KR100274315B1 - Novel spirohidnatoin derivative for lowering lipid concentraion in blood - Google Patents

Abstract

PURPOSE: Provided are the novel spirohydantoin compounds inhibiting the bio-synthesis of cholesterol thereby lowering the concentration of the blood lipids. CONSTITUTION: The novel compounds are represented by the chemical formula 1, where R1 is hydrogen, C1-4 alkyl or C3-4 cycloalkyl group; R2 is hydrogen, halogen or nitro group; A is carbon or nitrogen; m is 0 or 1; n is 1 or 2. The synthetic process comprises the steps of: decarboxylation of N-benzyl-N-ethoxycarbonylmethyl-β-alaninate(general formula II) with 6-12N concentrated HCl to obtain the compound of general formula III; reacting the compound III in ethanol or ethanol/water solution, with potassium or sodium cyanide and ammonium carbonate at 50-90deg.C for 10-48 hours to obtain compound of general formula IV; reacting the compound IV with diethoxy propyl bromide in the presence of bases such as sodium hydride, sodium ethoxide or potassium t-buthoxide to make the compound of general formula V-1; introducing R1 group to the amide group of the compound V-1 in the presence of base such as sodium hydride to make the compound of general formula V-2; converting the acetal group in the compounds V-1 and V-2 to aldehyde group in the presence of hydrochloric acid or p-toluenesulfonic acid to make the compound of general formula VI; carrying out aldol condensation of the compound VI with ethylacetoacetate in the presence of base such as n-butyl lithium to obtain the compound of general formula VII; converting β-carbonyl group in the compound VII to alcohol by reacting with triethylborane, sodium borohydride or sodium borocyanohydride in THF to make the compound of general formula VIII and lactonising to the final compound of the chemical formula 1 after hydrolysis of the compound VIII with base or acid.

Description

Novel Spirohydantoin Derivatives with Blood Lipid Lowering Activity

The present invention relates to novel spirohidantoin derivatives 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 intensive research and found the spirohydantoin 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 to provide a novel spirohidanto derivative, which is useful for lowering lipid concentration in blood by having good oral absorption, low chronic toxicity, and excellent tissue selectivity and excellent inhibitory effect of HMG-Co A reductase.

In order to achieve the above object, the present invention provides a spirohydantoin derivative of the general formula (I):

Formula 1

Where

R ₁ is hydrogen, C _1-4 alkyl or C _3-4 cycloalkyl;

R ₂ is hydrogen, halogen or nitro group;

A is carbon or nitrogen;

m is 0 or 1;

n is 1 or 2.

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

According to the invention, R ₁ in general formula (I) is preferably hydrogen, methyl or cyclopropyl.

Spirohydantoin derivatives of the general formula (I) of the present invention may be prepared by the same process as in Scheme 1 below:

Wherein R ₁ ′ is the same as R ₁ except for hydrogen, and R ₁ , R ₂ , A, m and n are as defined above.

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

a) known methods (Tetrahedron Letters,1991, l32, 1565-1568] and [J. Org. Chem., 1965, 30, 740) to decarboxylate the compound of formula (II) in the presence of 6 to 12N concentrated hydrochloric acid to prepare a compound of formula (III),

b) reacting the compound prepared in step a) with potassium cyanide or sodium cyanide and ammonium carbonate for 10 to 48 hours in the presence of ethanol or a mixed solvent of ethanol and water to prepare a compound of formula (IV) and,

c) reacting the compound prepared in step b) with diethoxypropyl bromide in the presence of a base such as sodium hydride, sodium ethoxide or potassium t-butoxide to prepare a compound of formula (V-1),

c ') preparing a compound of formula (V-2) by introducing a R ₁ ' group in the presence of a base such as sodium hydride to the amide group of the compound prepared in step c) (wherein R ₁ is hydrogen) Is omitted),

d) converting the acetal group of the compound prepared in step c) or c ') to an aldehyde group in the presence of an acid such as hydrochloric acid or p-toluenesulfonic acid to prepare a compound of formula (VI),

e) an aldol condensation reaction of the compound prepared in step d) with ethyl acetoacetate in the presence of a base such as n-butyllithium to prepare a compound of formula (VII),

f) The beta carbonyl group of the compound prepared in step e) is reacted with triethylborane and sodium borohydride or sodium borocyanohydride in tetrahydrofuran solvent to reduce the alcohol to the compound of formula (VIII). Manufacturing,

g) hydrolyzing the compound prepared in step f) in the presence of a base or an acid, and then using a condensing agent such as 1,3-dicyclohexylcarbodiimide (DCC) Spirohydantoin derivatives can be prepared.

Specific examples of the spirohidantoin derivative of the general formula (I),

3-N- [2 ''-(3-hydroxy-5-oxopyranyl) ethyl] -1,3-diaza-2,4-cyclopentadione-5-spiro-3- (1-N- Benzyl) piperidine,

1-N-benzylpyrrolidine-3-spiro-1 ', 3'-diaza-1'-methyl-3'-[2 ''-(3-hydroxy-5-oxopyranyl) ethyl]- 2 ', 4'-cyclopentadione,

1-N-benzylpyrrolidine-3-spiro-1 ', 3'-diaza-3'-[2 ''-(3-hydroxy-5-oxopyranyl) ethyl] -2 ', 4' Cyclopentadione,

1-N- (pyridin-3-ylmethyl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-isopropyl-3'-[2 ''-(3-hydroxy-5 Oxopyranyl) ethyl] -2 ', 4'-cyclopentadione,

1-N- (pyridin-2-ylmethyl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-ethyl-3'-[2 ''-(3-hydroxy-5- Oxopyranyl) ethyl] -2 ', 4'-cyclopentadione,

1-N- (pyridin-4-ylmethyl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-cyclopropyl-3'-[2 ''-(3-hydroxy-5 Oxopyranyl) ethyl] -2 ', 4'-cyclopentadione,

1-N- (2-nitrobenzyl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-isopropyl-3'-[2 ''-(3-hydroxy-5-oxo Pyranyl) ethyl] -2 ', 4'-cyclopentadione,

1-N- (2-fluorobenzyl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-methyl-3'-[2 ''-(3-hydroxy-5-oxo Pyranyl) ethyl] -2 ', 4'-cyclopentadione,

1-N- (3-fluorobenzyl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-methyl-3'-[2 ''-(3-hydroxy-5-oxo Pyranyl) ethyl] -2 ', 4'-cyclopentadione,

1-N- (2,4-difluorobenzyl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-methyl-3'-[2 ''-(3-hydroxy- 5-oxopyranyl) ethyl] -2 ', 4'-cyclopentadione,

