KR100398055B1 - Quinone derivatives which exhibit antioxidant activity - Google Patents

Abstract

The present invention relates to a quinone compound represented by the following formula (1) having an antioxidant activity and a pharmaceutically acceptable salt thereof.

In Formula 1: R ₁ , R ₂ , R ₃ , X and n are as defined in the detailed description of the invention, respectively.

Description

Quinone derivatives which exhibit antioxidant activity

The present invention relates to a quinone compound represented by the following formula (1) having an antioxidant activity and a pharmaceutically acceptable salt thereof.

Formula 1

In Formula 1 above:

R ₁ and R ₂ are each independently a methyl group or a methoxy group, or R ₁ and R ₂ are each connected to represent -CH = CH-CH = CH-; R ₃ is , -NH- (CH ₂ ) _m -R ₅ , , -CO ₂ R ₆ , or -OH; Wherein R ₄ is a halogen atom, -O (CH ₂ ) _n CH ₃ , -O (CH ₂ ) _n OH, -O (CH ₂ ) _n O (CO) CH ₃ , -O (CH ₂ ) _n R ₅ Or -O (CH ₂ ) CO ₂ R ₆ ; R ₅ represents a methyl group, a phenyl group, a benzyl group, a naphthyl group, a thiophene group, or a pyridine group; R ₆ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; X represents CH ₂ , or C═O; n and m represent 0 or the integer of 1-10, respectively.

Oxygen in the air that we breathe is oxidized nutrients in the mitochondria cells in the act that made ATP, though, the oxygen of 2-5% of the inevitable · O ₂ ^-, H ₂ O _2, · OH, etc. It turns into free radicals that are harmful to the human body. As a defense against these, antioxidants such as superoxide dismutase (SOD), catalase, and peroxidase, and antioxidants such as glutathione and coenzyme Q (CoQ) are present in vivo. You can also get antioxidants, such as vitamin E or vitamin C, from food. In certain circumstances, however, excessive amounts of free radicals can cause excess oxidative stress. That is, free radicals attack living cells, destroy lipids, proteins and nucleic acids (DNA, RNA) and inhibit various enzyme functions, resulting in disease and aging. In particular, it attacks lipid components, produces lipid peroxides that act as cytotoxicity, destroys cell membranes, induces cancer, and promotes aging, arteriosclerosis, diabetes and dementia, stroke, and neurological diseases such as Parkin's disease. Therefore, antioxidants that inevitably eliminate or inhibit the production of free radicals that are inevitably produced during metabolic processes in the body can be used as anti-aging agents and anticancer agents, as well as in treating neurodegenerative diseases such as dementia, Parkin's disease, strokes, and Hentinton. It can be used as a therapeutic agent for diseases such as diabetes and epilepsy. Therefore, the development of new antioxidants is urgently needed.

Recently, there has been great interest in coenzyme Q (CoQ) substances as a new antioxidant development, because it is linked to the respiratory complex in mitochondria and the reduced form CoQH ₂ is known to act as an antioxidant. `` Idebenone '', an antioxidant developed by Todada Pharmaceutical Co., Ltd., is an analog of CoQ and is currently marketed in Japan and Korea as a brain function improver for patients with Alzheimer's disease. . However, recently, the drug efficacy of idebenone has been raised, which may be due in part to the low antioxidant activity of idebenone.

On the other hand, both CoQ and idebenone are structurally quinone compounds, and since the development of idebenone, quinone-based antioxidant development has been intensively studied. Quinone-based antioxidants developed by Nippon Pharmaceutical Co., Ltd. are described in US Pat. Nos. 5,480,907, 5,304,658, 5,229,385, 5,180,742, 5,106,858, and the like.

The present inventors have tried to develop a novel quinone compound that is more excellent in antioxidant activity than the existing quinone compounds such as idebenone, and as a result, the antioxidative activity of the novel compound prepared by changing the structure of idebenone is excellent. Knowing this has led to the completion of the present invention.

Accordingly, it is an object of the present invention to provide novel quinone compounds having antioxidant activity and pharmaceutically acceptable salts thereof.

Another object of the present invention is to contain a novel quinone compound having antioxidant activity and a pharmaceutically acceptable salt thereof as an active ingredient, anti-aging agent and treatment of cancer, diabetes, epilepsy and the like, and dementia, Parkin's disease, stroke The present invention provides a pharmaceutical composition that can be used as a therapeutic agent for neurodegenerative diseases such as Hectinton.

The present invention is characterized by a quinone compound represented by the following formula (1) having an antioxidant activity and a pharmaceutically acceptable salt thereof.

Formula 1

In Formula 1 above:

R ₁ and R ₂ are each independently a methyl group or a methoxy group, or R ₁ and R ₂ are each connected to represent -CH = CH-CH = CH-; R ₃ is , -NH- (CH ₂ ) _m -R ₅ , , -CO ₂ R ₆ , or -OH; Wherein R ₄ is a halogen atom, -O (CH ₂ ) _n CH ₃ , -O (CH ₂ ) _n OH, -O (CH ₂ ) _n O (CO) CH ₃ , -O (CH ₂ ) _n R ₅ Or -O (CH ₂ ) CO ₂ R ₆ ; R ₅ represents a methyl group, a phenyl group, a benzyl group, a naphthyl group, a thiophene group, or a pyridine group; R ₆ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; X represents CH ₂ , or C═O; n and m represent 0 or the integer of 1-10, respectively.

Referring to the present invention in more detail as follows.

In the quinone compound represented by Chemical Formula 1 according to the present invention, preferably, R ₁ and R ₂ each independently represent a methyl group or a methoxy group; R ₃ is , -NH- (CH ₂ ) _m -R ₅ , , -CO ₂ R ₆ or -OH; Wherein R ₄ is a halogen atom, -O (CH ₂ ) _n CH ₃ , -O (CH ₂ ) _n OH, -O (CH ₂ ) _n O (CO) CH ₃ , -O (CH ₂ ) _n R ₅ Or -O (CH ₂ ) CO ₂ R ₆ ; R ₅ represents a methyl group, a phenyl group or a benzyl group; R ₆ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; X represents CH ₂ or C═O; n and m are each 0 or an integer of 1 to 10.

In the quinone compound represented by Chemical Formula 1 according to the present invention, more preferably, R ₁ and R ₂ represent a methyl group; R ₃ is Or -CO ₂ R ₆ ; Wherein R ₄ is a halogen atom, -O (CH ₂ ) _n CH ₃ , -O (CH ₂ ) _n OH, -O (CH ₂ ) _n O (CO) CH ₃ , -O (CH ₂ ) _n R ₅ Or -O (CH ₂ ) CO ₂ R ₆ ; R ₅ represents a methyl group or a phenyl group; R ₆ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; X represents C = 0; n and m are each 0 or an integer of 1 to 10.

