KR100263023B1 - Novel quinolone derivatives with blood lipid lowering action and preparation method thereof - Google Patents

Abstract

PURPOSE: Provided are the quinolone derivatives of chemical formula (I) and (II) which show the activity of lowering blood lipids concentration by inhibiting the functions of HMG-CoA reductase. CONSTITUTION: In the chemical formula (I) and (II), X is CY and N (where Y is hydrogen, halogen, C1-2 alkyl); R1 is C1-4 alkyl, C3-4 cycloalkyl or phenyl group substituted with one or more fluorine atom. Quinolone-3-ethenyl-3'β5'β-dihydroxypentanoic acid (chemical formula I) is prepared by the steps consisting of: converting the acid (III) to aldehyde; converting this aldehyde to enoic acid by the Wittig reaction; changing this acid into the corresponding aldehyde; condensing the aldehyde with ethyl acetoacetate to have the product of chemical formula I, with racemic 5' hydroxy group and reducing the product into the chemical formula II. The compounds and their pharmaceutically acceptable salts lower the blood lipids by inhibition of the HMG-CoA reductase.

Description

Novel quinolone derivatives having blood lipid lowering action and preparation method thereof

The present invention relates to novel quinoline derivatives or pharmaceutically acceptable salts thereof and methods for their preparation, which are useful for lowering blood lipid concentrations.

Hyperlipidemia, which is expressed by increased lipid concentrations in the blood, is a cause of geriatric diseases centered on vascular disorders, such as triglycerides such as arteriosclerosis, cholesterol, and phospholipids. Inhibition of the action of reductase has been reported to prevent and treat the disease.

Inhibitors of HMG-Co A reductase currently on the market include Pravastatin (see Drugs of the Future, 1987, 12 (5), 437), Simvastatin (Drugs of the Future, 1988, 13 (6), 531), Lovastatin (see Drugs of the Future, 1984, 9 (3), 197), Dalvastatin (Drugs of the Future, 1992) , 17 (5), 377), fluvastatin (see Drugs of the Future, 1991, 16 (9), 804) and mevastatin (Endo, AJ Antibiotic. , 1976, 29, 1346), but they are not well absorbed orally, have long-term side effects such as drowsiness, poor tissue selectivity, and chronic toxicity. .

Accordingly, the present inventors have continued the research, finding a quinolone derivative excellent in the inhibitory action of HMG-Co A reductase while solving the above problems and completed the present invention.

An object of the present invention is a novel 3-position ethyl or ethenyl-3 ', which is useful for reducing oral blood lipid concentration due to good oral absorption, low chronic toxicity and excellent selectivity, and excellent inhibitory effect of HMG-Co A reductase. It is to provide a quinolone derivative having a β, 5'β-dihydroxypentanoic acid residue and a preparation method thereof.

In order to achieve the above object, the present invention provides a quinolone-3-ethenyl-3'β, 5'β-dihydroxypentanoic acid derivative of the general formula (I) or a pharmaceutically acceptable salt thereof, and their And a quinolone-3-ethyl-3'β, 5'β-dihydroxypentanoic acid derivative of formula (II), or a pharmaceutically acceptable salt thereof, and a process for preparing the same:

Formula 1

Formula 2

Where

X is CY or N, wherein Y is hydrogen, halogen, C _1-4 alkoxy or C _1-4 alkyl;

R ₁ is C _1-4 alkyl, C _3-4 cycloalkyl or phenyl substituted with one or more fluorine.

Hereinafter, the present invention will be described in more detail.

According to the invention, X in said general formula (I) or (II) is preferably CH, CF, CCl, COCH ₃ or N, and R ₁ is preferably ethyl, cyclopropyl, 2,4-difluoro Rophenyl or 4-fluorophenyl.

Quinolone-3-ethenyl-3'β, 5'β-dihydroxypentanoic acid derivatives of the general formula (I) of the present invention may be prepared by the same process as in Scheme 1 below:

Wherein X and R ₁ are as defined above.

The reaction is described in detail for each step as follows:

a) Compound (III) is reacted with 2.1 equivalents of p-toluenesulfonic acid (p-TsOH) and 1.2 equivalents of sodium borohydride at 40 to 70 DEG C in a methanol solvent for about 5 hours to To a compound of

b) reacting the compound of formula (IV) prepared in step a) with 5.0 equivalents of potassium t-butoxide and 5.0 equivalents of ethylformate at room temperature for about 12 hours in a dichloromethane solvent to formula (V) To prepare a compound of

c) preparing a compound of formula (VI) by reacting the compound of formula (V) prepared in step b) with 20 equivalents of manganese dioxide (MnO ₂ ) in a methanol solvent for about 12 hours at room temperature,

d) The compound of formula (VI) prepared in step c) is added at 1.1 to 1.5 equivalents of triphenylphosphonylidenemethylester in toluene or dichloromethane solvent at 50 to 70 ^° C., preferably in toluene solvent. 12 wt of triphenylphosphonylidene methyl ester at 60 ^° C. for 12 hours to prepare a compound of formula (VII) by Wittig reaction,

e) reacting the compound of formula (VII) prepared in step d) with 1.1 to 1.4 equivalents of diisobutylaluminum hydride for about 5 to 8 hours at about -78 ^o C in anhydrous toluene solvent and then dichloromethane solvent 15 to 20 equivalents of manganese dioxide for 10 to 12 hours, preferably 1.2 equivalents of diisobutylaluminium hydroxide for 5 hours at -78 ^o C and then 20 equivalents of manganese dioxide in a dichloromethane solvent And refluxed for 12 hours to prepare a compound of formula (VIII),

f) 1.1 equivalents of ethylacetoacetate, sodium hydride (60% dispersion oil) and n-butyllithium (1.6M in hexane) were dissolved in anhydrous tetrahydrofuran solvent in the compound of formula (VIII) prepared in step e). And reacted at -78 to 0 ^o C for about 1 hour to prepare a compound of formula (IX) having a hydroxyl group at the 5 'position,

g) A compound of formula (IX) prepared in step f) is reacted with 1.0 equivalent of triethylborane (1.0M in tetrahydrofuran) and sodium borohydride at -78 ° C to form a hydroxyl group of 3 'and 5'. After preparing a mixture in the form of a valence erythro or threo, the product was hydrolyzed with 2N-NaOH aqueous solution and acidified (pH about 5-6) with 2N-hydrochloric acid aqueous solution at 0 ^o C to obtain a product. Column chromatography (developing solvent: chloroform / methanol = 3/1) to prepare quinolone-3-ethenyl-3'β, 5'β-dihydroxypentanoic acid derivatives of general formula (I) as pure optical isomers can do.

