JPH0789898A - Biphenyl derivative - Google Patents

Abstract

PURPOSE:To provide the subject biphenyl derivative having HMG-CoA reductase inhibitory activity, cholesterol biosynthesis inhibitory activity and antioxidative activity, thus useful for preventing and treating hyperlipemia, atherosclerosis, hypercholesterolemia, etc. CONSTITUTION:The objective compound of formula I [R<1> is 1-6C alkyl or 3-7C cycloalkyl; R<2> and R<4> are each H, 1-8C alkyl, 1-4C alkoxyl, halogen, trifluoromethyl, 3-7C cycloalkyl or tri(1-4C alkyl)silyl; R<3> is H or 2-5C acyl; R<5> is 1-6C alkyl, 3-7C cycloalkyl or p-fluorophenyl; L is of formula II, etc.], e.g. a compound of formula III. The compound of the formula I can be obtained, for example, by cyclization of a compound of formula IV (R<31> is 2-5C acyl) in an organic solvent such as benzene in the presence of p-toluenesufonic acid, etc.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a biphenyl derivative. More specifically, 1) General formula (I)

[0002]

[Chemical 4]

(In the formula, all symbols have the same meanings as described below.) Biphenyl derivatives and their non-toxic salts, 2) their production method, and 3) drugs containing them as active ingredients. .

[0004]

Background of the Invention Mortality from ischemic heart disease caused by hardening of the coronary arteries that supply blood to the heart has increased in recent years. As a risk factor for this ischemic heart disease, it is said that the concentration of cholesterol, which is a lipid in serum, is high. Cholesterol begins with acetic acid, 20
Although it is biosynthesized through several steps, at this time, HMG-CoA reductase, which acts in the process of converting 3-hydroxy-3-methyl-coenzyme A (HMG-CoA) to mevalonate, is the rate-limiting enzyme. .

[0005]

[Chemical 5]

[0006] By specifically inhibiting this HMG-CoA reductase, cholesterol biosynthesis can be directly suppressed. As a result, intracellular cholesterol synthesis is suppressed, the intracellular cholesterol content is reduced, and cholesterol demand is increased. For this reason, it is considered that cholesterol in blood is taken up into cells, and accompanying this, cholesterol in blood is reduced. So far HM
From the idea of suppressing cholesterol synthesis by competing with HMG-CoA for G-CoA reductase, a compound having a partial structure similar to HMG-CoA in the molecule has been studied as an HMG-CoA reductase inhibitor. ing.

Probucol has been used as a substance having a cholesterol lowering action, but the mechanism of its action is not clear yet. However, probucol is known to have a cholesterol-lowering effect and an effect of avoiding the progression of atherosclerosis. It is said that this arteriosclerosis becomes foam cells in which low density lipoprotein (LDL) denatured by macrophagy due to oxidative action is taken up and cholesterol ester is fully stored and the foam cells accumulate. Propcol is considered to have the effect of preventing the degeneration of LDL by its antioxidant action and suppressing the formation of foam cells.

[0008]

2. Description of the Related Art As a result of recent research, HMG-Co
It has been found that a drug having both an A reductase inhibitory action and an antioxidant action is useful. For example, the general formula (X-
I)

[0009]

[Chemical 6]

[Wherein X ^X and Y ^X are the same or different and are an oxygen atom or a sulfur atom, and R ^1X and R ^5X are both isopropyl or different, and are isopropyl, cyclopropyl or phenyl radicals. And the latter may be mono- or tri-substituted on the nucleus by fluorine, chlorine, bromine, trifluoromethyl and / or alkyl or alkoxy each having 1 to 4 carbon atoms, R ^2X and R ^4X are Same or different,
Hydrogen or isopropyl, cyclopropyl or phenyl radical, the latter of which the nucleus is mono- or tri-substituted by fluorine, chlorine, bromine, trifluoromethyl and / or alkyl or alkoxy each having 1 to 4 carbon atoms. R ^3X may also be a) hydrogen, methyl or ethyl, b) a linear or branched alkyl radical having 3 to 8 carbon atoms, which radical is of the formula

[0011]

[Chemical 7]

(Wherein X ^X , R ^1X , R ^2X , R ^4X and R
^5X has its previous significance and Z ^X is a hydrogen atom, a pharmaceutically acceptable cation or formula,

[0013]

[Chemical 8]

4 (R) -hydroxy-6- represented by
(S) -Methylene 3,4,5,6, -tetrahydro-2
H-pyran-2-one radical or formula

[0015]

[Chemical 9]

Corresponding 3 (R), 5 (S)-
Dihydroxyhexanoic acid-6-yl radical, a salt thereof with a pharmaceutically acceptable base or a pharmaceutically acceptable ester thereof. ) May be substituted by a radical represented by)),

C) cycloalkyl having 3 to 8 carbon atoms, or mono- or trisubstituted in the nucleus by halogen, trifluoromethyl and / or alkyl or alkoxy each having 1 to 4 carbon atoms. Phenyl radical, or

D) Acetyl, provided that Y ^X is oxygen. ] 4-Hydroxytetrahydropyran-2-one compound represented by the formula and the formula (X-II)

[0019]

[Chemical 10]

(Wherein R ^1X , R ^2X , R ^3X , R ^4X , R ^5X ,
X ^X and Y ^X have the meanings given above. It is disclosed that the corresponding open-chain dihydroxycarboxylic acid represented by the formula (4) and pharmaceutically acceptable salts thereof have both an HMG-CoA reductase inhibitory action and an antioxidant action (JP-A-3-99075). ). On the other hand, the general formula (YI)

[0021]

[Chemical 11]

(Wherein X ^Y is oxygen or sulfur,
Y ^Y is a) either a straight or branched chain alkyl group having 3 to 12 carbon atoms, b) a cycloalkyl having 3 to 8 carbon atoms, or halogen, trifluoromethyl, And / or a phenyl group which may be substituted in the ring with 1 to 3 substituents selected from the group consisting of alkyl or alkoxy each having 1 to 4 carbon atoms, Z ^Y is hydrogen or 1 to 4 It is a straight chain or branched chain alkyl having carbon atoms. ) 6-phenoxymethyl-4-
Hydroxy-tetrahydropyran-2-one and 6-
Thiophenoxymethyl-4-hydroxy-tetrahydropyran-2-one, and general formula (Y-II) in which the compound of general formula (YI) is opened.