In more detail, the quinone compound represented by Formula 1 according to the present invention is as follows:

2-benzoyl-5,6-dimethoxy-3-methylbenzo-1,4-quinone;

2- (4-fluorobenzoyl) -5,6-dimethoxy-3-methyl- [1,4] benzoquinone;

2- (2-chlorobenzoyl) -5,6-dimethoxy-3-methyl- [1,4] benzoquinone;

4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dienecarboxylic acid benzylamide;

4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dienecarboxylic acid phenylethylamide;

4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dienecarboxylic acid-3-phenylpropylamide;

2,3-dimethoxy-5-methyl-6- (4-pyridin-2-yl-piperazine-1-carbonyl)-[1,4] benzoquinone;

1- (4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadienyl) decyl acetate;

2- (4-benzyloxybenzyl) -5,6-dimethoxy-3-methylbenzo-1,4-quinone;

2,3-dimethoxy-5- (4-methoxybenzyl) -6-methylbenzo-1,4-quinone;

2- (4-ethylbenzyl) -5,6-dimethoxy-3-methylbenzo-1,4-quinone;

2- (4-butoxybenzyl) -5,6-dimethoxy-3-methylbenzo-1,4-quinone;

9- [4- (4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadienylmethyl) phenyloxy] nonyl acetate;

10- [4- (4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadienylmethyl) phenyloxy] decyl acetate;

2- [4- (9-hydroxynonyloxy) benzyl] -5,6-dimethoxy-3-methylbenzo-1,4-quinone;

2- [4- (10-hydroxydecyloxy) benzyl] -5,6-dimethoxy-3-methylbenzo-1,4-quinone;

Methyl 2- [4- (4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadienylmethyl) phenyloxy] acetate;

2- [4- (4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadienylmethyl) phenyloxy] ethyl acetate;

2- [4- (2-hydroxyethanol) benzyl] -5,6-dimethoxy-3-methylbenzo-1,4-quinone;

2,3-dimethoxy-5-methyl-6- (4-methylpiperazin-1-yl-methyl)-[1,4] benzoquinone;

2,3-dimethoxy-5-methyl-6- (4-pyridin-2-yl-piperazin-1-yl-methyl)-[1,4] benzoquinone.

In addition, the quinone compound represented by Formula 1 according to the present invention may form a pharmaceutically acceptable salt by a conventional method in the art. For example, salts with inorganic acids such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, carbonic acid or formic acid, acetic acid, oxalic acid, benzoic acid, citric acid, tartaric acid, gluconic acid, gesty acid, fumaric acid, lactobionic acid, Forming salts of pharmaceutically acceptable salts of these acids with organic acids such as salicylic acid or acetylsalicylic acid (aspirin), or reacting with alkali metal ions such as sodium or potassium to form their metal salts, Or may be reacted with ammonium ions to form another form of a pharmaceutically acceptable salt.

In addition, the quinone compound represented by Formula 1 and pharmaceutically acceptable salts thereof according to the present invention may exhibit polymorphism crystals.

On the other hand, if the quinone compound represented by the formula (1) according to the present invention and a method for preparing a pharmaceutically acceptable salt thereof are briefly shown in the following scheme 1.

In Reaction Scheme 1: R ₁ , R ₂ , R ₃ , X and n are as defined in Formula 1, respectively.

The preparation method as shown in Scheme 1 includes two steps as follows: (i) converting the compound represented by Chemical Formula 2 to the compound represented by Chemical Formula 3 by acylation or alkylation; And (ii) preparing the compound represented by Chemical Formula 1 by reacting the compound represented by Chemical Formula 3 with cerium (Ce) reagent or silver oxide (AgO).

In addition, the compound represented by Formula 3 synthesized as an intermediate during the preparation process according to Scheme 1 is a novel compound, the present invention provides a novel intermediate compound represented by Formula 3 useful for preparing the quinone compound represented by Formula 1 Include.

In the preparation method according to Scheme 1, as a first process, the reaction of converting the compound represented by the formula (2) into the compound represented by the formula (3) is a kind of alkylation or acylation reaction, and such alkylation or acylation reaction is known. Done by the method.

The following Reaction Schemes 2 to 5 illustrate some alkylation or acylation reactions for the preparation of compounds represented by Formula 3 from the compounds represented by Formula 2, and the process for preparing compounds represented by Formula 3 according to the present invention It is not limited by this, It can manufacture also by another conventional method.

In Reaction Scheme 2: R ₁ , R ₂ , R ₃ , and n are as defined in Formula 1, respectively.

The acylation reaction according to Scheme 2 may be completed using a catalyst such as AlCl ₃ and a carboxylic acid chloride compound corresponding to the compound represented by Chemical Formula 3a in a solvent of dichloromethane, tetrahydrofuran, benzene or nitrobenzene. The above acylation reaction temperature range is between room temperature and solvent boiling point temperature and the reaction time is usually within 12 hours.

In Scheme 3: R ₁ , R ₂ and R ₄ are the same as defined in Chemical Formula 1, respectively.

In the preparation method according to Scheme 3, a process for preparing the compound represented by Formula 4 from the compound represented by Formula 2 is a method already known in the literature [ J. Med. Chem . 267-276 (1991). In the process of preparing the compound represented by Chemical Formula 5 from the compound represented by Chemical Formula 4, a Grignard reagent is used to perform a known method. In the process of preparing the compound represented by Chemical Formula 3b from the compound represented by Chemical Formula 5, a conventional oxidizing agent including pyridinium chlorochromate (PCC) may be used by a known method.

In Scheme 4: R ₁ , R ₂ , R ₅ and m are as defined in Formula 1, respectively.

In the preparation method according to Scheme 4, in the process for preparing the compound represented by the formula (6) from the compound represented by the formula (2) using a bromination reagent, including Br ₂ or N -bromosuccinimide (NBS) Brominated to the ring, followed by treatment with n-butyllithium followed by injection of CO ₂ . Then, the compound represented by Chemical Formula 3c or 3d is prepared by condensation reaction between the compound represented by Chemical Formula 6 and the primary amine or piperazine corresponding to the desired compound.

In Scheme 5: R ₁ , R ₂ , R ₄ and R ₅ are as defined in Chemical Formula 1, respectively.