Specific examples of the quinolone-3-ethenyl-3'β, 5'β-dihydroxypentanoic acid derivative of the general formula (I),

[3'β, 5'β ( E )]-7 '-[[1- (cyclopropyl) -6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoli Nil] ethenyl] -3 ', 5'-dihydroxy-pentanoic acid,

[3'β, 5'β ( E )]-7 '-[[1- (cyclopropyl) -6,7-difluoro-1,4-dihydro-4-oxoquinolinyl] ethenyl] -3 ', 5'-dihydroxypentanoic acid,

To [3'β, 5'β ( E )]-7 '-[[1- (cyclopropyl) -6,7,8-trifluoro-1,4-dihydro-4-oxoquinolinyl] Tenyl] -3 ', 5'-dihydroxypentanoic acid,

[3'β, 5'β ( E )]-7 '-[[1- (cyclopropyl) -6,7-difluoro-8-chloro-1,4-dihydro-4-oxoquinolinyl ] Ethenyl] -3 ', 5'-dihydroxypentanoic acid,

[3'β, 5'β ( E )]-7 '-[[1- (2,4-difluorophenyl) -6,7-difluoro-1,4-dihydro-4-oxoqui Nolinyl] ethenyl] -3 ', 5'-dihydroxypentanoic acid,

[3'β, 5'β ( E )]-7 '-[[1- (2,4-difluorophenyl) -6,7-difluoro-1,4-dihydro-4-oxonaphthy Ridinyl] ethenyl] -3 ', 5'-dihydroxypentanoic acid, and

[3'β, 5'β ( E )]-7 '-[[1- (ethyl) -6,7-difluoro-1,4-dihydro-4-oxoquinolinyl] ethenyl]- 3 ', 5'-dihydroxypentanoic acid

Etc. can be mentioned.

In addition, the quinolone-3-ethyl-3'β, 5'β-dihydroxypentanoic acid derivative of the general formula (II) of the present invention may be prepared by the same process as in Scheme 2 below:

Wherein X and R ₁ are as defined above.

The reaction is described in detail for each step as follows:

a) a compound of formula (IV) is prepared from a compound of formula (III) by the same reaction as in Scheme 1;

b ') The compound of formula (IV) prepared in step a) is prepared in 4.0-6.0 equivalents of 1,1-methoxy-3-bromopropane and 5.0-7.0 equivalents of sodium in dichloromethane or tetrahydrofuran solvent. Ethoxide with room temperature (25-30 ^° C.) for 10-13 hours, preferably 12 equivalents at 25 ^° C. with 5.0 equivalents of 1,1-methoxy-3-bromopropane and sodium ethoxide in dichloromethane solvent. For a period of time, reacting to produce the compound of formula (X),

c ') The compound of formula (X) prepared in step b') is added with a catalytic amount of p-TsOH in a mixed solution of water and acetone (1: 5) and heated to reflux for about 48 hours to give general formula (XI) To prepare a compound of

d ') The compound of formula (XI) prepared in step c') was dissolved in tetrahydrofuran solvent with 1.1 equivalents of ethylacetoacetate, sodium hydride (60% dispersion oil) and n-butyllithium (1.6M in hexane). ) And -30 to 0 ℃ for about 30 minutes to prepare a compound of formula (XII) wherein the hydroxyl group of the 5 'position is racemic,

e ') The compound of formula (XII) prepared in step d') is prepared at about -78 ^° C. with 1.0 equivalent of triethylborane (1.0M in tetrahydrofuran) and sodium borohydride in a tetrahydrofuran solvent. Reacting for about 5 hours to prepare a compound of formula (XIII),

f ') When the compound of Formula (XIII) prepared in step e') is added with catalytic amount of p-TsOH and reacted with acetone at room temperature (about 25 ^o C) for about 12 hours, the hydroxyl groups of 3 'and 5' A mixture in the form of threo and erythro is obtained, which is column chromatographed (developing solvent: Hex / EtOAc = 3/1) to form a 3'β, 5'β-dihydroketal form protected with acetonide in pure form. To prepare a compound of formula (XIV),

g ') The compound of formula (XIV) prepared in step f') was reacted at about -78 ^o C with 1.1 equivalents of DMSO, oxalyl chloride and 3.0 equivalents of triethylamine by Swern oxidation. Reaction to prepare a compound of formula (XV),

h ') The compound of formula (XV) prepared in step g') is hydrolyzed with aqueous 2N-NaOH solution and acidified in aqueous 2N-hydrochloric acid solution (pH about 4 to 5) to about room temperature (about 25 ^o C) After reacting for 12 hours, column chromatography (developing solvent: chloroform / methanol = 3/1) was used to provide the pure optical isomer of Quinolone-3-ethyl-3'β, 5'β-dihydroxypenta. Noric acid derivatives can be prepared.

Specific examples of the quinolone-3-ethyl-3'β, 5'β-dihydroxypentanoic acid derivative of the general formula (II),

[3'β, 5'β (E)]-7 '-[[1- (cyclopropyl) -6,7-difluoro-8-methoxy-1,2,3,4-tetrahydro-4 Oxoquinolinyl] ethyl] -3 ', 5'-dihydroxypentanoic acid,

[3'β, 5'β (E)]-7 '-[[1- (cyclopropyl) -6,7-difluoro-8-chloro-1,2,3,4-tetrahydro-4- Oxoquinolinyl] ethyl] -3 ', 5'-dihydroxypentanoic acid,

[3'β, 5'β (E)]-7 '-[[1- (2,4-difluorophenyl) -6,7-difluoro-1,2,3,4-tetrahydro- 4-oxoquinolinyl] ethyl] -3 ', 5'-dihydroxy-pentanoic acid,

[3'β, 5'β (E)]-7 '-[[1- (2,4-difluorophenyl) -6,7-difluoro-1,2,3,4-tetrahydro- 4-oxonaphthyridinyl] ethyl] -3 ', 5'-dihydroxypentanoic acid, and

[3'β, 5'β (E)]-7 '-[[1- (ethyl) -6,7-difluoro-1,2,3,4-tetrahydro-4-oxoquinolinyl] Ethyl] -3 ', 5'-dihydroxypentanoic acid

Etc. can be mentioned.