[0023]

[Chemical 12]

It has been disclosed that the dihydroxycarboxylic acid represented by: and salts thereof with pharmaceutically acceptable bases and pharmaceutically acceptable esters have an HMG-CoA reductase inhibitory action (JP-A-1- 319472
issue).

[0025]

OBJECTS OF THE INVENTION The present inventors have conducted research to find out novel compounds having both an HMG-CoA reductase inhibitory action and an antioxidant action, and have found that the biphenyl derivative represented by the general formula (I) achieves the objective. Heading, completed the present invention.

[0026]

Comparison with the Prior Art So far, no biphenyl derivative having both HMG-CoA reductase inhibitory action and antioxidant action has been known. That is, it is described that the compound represented by the above formula (XI) or (X-II) has both HMG-CoA reductase inhibition and antioxidant activity. ^The phenyl group (R ^3X ) is always bonded to the para-position of the phenyl group to which ^X is bonded via an oxygen or sulfur atom (Y ^X ). On the other hand, in the compound of the present invention, it is essential that the phenyl group is directly bonded to the para-position of the phenyl group to which L is bonded.

On the other hand, the compound represented by the formula (YI) or (Y-II) may have a biphenyl structure when Y ^Y represents a substituted or unsubstituted phenyl group, and the substituent is a hydroxyl group or an acyloxy group. Don't take it. In this respect, it can be said that the compound of the present invention has a different chemical structure. Further, the compound represented by the formula (YI) or (Y-II) has only an HMG-CoA reductase inhibitory action, whereas the compound of the present invention has an antioxidant action in addition to this action. This is not easily predictable. From the above, it can be said that the biphenyl compound of the present invention is a novel compound and cannot be easily predicted from the above-mentioned conventional techniques.

[0028]

DISCLOSURE OF THE INVENTION The present invention includes 1) general formula (I)

[Chemical 13] (In the formula, R ¹ represents a C 1-6 alkyl group or a C 3-7 cycloalkyl group, R ² and R ⁴ are the same or different, and are a hydrogen atom, a C 1-8 alkyl group, C 1-4
Alkoxy group, halogen atom, trifluoromethyl group, C3-7 cycloalkyl group or tri (C1-4
An alkyl) silyl group, R ³ is a hydrogen atom or C
2 to 5 represents an acyl group, R ⁵ represents a C 1 to ⁶ alkyl group, a C 3 to 7 cycloalkyl group or a p-fluorophenyl group, and L represents

[0029]

[Chemical 14] Or

[Chemical 15]

Represents And a non-toxic salt thereof, 2) a method for producing them, and 3) a drug containing them as an active ingredient.

In the present invention, all isomers are included unless otherwise specified. For example, the alkyl group, the alkoxy group, the alkylene group, the alkenyl group and the alkenylene group include straight-chain and branched-chain ones, and the double bond in the alkenylene group is E, Z and a mixture of EZ. Including. Also included are isomers formed by the presence of asymmetric carbon atoms, such as when a branched chain alkyl group is present.

In the general formula (I), the C1-6 alkyl group represented by R ¹ and R ⁵ is a methyl, ethyl, propyl, butyl, pentyl, hexyl group or an isomer group thereof. The R ^1, R ^2, cycloalkyl group C3~7 represented by R ⁴ and R ^5, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups.

C1 represented by R ² and R ⁴
The alkyl group of 8 is a methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl group or an isomer group thereof. The C1-4 alkoxy group is a methoxy group, an ethoxy group, a propoxy group, a butoxy group or an isomer group thereof. Halogen atoms are fluorine, chlorine, bromine and iodine atoms. The tri (C1-4 alkyl) silyl group is a silyl group in which a methyl, ethyl, propyl, butyl group or an isomer group thereof is tri-substituted. The acyl group C2~5 represented by R ^3, acetyl, propionyl, butyryl, valeryl and the isomers thereof.

[0034]

[Salt] Of the compounds of the present invention represented by the general formula (I), L is

[Chemical 16] Compounds of the formula are converted into the corresponding salts by known methods.

The salt is preferably non-toxic and water-soluble. Suitable salts include salts of alkali metals (potassium, sodium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts, pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine, methylamine). , Dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) amine, lysine, arginine, N-methyl-D-glucamine, etc.). Specific compounds of the present invention include the compounds listed in Table 1, their non-toxic salts and the compounds listed in Examples.

[0036]

[Table 1]

[0037]

Production Method of the Compound of the Present Invention The compound of the present invention represented by the general formula (I) is produced by the method shown in the reaction scheme 1.

[0038]

[Chemical 17]

In the reaction scheme 1, R ³¹ represents a C2-5 acyl group, and G represents a hydroxyl-protecting group that does not deprotect under alkaline conditions (eg, tetrahydropyran-2-yl group, methoxymethyl group and t-group). Butyldimethylsilyl group, etc.)
And other symbols have the same meanings as described above.