In the preparation method according to Scheme 5, the process for preparing the compound represented by Formula 7 from the compound represented by Formula 2 is performed by a method already known in the literature [ J. Med. Chem . 267-276 (1991). In the process of preparing the compound represented by Chemical Formula 3e from the compound represented by Chemical Formula 7, the aryl lithium or Grignard reagent is used. In the process of preparing the compound represented by Chemical Formula 3f from the compound represented by Chemical Formula 7, various piperazine derivatives are combined and reacted.

The following reaction scheme 6 is shown as an example of the conversion reaction from the novel intermediate compound represented by the above formula (3) to the compound represented by the formula (1). However, the manufacturing method of the compound represented by the formula (1) according to the present invention is not limited thereto, and may be prepared by other conventional methods.

In Scheme 6: R ₁ , R ₂ , R ₃ , X and n are the same as defined in Chemical Formula 1.

In the preparation method according to Scheme 6, the new intermediate represented by Formula 3 is reacted with a cerium (Ce) reagent, for example, ceric ammonium nitrate (CAN), or silver oxide (AgO) to give a compound represented by Formula 1 Can be prepared. In a reaction using a cerium reagent (e.g., CAN), 2 to 10 equivalents of the reagent are used, and as a reaction solvent, a mixed solvent of water and an organic solvent, for example, a mixed solvent of water and tetrahydrofuran, or of water and acetonitrile It is preferable to use a mixed solvent, and the reaction is usually completed within 24 hours at 0 to 30 ° C. In addition, in the reaction using silver oxide (AgO), it is preferable to add 2 to 10 equivalents of reagent and nitric acid, and to use a mixed solvent of water and an organic solvent as described above, and the reaction is usually performed at 0 to 30 ° C. It will be completed within 24 hours.

Separation and purification methods of the novel intermediate represented by the general formula (3) and the quinone compound represented by the general formula (1) synthesized from the above production methods are based on conventional methods such as chromatography and recrystallization.

Meanwhile, since the quinone compound represented by Chemical Formula 1 according to the present invention has excellent antioxidant activity, anti-aging agents and therapeutic agents such as cancer, diabetes, and epilepsy, and neurodegenerative diseases treatment agents such as dementia, Parkin's disease, stroke, and Hentinton As it is very effective, the present invention includes a pharmaceutical composition containing a novel quinone compound represented by the formula (1) as an active ingredient. The pharmaceutical composition may be added to the quinone compound represented by Chemical Formula 1 by a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and excipient, and the like, which are conventional agents in the pharmaceutical field, for example, tablets, capsules, troches, solutions, and suspensions. It may be formulated into a formulation for oral administration or a formulation for parenteral administration. In addition, the dosage of the compound represented by Chemical Formula 1 to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and is based on an adult patient having a weight of 70 kg. Generally, it is 0.01-1000 mg / day, and may be divided once a day or several times at regular time intervals according to the judgment of a doctor or a pharmacist.

The present invention as described above will be described in more detail based on the following Examples and Experimental Examples, but the present invention is not limited thereto.

Example 1 Preparation of 2-benzoyl-5,6-dimethoxy-3-methylbenzo-1,4-quinone

Phenyl-2,3,4,5-tetramethoxy-6-methylphenylmethanone (200 mg, 0.64 mmol) was dissolved in CH ₃ CN (3 mL) and then lowered to 0 ° C. CAN (ceric ammonium nitrate, 728 mg, 1.33 mmol) was dissolved in H ₂ O (1.5 mL) and slowly titrated for 5 minutes. After completion of the reaction, saturated aqueous NaHCO ₃ solution (10 mL) was poured out, extracted with ethyl acetate (10 mL × 3), and dried over Na ₂ SO ₄ . After concentration of the solvent under reduced pressure, the residue was purified by column chromatography (hexane / ethyl acetate = 2/1) to give 110 mg (61%) of the title compound.

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.91 (s, 3H, CH ₃ ), 4.02 (s, 3H, OCH ₃ ), 4.07 (s, 3H, OCH ₃ ), 7.49 to 7.87 (m, 5H, ArH); Mass m / z (Rel. Intensity) 286 (M ⁺ , 40), 105 (100), 77 (52); mp 89-92 ° C

Example 2: Preparation of 2- (4-fluorobenzoyl) -5,6-dimethoxy-3-methyl- [1,4] benzoquinone

(4-fluorophenyl)-(2,3,4,5-tetramethoxy-6-methylphenyl) methanone (45 mg, 0.13 mmol) was dissolved in CH ₃ CN (2 mL) and then CAN (153 mg) , 0.28 mmol) was dissolved in H ₂ O (1 mL) and slowly titrated at 0 ° C. After 5 minutes, saturated aqueous NaHCO ₃ solution (10 mL) was poured out, extracted with ethyl acetate (5 mL × 3), dried over Na ₂ SO _4, and the solvent was concentrated under reduced pressure. The residue was subjected to column chromatography (hexane / ethyl acetate = 2/1) to give 15.6 mg (39%) of the title title compound.

¹ H NMR (200 MHz, CDCl ₃ ) δ1.09 (s, 3H, CH ₃ ), 4.00 (s, 3H, OCH ₃ ), 4.05 (s, 3H, OCH ₃ ), 7.16 (t, J = 8.6 Hz , 2H, ArH), 7.26 (t, J = 8.7 Hz, 2H, ArH); Mass m / z (Rel. Intensity) 304 (M ⁺ , 56), 245 (55), 84 (100); mp 93-94 ℃

Example 3: Preparation of 2- (2-chlorobenzoyl) -5,6-dimethoxy-3-methyl- [1,4] benzoquinone

(2-chlorophenyl)-(2,3,4,5-tetramethoxy-6-methylphenyl) methanone (87.8 mg, 0.25 mmol) was dissolved in CH ₃ CN (2 mL) and then CAN (285 mg, 0.52 mmol) was dissolved in H ₂ O (1 mL) and slowly titrated at 0 ° C. After 5 minutes, saturated aqueous NaHCO ₃ solution (5 mL) was poured out, extracted with ethyl acetate (5 mL × 3), dried over Na ₂ SO _4, and the solvent was concentrated under reduced pressure. The residue was subjected to column chromatography (hexane / ethyl acetate = 2/1) to give 15.6 mg (20%) of the title compound on oil.