According to the present invention, salts of the quinoline derivatives of the present invention can be prepared according to conventional methods, preferably sodium or potassium salts.

Compounds of the general formula (I) or (II) of the present invention has excellent inhibitory activity of HMG-Co A reductase, good oral absorption, low chronic toxicity and excellent selectivity, which can be usefully used for lowering blood lipid concentration. have.

Therefore, in the present invention, a composition containing an effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof as an active ingredient can be formulated in oral or injection dosage form.

In addition, the formulations may be prepared by conventional mixing, granulating or coating methods and may contain the active ingredient in the range of 60 to 80%, preferably 70 to 80%, and include a mammal including a human. It can be administered twice a day in an amount of 0.5 to 1 g / kg (body weight), preferably 0.5 to 0.8 g / kg relative to.

Hereinafter, the present invention will be described in more detail based on the following examples. However, the following examples are not intended to limit the invention only.

Example 1 [3'β, 5'β ( E )]-7 '-[[1- (cyclopropyl) -6,7-difluoro-8-methoxy-1,4-dihydro-4 Preparation of oxoquinolinyl] ethenyl] -3 ', 5'-dihydroxy-pentanoic acid (compound of formula (I))

Step a) Preparation of 1- (cyclopropyl) -6,7-difluoro-8-methoxy-1,2,3,4-tetrahydro-4-oxoquinoline (compound of formula (IV))

5 g of 1- (cyclopropyl) -6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (compound of formula (III)) was added to MeOH 100 After dissolving in ml, a solution of 2.6 g of NaBH _{4 in} 50 ml of MeOH was slowly added. Then, 20 mg of p- TsOH was added thereto, stirred at 65 ^° C. for 5 hours, and the reaction solvent was concentrated under reduced pressure and CHCl ₃ was added to the remaining residue. The reaction solution was dried over anhydrous MgSO ₄ , concentrated under reduced pressure, and purified by silica gel column chromatography (developing solvent: EtOAc) to obtain 3.6 g of the desired yellow solid compound in a yield of 80%.

¹ H-NMR (δ, CDCl ₃ ): 0.70-0.85 (m, 4H), 2.55 (t, 2H), 3.00 (t, 2H), 3.90 (s, 3H), 7.41-7.51 (m, 1H), 8.45 (s, 1 H)

Mass (EI,m / e): 253 (M⁺), 238, 222, 197

Steps b and c) 1- (cyclopropyl) -6,7-difluoro-8-methoxy-1,4-dihydro-4-oxo-3-formylquinoline (compound of formula (VI)) Manufacture

2.6 g of the compound prepared in step a was dissolved in 100 ml of dichloromethane, and 5.6 g of t- BuOK and 5.8 ml of HCO ₂ Et were added thereto, followed by stirring at room temperature overnight. 100 ml of ice water was added to the reaction mixture, and the water layer was separated. The organic layer was washed with 5% aqueous NaOH solution, mixed with the water layer, and the water layer was washed with chloroform. The aqueous layer was acidified with 6N-HCl aqueous solution (pH 4), extracted with dichloromethane, and the organic layer was washed with brine. After drying over anhydrous MgSO ₄ and concentrated under reduced pressure, the product was dissolved in 100 ml of MeOH, 6.0 g of MnO ₂ was added, followed by stirring at room temperature overnight. The filtrate filtered under a Celite Pad was concentrated under reduced pressure and silica gel column chromatography (developing solvent: Hex / EtOAc = 2/1) afforded 2.5 g of the desired yellow solid compound in a yield of 65%.

¹ H-NMR (δ, CDCl ₃ ): 0.95-1.05 (m, 4H), 3.28 (m, 1H), 4.05 (s, 3H), 7.80-7.94 (m, 1H), 8.40 (s, 1H), 10.02 (s, 1 H)

Mass (EI,m / e): 279 (M⁺), 250, 236, 195, 179

Step d) Methyl ( E ) -3 ′-[[1- (cyclopropyl) -6,7-difluoro-8-methoxy-1,4-dihydro-4-oxo] quinolinyl] -2 Preparation of '-propenoate (compound of formula (VII))

2.9 g of the compound prepared in steps b and c were dissolved in 100 ml of toluene, 4.2 g of Ph ₃ P = CHCO ₂ Me was added, and the mixture was stirred at 40 ^° C. overnight. The reaction mixture was concentrated under reduced pressure and silica gel column chromatography (developing solvent: EtOAc) gave 3.0 g of the desired yellow liquid compound in 88% yield.

¹ H-NMR (δ, CDCl ₃ ): 0.97-1.03 (m, 4H), 3.72 (m, 1H), 3.75 (s, 3H), 4.05 (s, 3H), 5.85 (m, 1H), 7.45 ( m, 1H), 7.60 (m, 1H), 7.80-7.94 (m, 1H), 9.40 (s, 1H)

Mass (EI,m / e): 336 (M⁺), 307, 263, 248, 207, 191, 165

Step e) ( E ) -3 '-[[1- (cyclopropyl) -6,7-difluoro-8-methoxy-1,4-dihydro-4-oxo] quinolinyl] -2' Preparation of Propane (Compound of Formula (VIII))

0.8 g of the compound prepared in step d was dissolved in 10 ml of dichloromethane, cooled to −78 ^° C., and then 5.8 ml of DIBAL-H (1.0 M in toluene) was slowly added. After complete addition, the mixture was stirred for 2 hours and the reaction was stopped with 10 ml of saturated aqueous Na ₂ SO ₄ solution. The reaction temperature was raised to room temperature, filtered under a pad of celite, and the filtrate was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain 0.67 g of ( E ) -3 '-[[1- (cyclopropyl) -6,7-di Fluoro-8-methoxy-1,4-dihydro-4-oxo] quinolinyl] -2'-propene-1'-ol was produced. 0.6 g of this product and 6.0 g of MnO ₂ were added to 20 ml of dichloromethane and heated to reflux overnight. Filtration was carried out under a pad of celite and the filtrate was concentrated under reduced pressure to yield 0.3 g of the desired yellow liquid compound in 76% yield.