In the reaction process formula 1, (I-2) to (I-1), (I-
The cyclization reaction of 4) to (I-3) and (II-1) to (I-3) is known, and for example, in an organic solvent (benzene, toluene, xylene, etc.), an organic acid (camphor sulfone) is used. Acid, p-toluenesulfonic acid or pyridinium p-toluenesulfonic acid) in the presence or absence of 80 to
It is carried out by reacting at a temperature of 150 ° C.

In the reaction process formula 1, (II-1) to (I-2), (I-
Alkaline hydrolysis reactions of 3) to (I-2) and (I-4) to (I-2) are known, and, for example, in an organic solvent miscible with water (methanol, tetrahydrofuran, dioxane, etc.). , In the presence of an aqueous solution of an alkali metal hydrate (sodium hydroxide or potassium hydroxide) and an alkali metal carbonate (sodium carbonate or potassium carbonate) 0
It is carried out at a temperature of -40 ° C.

In the reaction scheme 1, the deprotection reaction from (II-2) to (I-4) is known. For example, the deprotection reaction with an acid is carried out in an organic solvent (methanol, ethanol,
Tetrahydrofuran or dioxane) in the presence of an organic acid (acetic acid or trifluoroacetic acid) or an inorganic acid (hydrochloric acid or sulfuric acid) at a temperature of 0 to 40 ° C.

The compound represented by the general formula (II-2) is represented by the general formula (I
It can be produced from the compound represented by I-1) by a known method. For example, it can be produced by the method represented by the following reaction process formula 2.

[0044]

[Chemical 18]

The compound represented by the general formula (II-1) can be produced by using a known reaction. For example, it can be produced by the method represented by the following reaction process formula 3.

[0046]

[Chemical 19]

The compound represented by the general formula (III) can be produced by using a known reaction. For example, it can be produced by the method described in the examples. The compound represented by the general formula (IV) is known (Japanese Patent Laid-Open No. 3-990).
No. 75).

In each reaction in the present specification, the reaction product is a conventional purification means, for example, distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, or It can be purified by a method such as column chromatography, washing, or recrystallization. Purification may be carried out for each reaction or after completion of some reactions. Other starting materials and respective reagents in the present invention are known per se or can be produced by known methods.

[0049]

[Pharmacological activity of the compound of the present invention] It was proved by the following experiments that the compound represented by the general formula (I) has HMG-CoA reductase inhibitory activity and / or cholesterol biosynthesis inhibitory activity and / or antioxidant activity.

I) HMG using rat liver microsomes
-Inhibitory effect of CoA reductase [Experimental method] Rat liver microsome fractions stored at -80 ° C were treated with 0.2 M KCl, 10 mM EDTA and 10 m.
The suspension was suspended in 0.1 M potassium phosphate buffer (pH 7.0) containing M dithiothreitol. This microsome solution 60
20 μl of 25 mM per μl (protein amount 50-80 μg)
After adding NADPH and incubating at 37 ° C. for 15 minutes, 1 μl (ethanol or dimethylsulfoxide solution) of the test compound was incubated at 37 ° C. for 15 minutes.

The HMG-CoA reductase activity was measured by adding 20 μl of 0.5 mM DL-3-hydroxy-to this reaction solution.
3-methyl [3- ¹⁴ C] - glutaryl-CoA (2 mC
i / mmol) to make the total volume 100 μl and 2 at 37 ° C.
It was determined by incubating for 0 minutes and measuring the amount of [ ¹⁴ C] -mevalonic acid produced.

The reaction was terminated by adding 10 μl of 5N hydrochloric acid to the reaction solution. Then, as an internal standard [2- ³ H] -
Mevalonolactone (0.01 μCi) was added to the reaction solution and incubated at 37 ° C for 15 minutes [ ¹⁴ C].
-Mevalonic acid was converted to [ ¹⁴ C] -mevalonolactone. [ ¹⁴ C] -mevalonolactone in the reaction solution is TLC
(Separation solvent; acetone: toluene = 1: 1, v / v) was used for separation, and measurement was performed with a liquid scintillation counter.

Ii) Cholesterol biosynthesis inhibitory action in Hep G2 cells [Experimental method] Hep G2 cells were treated with 10% F by the conventional method.
CS, 100 U / ml penicillin and 100 μg / m
D-MEM (DULBECO'S MO containing streptomycin
DIFIED EAGLE MEDIUM) (hereinafter abbreviated as mediam)
And submerged in an experimental well with a diameter of 22 mm (12 well
Secondary culturing was carried out in the plate).

Cholesterol biosynthesis activity is about 70-9.
Hep G2 cells (12-well plate) at 0% confluence were treated with 500 μl of medium and 1
Add μl (ethanol or dimethylsulfoxide solution) of the test compound, and in humidified atmosphere (5% CO ₂ ) at 37 ° C.
After incubating for 1 hour in 10 μl of 50 mM [
¹⁴ C] acetate (1 mCi / mmol) was added, the mixture was further incubated for 3 hours, and the amount of produced [ ¹⁴ C] cholesterol was measured. To measure [ ¹⁴ C] cholesterol, 500 μl of 15% KO was added to the cells.
Dissolve in H and transfer to a test tube (200 μl of 15% K
Wash wells with OH), 10 μl [1 as internal standard
α, 2α (n) ^-3 H] cholesterol (0.03 μCi)
Was added. To this solution, 1 ml of 10% KOH / ethanol (w / v) was added and heated at 90 ° C. for 1 hour. After ice-cooling, extract with petroleum ether, air-dry with nitrogen gas, and dissolve in chloroform / hexane (1/1, v / v) for TLC.
(Developing solvent; hexane: diethyl ether: acetic acid = 8
5: 15: 4) and separated with a liquid scintillation counter.