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.99 (s, 3H, CH ₃ ), 3.98 (s, 3H, OCH ₃ ), 4.06 (s, 3H, OCH ₃ ), 7.29 to 7.54 (m, 4H, ArH); Mass m / z (Rel. Intensity) 320 (M ⁺ , 65), 285 (72), 139 (100)

Example 4 Preparation of 4,5-Dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dienecarboxylic acid benzylamide

N-benzyl-2,3,4,5-tetramethoxy-6-methylbenzamide (50 mg, 0.14 mmol) was dissolved in CH ₃ CN (2 mL) and then lowered to 0 ° C. CAN (165 mg, 0.30 mmol) was dissolved in H ₂ O (1 mL) and slowly titrated for 5 minutes. After completion of the reaction, saturated aqueous NaHCO ₃ solution (10 mL) was poured out, extracted with ethyl acetate (10 mL × 3), and dried over Na ₂ SO ₄ . The solvent was concentrated under reduced pressure and the residue was subjected to column chromatography (hexane / ethyl acetate = 2/1) to give 22.6 mg (54%) of the title compound.

¹ H NMR (200 MHz, CDCl ₃ ) δ 2.18 (s, 3H, CH ₃ ), 3.99 (s, 3H, OCH ₃ ), 4.00 (s, 3H, OCH ₃ ), 4.63 (d, J = 5.7 Hz , 2H, CH ₂ ), 6.48 (br s, 1H, NH), 7.35 to 7.37 (m, 5H, ArH); Mass m / z (Rel. Intensity) 315 (M ⁺ , 16), 302 (5), 210 (83), 192 (20), 106 (100); mp 103-105 ℃

Example 5 Preparation of 4,5-Dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dienecarboxylic acid phenylethylamide

Benzyl-2,3,4,5-tetramethoxy-6-methyl-N-phenylethylamide (71 mg, 0.19 mmol) was dissolved in CH ₃ CN (2 mL) and then lowered to 0 ° C. CAN (332 mg, 0.59 mmol) was dissolved in H ₂ O (1 mL) and slowly titrated for 5 minutes. After completion of the reaction, saturated aqueous NaHCO ₃ solution (10 mL) was poured out, extracted with ethyl acetate (10 mL × 3), and dried over Na ₂ SO ₄ . The solvent was concentrated under reduced pressure and the residue was subjected to column chromatography (hexane / ethyl acetate = 2/1) to give 32 mg (52%) of the title compound as an oil.

¹ H NMR (200 MHz, CDCl ₃ ) δ2.04 (s, 3H, CH ₃ ), 2.91 (t, J = 6.9 Hz, 2H, CH ₂ ), 3.70 (q, J = 6.1 Hz, 2H, CH ₂ ), 3.98 (s, 3H, OCH ₃ ), 4.01 (s, 3H, OCH ₃ ), 6.21 (br s, 1H, NH), 7.21 to 7.39 (m, 5H, ArH); Mass m / z (Rel. Intensity) 329 (M ⁺ , 7), 209 (100), 181 (28), 106 (24)

Example 6 Preparation of 4,5-Dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dienecarboxylic acid-3-phenylpropylamide

Benzyl-2,3,4,5-tetramethoxy-6-methyl-N-phenylpropylamide (77.6 mg, 0.20 mmol) was dissolved in CH ₃ CN (2 mL) and then lowered to 0 ° C. CAN (340 mg, 0.64 mmol) was dissolved in H ₂ O (1 mL) and slowly stirred for 5 minutes. After completion of the reaction, saturated aqueous NaHCO ₃ solution (10 mL) was poured out, extracted with ethyl acetate (10 mL × 3), and dried over Na ₂ SO ₄ . The solvent was concentrated under reduced pressure and the residue was subjected to column chromatography (hexane / ethyl acetate = 2/1) to give 28 mg (41%) of the title compound as an oil.

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.89-1.97 (m, 2H, CH ₂ ), 2.13 (s, 3H, CH ₃ ), 2.73 (t, J = 7.7 Hz, 2H, CH ₂ ), 3.42 (q, J = 6.4 Hz, 2H, CH ₂ ), 3.99 (s, 3H, OCH ₃ ), 4.00 (s, 3H, OCH ₃ ), 6.37 (br s, 1H, NH), 7.18 to 7.33 (m, 5H, ArH); Mass m / z (Rel. Intensity) 343 (M ⁺ , 24), 328 (5), 210 (100), 192 (37)

Example 7: Preparation of 2,3-dimethoxy-5-methyl-6- (4-pyridin-2-yl-piperazine-1-carbonyl)-[1,4] benzoquinone

4-pyridin-2-yl-piperazin-1-yl- (2,3,4,5-tetramethoxy-6-methylphenyl) methanone (30 mg, 0.07 mmol) and AgO (46 mg, 0.37 mmol) Was dissolved in THF (2 mL) and stirred for 30 min with 6N HNO ₃ (0.5 mL). After completion of the reaction, H ₂ O (5 mL) was poured, extracted with ethyl acetate (5 mL × 5), and dried over Na ₂ SO ₄ . The solvent was concentrated under reduced pressure and the residue was subjected to column chromatography (hexane / ethyl acetate = 1/1, MeOH trace) to give 5 mg (19%) of the title compound as an oil.

¹ H NMR (200 MHz, CDCl ₃ ) δ2.02 (s, 3H, CH ₃ ), 3.54 to 3.96 (m, 8H, 4CH ₂ ), 4.01 (s, 3H, OCH ₃ ), 4.04 (s, 3H, OCH ₃ ), 6.61-66.6 (m, 2H, 2CH ₂ ), 7.46 (t, J = 6.9 Hz, 1H, ArH), 8.21 (d, J = 5.6 Hz, 1H, ArH); Mass m / z (Rel. Intensity) 371 (M ⁺ , 15), 356 (4), 255 (21), 239 (100), 106 (46)

Example 8 Preparation of 1- (4,5-Dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadienyl) decylacetate

Methyl 10- (2,3,4,5-tetramethoxy-6-methylphenyl) -10-undecenoate (15 mg, 0.036 mmol) was dissolved in dried CH ₃ CN (2 mL) and then 0 ° C. It was lowered and the CAN (108 mg, 0.19 mmol) was slowly dissolved by dissolving in H ₂ O (1 mL). After stirring for 15 minutes, saturated aqueous NaHCO ₃ solution was poured and extracted with ethyl acetate (5 mL × 5). The organic layer was dried over Na ₂ SO ₄ , the solvent was concentrated under reduced pressure, and the residue was purified by column chromatography (hexane / ethyl acetate = 3/1) to give 11.5 mg (84%) of the title compound.