1-N-phenylpyrrolidine-3-spiro-1 ', 3'-diaza-1'-ethyl-3'-[2 ''-(3-hydroxy-5-oxopyranyl) ethyl]- 2 ', 4'-cyclopentadione,

1-N- (pyridin-2-yl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-ethyl-3'-[2 ''-(3-hydroxy-5-oxo Pyranyl) ethyl] -2 ', 4'-cyclopentadione,

1-N- (pyridin-3-yl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-ethyl-3'-[2 ''-(3-hydroxy-5-oxo Pyranyl) ethyl] -2 ', 4'-cyclopentadione,

1-N- (pyridin-4-yl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-ethyl-3'-[2 ''-(3-hydroxy-5-oxo Pyranyl) ethyl] -2 ', 4'-cyclopentadione,

1-N- (5-fluoropyridin-2-ylmethyl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-isopropyl-3'-[2 ''-(3- Hydroxy-5-oxopyranyl) ethyl] -2 ', 4'-cyclopentadione,

1-N- (5-fluoropyridin-2-yl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-isopropyl-3'-[2 ''-(3-hydrate Hydroxy-5-oxopyranyl) ethyl] -2 ', 4'-cyclopentadione,

1-N-phenylpiperidine-3-spiro-1 ', 3'-diaza-1'-isopropyl-3'-[2 ''-(3-hydroxy-5-oxopyranyl) ethyl] -2 ', 4'-cyclopentadione,

1-N- (5-fluoropyridin-2-ylmethyl) piperidine-3-spiro-1 ', 3'-diaza-1'-isopropyl-3'-[2 ''-(3- Hydroxy-5-oxopyranyl) ethyl] -2 ', 4'-cyclopentadione,

1-N- (pyridin-4-ylmethyl) piperidine-3-spiro-1 ', 3'-diaza-1'-methyl-3'-[2 ''-(3-hydroxy-5- Oxopyranyl) ethyl] -2 ', 4'-cyclopentadione,

1-N- (pyridin-4-ylmethyl) piperidine-3-spiro-1 ', 3'-diaza-1'-cyclopropyl-3'-[2 ''-(3-hydroxy-5 Oxopyranyl) ethyl] -2 ', 4'-cyclopentadione,

1-N- (5-fluoropyridin-2-yl) piperidine-3-spiro-1 ', 3'-diaza-1'-isopropyl-3'-[2 ''-(3-hydrate Oxy-5-oxopyranyl) ethyl] -2 ', 4'-cyclopentadione, and

1-N- (pyridin-4-yl) piperidine-3-spiro-1 ', 3'-diaza-1'-isopropyl-3'-[2 ''-(3-hydroxy-5- Oxopyranyl) ethyl] -2 ', 4'-cyclopentadione

Etc. can be mentioned.

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

Therefore, in the present invention, a composition containing an effective amount of the compound of formula (I) 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 70 to 80%, preferably 70 to 75%, 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 0.6 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.

Preparation Example 1 Preparation of N-benzyl-3-oxopyrrolidine (Compound of Formula (III))

207 g of ethyl β-N-benzyl alanate and 111 g of triethylamine were added to 1 L of anhydrous ethanol, and 167 g of ethyl bromoacetate was added dropwise while stirring well at 0 ° C or lower. After further stirring at room temperature for 10 hours, the resulting solid was filtered, the filtrate was evaporated under reduced pressure, dissolved in ethyl acetate, washed with water, 5% hydrochloric acid, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Subsequently, 250 g of potassium t-butoxide was added to 1.2 L of anhydrous toluene and the reaction temperature was maintained at 20 ° C. or lower, and the above-mentioned ethyl N-benzyl-N-ethoxycarbonylmethyl-β-alanine (general formula ( A solution in which 544 g of the compound of II) was dissolved in 1.2 L of anhydrous toluene was slowly added. After further stirring at room temperature for 2 hours, the reaction mixture was cooled to 0 ° C. or lower, and 30 ml of water was added dropwise with vigorous stirring, and the resulting solid was filtered under reduced pressure. The reflux was stirred. The reaction mixture was cooled, neutralized with 5N-NaOH aqueous solution, extracted twice with 1 L of ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1/1). 192 g of the desired compound was prepared in a yield of 72%.

Elemental analysis (C ₁₁ H ₁₃ NO) theory; C: 75.40% H: 7.48% N: 7.99%

Measurements; C: 75.48% H: 7.53% N: 7.93%

Preparation Example 2 Preparation of N-phenyl-3-oxopyrrolidine (Compound of Formula (III))

A target compound was prepared by the same reaction as in Preparation Example 1, except that ethyl β-N-phenylalanine was used instead of ethyl β-N-benzylalanine.

Elemental analysis (C ₁₀ H ₁₁ NO) theory; C: 74.51% H: 6.88% N: 8.69%

Measurements; C: 74.48% H: 7.83% N: 8.73%

Preparation Example 3 Preparation of N- (Pyridin-4-yl) -3-oxopyrrolidine (Compound of Formula (III))

Except for using ethyl β-N- (pyridin-4-yl) alanine instead of ethyl β-N-benzylalanineate, the target compound was prepared in the same manner as in Preparation Example 1. .

Elemental analysis (C ₉ H ₁₀ N ₂ O) theory; C: 66.65% H: 6.21% N: 17.27%

Measurements; C: 66.71% H: 6.21% N: 17.31%

Preparation Example 4 Preparation of N- (pyridin-2-yl) -3-oxopyrrolidine (Compound of Formula (III))

Except for using ethyl β-N- (pyridin-2-yl) alanine instead of ethyl β-N-benzylalanineate, the target compound was prepared in the same manner as in Preparation Example 1. .

Elemental analysis (C ₉ H ₁₀ N ₂ O) theory; C: 66.65% H: 6.21% N: 17.27%

Measurements; C: 66.72% H: 6.26% N: 17.23%

Preparation Example 5 Preparation of N- (Pyridin-3-yl) -3-oxopyrrolidine (Compound of Formula (III))

Except for using ethyl β-N- (pyridin-3-yl) alanine instead of ethyl β-N-benzylalanineate, the target compound was prepared in the same manner as in Preparation Example 1. .

Elemental analysis (C ₉ H ₁₀ N ₂ O) theory; C: 66.65% H: 6.21% N: 17.27%

Measurements; C: 66.60% H: 6.26% N: 17.32%

Preparation Example 6 Preparation of N- (Pyridin-4-yl) methyl-3-oxopyrrolidine (Compound of Formula (III))

Preparation of the desired compound was carried out in the same manner as in Preparation Example 1, except that ethyl β-N- (pyridin-4-ylmethyl) alanine was used instead of ethyl β-N-benzylalanine. It was.