Iii) In Vitro Antioxidant Action [Experimental Method] SD rats (body weight: 200 to 350 g) were exsanguinated by transection of the jugular artery, and the liver was perfused with ice-cold physiological saline and excised. 45 ml of 1.15% for 5 g of liver
KCl was added to homogenate to prepare a rat liver 10% homogenate.

For in vitro antioxidant activity, 10 μl (ethanol or dimethylsulfoxide solution) of the test compound and 185 μl of rat liver 10% homogenate were incubated at 37 ° C. for 1 hour.
After incubating for 0 minutes, 5 μl of 8 mM
It was determined by adding a FeCl ₂ solution and further incubating at 37 ° C. for 60 minutes to measure the amount of lipid peroxide produced. The reaction was 25 μl of 10 mM B
It was terminated by adding HT and 25 μl of 250 mM EDTA solution. The lipid peroxide in the reaction solution was quantified by the TBA (thiobarbituric acid) method.

The TBA reaction substance was quantified by adding 0.2 to the reaction solution.
ml 8.1% SDS, 1.5 ml 20% acetic acid (pH 3.5
), 0.6 ml distilled water and 1.5 ml 0.8% TBA
Add the reagent solution, heat at 95 ° C. for 1 hour, then cool, add 1.0 ml of distilled water and 5.0 ml of n-butanol-pyridine mixture (15: 1), stir and centrifuge, n-butanol- Absorbance measurement of pyridine layer (53
2 nm). The amount of lipid peroxide was determined by carrying out the same operation using 1 to 10 nmol of tetramethoxypropane and preparing a calibration curve. Table 2 shows the results of HMG-CoA reductase inhibitory action, cholesterol biosynthesis inhibitory action, and antioxidant action.

[0058]

[Table 2]

[0059]

[Chemical 20]

[0060]

The compounds of the present invention are all potent HMGs.
-It is understood that it has a CoA reductase inhibitory action and a cholesterol biosynthesis inhibitory action. This action is
It is almost equal to or slightly weaker than the compound represented by the formula (X-II). On the other hand, it was found that the compounds of the present invention have a strong antioxidative action, and are several times to 100 times or more that of the comparative compound represented by the general formula (X-II).

[0061]

[Application to Pharmaceuticals] Since the compound of the present invention represented by the general formula (I) has HMG-CoA reductase inhibition and / or cholesterol biosynthesis inhibition and / or antioxidant activity, it is hyperlipidemic and atherogenic. It is useful for the prevention and / or treatment of diseases such as arteriosclerosis, hypercholesterolemia, hyperlipoproteinemia, ischemic heart disease, and coronary heart disease. In order to use the compound of the present invention represented by the general formula (I), a non-toxic salt thereof, an acid addition salt or a hydrate thereof for the above-mentioned purpose, it is usually systemically or topically, orally or parenterally. Administered in. The dose varies depending on age, weight, symptoms, therapeutic effect, administration method, treatment time and the like. Usually 1mg to 1,000m per adult per dose
orally administered once to several times a day in the range of g, or 100 μg to 100 m per adult once
It is administered parenterally once to several times a day in the range of g, or intravenously in the range of 1 hour to 24 hours a day. Of course, as described above, since the dose varies depending on various conditions, a dose smaller than the above dose may be sufficient in some cases, or a dose exceeding the range may be necessary in some cases.

When the compound of the present invention is administered, it is used as a solid composition, a liquid composition and other compositions for oral administration, an injection for parenteral administration, an external preparation, a suppository and the like. Solid compositions for oral administration include tablets,
Pills, capsules, powders, granules and the like are included. Capsules include hard capsules and soft capsules. In such solid compositions, the one or more active substances are at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminometasilicate. Mixed with magnesium acid. The composition comprises, according to a conventional method, additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrating agent such as calcium fibrin glycolate, a stabilizer such as lactose, glutamic acid or asparagine. It may contain a solubilizing agent such as an acid. If necessary, the tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or may be coated with two or more layers. Also included are capsules of absorbable material such as gelatin.

Liquid compositions for oral administration include pharmaceutically acceptable solutions, emulsions, syrups, elixirs and the like, and generally used inert diluents (purified water, ethanol). ) May be included. This composition may contain, in addition to an inert diluent, auxiliary agents such as a wetting agent and a suspending agent, a sweetening agent, a flavoring agent, an aromatic agent and a preservative.
Other compositions for oral administration include spray formulations which contain one or more active substances and are formulated in a manner known per se. The composition may contain, in addition to an inert diluent, a stabilizer such as sodium bisulfite and a buffer such as sodium chloride, sodium citrate or citric acid to provide isotonicity. A method for producing a spray agent is described in, for example, US Pat. No. 2868.
Details are given in 691 and 3095355.

Injections for parenteral administration according to the present invention include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of the aqueous solution and suspension include distilled water for injection and physiological saline. Examples of the non-water soluble solution and suspension include propylene glycol, polyethylene glycol, olive oil, ethanol, polysorbate 80 and the like. Such compositions may further contain adjuvants such as preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg lactose), solubilizers (eg glutamic acid, aspartic acid). These are sterilized by, for example, filtration through a bacteria-retaining filter, blending of a bactericide, or irradiation. They can also be used by producing a sterile solid composition, for example, by dissolving them in sterilized water or a sterile solvent for injection before using the lyophilized product. Other compositions for parenteral administration include one or more active substances, a liquid preparation for external use, a soft ko, an ointment, which is prescribed by a conventional method.
Suppositories and pessaries are included.