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.29 (br s, 8H, 4CH ₂ ), 1.62 (br s, 4H, 2CH ₂ ), 1.93 (s, 3H, CH ₃ ), 2.29 (t, J = 7.5 Hz, 2H, CH ₂ ), 2.63 (t, J = 7.3 Hz, 2H, CH ₂ ), 3.66 (s, 3H, CO ₂ CH ₃ ), 4.00 (s, 3H, OCH ₃ ), 4.01 (s, 3H , OCH ₃ ); Mass m / z (Rel. Intensity) 380 (M ⁺ , 100), 237 (5), 224 (37), 210 (24), 184 (29); mp 47-48 ℃

Example 9 Preparation of 2- (4-benzyloxybenzyl) -5,6-dimethoxy-3-methylbenzo-1,4-quinone

1- (4-benzyloxybenzyl) -2,3,4,5-tetramethoxy-6-methylbenzene (65 mg, 0.16 mmol) was dissolved in CH ₃ CN (1 mL) and then lowered to 0 ° C. . CAN (183 mg, 0.33 mmol) was dissolved in H ₂ O (1 mL) and slowly dropped. After stirring for 5 minutes, saturated aqueous NaHCO ₃ solution (1 mL) was poured, the organic layer was extracted with ethyl acetate (5 mL × 3), dried over Na ₂ SO _4, and the solvent was concentrated under reduced pressure. The residue was subjected to column chromatography (hexane / ethyl acetate = 5/1) to give 44 mg (68%) of the title compound.

¹ H NMR (200 MHz, CDCl ₃ ) δ2.08 (s, 3H, CH ₃ ), 3.77 (s, 2H, CH ₂ ), 3.97 (s, 6H, 2OCH ₃ ), 5.01 (s, 2H, OCH ₂ ) 6.88 (d, J = 8.7 Hz, 2H, ArH), 7.07 (d, J = 8.7 Hz, 2H, ArH); Mass m / z (Rel. Intensity) 378 (M ⁺ , 100), 363 (26), 346 (6), 287 (41); mp 83-84 ℃

Example 10 Preparation of 2,3-Dimethoxy-5- (4-methoxybenzyl) -6-methylbenzo-1,4-quinone

1,2,3,4-tetramethoxy-5- (4-methoxybenzyl) -6-methylbenzene (147 mg, 0.44 mmol) was dissolved in CH ₃ CN (1 mL) and then CAN (506 mg, 0.92 mmol) was dissolved in H ₂ O (1 mL) and slowly dropped at 0 ° C. After stirring for 5 minutes, saturated aqueous NaHCO ₃ solution (1 mL) was poured, the organic layer was extracted with ethyl acetate (5 mL × 3), dried over Na ₂ SO _4, and the solvent was concentrated under reduced pressure. The residue was subjected to column chromatography (hexane / ethyl acetate = 4/1) to give 96.8 mg (73%) of the title compound.

¹ H NMR (200 MHz, CDCl ₃ ) δ2.08 (s, 3H, CH ₃ ), 3.76 (s, 3H, CH ₃ ), 3.77 (s, 2H, CH ₂ ), 3.98 (s, 6H, 2OCH ₃ ) 6.88 (d, J = 8.7 Hz, 2H, ArH), 7.07 (d, J = 8.7 Hz, 2H, ArH); Mass m / z (Rel. Intensity) 302 (M ⁺ , 53), 287 (100), 272 (14), 257 (10); mp 83-84 ℃

Example 11 Preparation of 2- (4-ethylbenzyl) -5,6-dimethoxy-3-methylbenzo-1,4-quinone

1- (4-ethoxybenzyl) -2,3,4,5-tetramethoxy-6-methylbenzene (89 mg, 0.25 mmol) was dissolved in CH ₃ CN (1 mL) followed by CAN (296 mg, 0.54 mmol) was dissolved in H ₂ O (1 mL) and slowly dropped at 0 ° C. After stirring for 5 minutes, saturated aqueous NaHCO ₃ solution (1 mL) was poured, the organic layer was extracted with ethyl acetate (5 mL × 3), dried over Na ₂ SO _4, and the solvent was concentrated under reduced pressure. The residue was subjected to column chromatography (hexane / ethyl acetate = 3/1) to give 66.6 mg (84%) of the title compound on oil.

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.38 (t, J = 6.9 Hz, 3H, CH ₃ ), 2.08 (s, 3H, CH ₃ ), 3.77 (s, 2H, CH ₂ ), 3.98 (s, 6H, 20CH ₃ ), 3.98 (q, J = 6.9 Hz, 2H, OCH ₂ ), 6.80 (d, J = 8.5 Hz, 2H, ArH), 7.10 (d, J = 8.3 Hz, 2H, ArH); Mass m / z (Rel. Intensity) 316 (M ⁺ , 44), 301 (100), 286 (19), 271 (16)

Example 12 Preparation of 2- (4-butoxybenzyl) -5,6-dimethoxy-3-methylbenzo-1,4-quinone

Dissolve 1- (4-butoxythoxybenzyl) -2,3,4,5-tetramethoxy-6-methylbenzene (70 mg, 0.18 mmol) in CH ₃ CN (1 mL) and lower to 0 ° C. It was. CAN (215 mg, 0.39 mmol) was dissolved in H ₂ O (1 mL) and slowly titrated for 5 minutes. After completion of the reaction, saturated aqueous NaHCO ₃ solution (10 mL) was poured out, extracted with ethyl acetate (10 mL × 3), and dried over Na ₂ SO ₄ . After concentration of the solvent under reduced pressure, the residue was purified by column chromatography (hexane / ethyl acetate = 2/1) to give 42 mg (68%) of the title compound.

¹ H NMR (200 MHz, CDCl ₃ ) δ 0.95 (t, J = 7.3 Hz, 3H, CH ₃ ), 1.48 (sext, J = 7.9 Hz, 2H, CH ₂ ), 1.74 (quint, J = 6.3 Hz, 2H, CH ₂ ), 2.08 (s, 3H, CH ₃ ), 3.77 (s, 2H, CH ₂ ), 3.91 (t, J = 6.5 Hz, 2H, CH ₂ O), 3.98 (s, 6H, 2OCH ₃ ), 6.81 (d, J = 8.7 Hz, 2H, ArH), 7.06 (d, J = 8.7 Hz, 2H, ArH); Mass m / z (Rel. Intensity) 344 (M ⁺ , 45), 329 (100), 255 (17); mp 34-35 ℃

Example 13: Preparation of 9- [4- (4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadienylmethyl) phenyloxy] nonyl acetate

9- [4- (2,3,4,5-tetramethoxy-6-methylbenzyl) phenyloxy] nonyl acetate (302 mg, 0.59 mmol) was dissolved in CH ₃ CN (3 mL) and then heated to 0 ° C. Lowered. Here, ceramic ammonium nitrate (CAN; 733 mg, 1.33 mmol) was dissolved in H ₂ O (1.5 mL) and slowly titrated for 5 minutes. After completion of the reaction, saturated aqueous NaHCO ₃ solution (10 mL) was poured out, extracted with ethyl acetate (10 mL × 3), and dried over Na ₂ SO ₄ . The solvent was concentrated under reduced pressure and the residue was subjected to column chromatography (hexane / ethyl acetate = 2/1) to give 158 mg (57%) of the title compound.