¹ H-NMR (δ, CDCl ₃ ): 0.95-1.05 (m, 4H), 3.80 (m, 1H), 4.05 (s, 3H), 6.03 (m, 1H), 7.12 (m, 1H), 7.42 ( m, 1H), 9.25 (s, 1H)

Mass (EI,m / e): 305 (M⁺), 276, 261, 245, 204, 178

Step f) Ethyl ( E ) -7 '-[[1- (cyclopropyl) -6,7-difluoro-8-methoxy-1,4-dihydro-4-oxo] quinolinyl] -5 Preparation of '-hydroxy-3'-oxo-6'-heptanoate (compound of formula (IX))

0.074 g of NaH (60% dispersed oil) was suspended in 10 ml of dry THF, and a solution of 0.23 g of ethyl acetoacetate in 10 ml of dry THF was slowly added thereto. After gas evolution ceased, 0.72 ml of n- BuLi (2.4 M in hexane) was added over 30 minutes at 0 ^° C. under nitrogen. The reaction mixture was cooled to −78 ^° C., and a solution of 0.34 g (1.1 mmol) of the compound prepared in step e in anhydrous THF was added and stirred for 1 hour. The reaction was stopped with 2 ml of glacial acetic acid and extracted with Et ₂ O. The organic layer was washed with saturated aqueous NaHCO ₃ solution, dried over anhydrous MgSO ₄ , concentrated under reduced pressure, and purified by silica gel column chromatography (developing solvent: EtOAc) to obtain 0.38 g of the desired yellow liquid compound in a yield of 56%.

¹ H-NMR (δ, CDCl ₃ ): 1.05-1.08 (m, 4H), 1.20 (t, 3H), 2.20 (s, 2H), 2.70 (dd, 2H), 3.80 (m, 1H), 4.05 ( s, 3H), 4.12 (q, 2H), 6.05 (m, 2H), 6.25 (m, 1H), 7.18 (m, 1H), 7.42 (m, 1H), 9.25 (s, 1H)

Mass (EI,m / e): 435 (M⁺), 406, 362, 345, 310, 263

Step g) [3'β, 5'β ( E )]-7 '-[[1- (cyclopropyl) -6,7-difluoro-8-methoxy-1,4-dihydro-4- Preparation of oxoquinolinyl] ethenyl] -3 ', 5'-dihydroxy-pentanoic acid (compound of formula (I))

To 13 ml of dry THF was added 2.5 ml of triethylborane (1.0 M in tetrahydrofuran) and 4.6 ml of MeOH under nitrogen. The mixture was stirred at 20 ^o C for 1 h and then cooled to -78 ^o C. A solution of 0.85 g of the compound prepared in step f was dissolved in 18 ml of dry THF, and then slowly stirred at the same temperature for 1.3 hours. To this was added 0.09 g of NaBH ₄ and stirred for 5 hours, after which the reaction was stopped with a saturated NH ₄ Cl aqueous solution and stirred at 20 ^° C. overnight. 50 ml of water was added thereto, extracted with EtOAc, dried over anhydrous Ns ₂ SO ₄ , concentrated under reduced pressure, and silica gel column chromatography (developing solvent: EtOAc). The obtained product was hydrolyzed with 20 ml of 2N-NaOH aqueous solution without purification, acidified with 2N-HCl aqueous solution under cooling (pH 6) and extracted with Et ₂ O. It was dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and solidified again under Et ₂ O to obtain 0.36 g of the desired white solid compound in a yield of 83%.

¹ H-NMR (δ, CDCl ₃ ): 1.02-1.06 (m, 4H), 1.78-1.89 (m, 2H), 2.31-2.67 (m, 2H), 3.48 (m, 1H), 4.00 (bs, 1H ), 4.05 (s, 3H), 5.00-5.10 (m, 1H), 5.24 (bs, 1H), 5.48 (dd, 2H), 6.69 (d, 1H), 7.38 (m, 1H), 9.25 (s, 1H), 10.3 (bs, 1H)

Mass (EI,m / e): 435 (M⁺), 410, 365, 291, 276, 235

Example 2 [3'β, 5'β ( E )]-7 '-[[1- (cyclopropyl) -6,7-difluoro-1,4-dihydro-4-oxoquinolinyl ] Ethenyl]-Preparation of 3 ', 5'-dihydroxypentanoic acid (compound of formula (I))

1- (cyclopropyl) -6,7-difluoro-1,4-tetrahydro-4-oxoquinoline (compound of formula (IV)) was treated in the same manner as in Example 1 to obtain the desired compound. Prepared.

¹ H-NMR (δ, CDCl ₃ ): 1.02-1.06 (m, 4H), 1.78-1.89 (m, 2H), 2.31-2.67 (m, 2H), 3.48 (m, 1H), 4.00 (bs, 1H ), 5.00-5.10 (m, 1H), 5.24 (bs, 1H), 5.48 (dd, 1H), 6.69 (d, 1H), 7.38 -7.41 (m, 2H), 9.25 (s, 1H), 10.3 ( bs, 1 H)

Mass (EI,m / e): 417 (M⁺), 382, 347, 273, 258, 217

Example 3 [3'β, 5'β ( E )]-7 '-[[1- (cyclopropyl) -6,7,8-trifluoro-1,4-dihydro-4-oxoqui Preparation of Nolinyl] ethenyl] -3 ', 5'-dihydroxypentanoic acid (compound of formula (I))

1- (cyclopropyl) -6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline (compound of formula (IV)) was treated in the same manner as in Example 1 to obtain the desired The compound was prepared.

¹ H-NMR (δ, CDCl ₃ ): 1.02-1.06 (m, 4H), 1.78-1.89 (m, 2H), 2.31-2.67 (m, 2H), 3.48 (m, 1H), 4.00 (bs, 1H ), 5.00-5.10 (m, 1H), 5.24 (bs, 1H), 5.48 (dd, 1H), 6.69 (d, 1H), 7.28 -7.34 (m, 1H), 8.35 (s, 1H), 9.25 ( s, 1H), 10.3 (bs, 1H)

Mass (EI,m / e): 435 (M⁺), 400, 355, 291, 276, 235

Example 4 [3'β, 5'β ( E )]-7 '-[[1- (cyclopropyl) -6,7-difluoro-8-chloro-1,4-dihydro-4- Preparation of oxoquinolinyl] ethenyl] -3 ', 5'-dihydroxypentanoic acid (compound of formula (I))

1- (cyclopropyl) -6,7-difluoro-8-chloro-1,4-dihydro-4-oxoquinoline (compound of formula (IV)) was treated in the same manner as in Example 1 The desired compound was prepared.