Elemental analysis (C ₁₀ H ₁₂ N ₂ O) theory; C: 68.16% H: 6.66% N: 15.90%

Measurements; C: 68.13% H: 6.85% N: 15.87%

Preparation Example 7 Preparation of N- (pyridin-3-yl) methyl-3-oxopyrrolidine (Compound of Formula (III))

Except for using ethyl β-N- (pyridin-3-ylmethyl) alaninate instead of ethyl β-N-benzylalanineate, the same reaction as in Preparation Example 1 was carried out to prepare a desired compound. It was.

Elemental analysis (C ₁₀ H ₁₂ N ₂ O) theory; C: 68.16% H: 6.66% N: 15.90%

Measurements; C: 68.21% H: 6.88% N: 15.91%

Preparation Example 8 Preparation of N- (Pyridin-2-yl) methyl-3-oxopyrrolidine (Compound of Formula (III))

Preparation of the desired compound was carried out in the same manner as in Preparation Example 1, except that ethyl β-N- (pyridin-2-ylmethyl) alanine was used instead of ethyl β-N-benzylalanine. It was.

Elemental analysis (C ₁₀ H ₁₂ N ₂ O) theory; C: 68.16% H: 6.66% N: 15.90%

Measurements; C: 68.21% H: 6.86% N: 15.95%

Preparation Example 9 Preparation of N- (2,4-difluorophenyl) -3-oxopyrrolidine (Compound of Formula (III))

Except for using ethyl β-N- (2,4-difluorophenyl) alanine in place of ethyl β-N-benzylalanineate, the target compound was subjected to the same reaction as in Preparation Example 1 above. Was prepared.

Elemental analysis (C ₁₀ H ₉ F ₂ NO) theory; C: 60.91% H: 4.60% N: 7.10%

Measurements; C: 6.98% H: 4.72% N: 7.16%

Preparation Example 10 Preparation of N- (2-fluorobenzyl) -3-oxopyrrolidine (Compound of Formula (III))

Except for using ethyl β-N- (2-fluorobenzyl) alanine instead of ethyl β-N-benzylalanineate, the target compound was prepared in the same manner as in Preparation Example 1. .

Elemental analysis (C ₁₁ H ₁₂ FNO) theory; C: 68.38% H: 6.26% N: 7.25%

Measurements; C: 68.41% H: 6.31% N: 7.30%

Preparation Example 11 Preparation of N- (4-Fluorobenzyl) -3-oxopyrrolidine (Compound of Formula (III))

Except for using ethyl β-N- (4-fluorobenzyl) alanine instead of ethyl β-N-benzylalanineate, the target compound was prepared in the same manner as in Preparation Example 1. .

Elemental analysis (C ₁₁ H ₁₂ FNO) theory; C: 68.38% H: 6.26% N: 7.25%

Measurements; C: 68.41% H: 6.31% N: 7.31%

Preparation Example 12 Preparation of N- (3-fluorobenzyl) -3-oxopyrrolidine (Compound of Formula (III))

Except for using ethyl β-N- (3-fluorobenzyl) alanine instead of ethyl β-N-benzylalanineate, the target compound was prepared in the same manner as in Preparation Example 1. .

Elemental analysis (C ₁₁ H ₁₂ FNO) theory; C: 68.38% H: 6.26% N: 7.25%

Measurements; C: 68.41% H: 6.44% N: 7.29%

Preparation Example 13 Preparation of N- (2-Nitrobenzyl) -3-oxopyrrolidine (Compound of Formula (III))

Except for using ethyl β-N- (2-nitrobenzyl) alanine instead of ethyl β-N-benzyl alanate, the target compound was prepared in the same manner as in Preparation Example 1.

Elemental analysis (C ₁₁ H ₁₂ N ₂ O ₃ ) theory; C: 59.99% H: 5.49% N: 12.72%

Measurements; C: 60.4% H: 5.44% N: 12.68%

Preparation Example 14 Preparation of N- (5-fluoropyridin-2-yl) methyl-3-oxopyrrolidine (Compound of Formula (III))

The same reaction as in Preparation Example 1 was carried out except that ethyl β-N- (5-fluoropyridin-2-ylmethyl) alanine was used instead of ethyl β-N-benzylalanine. To prepare a compound.

Elemental analysis (C ₁₀ H ₁₁ FN ₂ O) theory; C: 61.85% H: 5.71% N: 14.42%

Measurements; C: 61.80% H: 5.71% N: 14.46%

Preparation Example 15 Preparation of N- (5-fluoropyridin-2-yl) -3-oxopyrrolidine (Compound of Formula (III))

Except for using ethyl β-N- (5-fluoropyridin-2-yl) alanine instead of ethyl β-N-benzylalanineate, the same reaction as in Preparation Example 1 was conducted. The compound was prepared.

Elemental analysis (C ₉ H ₉ FN ₂ O) theory; C: 59.99% H: 5.03% N: 15.55%

Measurements; C: 60.04% H: 5.08% N: 15.60%

Preparation Example 16 Preparation of N-benzyl-3-oxopiperidine (Compound of Formula (III))

207 g of ethyl 3-N-benzylaminopropionate and 111 g of triethylamine were added to 1 L of anhydrous ethanol, and 167 g of ethyl bromoacetate was added dropwise while stirring well at 0 ° C or lower. After further stirring at room temperature for 16 hours, the resulting solid was filtered, the filtrate was evaporated under reduced pressure, dissolved in ethyl acetate, washed with water, 5% hydrochloric acid, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Subsequently, 250 g of potassium t-butoxide was added to 1.2 L of anhydrous toluene and the reaction temperature was maintained at 20 ° C. or lower. A solution in which 661 g of the compound of formula (II) was dissolved in 1.2 L of anhydrous toluene was slowly added. After further stirring at room temperature for 2 hours, the reaction mixture was cooled to 0 ° C. or lower, and 30 ml of water was added dropwise with vigorous stirring, and the resulting solid was filtered under reduced pressure. The reflux was stirred. The reaction mixture was cooled, neutralized with 5N-NaOH aqueous solution, extracted twice with 1 L of ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1/1). 235 g of the desired compound was prepared in a yield of 70%.

Elemental analysis (C ₁₂ H ₁₅ NO) theory; C: 75.79% H: 7.74% N: 7.69%

Measurements; C: 75.74% H: 7.78% N: 7.65%

Preparation Example 17 Preparation of N-phenyl-3-oxopiperidine (Compound of Formula (III))

A desired compound was prepared in the same manner as in Preparation Example 16, except that ethyl 3-N-phenylaminopropionate was used instead of ethyl 3-N-benzylaminopropionate.