¹ H NMR (200 MHz, CDCl ₃ ) δ1.32 to 1.81 (m, 14H, 7CH ₂ ), 2.04 (s, 3H, OAc), 2.08 (s, 3H, CH ₃ ), 3.77 (s, 2H, CH ₂ ), 3.89 (t, J = 6.7 Hz, 2H, CH ₂ O), 3.98 (s, 6H, 20CH ₃ ), 4.04 (t, J = 6.7 Hz, 2H, OCH ₂ ), 6.80 (d, J = 8.6 Hz, 2H, ArH), 7.05 (d, J = 8.6 Hz, 2H, ArH); Mass m / z (Rel. Intensity) 472 (M ⁺ , 39), 485 (100), 440 (18), 287 (21), 273 (30); mp 40-41 ℃

Example 14 Preparation of 10- [4- (4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadienylmethyl) phenyloxy] decyl acetate

Dissolve 10- [4- (2,3,4,5-tetramethoxy-6-methylbenzyl) phenyloxy] decyl acetate (210 mg, 0.40 mmol) in CH ₃ CN (3 mL) and then proceed to 0 ° C. Lowered. Here, ceramic ammonium nitrate (CAN; 468 mg, 0.85 mmol) was dissolved in H ₂ O (1.5 mL) and slowly titrated for 5 minutes. After completion of the reaction, saturated aqueous NaHCO ₃ solution (10 mL) was poured out, extracted with ethyl acetate (10 mL × 3), and dried over Na ₂ SO ₄ . After concentration of the solvent under reduced pressure, the residue was purified by column chromatography (hexane / ethyl acetate = 2/1) to give 110 mg (61%) of the title compound.

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.29 to 1.74 (m, 16H, 8CH ₂ ), 2.04 (s, 3H, OAc), 2.08 (s, 3H, CH ₃ ), 3.76 (s, 2H, CH ₂ ), 3.89 (t, J = 6.7 Hz, 2H, CH ₂ O), 3.98 (s, 6H, 20CH ₃ ), 4.05 (t, J = 6.7 Hz, 2H, OCH ₂ ), 6.81 (d, J = 8.6 Hz, 2H, ArH), 7.06 (d, J = 8.6 Hz, 2H, ArH); Mass m / z (Rel. Intensity) 486 (M ⁺ , 36), 470 (100), 454 (26), 286 (25), 272 (23); mp 54-55 ℃

Example 15 Preparation of 2- [4- (9-hydroxynonyloxy) benzyl] -5,6-dimethoxy-3-methylbenzo-1,4-quinone

9- [4- (4,5-Dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadienylmethyl) phenyloxy] nonyl acetate (138 mg, 0.29 mmol) was dissolved in MeOH (1.4). ML), and concentrated HCl (0.01 mL) was stirred at room temperature for 22 hours. After completion of the reaction, H ₂ O (5 mL) was poured out, extracted with ethyl acetate (10 mL × 3), dried over Na ₂ SO ₄ , and the solvent was concentrated under reduced pressure. The residue was subjected to column chromatography (hexane / ethyl acetate = 2/1) to give 80 mg (65%) of the title compound.

¹ H NMR (200 MHz, CDCl ₃ ) δ 1.25 to 1.74 (m, 14H, 7CH ₂ ), 2.07 (s, 3H, CH ₃ ), 3.62 (t, J = 6.7 Hz, 2H, CH ₂ O), 3.76 (s, 2H, CH ₂ ), 3.89 (t, J = 6.7 Hz, 2H, OCH ₂ ), 3.98 (s, 6H, 20CH ₃ ), 6.79 (d, J = 8.6 Hz, 2H, ArH), 7.05 (d, J = 8.6 Hz, 2H, ArH); Mass m / z (Rel. Intensity) 430 (M ⁺ , 47), 415 (100), 287 (12), 273 (40); mp 59-60 ℃

Example 16 Preparation of 2- [4- (10-hydroxydecyloxy) benzyl] -5,6-dimethoxy-3-methylbenzo-1,4-quinone

10- [4- (4,5-Dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadienylmethyl) phenyloxy] decyl acetate (94 mg, 0.19 mmol) was dissolved in MeOH (1.4). ML), and concentrated HCl (0.01 mL) was stirred at room temperature for 22 hours. After completion of the reaction, H ₂ O (5 mL) was poured out, extracted with ethyl acetate (10 mL × 3), dried over Na ₂ SO ₄ , and the solvent was concentrated under reduced pressure. The residue was subjected to column chromatography (hexane / ethyl acetate = 2/1) to give 72 mg (85%) of the title compound.

^OneH NMR (200 MHz, CDCl₃δ 1.30 to 1.74 (m, 16H, 8CH)₂), 2.08 (s, 3 H, CH₃), 3.63 (t,J =6.6 Hz, 2H, CH₂O), 3.77 (s, 2 H, CH₂), 3.89 (t,J =6.6 Hz, 2H, OCH₂), 3.98 (s, 6H, 2OCH)₃), 6.80 (d,J =8.7 Hz, 2H, ArH), 7.05 (d,J =8.7 Hz, 2H, ArH); MassmOfz(Rel.intensity) 444 (M⁺, 40), 429 (100), 411 (9), 287 (15), 273 (44); mp 67 ~ 68 ℃

Example 17 Preparation of Methyl 2- [4- (4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadienylmethyl) phenyloxy] acetate

Methyl 2- [4- (2,3,4,5-tetramethoxy-6-methylbenzyl) phenyloxy] acetate (71 mg, 0.18 mmol) was dissolved in CH ₃ CN (1 mL) followed by ceramic ammonium nitrate (CAN; 209 mg, 0.38 mmol) was dissolved in H ₂ O (1 mL) and slowly dropped at 0 ° C. After stirring for 5 minutes, saturated aqueous NaHCO ₃ solution (1 mL) was poured, the organic layer was extracted with ethyl acetate (5 mL × 3), dried over Na ₂ SO _4, and the solvent was concentrated under reduced pressure. The residue was subjected to column chromatography (hexane / ethyl acetate = 2/1) to give 51 mg (79%) of the title compound on oil.