¹ H-NMR (δ, CDCl ₃ ): 1.02-1.06 (m, 4H), 1.78-1.89 (m, 2H), 2.31-2.67 (m, 2H), 3.48 (m, 1H), 4.00 (bs, 1H ), 5.00-5.10 (m, 1H), 5.24 (bs, 1H), 5.48 (dd, 1H), 6.69 (d, 1H), 7.28 -7.34 (m, 1H), 8.84 (s, 1H), 9.25 ( s, 1H), 10.3 (bs, 1H)

Mass (EI,m / e): 453 (M⁺), 418, 373, 309, 294, 263

Example 5 [3′β, 5′β ( E )]-7 ′-[[1- (2,4-difluorophenyl) -6,7-difluoro-1,4-dihydro- Preparation of 4-oxoquinolinyl] ethenyl] -3 ', 5'-dihydroxypentanoic acid (compound of formula (I))

1- (2,4-difluorophenyl) -6,7-difluoro-1,4-dihydro-4-oxoquinoline (compound of formula (IV)) in the same manner as in Example 1 above Treatment gave the desired compound.

¹ H-NMR (δ, CDCl ₃ ): 1.45-1.56 (m, 2H), 2.31-2.67 (m, 2H), 4.00 (bs, 1H), 5.00-5.10 (m, 1H), 5.24 (bs, 1H ), 5.48 (dd, 1H), 6.69 (d, 1H), 7.18 -7.24 (m, 3H), 7.34-7.44 (m, 2H), 8.45 (s, 1H), 9.25 (s, 1H), 10.3 ( bs, 1 H)

Mass (EI,m / e): 490 (M⁺), 445, 410, 346, 331, 300

Example 6 [3′β, 5′β ( E )]-7 ′-[[1- (2,4-difluorophenyl) -6,7-difluoro-1,4-dihydro- Preparation of 4-oxonaphthyridinyl] ethenyl] -3 ', 5'-dihydroxypentanoic acid (compound of formula (IV))

1- (2,4-difluorophenyl) -6,7-difluoro-1,4-dihydro-4-oxonaphthyridine (compound of formula (IV)) in the same manner as in Example 1 Treatment to prepare the desired compound.

¹ H-NMR (δ, CDCl ₃ ): 2.31-2.67 (m, 2H), 4.00 (bs, 1H), 5.00-5.10 (m, 1H), 5.24 (bs, 1H), 5.48 (dd, 1H), 6.69 (d, 1H), 7.18 -7.24 (m, 3H), 7.34 -7.44 (m, 2H), 8.45 (s, 1H), 9.25 (s, 1H), 10.3 (bs, 1H)

Mass (EI,m / e): 492 (M⁺), 447, 412, 348, 333, 302

Example 7: [3'β, 5'β ( E )]-7 '-[[1- (ethyl) -6,7-difluoro-1,4-dihydro-4-oxoquinolinyl] Preparation of ethenyl] -3 ', 5'-dihydroxypentanoic acid (compound of formula (I))

1- (ethyl) -6,7-difluoro-1,4-dihydro-4-oxoquinoline (compound of formula (IV)) was treated in the same manner as in Example 1 to prepare a desired compound. It was.

¹ H-NMR (δ, CDCl ₃ ): 1.12 (t, 3H), 1.78-1.89 (m, 2H), 2.31-2.67 (m, 2H), 3.48 (m, 1H), 3.56 (q, 2H), 4.00 (bs, 1H), 5.00-5.10 (m, 1H), 5.24 (bs, 1H), 5.48 (dd, 1H), 6.69 (d, 1H), 7.28 -7.34 (m, 1H), 7.45-7.49 ( m, 1H), 8.84 (s, 1H), 9.25 (s, 1H), 10.3 (bs, 1H)

Mass (EI,m / e): 406 (M⁺), 361, 326, 262, 247, 213

Example 8 [3'β, 5'β (E)]-7 '-[[1- (cyclopropyl) -6,7-difluoro-8-methoxy-1,2,3,4- Tetrahydro-4-oxoquinolinyl] ethyl] -3 ', 5'-dihydroxypentanoic acid (compound of formula (II))

Step b ') 3'-[1- (cyclopropyl) -6,7-difluoro-8-methoxy-1,2,3,4-tetrahydro-4-oxoquinoline] -1 ', 1' Preparation of Dimethoxy Propane (Compound of Formula (X))

1- (cyclopropyl) -6,7-difluoro-8-methoxy-1,2,3,4-tetrahydro-4-oxoquinoline obtained by carrying out the same reaction as in step a of Example 1 above 1.3 g of the compound of formula IV were dissolved in 50 ml of dichloromethane, and 1.98 g of NaOEt and 3.2 ml of 3-bromopropanal dimethylacetal were added thereto, followed by stirring at room temperature overnight. 100 ml of ice water was added to the reaction mixture, and the water layer was separated. The organic layer was washed with 5% aqueous NaOH solution, mixed with the water layer, and the aqueous layer was washed with chloroform. The aqueous layer was acidified with 5% HCl aqueous solution, extracted with dichloromethane, and the organic layer was washed with brine. Drying with anhydrous MgSO ₄ and concentration under reduced pressure and silica gel column chromatography (developing solvent: Hex / EtOAc = 2/1) afforded 1.0 g of the desired yellow solid compound in a yield of 79%.

¹ H-NMR (δ, CDCl ₃ ): 0.75-0.85 (m, 4H), 2.10 (m, 1H), 2.60 (t, 2H), 2.95-3.02 (m, 1H), 3.40 (s, 6H), 3.45 (t, 2H), 3.90 (s, 3H), 4.51 (t, 1H), 7.30-7.45 (m, 1H)

Mass (EI,m / e): 356 (M⁺+1), 355 (M⁺), 292, 279, 264, 223

Step c ') 3'-[1- (cyclopropyl) -6,7-difluoro-8-methoxy-1,2,3,4-tetrahydro-4-oxoquinoline] -1'-propanal Preparation of (Compound of Formula (XI))

To 20 ml of acetone and water mixed solution (5: 1), 0.6 g of the compound prepared in step b 'and 0.42 g of p- TsOH were added thereto, followed by heating to reflux for 48 hours. The reaction mixture was cooled and concentrated, extracted with Et ₂ O, washed with saturated aqueous NaHCO ₃ and brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure to give 0.43 g of the desired yellow liquid compound in 94% yield. It was.

