture was extracted three times (5 ml x 3) with 5 ml of ethyl acetate. The extracts were combined, washed with 10 ml of saturated saline, and concentrated to dryness under reduced pressure to obtain 11 mg of isoM-4 carboxylic acid as a colorless candy.

1 Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 3550, 2780, 1725, 1600 The isoM-4 carboxylic acid was gradually converted into a lactone form when left at room temperature.

Example 4 35 mg of isoM-4 sodium salt was dissolved in 2 ml of dimethylformamide, then 0.5 ml of methyl iodide was added and heated at 60°C for 3 hours. After the reaction was completed, 10 ml of water was added to the reaction mixture, followed by extraction with 10 ml of ethyl acetate three times (10 ml x 3). The extracts were combined, washed sequentially with 20 ml of water and 20 ml of saturated saline, and then dried over sodium sulfate. The extract was concentrated to dryness to obtain 32 mg of isoM-4 methyl ester as a colorless foam.

1 Elemental analysis value (%) As C ₂₄ H ₃₈ O ₇ Calculated value C, 65.72 H, 8.73 Actual value C, 65.68 H, 8.51 2 Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 3450, 1725, 1700, 1600 3 Nuclear magnetic resonance spectra Measured at 200MHz in deuterated chloroform using TMS as an internal standard. (CDCl ₃ , δ: ppm) 3.70 (3H, s), 3.82 (1H, m), 4.25 (1H,
m), 4.45 (1H, m), 5.45 (1H, br.s), 5.48
(1H, m), 5.63 (1H, d), 6.02 (1H, m)

[Brief explanation of drawings]

FIG. 1 shows the nuclear magnetic resonance spectrum of isoM-4 lactone, and FIG. 2 shows the ultraviolet absorption spectrum of the same substance.

Claims (1)

[Claims] 1 formula a pharmacologically acceptable salt thereof,
6β-hydroxy-iso ML-236B derivatives, which are its lower alkyl esters or its lactones. 2. The compound according to claim 1, which is a carboxylic acid having the formula (). 3. The compound according to claim 1, which is a pharmacologically acceptable salt of a carboxylic acid having the formula (). 4. The compound according to claim 1, which is a lower alkyl ester of a carboxylic acid having the formula (). 5. The compound according to claim 1, which is a lactone form of a carboxylic acid having the formula (). 6. The compound according to claim 3, wherein the pharmacologically acceptable salt of the carboxylic acid having formula () is an alkali metal salt.