Elemental analysis (C ₁₁ H ₁₃ NO) theory; C: 75.40% H: 7.48% N: 7.99%

Measurements; C: 75.44% H: 7.51% N: 8.04%

Preparation Example 18 Preparation of N- (Pyridin-4-yl) -3-oxopiperidine (Compound of Formula (III))

Except for using ethyl 3-N- (pyridin-4-yl) aminopropionate instead of ethyl 3-N-benzylaminopropionate, the target compound was subjected to the same reaction as in Preparation Example 16, except that Prepared.

Elemental analysis (C ₁₁ H ₁₄ N ₂ O) theory; C: 69.45% H: 7.42% N: 14.72%

Measurements; C: 69.50% H: 7.46% N: 14.77%

Preparation Example 19 Preparation of N- (5-fluoropyridin-2-yl) methyl-3-oxopiperidine (Compound of Formula (III))

The same reaction as in Preparation Example 16 was carried out except that ethyl 3-N- (5-fluoropyridin-2-ylmethyl) aminopropionate was used instead of ethyl 3-N-benzylaminopropionate. To prepare the desired compound.

Elemental analysis (C ₁₁ H ₁₃ FN ₂ O) theory; C: 63.45% H: 6.29% N: 13.45%

Measurements; C: 63.50% H: 6.31% N: 13.49%

Preparation Example 20 Preparation of N- (pyridin-4-yl) -3-oxopiperidine (Compound of Formula (III))

Except for using ethyl 3-N- (pyridin-4-yl) aminopropionate instead of ethyl 3-N-benzylaminopropionate, the target compound was subjected to the same reaction as in Preparation Example 16, except that Prepared.

Elemental analysis (C ₁₀ H ₁₂ N ₂ O) theory; C: 68.16% H: 6.66% N: 15.90%

Measurements; C: 68.13% H: 6.82% N: 15.96%

Preparation Example 21 Preparation of N- (5-fluoropyridin-2-yl) -3-oxopiperidine (Compound of Formula (III))

The same reaction as in Preparation Example 16 was carried out except that ethyl 3-N- (5-fluoropyridin-2-yl) aminopropionate was used instead of ethyl 3-N-benzylaminopropionate. The desired compound was prepared.

Elemental analysis (C ₁₀ H ₁₁ FN ₂ O) theory; C: 61.85% H: 5.71% N: 14.42%

Measurements; C: 61.83% H: 5.72% N: 14.42%

Example 1 3-N- [2 ''-(3-hydroxy-5-oxopyranyl) ethyl] -1,3-diaza-2,4-cyclopentadione-5-spiro-3- ( Preparation of 1-N-benzyl) piperidine (compound of formula (I))

Step 1) Preparation of 1-N-benzylpiperidine-3-spiro-1 ', 3'-diaza-2', 4'-cyclopentadione (compound of formula (IV))

10 g of N-benzyl-3-oxopiperidine prepared in Preparation Example 16 was added to 100 ml of an aqueous 50% ethanol solution, and then 5.3 g of potassium cyanide and 20.6 g of ammonium carbonate were added to the flask and sealed with stirring. The reactor temperature was stirred for 48 hours while heating to 70-80 ^° C. After cooling the reaction mixture, the solvent was evaporated under reduced pressure, 150 ml of water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, ethyl ether was added, the resulting solid was filtered and dried under reduced pressure to obtain 9 g of the desired yellow solid compound in a yield of 80%.

Elemental analysis (C ₁₄ H ₁₇ N ₃ O ₂ ) theory; C: 64.85% H: 6.61% N: 16.20%

Measurements; C: 64.83% H: 6.62% N: 16.26%

Step 2) 3-N- (3 ', 3'-dioxolaneethyl) -1,3-diaza-2,4-cyclopentadione-5-spiro-3- (1-N-benzyl) piperidine Preparation of (Compound of General Formula (V-1))

0.8 g of 60% sodium hydride was added to 16 ml of dimethylformamide, and a solution of 4.0 g of the compound prepared in step 1) was added to 16 ml of dimethylformamide at room temperature, followed by stirring until gas evolution stopped. It was. After gas evolution ceased, a catalytic amount of sodium iodide was added, and immediately 1.8 ml of 3-bromoethyl-1,1-dioxolane was added at room temperature, followed by stirring for 80 hours while heating the reaction temperature to 90 ^° C. The reaction mixture was poured into 100 ml of iced water, extracted three times with ethyl ether, the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and purified by silica gel column chromatography (Hex / EtOAc = 1/3). 4.6 g of a yellow liquid compound were obtained in a yield of 78%.

Elemental analysis (C ₂₁ H ₃₁ N ₃ O ₄ ) theory; C: 64.76% H: 8.02% N: 10.79%

Measurements; C: 64.83% H: 8.02% N: 10.76%

Step 3) 3-N- (3'-formylethyl) -1,3-diaza-2,4-cyclopentadione-5-spiro-3- (1-N-benzyl) piperidine Preparation of the compound of (VI)

0.4 g of the compound prepared in Step 2) was added to a 20 ml solution of 1N hydrochloric acid, and stirred overnight at room temperature. Saturated sodium bicarbonate solution was slowly added to the reaction solution to adjust the pH of the solution to about 7.5 to 8.0, and then extracted three times with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (CH ₂ Cl ₂ / acetone = 6/1) to give 0.36 g of the desired yellow liquid compound as 90%. Obtained in yield.

Elemental analysis (C ₁₇ H ₂₁ N ₃ O ₃ ) theory; C: 64.74% H: 6.71% N: 13.32%

Measurements; C: 64.81% H: 6.72% N: 13.32%

Step 4) 3-N- (3'-hydroxy-5'-oxo-6'-ethoxycarbonylhexyl) -1,3-diaza-2,4-cyclopentadione-5-spiro-3- Preparation of (1-N-benzyl) piperidine (compound of formula (VII))

0.36 g of sodium hydride was suspended in 5 ml of dry THF and the reaction temperature was cooled to 0 ^° C. 0.46 g of ethyl acetoacetate was slowly added to the cooled mixture, followed by stirring for 5 minutes, and 2.3 ml of n -butyllithium 1.6 M hexane solution was added dropwise and stirred at the same temperature for 10 minutes. The compound prepared in step 3) dissolved in 20 ml of dry THF was added dropwise at the same temperature and stirred at room temperature for 30 minutes. The reaction was stopped with a saturated aqueous ammonium chloride solution and extracted twice with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, evaporated under reduced pressure, and purified by silica gel column chromatography (CH ₂ Cl ₂ / acetone = 6/1). 0.32 g of a yellow liquid compound was obtained in a yield of 65%.