[0065]

Reference Examples and Examples Hereinafter, the present invention will be described in detail with reference to Reference Examples and Examples, but the present invention is not limited thereto. The solvent in the parentheses shown in the chromatographic separation indicates the elution solvent or the developing solvent used, and the ratio represents the volume ratio. IR is measured by the KBr tablet method unless otherwise specified.

Reference Example 1

[Chemical 21]

Sodium hydroxide (47 g) in water (200
bromine (1.98 ml) was added to the solution at -10 to 0 ° C. After stirring at the same temperature for 30 minutes, 50% dimethylamine aqueous solution (40.8 ml) was added to the mixture at -10 to 0 ° C. The reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was extracted with methylene chloride (200 ml). The extract was dried over anhydrous magnesium sulfate. A solution of 2-isopropylphenol (50 g) in methylene chloride (90 ml) was added to the extract thus obtained at -10 to 0 ° C.
The reaction mixture was stirred at the same temperature for 2 hours. 2 in the reaction mixture
After adding an aqueous solution of N-sulfuric acid (100 ml), an aqueous solution of saturated sodium hydrogen carbonate was added until the pH reached 7. The organic layer of the mixture was separated, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: methylene chloride = 4: 1) to give the title compound (48 g) having the following physical data. TLC: Rf 0.56 (hexane: ethyl acetate = 4:
1).

Reference Example 2

[Chemical formula 22]

Tetrakis (triphenylphosphine) palladium (0) (1.03 g) was added to a solution of the compound (30 g) produced in Reference Example 1 in tetrahydrofuran (80 ml), and the mixture was stirred at room temperature for 15 minutes. 1.0 M p- in the mixture
A tetrahydrofuran solution of fluorophenyl magnesium bromide (280 ml) was added dropwise. 8 reaction mixtures
Stirred at 0 ° C. for 9 hours. The reaction mixture was poured into a 2N aqueous hydrochloric acid solution at 0 ° C and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane) to give the title compound (12 g) having the following physical data. TLC: Rf 0.22 (hexane: methylene chloride = 4:
1).

Reference Example 3

[Chemical formula 23]

Bromine (1.08 ml) was added to a carbon tetrachloride (15 ml) solution of the compound (4.0 g) produced in Reference Example 2 at 0 ° C. The reaction mixture was stirred at 0 ° C. for 30 minutes. A saturated aqueous sodium thiosulfate solution was added to the reaction mixture at 0 ° C., and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1) to give the title compound (5.38 g) having the following physical data. TLC: Rf 0.40 (hexane: ethyl acetate = 10:
1).

Reference Example 4

[Chemical formula 24]

Compound prepared in Reference Example 3 (800 mg)
To a tetrahydrofuran (10 ml) solution of was added sodium hydride (112 mg, containing 60%) at 0 ° C. After stirring at room temperature for 10 minutes, methoxymethyl chloride (0.22 ml) was added at 0 ° C. The reaction mixture was stirred at room temperature for 1 hour. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1) to give the title compound (840 mg) having the following physical data. TLC: Rf 0.32 (hexane: ethyl acetate = 30:
1).

Reference Example 5

[Chemical 25]

To a mixed solution of 4-bromo-2,6-dimethylphenol (6.4 g) in tetrahydrofuran (40 ml) and dimethylformamide (20 ml) was added sodium hydride (1.3 g, 60% content) at 0 ° C. . After stirring for 10 minutes at room temperature, benzyl bromide (3.44 ml) at 0 ° C
Was added. The reaction mixture was stirred at room temperature for 3 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract,
It was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane) to give the title compound (9.3 g) having the following physical data. TLC: Rf 0.50 (hexane: ethyl acetate = 30:
1).

Reference Example 6

[Chemical formula 26]

1-2 drops of 1,2-dibromoethane was added to a suspension of magnesium (139 mg) in tetrahydrofuran (1 ml). A tetrahydrofuran solution (3 ml) of the compound (1.39 g) produced in Reference Example 5 was slowly added dropwise to the mixture. The mixture was stirred at 80 ° C. for 3 hours. This mixture was added dropwise to a solution of the compound (840 mg) produced in Reference Example 4 in tetrahydrofuran (3 ml) with tetrakis (triphenylphosphine) palladium (0) (28 mg), and the mixture was added dropwise to the solution with stirring for 15 minutes. The reaction mixture was stirred at 80 ° C. overnight. The reaction mixture is cooled to room temperature,
It was poured into ice-1N hydrochloric acid aqueous solution and extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1) to give the title compound (876 mg) having the following physical data. TLC: Rf 0.33 (hexane: ethyl acetate = 20:
1).

Reference Examples 6 (a) to (j) By using the corresponding compound instead of the compound produced in Reference Example 5, the same operation as in Reference Example 6 was carried out to obtain the following compounds.

Reference Example 6 (a)

[Chemical 27] TLC: Rf 0.18 (hexane: ethyl acetate = 30:
1).

Reference Example 6 (b)

[Chemical 28] TLC: Rf 0.15 (hexane: ethyl acetate = 30:
1).

Reference Example 6 (c)

[Chemical 29] TLC: Rf 0.38 (hexane: ethyl acetate = 10:
1).

Reference Example 6 (d)

[Chemical 30] TLC: Rf 0.34 (hexane: ethyl acetate = 10:
1).