¹ H NMR (200 MHz, CDCl ₃ ) δ2.07 (s, 3H, CH ₃ ), 3.76 (s, 2H, CH ₂ ), 3.78 (s, 3H, OCH ₃ ), 3.97 (s, 6H, 2OCH ₃ ) , 4.58 (s, 2H, OCH ₂ ), 6.81 (d, J = 8.7 Hz, 2H, ArH), 7.07 (d, J = 8.5 Hz, 2H, ArH); Mass m / z (Rel. Intensity) 360 (M ⁺ , 42), 345 (100), 315 (12), 287 (12)

Example 18 Preparation of 2- [4- (4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadienylmethyl) phenyloxy] ethyl acetate

2- [4- (2,3,4,5-tetramethoxy-6-methylbenzyl) phenyloxy] ethyl acetate (205 mg, 0.50 mmol) was dissolved in CH ₃ CN (3 mL) and then heated to 0 ° C. Lowered. Ceramic ammonium nitrate (CAN; 583 mg, 1.06 mmol) was dissolved in H ₂ O (1.5 mL) and slowly titrated for 5 minutes. After completion of the reaction, saturated aqueous NaHCO ₃ solution (10 mL) was poured out, extracted with ethyl acetate (10 mL × 3), and dried over Na ₂ SO ₄ . The solvent was concentrated under reduced pressure and the residue was subjected to column chromatography (hexane / ethyl acetate = 2/1) to give 130 mg (69%) of the title compound as an oil.

¹ H NMR (200 MHz, CDCl ₃ ) δ 2.08 (s, 6H, CH _3, OAc), 3.77 (s, 2H, CH ₂ ), 3.98 (s, 6H, 2OCH ₃ ), 4.12 (t, J = 4.7 Hz, 2H, OCH ₂ ), 4.39 (t, J = 4.7 Hz, 2H, CH ₂ O), 6.81 (d, J = 8.7 Hz, 2H, ArH), 7.06 (d, J = 8.7 Hz, 2H, ArH ); Mass m / z (Rel. Intensity) 374 (M ⁺ , 8), 359 (4), 273 (11), 87 (100), 43 (45)

Example 19 Preparation of 2- [4- (2-hydroxyethanol) benzyl] -5,6-dimethoxy-3-methylbenzo-1,4-quinone

2- [4- (4,5-Dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadienylmethyl) phenyloxy] ethyl acetate (120 mg, 0.32 mmol) was dissolved in MeOH (1.4 ML), and concentrated HCl (0.01 mL) was stirred at room temperature for 22 hours. After completion of the reaction, H ₂ O (5 mL) was poured out, extracted with ethyl acetate (10 mL × 3), dried over Na ₂ SO ₄ , and the solvent was concentrated under reduced pressure. The residue was subjected to column chromatography (hexane / ethyl acetate = 2/1) to give 103 mg (97%) of the title compound.

¹ H NMR (200 MHz, CDCl ₃ ) δ2.08 (s, 6H, CH _3, OAc), 3.77 (s, 2H, CH ₂ ), 3.98 (s, 6H, 20CH ₃ ), 3.94 to 3.98 (m, 4H, 20CH ₂ ), 6.83 (d, J = 8.7 Hz, 2H, ArH), 7.08 (d, J = 8.7 Hz, 2H, ArH); Mass m / z (Rel. Intensity) 332 (M ⁺ , 30), 317 (100), 299 (15); mp 69-70 ℃

Example 20 Preparation of 2,3-Dimethoxy-5-methyl-6- (4-methylpiperazin-1-yl-methyl)-[1,4] benzoquinone

2-chloromethyl-5,6-methoxy-3-methyl [1,4] benzoquinone (71 mg, 0.30 mmol) was dissolved in N, N -dimethylformamide (DMF; 1 mL) and then 1-methyl Piperazine (0.051 mL, 0.46 mmol) was titrated and Et ₃ N (0.086 mL, 0.61 mmol) was added and stirred for 30 minutes. After completion of the reaction, H ₂ O (10 mL) was poured out, extracted with ethyl acetate (10 mL × 3), dried over Na ₂ SO _4, and the solvent was concentrated under reduced pressure. The residue was subjected to short column chromatography (CHCl ₃ ) to give 43 mg (49%) of the title compound as an oil.

¹ H NMR (200 MHz, CDCl ₃ ) δ 2.11 (s, 3H, CH ₃ ), 2.49 (s, 3H, NCH ₃ ), 2.29 to 2.47 (m, 8H, 4CH ₂ ), 3.39 (s, 2H, CH ₂ ), 3.98 (s, 3H, OCH ₃ ), 3.99 (s, 3H, OCH ₃ ); Mass m / z (Rel. Intensity) 294 (M ⁺ , 13), 196 (10), 167 (34), 149 (100)

Example 21 Preparation of 2,3-Dimethoxy-5-methyl-6- (4-pyridin-2-yl-piperazin-1-yl-methyl)-[1,4] benzoquinone

2-chloromethyl-5,6-methoxy-3-methyl [1,4] benzoquinone (72 mg, 0.31 mmol) was dissolved in N, N -dimethylformamide (1 mL) and then 1- (2- Pyridyl) piperazine (0.036 mL, 0.24 mmol) was added to the mixture, and Et ₃ N (0.065 mL, 0.47 mmol) was added thereto, followed by stirring for 30 minutes. After completion of the reaction, H ₂ O (10 mL) was poured out, extracted with ethyl acetate (10 mL × 3), dried over Na ₂ SO _4, and the solvent was concentrated under reduced pressure. The residue was subjected to column chromatography (hexane / ethyl acetate = 2/1) to give 45.4 mg (41%) of the title compound on oil.