¹ H-NMR (δ, CDCl ₃ ): 0.75-0.85 (m, 4H), 2.60 (t, 2H), 2.95-3.02 (m, 1H), 3.65 (t, 2H), 3.90 (s, 3H), 4.05 (m, 1H), 7.30-7.45 (m, 1H)

Mass (EI,m / e): 309 (M⁺), 280, 252, 237, 196

Step d ') ethyl-7'-[1- (cyclopropyl) -6,7-difluoro-8-methoxy-1,2,3,4-tetrahydro-4-oxoquinoline] -5'- Preparation of Hydroxy-3'-oxo-6'-heptanoate (Compound of Formula (XII))

0.29 g of NaH (60% dispersed oil) was suspended in 10 ml of anhydrous THF, and a solution of 0.34 ml of ethylacetoacetate in 10 ml of anhydrous THF was slowly added thereto. After gas evolution had ceased, 2.11 ml of n- BuLi (1.6 M in hexane) was added over 30 minutes at 0 ^° C. under nitrogen. The reaction mixture was cooled to −78 ^° C. and a solution of 0.80 g of the compound prepared in step c ′ was dissolved in 20 ml of dry THF, and stirred for 1 hour. The reaction was stopped with 50 ml of saturated NH ₄ Cl aqueous solution and extracted with EtOAc. The organic layer was washed with saturated NaHCO ₃ aqueous solution, dried over anhydrous MgSO ₄ , concentrated under reduced pressure and purified by silica gel column chromatography (developing solvent: Hex / EtOAc = 3/1). 0.92 g of the desired yellow liquid compound was obtained in a yield of 58%.

¹ H-NMR (δ, CDCl ₃ ): 0.85-0.95 (m, 4H), 1.20-1.45 (m, 8H), 2.20 (s, 2H), 2.35 (dd, 2H), 3.20 (dd, 2H), 3.80 (m, 1H), 3.95 (s, 3H), 4.02 (m, 1H), 4.05 (m, 1H), 4.12 (q, 2H), 7.38-7.42 (m, 1H)

Mass (EI,m / e): 439 (M⁺), 410, 366, 294, 266, 251, 210

Step e ') ethyl- [3'β, 5'β] -7-[[1- (cyclopropyl) -6,7-difluoro-8-methok-1,2,3,4-tetrahydro- Preparation of 4-hydroxyquinoline] ethyl] -3 ', 5'-dihydroxypentanoate (compound of formula (XIII))

To 13 ml of dry THF was added 2.5 ml of triethylborane (1.0 M soln in THF) and 4.6 ml of MeOH under nitrogen. After stirring for 1 h at 20 ^o C it was cooled to -78 ^o C. Here, a solution of 0.86 g of the compound prepared in step d 'was dissolved in 18 ml of dry THF, and then slowly added thereto, followed by stirring at the same temperature for 1.3 hours. To this, 0.09 g of NaBH ₄ was added and stirred for 5 hours. The reaction was stopped with saturated aqueous NH ₄ Cl and stirred at 20 ^° C. overnight. To this was added 50 ml of water, extracted with EtOAc, dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and silica gel column chromatography (developing solvent: EtOAc) to obtain 0.39 g of the desired yellow liquid compound in a yield of 78%.

¹ H-NMR (δ, CDCl ₃ ): 0.83-0.91 (m, 4H), 1.20-1.50 (m, 8H), 1.89 (m, 2H), 2.25 (dd, 2H), 3.20 (dd, 2H), 3.95 (s, 3H), 4.02-4.10 (m, 3H), 4.14 (q, 2H), 7.38-7.42 (m, 1H)

Mass (EI,m / e): 443 (M⁺), 441, 397, 281, 266, 251, 234

Step f ') ethyl- [3'β, 5'β] -7-[[1- (cyclopropyl) -6,7-difluoro-8-methoxy-1,2,3,4-tetrahydro Preparation of -4-hydroxyquinoline] ethyl] -3 ', 5'-isopropylidene ketalpentanoate (compound of formula (XIV))

To 10 ml of acetone, 0.3 g of the compound prepared in step e 'and a catalytic amount of p- TsOH were added and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and silica gel column chromatography (developing solvent: Hex / EtOAc = 2/1) afforded 0.31 g of the desired yellow liquid compound in a yield of 94%.

¹ H-NMR (δ, CDCl ₃ ): 0.84-0.93 (m, 4H), 1.20-1.50 (m, 8H), 1.89 (m, 2H), 2.2 (dd, 2H), 2.55 (s, 6H), 3.18 (dd, 2H), 3.87 (s, 3H), 4.00-4.05 (m, 3H), 4.12 (q, 2H), 7.38-7.42 (m, 1H)

Mass (EI,m / e): 483 (M⁺), 441, 412, 368, 254, 239, 198

Step g ') ethyl- [3'β, 5'β] -7-[[1- (cyclopropyl) -6,7-difluoro-8-methoxy-1,2,3,4-tetrahydro Preparation of -4-oxoquinoline] ethyl] -3 ', 5'-isopropylidene ketal-pentanoate (compound of general formula (XV))

0.23 ml of (COCl) ₂ was added to 5 ml of anhydrous dichloromethane and cooled to -78 ^° C. under nitrogen. To this, 0.38 ml of DMSO was added and stirred for 15 minutes. To this was slowly added a solution in which 0.96 g of the compound prepared in step f 'was dissolved in 5 ml of anhydrous dichloromethane at the same temperature. After stirring for 1 hour, 1.4 ml of Et ₃ N was added very slowly and completely, and the reaction was stopped with a saturated aqueous NH ₄ Cl solution. Extracted with dichloromethane, dried over anhydrous MgSO ₄ and concentrated under reduced pressure to obtain 0.94 g of the desired yellow liquid compound in 89% yield.