Reference Example 6 (e)

[Chemical 31] TLC: Rf 0.24 (hexane: ethyl acetate = 30:
1).

Reference Example 6 (f)

[Chemical 32] TLC: Rf 0.28 (hexane: ethyl acetate = 30:
1).

Reference Example 6 (g)

[Chemical 33] TLC: Rf 0.33 (hexane: ethyl acetate = 30:
1).

Reference Example 6 (h)

[Chemical 34] TLC: Rf 0.40 (hexane: ethyl acetate = 30:
1).

Reference Example 6 (i)

[Chemical 35] TLC: Rf 0.30 (hexane: ethyl acetate = 30:
1).

Reference Example 6 (j)

[Chemical 36] TLC: Rf 0.20 (hexane: ethyl acetate = 30:
1).

Reference Example 7

[Chemical 37] 2,6-diisopropylphenol was used in place of the compound prepared in Reference Example 2 and the same operation as in Reference Example 3 → Reference Example 4 was carried out to obtain the title compound having the following physical properties. TLC: Rf 0.70 (hexane: ethyl acetate = 30:
1).

Reference Example 8

[Chemical 38] The title compound having the following physical data was obtained by the same procedure as in Reference Example 6 except that the compound prepared in Reference Example 7 was used instead of the compound prepared in Reference Example 4. TLC: Rf 0.34 (hexane: ethyl acetate = 30:
1).

Reference Examples 8 (a) and 8 (b) The following compounds were obtained in the same manner as in Reference Example 8 except that the corresponding compound was used instead of the compound prepared in Reference Example 5.

Reference Example 8 (a)

[Chemical Formula 39] TLC: Rf 0.36 (hexane: ethyl acetate = 30:
1).

Reference Example 8 (b)

[Chemical 40] TLC: Rf 0.19 (hexane: ethyl acetate = 30:
1).

Reference Example 9

[Chemical 41]

Compound prepared in Reference Example 6 (860 mg)
Methanol (20 ml) and tetrahydrofuran (5 m
l) mixed solution of 10% palladium-carbon (860 m
g) was added. 1 at room temperature under hydrogen gas atmosphere
Stir for hours. The reaction mixture was filtered through Celite (trade name), and the filtrate was concentrated to give the title compound (700 mg) having the following physical data. TLC: Rf 0.22 (hexane: ethyl acetate = 10:
1).

Reference Example 10

[Chemical 42]

Compound produced in Reference Example 9 (700 mg)
In pyridine (10 ml) at room temperature and acetic anhydride (2 m
l) was added. The reaction mixture was poured into a 1N aqueous hydrochloric acid solution and extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated to give the title compound (736 having the following physical properties).
mg) was obtained. TLC: Rf 0.29 (hexane: ethyl acetate = 10:
1).

Reference Example 11

[Chemical 43]

The compound prepared in Reference Example 10 (726 m
To 4g) was added a 4N hydrochloric acid dioxane solution (10 ml).
The reaction mixture was stirred at room temperature for 30 minutes. 2 in the reaction mixture
Aqueous N sodium hydroxide solution was added until the pH reached 5, and the mixture was extracted with ethyl acetate. The extract was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution,
It was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to give the title compound (651 mg) having the following physical data. TLC: Rf 0.26 (hexane: ethyl acetate = 10:
1).

Reference Example 12

[Chemical 44]

The compound prepared in Reference Example 11 (651 m
g) in dimethylsulfoxide (10 ml) under argon atmosphere, potassium carbonate (550 mg), 18-crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane) (2 mg) and tert-. Butyl (3R, 5S) -6-methylsulfonyloxy-3,
5-O-isopropylidene-3,5-dihydroxyhexanoate (673 mg) was added sequentially. The reaction mixture was stirred at 80 ° C. for 16 hours. The reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 15: 1) to give the title compound (716m) having the following physical data.
g) was obtained. TLC: Rf 0.46 (hexane: ethyl acetate = 4:
1).

Reference Example 13

[Chemical formula 45]

The compound prepared in Reference Example 12 (716 m
g) in a mixed solution of ethanol (10 ml) and tetrahydrofuran (10 ml) at 0 ° C. in a 2N hydrochloric acid aqueous solution (1 m
l) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed successively with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate,
Concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give the title compound (547 mg) having the following physical data. TLC: Rf 0.31 (hexane: ethyl acetate = 2:
1).

Example 1

[Chemical formula 46]

The compound prepared in Reference Example 13 (270 m
Camphorsulfonic acid (1 mg) was added to a solution of g) in toluene (10 ml). The reaction mixture was stirred at 120 ° C. for 18 hours. The reaction mixture was cooled to room temperature and concentrated.
The residue is subjected to silica gel column chromatography (hexane:
Purification by ethyl acetate = 2: 1 → 1: 1) gave the title compound (90 mg) having the following physical data. TLC: Rf 0.28 (hexane: ethyl acetate = 1: 1
1); IR: 3433, 2965, 1753, 1708, 1606, 1511, 1461, 13
71, 1349, 1263, 1229, 1198, 1159, 1082, 998, 977
, 915, 864, 838 cm ^-1 .

Examples 1 (a) -1 (m) Instead of the compound prepared in Reference Example 6, Reference Examples 6 (a)-
6 (j), Reference Example 8, Reference Example 8 (a) and Reference Example 8
Reference Example 9 → Reference Example 10 using the compound produced in (b)
-> Reference example 11-> Reference example 12-> Reference example 13-> The same operation as Example 1 was carried out to obtain the compound of the present invention shown below.