Elemental analysis (C ₂₃ H ₃₁ N ₃ O ₆ ) theory; C: 62.01% H: 7.01% N: 9.43%

Measurements; C: 62.01% H: 6.96% N: 9.37%

Step 5) 3-N- (3 ', 5'-hydroxy-6'-ethoxycarbonylhexyl) -1,3-dia-2,4-cyclopentadione-5-spiro-3- (1- Preparation of N-benzyl) piperidine (compound of formula (VIII))

0.52 ml of triethylborane 1M THF solution was added to 3 ml of anhydrous THF, 0.95 ml of anhydrous methanol was added at room temperature, and the mixture was stirred for 1 hour. The reaction temperature was cooled to −78 ^° C., and a solution of 0.18 g of the compound prepared in Step 4) was added to 4 ml of dry THF, followed by stirring at the same temperature for 90 minutes. 17.6 mg (1.2 equiv) of NaBH ₄ were added and stirred at the same temperature for 5 hours, then 10 ml of saturated aqueous ammonium chloride solution was added to terminate the reaction and stirred overnight at room temperature. 5 ml of water was added, extracted three times with ethyl acetate, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, 5 ml of methanol was added to the residue, and the resulting mixture was concentrated under reduced pressure, followed by silica gel column chromatography (CH ₂ Cl ₂ / acetone = 4/1). 70 mg of the desired yellow solid compound was obtained in a yield of 56%.

Elemental analysis (C ₂₃ H ₃₃ N ₃ O ₆ ) theory; C: 61.73% H: 7.43% N: 9.39%

Measurements; C: 61.71% H: 7.46% N: 9.37%

Step 6) 3-N- (2 ''-(3-hydroxy-5-oxopyranyl) ethyl) -1,3-diaza-2,4-cyclopentadione-5-spiro-3- (1 Preparation of -N-benzyl) piperidine (compound of formula (I))

70 mg (0.16 mmol) of the compound prepared in Step 5) was dissolved in 10 ml of anhydrous THF, and 1 ml of methanol was added thereto, followed by stirring for 10 minutes. 2.7 ml of 3N lithium hydroxide aqueous solution was added thereto, and the mixture was stirred overnight at room temperature. 10 ml of diethyl ether was added to the reaction solution, followed by stirring for 20 minutes, and the organic layer was separated. 5 ml of water was further added to the aqueous layer, followed by extraction three times with diethyl ether. The organic layer was mixed and washed with 2N aqueous lithium hydroxide solution. The aqueous layer was acidified with 6N hydrochloric acid (pH 4), extracted three times with ethyl acetate, evaporated under reduced pressure, and purified by silica gel column chromatography (CH ₂ Cl ₂ ) to give 25 mg of the desired yellow solid compound in a yield of 52%. Obtained.

Elemental analysis (C ₂₁ H ₂₇ N ₃ O ₅ ) theory; C: 62.83% H: 6.78% N: 10.47%

Measurements; C: 62.81% H: 6.76% N: 10.37%

Example 2 1-N-benzylpyrrolidine-3-spiro-1 ', 3'-diaza-1'-methyl-3'-[2 ''-(3-hydroxy-5-oxopyranyl ) Ethyl] -2 ', 4'-cyclopentadione (compound of general formula (I))

Step 1) Preparation of 1-N-benzylpyrrolidine-3-spiro-1 ', 3'-diaza-2', 4'-cyclopentadione (compound of formula (IV))

10 g of N-benzyl-3-oxopyrrolidine prepared in Preparation Example 1 was added to 100 ml of an aqueous 50% ethanol solution, and then 5.3 g of potassium potassium cyanide and 20.6 g of ammonium carbonate were added to the flask and sealed with stirring. The reactor temperature was stirred for 48 hours while heating to 70-80 ^° C. After cooling the reaction mixture, the solvent was evaporated under reduced pressure, 150 ml of water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, ethyl ether was added, the resulting white solid was filtered and dried under reduced pressure to obtain 9 g of the desired yellow solid compound in a yield of 80%.

Elemental analysis (C ₁₃ H ₁₅ N ₃ O ₂ ) theory; C: 63.66% H: 6.16% N: 17.13%

Measurements; C: 63.71% H: 6.16% N: 17.17%

Step 2) 1-N-benzylpyrrolidine-3-spiro-1 ', 3'-diaza-3'-(3 '', 3 ''-diethoxypropyl) -2 ', 4'-cyclopenta Preparation of Dione (Compound of Formula (V-1))

3 g of the compound prepared in step 1) was dissolved in dimethylformamide, and 0.35 g of 60% sodium hydride was added. After stirring for 2 hours at room temperature, a solution of 2.23 ml of 3-chloropropionaldehyde diethylacetal dissolved in dimethylformamide was added dropwise. At the end of the dropwise addition, the reaction mixture was warmed to 60 ^° C. and further stirred for 2 hours. The reaction mixture was poured into water, extracted with ethyl acetate, the solvent was evaporated under reduced pressure, and silica gel column chromatography (ethyl acetate / hexane = 90/1) afforded 2.94 g of the desired yellow solid compound in 86% yield.

Elemental analysis (C ₂₀ H ₂₉ N ₃ O ₄ ) theory; C: 63.98% H: 7.79% N: 11.19%

Measurements; C: 63.91% H: 7.76% N: 11.17%

Step 3) 1-N-benzylpyrrolidine-3-spiro-1 ', 3'-diaza-1'-methyl-3'-(3 '', 3 ''-diethoxypropyl) -2 ', Preparation of 4'-cyclopentadione (compound of formula (V-2))

3 g of the compound prepared in step 2) was dissolved in DMF and 0.35 g of 60% sodium hydride was added. The mixture was stirred at room temperature for 4 hours and then a solution of 0.75 g of methane iodide dissolved in DMF was added dropwise. At the end of the dropwise addition the reaction mixture was warmed up to 60 ° C. and stirred for 6 h. The reaction mixture was poured into water, extracted with ethyl acetate, the solvent was evaporated under reduced pressure, and silica gel column chromatography (ethyl acetate / hexane = 10/1) afforded 2.94 g of the desired yellow liquid compound in 80% yield.

Elemental analysis (C ₂₁ H ₃₁ N ₃ O ₄ ) theory; C: 64.76% H: 8.02% N: 16.43%

Measurements; C: 64.71% H: 8.06% N: 16.37%

Step 4) 1-N-benzylpyrrolidine-3-spiro-1 ', 3'-diaza-1'-methyl-3'-[2 ''-(3-hydroxy-5-oxopyranyl) Preparation of ethyl] -2 ', 4'-cyclopentadione (compound of formula (I))

40 mg of the desired yellow solid compound was obtained in the yield of 56% by the same procedure as in Steps 3 to 6 of Example 1, using the compound prepared in Step 3).