¹ H-NMR (δ, CDCl ₃ ): 0.85-0.94 (m, 4H), 1.25-1.67 (m, 8H), 2.02 (m, 2H), 2.25 (dd, 2H), 2.58 (s, 6H), 3.20 (dd, 2H), 3.95 (m, 1H), 4.02 (s, 3H), 4.06-4.10 (m, 2H), 4.12 (q, 2H), 7.28-7.32 (m, 1H)

Mass (EI,m / e): 481 (M⁺), 452, 408, 376, 262, 247, 206

Step h ') [3'β, 5'β (E)]-7-[[1- (cyclopropyl) -6,7-difluoro-8-methoxy-1,2,3,4-tetra Preparation of Hydro-4-oxoquinoline] ethyl] -3 ', 5'-dihydroxypentanoic acid (compound of formula (II))

In 20 ml of 2N-NaOH aqueous solution, 0.56 g of the compound prepared in Step g 'was added thereto, and the mixture was stirred overnight at room temperature. Acidified (pH 6) with 2N-HCl aqueous solution under cooling, and stirred overnight at room temperature. The mixture was extracted with Et ₂ O, dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure and solidified again under Et ₂ O to afford 0.40 g of the desired white solid compound in 78% yield.

¹ H-NMR (δ, CDCl ₃ ): 0.84-0.91 (m, 4H), 1.23-1.62 (m, 8H), 2.05 (m, 2H), 2.30 (dd, 1H), 3.24 (dd, 2H), 3.94 (m, 1H), 4.05 (s, 3H), 4.08-4.12 (m, 2H), 7.28-7.32 (m, 1H)

Mass (EI,m / e): 413 (M⁺), 369, 335, 320, 238, 197

Example 9 [3'β, 5'β (E)]-7 '-[[1- (cyclopropyl) -6,7-difluoro-8-chloro-1,2,3,4-tetra Preparation of Hydro-4-oxoquinolinyl] ethyl] -3 ', 5'-dihydroxypentanoic acid (compound of formula (II))

1- (cyclopropyl) -6,7-difluoro-8-chloro-1,2,3,4-tetrahydro-4-oxoquinoline (compound of formula (IV)) was the same as in Example 8. Processed to produce the desired compound.

¹ H-NMR (δ, CDCl ₃ ): 0.86-0.95 (m, 4H), 1.25-1.66 (m, 8H), 2.07 (m, 2H), 2.34 (dd, 1H), 3.28 (dd, 2H), 3.97 (m, 1H), 4.09-4.15 (m, 2H), 7.29-7.33 (m, 1H)

Mass (EI,m / e): 418 (M⁺), 375, 338, 325, 243, 202

Example 10 [3'β, 5'β (E)]-7 '-[[1- (2,4-difluorophenyl) -6,7-difluoro-1,2,3,4 -Tetrahydro-4-oxoquinolinyl] ethyl] -3 ', 5'-dihydroxy-pentanoic acid (compound of formula (II))

1- (2,4-difluorophenyl) -6,7-difluoro-1,2,3,4-tetrahydro-4-oxoquinoline (compound of formula (IV)) was prepared in Example 8 above. Treated in the same manner as to prepare the desired compound.

¹ H-NMR (δ, CDCl ₃ ): 2.12 (m, 2H), 2.44 (dd, 1H), 3.38 (dd, 2H), 3.97 (m, 1H), 4.09-4.15 (m, 2H), 7.29- 7.33 (m, 2H), 7.45-7.55 (m, 2H)

Mass (EI,m / e): 455 (M⁺), 412, 375, 362, 280, 239

Example 11 [3'β, 5'β (E)]-7 '-[[1- (2,4-difluorophenyl) -6,7-difluoro-1,2,3,4 Preparation of tetrahydro-4-oxonaphthyridinyl] ethyl] -3 ', 5'-dihydroxypentanoic acid (compound of formula (II))

Example 1- (2,4-difluorophenyl) -6,7-difluoro-1,2,3,4-tetrahydro-4-oxonaphthyridine (compound of formula (IV)) The desired compound was prepared by treating in the same manner as 8.

¹ H-NMR (δ, CDCl ₃ ): 2.32 (m, 2H), 2.49 (dd, 1H), 3.48 (dd, 2H), 3.97 (m, 1H), 4.39-4.45 (m, 2H), 7.39- 7.42 (m, 2H), 7.48-7.55 (m, 2H)

Mass (EI,m / e): 457 (M⁺), 414, 377, 364, 282, 241

Example 12 [3'β, 5'β (E)]-7 '-[[1- (ethyl) -6,7-difluoro-1,2,3,4-tetrahydro-4-oxo Preparation of Quinolinyl] ethyl] -3 ', 5'-dihydroxypentanoic acid (compound of formula (II))

1- (ethyl) -6,7-difluoro-1,2,3,4-tetrahydro-4-oxoquinoline (compound of formula (IV)) was treated in the same manner as in Example 8 to obtain To prepare a compound.

¹ H-NMR (δ, DMSO-d ₆ ): 1.23 (t, 3H), 1.25-1.66 (m, 8H), 2.07 (m, 2H), 2.34 (dd, 1H), 3.28 (dd, 2H), 3.45 (q, 2H), 3.97 (m, 1H), 4.09-4.15 (m, 2H), 7.29-7.33 (m, 2H)

Mass (EI,m / e): 371 (M⁺), 328, 291, 278, 196, 155

The inhibitory activity of HMG-Co A reductase of the compound of the present invention prepared from the above Example was measured by the following method.

In vitro activity test

The inhibitory activity of the compounds of the present invention on HMG-Co A reductase isolated from rat liver was analyzed by Ebigan et al . ( J. Lipid. Res ., 1975, 16, 151, (2)) and { J Lipid.Res. , 1979, 20, 588}. The inhibitory activity of the compounds of the present invention on these enzymes is shown in Table 1 below as enzyme inhibitory concentration (IC ₅₀ ) as compared to lovastatin (manufactured by Merck) as a control compound. Means greater. At this time, the enzyme activity was determined by measuring the amount of ¹⁴ C-HMG-Co A substrate is converted to ¹⁴ C- mevalonilic acid.

Compound number Enzyme Inhibition Concentration (IC ₅₀ , nM) Relative strength Example 1 5.0 160 Example 4 4.2 190 Example 9 3.8 210 Lovastatin 8.0 100

Quinolone derivatives having an ethyl or ethenyl-3'β, 5'β-dihydroxypentanoic acid residue at the 3-position according to the present invention have an excellent inhibitory effect of HMG-Co A reductase to lower blood lipid concentration. It is advantageous.