Example 1 (a)

[Chemical 47] TLC: Rf 0.35 (hexane: ethyl acetate = 1: 1
1); IR: 3450, 2965, 2932, 2872, 1762, 1742, 1605, 15
11, 1443, 1386, 1367, 1331, 1224, 1196, 1135, 107
8,1055,997,915,875,840 cm ^-1 .

Example 1 (b)

[Chemical 48] TLC: Rf 0.25 (hexane: ethyl acetate = 1: 1
1); IR: 3446, 2964, 2930, 1741, 1606, 1510, 1465, 13
71, 1326, 1225, 1197, 1167, 1079, 1057, 1016, 997
, 915, 840 cm ^-1 .

Example 1 (c)

[Chemical 49] TLC: Rf 0.28 (hexane: ethyl acetate = 1: 1
1); IR: 3447, 2964, 1741, 1605, 1511, 1465, 1371, 13
27, 1223, 1197, 1162, 1121, 1079, 1057, 997, 915
, 839, 670, 553 cm ^-1 .

Example 1 (d)

[Chemical 50] TLC: Rf 0.28 (hexane: ethyl acetate = 1: 1
1); IR: 3436, 2969, 1761, 1714, 1606, 1511, 1463, 13
72, 1222, 1198, 1163, 1124, 1082, 998, 915, 880
, 841, 555 cm ^-1 .

Example 1 (e)

[Chemical 51] TLC: Rf 0.29 (hexane: ethyl acetate = 1: 1
1); IR: 3529, 2968, 1742, 1605, 1510, 1467, 1370, 13
40, 1220, 1196, 1160, 1078, 1053, 1027, 949, 914
, 888, 832, 589, 514 cm ^-1 .

Example 1 (f)

[Chemical 52] TLC: Rf 0.27 (hexane: ethyl acetate = 1: 1
1); IR: 3531, 2964, 1742, 1605, 1510, 1466, 1371, 13
44, 1252, 1194, 1171, 1160, 1083, 1052, 1024, 949
, 912, 888, 833, 588, 513 cm ^-1 .

Example 1 (g)

[Chemical 53] TLC: Rf 0.27 (hexane: ethyl acetate = 1: 1
1); IR: 3524, 2965, 2870, 1737, 1605, 1510, 1466, 14
51, 1373, 1328, 1236, 1214, 1202, 1132, 1077, 105
6,999, 881, 846, 705, 577, 514 cm ^-1 .

Example 1 (h)

[Chemical 54] TLC: Rf 0.27 (hexane: ethyl acetate = 1: 1
1); IR: 3370, 2963, 1756, 1718, 1605, 1562, 1511, 14
95, 1450, 1389, 1328, 1234, 1203, 1160, 1078, 105
9,996,866,839,800,554 cm ^-1 .

Example 1 (i)

[Chemical 55] TLC: Rf 0.27 (hexane: ethyl acetate = 2:
3); IR: 3431, 2965, 1754, 1718, 1605, 1531, 1510, 14
51, 1389, 1221, 1176, 1078, 1058, 1015, 839 c
m ^-1 .

Example 1 (j)

[Chemical 56] TLC: Rf 0.29 (hexane: ethyl acetate = 2:
3); IR: 3402, 2965, 1756, 1713, 1621, 1511, 1466, 14
43, 1409, 1387, 1351, 1316, 1295, 1261, 1229, 120
2, 1161, 1133, 1078, 1054, 997, 883, 837, 679,
599, 554, 518 cm ^-1 .

Example 1 (k)

[Chemical 57] TLC: Rf 0.25 (hexane: ethyl acetate = 1: 1
1); IR: 3406, 2968, 2873, 1755, 1719, 1469, 1446, 13
87, 1306, 1248, 1215, 1184, 1162, 1080, 1055, 999
, 913, 866, 703 cm ^-1 .

Example 1 (l)

[Chemical 58] TLC: Rf 0.27 (hexane: ethyl acetate = 1: 1
1); IR: 3557, 2966, 2871, 1742, 1598, 1548, 1467, 14
44, 1384, 1366, 1329, 1235, 1180, 1166, 1083, 105
8,1025,949,917,875,819 cm ^-1 .

Example 1 (m)

[Chemical 59] TLC: Rf 0.22 (hexane: ethyl acetate = 1: 1
1); IR: 3399, 2970, 2874, 1756, 1717, 1511, 1447, 13
87, 1300, 1252, 1227, 1201, 1184, 1168, 1089, 105
7,1016,997,917,888,850 cm ^-1 .

Example 2

[Chemical 60]

The compound prepared in Example 1 (270 mg)
1N aqueous sodium hydroxide solution (1 ml) was added to the ethanol (4 ml) solution of the above at 0 ° C. Reaction mixture at room temperature 1
Stir for hours. The reaction mixture was poured into a 1N aqueous hydrochloric acid solution at 0 ° C., and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in toluene (15 ml) and stirred at 120 ° C for 6 hours. The reaction mixture was cooled to room temperature and concentrated. The residue is subjected to silica gel column chromatography (hexane: acetic acid: ethyl = 2: 1 → 1: 1).
And the title compound (10
5 mg) was obtained. TLC: Rf 0.28 (hexane: ethyl acetate = 1: 1
1); IR: 3436, 2984, 1719, 1605, 1510, 1461, 1387, 12
56,1204,1078,996,870,839 cm ^-1 .

Examples 2 (a) -2 (m) Instead of the compound prepared in Example 1, Example 1 was used, respectively.
Using the compounds produced in (a) to 1 (m), the same operation as in Example 2 was carried out to obtain the compounds of the present invention shown below.