Elemental analysis (C ₂₁ H ₂₇ N ₃ O ₅ ) theory; C: 62.83% H: 6.78% N: 10.47%

Measurements; C: 62.81% H: 6.76% N: 10.37%

Example 3: 1-N-benzylpyrrolidine-3-spiro-1 ', 3'-diaza-3'-[2 ''-(3-hydroxy-5-oxopyranyl) ethyl] -2 Preparation of ', 4'-cyclopentadione (compound of formula (I))

60% of the desired yellow solid compound 60% by performing the same reaction as in Example 1 using N-benzyl-3-oxopyrrolidine (compound of Formula (III)) prepared in Preparation Example 1 above. Obtained in the yield.

Elemental analysis (C ₂₀ H ₂₅ N ₃ O ₅ ) theory; C: 62.00% H: 6.50% N: 10.85%

Measurements; C: 62.04% H: 6.56% N: 10.87%

Example 4 1-N- (pyridin-3-ylmethyl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-isopropyl-3'-[2 ''-(3- Preparation of hydroxy-5-oxopyranyl) ethyl] -2 ', 4'-cyclopentadione (compound of formula (I))

Using the N- (pyridin-3-yl) methyl-3-oxopyrrolidine (compound of formula (III)) prepared in Example 7 and subjected to the same reaction as in Example 2 to the desired yellow 45 mg of solid compound were obtained in 53% yield.

Elemental analysis (C ₂₂ H ₃₀ N ₄ O ₅ ) theory; C: 61.38% H: 7.02% N: 13.01%

Measurements; C: 62.81% H: 6.76% N: 10.37%

Example 5: 1-N- (pyridin-2-ylmethyl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-ethyl-3'-[2 ''-(3-hydric Preparation of Roxy-5-oxopyranyl) ethyl] -2 ', 4'-cyclopentadione (compound of formula (I))

Using the N- (pyridin-2-yl) methyl-3-oxopyrrolidine (compound of formula (III)) prepared in Preparation Example 8 and the same reaction as in Example 2, the desired yellow 25 mg of a solid compound were obtained in a yield of 51%.

Elemental analysis (C ₂₁ H ₂₈ N ₄ O ₅ ) theory; C: 60.56% H: 6.78% N: 13.45%

Measurements; C: 60.51% H: 6.76% N: 13.37%

Example 6: 1-N- (pyridin-4-ylmethyl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-cyclopropyl-3'-[2 ''-(3- Preparation of hydroxy-5-oxopyranyl) ethyl] -2 ', 4'-cyclopentadione (compound of formula (I))

Using the N- (pyridin-4-yl) methyl-3-oxopyrrolidine (compound of formula (III)) prepared in Example 6 and the same reaction as in Example 2 to give the desired yellow 30 mg of a solid compound were obtained in a yield of 52%.

Elemental analysis (C ₂₂ H ₂₈ N ₄ O ₅ ) theory; C: 61.67% H: 6.59% N: 13.08%

Measurements; C: 61.71% H: 6.56% N: 13.07%

Example 7: 1-N- (2-nitrobenzyl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-isopropyl-3'-[2 ''-(3-hydroxy Preparation of -5-oxopyranyl) ethyl] -2 ', 4'-cyclopentadione (compound of formula (I))

The desired yellow solid was subjected to the same reaction as in Example 2 using N- (2-nitrobenzyl) -3-oxopyrrolidine (compound of formula (III)) prepared in Preparation Example 13. 45 mg of compound was obtained in 60% yield.

Elemental analysis (C ₂₃ H ₃₀ N ₄ O ₇ ) theory; C: 58.22% H: 6.37% N: 11.81%

Measurements; C: 58.21% H: 6.42% N: 11.77%

Example 8 1-N- (2-fluorobenzyl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-methyl-3'-[2 ''-(3-hydroxy Preparation of -5-oxopyranyl) ethyl] -2 ', 4'-cyclopentadione (compound of formula (I))

Using the N- (2-fluorobenzyl) -3-oxopyrrolidine (compound of formula (III)) prepared in Preparation Example 10 and the same reaction as in Example 2 to give the desired yellow 30 mg of a solid compound were obtained in a yield of 50%.

Elemental analysis (C ₂₁ H ₂₆ FN ₃ O ₅ ) theory; C: 60.13% H: 6.25% N: 10.02%

Measurements; C: 60.11% H: 6.22% N: 10.07%

Example 9: 1-N- (3-fluorobenzyl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-methyl-3'-[2 ''-(3-hydroxy Preparation of -5-oxopyranyl) ethyl] -2 ', 4'-cyclopentadione (compound of formula (I))

Using the N- (3-fluorobenzyl) -3-oxopyrrolidine (compound of formula (III)) prepared in Preparation Example 12 and the same reaction as in Example 2 to give the desired yellow 50 mg of solid compound were obtained in a yield of 56%.

Elemental analysis (C ₂₁ H ₂₆ FN ₃ O ₅ ) theory; C: 60.13% H: 6.25% N: 10.02%

Measurements; C: 60.08% H: 6.32% N: 10.01%

Example 10 1-N- (2,4-difluorobenzyl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-methyl-3'-[2 ''-(3 -Hydroxy-5-oxopyranyl) ethyl] -2 ', 4'-cyclopentadione (compound of formula (I))

The same reaction as in Example 2 was carried out using N- (2,4-difluorobenzyl) -3-oxopyrrolidine (compound of formula (III)) prepared in Preparation Example 9 26 mg of a yellow solid compound was obtained in a yield of 49%.

Elemental analysis (C ₂₁ H ₂₅ F ₂ N ₃ O ₅ ) theory; C: 57.66% H: 5.76% N: 9.61%

Measurements; C: 57.71% H: 5.72% N: 9.67%

Example 11 1-N-phenylpyrrolidine-3-spiro-1 ', 3'-diaza-1'-ethyl-3'-[2 ''-(3-hydroxy-5-oxopyranyl ) Ethyl] -2 ', 4'-cyclopentadione (compound of general formula (I))

52% of the desired yellow solid compound (52 mg) was subjected to the same reaction as in Example 2 using N-phenyl-3-oxopyrrolidine (compound of Formula (III)) prepared in Preparation Example 2. Obtained in the yield.