Claims (6)

Quinolone-3-ethenyl-3'β, 5'β-dihydroxypentanoic acid derivatives of the general formula (I) or a pharmaceutically acceptable salt thereof: Formula 1 Where X is CY or N, wherein Y is hydrogen, halogen, C _1-4 alkoxy or C _1-4 alkyl; R ₁ is C _1-4 alkyl, C _3-4 cycloalkyl or phenyl substituted with one or more fluorine. Quinolone-3-ethyl-3'β, 5'β-dihydroxypentanoic acid derivatives of the general formula (II) or a pharmaceutically acceptable salt thereof: Formula 2 Where X is CY or N, wherein Y is hydrogen, halogen, C _1-4 alkoxy or C _1-4 alkyl; R ₁ is C _1-4 alkyl, C _3-4 cycloalkyl or phenyl substituted with one or more fluorine. The method of claim 1, [3'β, 5'β ( E )]-7 '-[[1- (cyclopropyl) -6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoli Nil] ethenyl] -3 ', 5'-dihydroxy-pentanoic acid, [3'β, 5'β ( E )]-7 '-[[1- (cyclopropyl) -6,7-difluoro-1,4-dihydro-4-oxoquinolinyl] ethenyl] -3 ', 5'-dihydroxypentanoic acid, To [3'β, 5'β ( E )]-7 '-[[1- (cyclopropyl) -6,7,8-trifluoro-1,4-dihydro-4-oxoquinolinyl] Tenyl] -3 ', 5'-dihydroxypentanoic acid, [3'β, 5'β ( E )]-7 '-[[1- (cyclopropyl) -6,7-difluoro-8-chloro-1,4-dihydro-4-oxoquinolinyl ] Ethenyl] -3 ', 5'-dihydroxypentanoic acid, [3'β, 5'β ( E )]-7 '-[[1- (2,4-difluorophenyl) -6,7-difluoro-1,4-dihydro-4-oxoqui Nolinyl] ethenyl] -3 ', 5'-dihydroxypentanoic acid, [3'β, 5'β ( E )]-7 '-[[1- (2,4-difluorophenyl) -6,7-difluoro-1,4-dihydro-4-oxonaphthy Ridinyl] ethenyl] -3 ', 5'-dihydroxypentanoic acid, and [3'β, 5'β ( E )]-7 '-[[1- (ethyl) -6,7-difluoro-1,4-dihydro-4-oxoquinolinyl] ethenyl]- 3 ', 5'-dihydroxypentanoic acid Quinolone derivatives or pharmaceutically acceptable salts thereof, characterized in that selected from the group consisting of. The method of claim 2, [3'β, 5'β (E)]-7 '-[[1- (cyclopropyl) -6,7-difluoro-8-methoxy-1,2,3,4-tetrahydro-4 Oxoquinolinyl] ethyl] -3 ', 5'-dihydroxypentanoic acid, [3'β, 5'β (E)]-7 '-[[1- (cyclopropyl) -6,7-difluoro-8-chloro-1,2,3,4-tetrahydro-4- Oxoquinolinyl] ethyl] -3 ', 5'-dihydroxypentanoic acid, [3'β, 5'β (E)]-7 '-[[1- (2,4-difluorophenyl) -6,7-difluoro-1,2,3,4-tetrahydro- 4-oxoquinolinyl] ethyl] -3 ', 5'-dihydroxy-pentanoic acid, [3'β, 5'β (E)]-7 '-[[1- (2,4-difluorophenyl) -6,7-difluoro-1,2,3,4-tetrahydro- 4-oxonaphthyridinyl] ethyl] -3 ', 5'-dihydroxypentanoic acid, and [3'β, 5'β (E)]-7 '-[[1- (ethyl) -6,7-difluoro-1,2,3,4-tetrahydro-4-oxoquinolinyl] Ethyl] -3 ', 5'-dihydroxypentanoic acid Quinolone derivatives or pharmaceutically acceptable salts thereof, characterized in that selected from the group consisting of. A process for preparing a compound of formula (I) according to claim 1 comprising the following steps a) to g); a) reacting a compound of formula (III) in the presence of p-toluenesulfonic acid (p-TsOH) and sodium borohydride to prepare a compound of formula (IV), b) reacting the compound of formula (IV) prepared in step a) with ethyl formate in the presence of potassium t-butoxide to prepare a compound of formula (V), c) reacting the compound of formula (V) prepared in step b) with manganese dioxide (MnO ₂ ) to prepare a compound of formula (VI), d) a Wittig reaction of the compound of Formula (VI) prepared in step c) with triphenylphosphonylidene methyl ester to prepare a compound of Formula (VII), e) heating the compound of formula (VII) prepared in step d) with manganese dioxide in the presence of diisobutylaluminum hydride to prepare a compound of formula (VIII), f) reacting the compound of formula (VIII) prepared in step e) with ethyl acetoacetate, sodium hydride and n-butyllithium to prepare a compound of formula (IX), and g) The compound of formula (IX) prepared in step f) is reacted with triethylborane and sodium borohydride and hydrolyzed, followed by column chromatography (developing solvent: chloroform / methanol = 3/1) To prepare a compound of formula (I): Formula 1 Wherein X and R ₁ are as defined in claim 1 above. A process for preparing a compound of formula (II) according to claim 2 comprising the steps a) to h ′) below; a) reacting a compound of formula (III) in the presence of p-toluenesulfonic acid and sodium borohydride to produce a compound of formula (IV), b ') reacting the compound of formula (IV) prepared in step a) with 1,1-methoxy-3-bromopropane and sodium ethoxide to prepare a compound of formula (X), c ') preparing a compound of formula (XI) by heating and refluxing the compound of formula (X) prepared in step b') in the presence of p-toluenesulfonic acid, d ') preparing a compound of formula (XII) by reacting the compound of formula (XI) prepared in step c') with ethyl acetoacetate, sodium hydride and n-butyllithium, e ') reacting the compound of formula (XII) prepared in step d') with triethylborane and sodium borohydride to prepare a compound of formula (XIII), f ') reacting a compound of formula (XIII) prepared in step e') with acetone and preparing a compound of formula (XIV) by column chromatography (developing solvent: Hex / EtOAc = 3/1) , g ') reacting a compound of formula (XIV) prepared in step f') with DMSO, oxalyl chloride and triethylamine to prepare a compound of formula (XV), and h ') preparing a compound of formula (II) by hydrolysis of the compound of formula (XV) prepared in step g') and column chromatography (developing solvent: chloroform / methanol = 3/1): Formula 2 Formula 3 Formula 4 Wherein X and R ₁ are as defined in claim 1 above.