Example 2 (a)

[Chemical formula 61] TLC: Rf 0.35 (hexane: ethyl acetate = 1: 1
1); IR: 3450, 2964, 1719, 1511, 1442, 1386, 1202, 11
58, 1078, 1054, 997, 874, 839 cm ^-1 .

Example 2 (b)

[Chemical formula 62] TLC: Rf 0.20 (hexane: ethyl acetate = 1: 1
1); IR: 3420, 2964, 1713, 1611, 1510, 1449, 1388, 12
64, 1230, 1202, 1078, 997, 835 cm ^-1 .

Example 2 (c)

[Chemical formula 63] TLC: Rf 0.26 (hexane: ethyl acetate = 1: 1
1); IR: 3351, 3516, 2966, 2361, 1718, 1606, 1510, 14
63, 1380, 1335, 1256, 1219, 1196, 1160, 1118, 107
9,1056,1020,994,884,844,815,557,520 c
m ^-1 .

Example 2 (d)

[Chemical 64] TLC: Rf 0.27 (hexane: ethyl acetate = 1: 1
1); IR: 3415, 2965, 2932, 2872, 2361, 1714, 1607, 15
10, 1465, 1440, 1387, 1255, 1201, 1160, 1127, 107
8,1058,996,881,839,554,517 cm ^-1 .

Example 2 (e)

[Chemical 65] TLC: Rf 0.27 (hexane: ethyl acetate = 1: 1
1); IR: 3406, 2963, 2871, 2362, 1714, 1606, 1510, 14
66, 1438, 1387, 1332, 1240, 1201, 1159, 1078, 105
7,996,882,838,556,517 cm ^-1 .

Example 2 (f)

[Chemical formula 66] TLC: Rf 0.27 (hexane: ethyl acetate = 1: 1
1); IR: 3413, 2963, 2873, 1714, 1607, 1511, 1464, 14
39, 1387, 1338, 1236, 1201, 1159, 1079, 997, 882
, 839, 516 cm ^-1 .

Example 2 (g)

[Chemical formula 67] TLC: Rf 0.27 (hexane: ethyl acetate = 1: 1
1); IR: 3424, 2960, 1698, 1606, 1510, 1467, 1388, 13
43, 1260, 1203, 1160, 1078, 1056, 997, 882, 840
, 552 cm ^-1 .

Example 2 (h)

[Chemical 68] TLC: Rf 0.27 (hexane: ethyl acetate = 1: 1
1); IR: 3370, 2963, 1718, 1605, 1562, 1511, 1495, 14
50, 1389, 1328, 1234, 1203, 1160, 1078, 1059, 996
, 866, 839, 800, 554 cm ^-1 .

Example 2 (i)

[Chemical 69] TLC: Rf 0.27 (hexane: ethyl acetate = 2:
3); IR: 3431, 2965, 1718, 1605, 1531, 1510, 1451, 13
89, 1221, 1176, 1078, 1058, 1015, 839 cm ^-1 .

Example 2 (j)

[Chemical 70] TLC: Rf 0.29 (hexane: ethyl acetate = 2:
3); IR: 3402, 2965, 1713, 1621, 1511, 1466, 1443, 14
09, 1387, 1351, 1316, 1295, 1261, 1229, 1202, 116
1, 1133, 1078, 1054, 997, 883, 837, 679, 599,
554 and 518 cm ^-1 .

Example 2 (k)

[Chemical 71] TLC: Rf 0.25 (hexane: ethyl acetate = 1: 1
1); IR: 3426, 2964, 2870, 1718, 1604, 1495, 1470, 13
87, 1304, 1324, 1255, 1197, 1080, 1027, 997, 947
, 868 cm ^-1 .

Example 2 (l)

[Chemical 72] TLC: Rf 0.28 (hexane: ethyl acetate = 1: 1
1); IR: 3436, 2964, 2871, 1719, 1460, 1442, 1385, 13
64, 1313, 1256, 1196, 1081, 1055, 998, 872c
m ^-1 .

Example 2 (m)

[Chemical formula 73] TLC: Rf 0.18 (hexane: ethyl acetate = 1: 1
1); IR: 3284, 2963, 1713, 1613, 1519, 1451, 1388, 13
63, 1341, 1299, 1270, 1256, 1228, 1183, 1075, 106
1,1048,1028,999,885,834 cm ^-1 .

Example 3

[Chemical 74]

The compound prepared in Example 2 (555 mg)
1N aqueous sodium hydroxide solution (1.16 ml) was added to the dioxane (5 ml) solution of. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was directly lyophilized to give the title compound (580 mg) having the following physical data. TLC: Rf 0.21 (methylene chloride: methanol = 1
0: 1); IR: 3431, 1568, 1510, 1452, 1404, 1327, 1219, 12
02, 1158, 1101, 1071, 1016, 873, 840, 557c
m ^-1 .

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07C 51/367 C07D 309/30 C07F 7/08 A

Claims (1)

[Claims] 1. A compound represented by the general formula (I): (In the formula, R ¹ represents a C 1-6 alkyl group or a C 3-7 cycloalkyl group, R ² and R ⁴ are the same or different, and are a hydrogen atom, a C 1-8 alkyl group, C 1-4
Alkoxy group, halogen atom, trifluoromethyl group, C3-7 cycloalkyl group or tri (C1-4
An alkyl) silyl group, R ³ is a hydrogen atom or C
2 to 5 represents an acyl group, R ⁵ represents a C 1 to ⁶ alkyl group, a C 3 to 7 cycloalkyl group or a p-fluorophenyl group, and L represents Or [Chemical 3] Represents ) And the non-toxic salts thereof.