Elemental analysis (C ₂₁ H ₂₇ N ₃ O ₅ ) theory; C: 62.83% H: 6.78% N: 10.47%

Measurements; C: 62.781% H: 6.72% N: 10.47%

Example 12 1-N- (pyridin-2-yl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-ethyl-3'-[2 ''-(3-hydroxy Preparation of -5-oxopyranyl) ethyl] -2 ', 4'-cyclopentadione (compound of formula (I))

Using the N- (pyridin-2-yl) -3-oxopyrrolidine (compound of formula (III)) prepared in Preparation Example 4 and the same reaction as in Example 2 to give the desired yellow 26 mg of solid compound were obtained in a yield of 50%.

Elemental analysis (C ₂₀ H ₂₆ N ₄ O ₅ ) theory; C: 59.69% H: 6.51% N: 13.92%

Measurements; C: 59.61% H: 6.52% N: 11.97%

Example 13: 1-N- (pyridin-3-yl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-ethyl-3'-[2 ''-(3-hydroxy Preparation of -5-oxopyranyl) ethyl] -2 ', 4'-cyclopentadione (compound of formula (I))

Using the N- (pyridin-3-yl) -3-oxopyrrolidine (compound of formula (III)) prepared in Preparation Example 5 and the same reaction as in Example 2 to give the desired yellow 26 mg of solid compound were obtained in 51% yield.

Elemental analysis (C ₂₀ H ₂₆ N ₄ O ₅ ) theory; C: 59.69% H: 6.51% N: 13.92%

Measurements; C: 59.71% H: 6.52% N: 13.87%

Example 14 1-N- (pyridin-4-yl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-ethyl-3'-[2 ''-(3-hydroxy Preparation of -5-oxopyranyl) ethyl] -2 ', 4'-cyclopentadione (compound of formula (I))

Using the N- (pyridin-4-yl) -3-oxopyrrolidine (compound of formula (III)) prepared in Preparation Example 3 and the same reaction as in Example 2 to give the desired yellow 25 mg of solid compound were obtained in 51% yield.

Elemental analysis (C ₂₀ H ₂₆ N ₄ O ₅ ) theory; C: 59.69% H: 6.51% N: 13.92%

Measurements; C: 59.64% H: 6.45% N: 13.92%

Example 15 1-N- (5-fluoropyridin-2-ylmethyl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-isopropyl-3'-[2 '' Preparation of-(3-hydroxy-5-oxopyranyl) ethyl] -2 ', 4'-cyclopentadione (compound of formula (I))

The same reaction as in Example 2 was carried out using N- (5-fluoropyridin-2-yl) methyl-3-oxopyrrolidine (compound of formula (III)) prepared in Preparation Example 14. To give 26 mg of the desired yellow solid compound in 52% yield.

Elemental analysis (C ₂₂ H ₂₉ FN ₄ O ₅ ) theory; C: 58.92% H: 6.52% N: 12.49%

Measurements; C: 58.91% H: 6.52% N: 12.47%

Example 16 1-N- (5-fluoropyridin-2-yl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-isopropyl-3'-[2 ''- Preparation of (3-hydroxy-5-oxopyranyl) ethyl] -2 ', 4'-cyclopentadione (compound of formula (I))

The same reaction as in Example 2 was carried out using N- (5-fluoropyridin-2-yl) -3-oxopyrrolidine (compound of formula (III)) prepared in Preparation Example 15. 44 mg of the desired yellow solid compound was obtained in a yield of 56%.

Elemental analysis (C ₂₁ H ₂₇ FN ₄ O ₅ ) theory; C: 58.06% H: 6.26% N: 12.90%

Measurements; C: 58.01% H: 6.32% N: 12.87%

Example 17 1-N-phenylpiperidine-3-spiro-1 ', 3'-diaza-1'-isopropyl-3'-[2 ''-(3-hydroxy-5-oxopyra Yl) ethyl] -2 ', 4'-cyclopentadione (compound of formula (I))

Using the N-phenyl-3-oxopiperidine (compound of Formula (III)) prepared in Example 16 and the same reaction as in Example 2, 51% of the desired yellow solid compound 28mg Obtained in the yield.

Elemental analysis (C ₂₃ H ₃₁ N ₃ O ₅ ) theory; C: 64.32% H: 7.27% N: 9.78%

Measurements; C: 64.31% H: 7.32% N: 9.81%

Example 18 1-N- (5-fluoropyridin-2-ylmethyl) piperidine-3-spiro-1 ', 3'-diaza-1'-isopropyl-3'-[2 '' Preparation of-(3-hydroxy-5-oxopyranyl) ethyl] -2 ', 4'-cyclopentadione (compound of formula (I))

The same reaction as in Example 2 was carried out using N- (5-fluoropyridin-2-yl) methyl-3-oxopiperidine (compound of formula (III)) prepared in Preparation Example 19. 24 mg of the desired yellow solid compound was obtained in 49% yield.

Elemental analysis (C ₂₃ H ₃₁ FN ₄ O ₅ ) theory; C: 59.73% H: 6.76% N: 12.11%

Measurements; C: 59.71% H: 6.72% N: 12.07%

Example 19 1-N- (pyridin-4-ylmethyl) piperidine-3-spiro-1 ', 3'-diaza-3'-[2 ''-(3-hydroxy-5-oxo Preparation of pyranyl) ethyl] -2 ', 4'-cyclopentadione (compound of formula (I))

Using the N- (pyridin-4-yl) methyl-3-oxopiperidine (compound of formula (III)) prepared in Example 18 and the same reaction as in Example 1 to give the desired yellow 40 mg of solid compound were obtained in 53% yield.

Elemental analysis (C ₂₀ H ₂₆ N ₄ O ₅ ) theory; C: 59.69% H: 6.51% N: 13.92%

Measurements; C: 59.63% H: 6.68% N: 13.87%

Example 20 1-N- (pyridin-4-ylmethyl) piperidine-3-spiro-1 ', 3'-diaza-1'-cyclopropyl-3'-[2 ''-(3- Preparation of hydroxy-5-oxopyranyl) ethyl] -2 ', 4'-cyclopentadione (compound of formula (I))

Using the N- (pyridin-4-yl) methyl-3-oxopiperidine (compound of formula (III)) prepared in Example 18 and the same reaction as in Example 2, the desired yellow 28 mg of a solid compound were obtained in a yield of 50%.

Elemental analysis (C ₂₃ H ₃₀ N ₄ O ₅ ) theory; C: 62.43% H: 6.63% N: 12.66%

Measurements; C: 62.41% H: 6.78% N: 12.67%

Example 21 1-N- (5-fluoropyridin-2-yl) piperidine-3-spiro-1 ', 3'-diaza-1'-isopropyl-3'-[2 ''- Preparation of (3-hydroxy-5-oxopyranyl) ethyl] -2 ', 4'-cyclopentadione (compound of formula (I))

The same reaction as in Example 2 was carried out using N- (5-fluoropyridin-2-yl) -3-oxopiperidine (compound of formula (III)) prepared in Preparation Example 21. 60 mg of the desired yellow solid compound was obtained in a yield of 75%.

Elemental analysis (C ₂₂ H ₂₉ FN ₄ O ₅ ) theory; C: 58.92% H: 6.52% N: 12.49%

Measurements; C: 58.91% H: 6.58% N: 12.47%

Example 22 1-N- (pyridin-4-yl) piperidine-3-spiro-1 ', 3'-diaza-1'-isopropyl-3'-[2 ''-(3-hydric Preparation of Roxy-5-oxopyranyl) ethyl] -2 ', 4'-cyclopentadione (compound of formula (I))

Using the N- (pyridin-4-yl) -3-oxopiperidine (compound of formula (III)) prepared in Example 20 and the same reaction as in Example 2 to give the desired yellow 24 mg of solid compound were obtained in 43% yield.

Elemental analysis (C ₂₂ H ₃₀ N ₄ O ₅ ) theory; C: 61.38% H: 7.02% N: 13.01%

Measurements; C: 61.41% H: 6.98% N: 13.07%

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 7.0 114 Example 2 6.1 131 Example 3 3.2 250 Lovastatin 8.0 100

The spirohydantoin derivative according to the present invention has an excellent inhibitory effect of HMG-Co A reductase, which is advantageous in reducing blood lipid concentration.

Claims (2)

Spirohydantoin derivatives of the general formula (I) Formula 1 Where R ₁ is hydrogen, C _1-4 alkyl or C _3-4 cycloalkyl; R ₂ is hydrogen, halogen or nitro group; A is carbon or nitrogen; m is 0 or 1; n is 1 or 2. The method of claim 1, 3-N- [2 ''-(3-hydroxy-5-oxopyranyl) ethyl] -1,3-diaza-2,4-cyclopentadione-5-spiro-3- (1-N- Benzyl) piperidine, 1-N-benzylpyrrolidine-3-spiro-1 ', 3'-diaza-1'-methyl-3'-[2 ''-(3-hydroxy-5-oxopyranyl) ethyl]- 2 ', 4'-cyclopentadione, 1-N-benzylpyrrolidine-3-spiro-1 ', 3'-diaza-3'-[2 ''-(3-hydroxy-5-oxopyranyl) ethyl] -2 ', 4' Cyclopentadione, 1-N- (pyridin-3-ylmethyl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-isopropyl-3'-[2 ''-(3-hydroxy-5 Oxopyranyl) ethyl] -2 ', 4'-cyclopentadione, 1-N- (pyridin-2-ylmethyl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-ethyl-3'-[2 ''-(3-hydroxy-5- Oxopyranyl) ethyl] -2 ', 4'-cyclopentadione, 1-N- (pyridin-4-ylmethyl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-cyclopropyl-3'-[2 ''-(3-hydroxy-5 Oxopyranyl) ethyl] -2 ', 4'-cyclopentadione, 1-N- (2-nitrobenzyl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-isopropyl-3'-[2 ''-(3-hydroxy-5-oxo Pyranyl) ethyl] -2 ', 4'-cyclopentadione, 1-N- (2-fluorobenzyl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-methyl-3'-[2 ''-(3-hydroxy-5-oxo Pyranyl) ethyl] -2 ', 4'-cyclopentadione, 1-N- (3-fluorobenzyl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-methyl-3'-[2 ''-(3-hydroxy-5-oxo Pyranyl) ethyl] -2 ', 4'-cyclopentadione, 1-N- (2,4-difluorobenzyl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-methyl-3'-[2 ''-(3-hydroxy- 5-oxopyranyl) ethyl] -2 ', 4'-cyclopentadione, 1-N-phenylpyrrolidine-3-spiro-1 ', 3'-diaza-1'-ethyl-3'-[2 ''-(3-hydroxy-5-oxopyranyl) ethyl]- 2 ', 4'-cyclopentadione, 1-N- (pyridin-2-yl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-ethyl-3'-[2 ''-(3-hydroxy-5-oxo Pyranyl) ethyl] -2 ', 4'-cyclopentadione, 1-N- (pyridin-3-yl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-ethyl-3'-[2 ''-(3-hydroxy-5-oxo Pyranyl) ethyl] -2 ', 4'-cyclopentadione, 1-N- (pyridin-4-yl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-ethyl-3'-[2 ''-(3-hydroxy-5-oxo Pyranyl) ethyl] -2 ', 4'-cyclopentadione, 1-N- (5-fluoropyridin-2-ylmethyl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-isopropyl-3'-[2 ''-(3- Hydroxy-5-oxopyranyl) ethyl] -2 ', 4'-cyclopentadione, 1-N- (5-fluoropyridin-2-yl) pyrrolidine-3-spiro-1 ', 3'-diaza-1'-isopropyl-3'-[2 ''-(3-hydrate Hydroxy-5-oxopyranyl) ethyl] -2 ', 4'-cyclopentadione, 1-N-phenylpiperidine-3-spiro-1 ', 3'-diaza-1'-isopropyl-3'-[2 ''-(3-hydroxy-5-oxopyranyl) ethyl] -2 ', 4'-cyclopentadione, 1-N- (5-fluoropyridin-2-ylmethyl) piperidine-3-spiro-1 ', 3'-diaza-1'-isopropyl-3'-[2 ''-(3- Hydroxy-5-oxopyranyl) ethyl] -2 ', 4'-cyclopentadione, 1-N- (pyridin-4-ylmethyl) piperidine-3-spiro-1 ', 3'-diaza-1'-methyl-3'-[2 ''-(3-hydroxy-5- Oxopyranyl) ethyl] -2 ', 4'-cyclopentadione, 1-N- (pyridin-4-ylmethyl) piperidine-3-spiro-1 ', 3'-diaza-1'-cyclopropyl-3'-[2 ''-(3-hydroxy-5 Oxopyranyl) ethyl] -2 ', 4'-cyclopentadione, 1-N- (5-fluoropyridin-2-yl) piperidine-3-spiro-1 ', 3'-diaza-1'-isopropyl-3'-[2 ''-(3-hydrate Oxy-5-oxopyranyl) ethyl] -2 ', 4'-cyclopentadione, and 1-N- (pyridin-4-yl) piperidine-3-spiro-1 ', 3'-diaza-1'-isopropyl-3'-[2 ''-(3-hydroxy-5- Oxopyranyl) ethyl] -2 ', 4'-cyclopentadione Spirohydantoin derivatives, characterized in that selected from the group consisting of.