¹ H NMR (200 MHz, CDCl ₃ ) δ 2.13 (s, 3H, CH ₃ ), 2.54 (t, J = 4.9 Hz, 4H, 2CH ₂ ), 3.48 (t, J = 4.9 Hz, 4H, 2CH ₂ ), 3.99 (s, 3H, OCH ₃ ), 4.00 (s, 3H, OCH ₃ ), 6.56 to 6.62 (m, 2H, ArH), 7.45 (t, J = 6.7 Hz, 1H, ArH), 8.17 (br) s, 1H, ArH); Mass m / z (Rel. Intensity) 357 (M ⁺ , 24), 196 (30), 161 (65), 121 (77), 107 (100)

Chemical structures of the quinone compound obtained by the method according to Examples 1 to 21 are shown in Table 1 below.

division R ₁ R ₂ X n R ₃ Example 1 OCH ₃ OCH ₃ C = O 0 Example 2 OCH ₃ OCH ₃ C = O 0 Example 3 OCH ₃ OCH ₃ C = O 0 Example 4 OCH ₃ OCH ₃ C = O 0 Example 5 OCH ₃ OCH ₃ C = O 0 Example 6 OCH ₃ OCH ₃ C = O 0 Example 7 OCH ₃ OCH ₃ C = O 0 Example 8 OCH ₃ OCH ₃ C = O 8 Example 9 OCH ₃ OCH ₃ CH ₂ 0 Example 10 OCH ₃ OCH ₃ CH ₂ 0 Example 11 OCH ₃ OCH ₃ CH ₂ 0 Example 12 OCH ₃ OCH ₃ CH ₂ 0 Example 13 OCH ₃ OCH ₃ CH ₂ 0 Example 14 OCH ₃ OCH ₃ CH ₂ 0 Example 15 OCH ₃ OCH ₃ CH ₂ 0 Example 16 OCH ₃ OCH ₃ CH ₂ 0 Example 17 OCH ₃ OCH ₃ CH ₂ 0 Example 18 OCH ₃ OCH ₃ CH ₂ 0 Example 19 OCH ₃ OCH ₃ CH ₂ 0 Example 20 OCH ₃ OCH ₃ CH ₂ 0 Example 21 OCH ₃ OCH ₃ CH ₂ 0

On the other hand, the quinone compound represented by Formula 1 according to the present invention can be formulated in various forms according to the purpose. The following illustrates some formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

Formulation 1 : tablet (direct pressure)

After sifting 5.0 mg of active ingredient, 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate were mixed and pressed to form a tablet.

Formulation 2 : Tablet (Wet Granulation)

After sifting 5.0 mg of the active ingredient, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of polysorbate 80 was dissolved in pure water and then an appropriate amount of this solution was added and then atomized. After drying, the fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressed into tablets.

Formulation 3 : Powders and Capsules

5.0 mg of the active ingredient was sieved, followed by mixing with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. No. solid the mixture using a suitable device. Filled in 5 gelatin capsules.

Formulation 4 : Injection

Injectables were prepared by containing 100 mg as the active ingredient, followed by the addition of 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ .12H ₂ O and 2974 mg of distilled water.

Experimental Example 1 Antioxidant Activity Test

1. Preparation of brain homogenate

SD rats (males, 10 to 12 weeks old) were singled out and brains were quickly removed and homogenized by adding 10 ml / brain of 10 mM Tris-HCl buffer (pH 7.4) containing 150 mM KCl. The homogenized brain mixture was centrifuged at 2,200 rpm and 4 ° C. for 10 minutes, and only the supernatant was taken to measure the exact amount of protein by protein assay and then stored at −20 ° C.

2. Lipid Peroxidation Assay

Dispense 250 μl of brain homogenate (5 mg protein / ml), 10 μl of test substance, and 20 μl of buffer solution in 96-well microplates, and incubate at 37 ° C. for 20 min in 20 μM FeCl ₂ and 250 μM. 10 μl each of ascorbic acid was added thereto and then incubated at 37 ° C. for 30 minutes. 50 μl of 35% HClO ₄ was added to stop the reaction. The microplates were centrifuged at 2000 rpm and 4 ° C. for 10 min to transfer 240 μl of the supernatant to 96-well microplates, followed by TBA (thiobarbituric acid; 5 mg). / Ml in 50% acetic acid) was added in 120 mu l. The microplates were reacted at 80 ° C. for 1 hour and then cooled at room temperature, and then absorbance was measured at 520 nm of TBARS (thiobarbituric acid reactive substances (MDA)) produced by the reaction.

Quantitative reaction curves of TBARS generated using tetraethoxypropane, a reactant of TBA, were used to calculate the amount of reaction product MDA of the test substance, and the inhibitory effect of the test drug was calculated by Equation 1 below. In addition, 50% inhibition concentration (IC ₅₀ ) was calculated by calculating the dose response curve.

In Equation 1: A represents the concentration (nmol) of the control protein (MDA / mg), B represents the concentration (nmol) of the test protein (MDA / mg).

Therefore, a smaller value of IC ₅₀ indicates a stronger antioxidant activity.

The experimental results are shown in Table 2 below. It is believed to have superior antioxidant activity.

Experimental compound Lipid Peroxidation Assay (IC ₅₀ ) Idebenon 74.24 μM 2- (4-fluorobenzoyl) -5,6-dimethoxy-3-methyl- [1,4] benzoquinone (Example 2) 8.36 μM 1- (4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadienyl) decyl acetate (Example 8) 7.92 μM

Test Example 2: Oral Toxicity Test

Some compounds according to the invention were subjected to acute toxicity testing in rats. As a result, up to 10 mg / kg oral dose did not cause serious toxicity symptoms, and up to 100 mg / kg oral dose did not cause any death.

As described above, the quinone compound represented by Chemical Formula 1 according to the present invention has excellent antioxidant activity and is effective for preventing and treating various diseases related thereto.

Claims (6)

A quinone compound or a pharmaceutically acceptable salt thereof, characterized in that represented by the following formula (1). [Formula 1] In Formula 1, R ₁ and R ₂ each independently represent a methyl group or a methoxy group; R ₃ is , , or Represents; Wherein R ₄ is a hydrogen atom, a halogen atom, -O (CH ₂ ) _k CH ₃ , -O (CH ₂ ) _k OH, -O (CH ₂ ) _k O (CO) CH ₃ , or -O (CH ₂₎ ) CO ₂ R ₆ ; R ₅ represents a methyl group or a pyridine group; R ₆ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; X represents CH ₂ , or C═O; n represents 0, k and m represent 0 or the integer of 1-10, respectively. A compound according to claim 1, wherein R ₁ and R ₂ each independently represent a methyl group or a methoxy group; R ₃ is , , or Represents; Wherein R ₄ is a halogen atom, —O (CH ₂ ) _k CH ₃ , —O (CH ₂ ) _k OH, —O (CH ₂ ) _k O (CO) CH ₃ , or —O (CH ₂ ) CO ₂ R ₆ is represented; R ₅ represents a methyl group; R ₆ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; X represents CH ₂ or C═O; n represents 0, and k and m represent 0 or an integer of 1 to 10, respectively. A compound according to claim 1, wherein R ₁ and R ₂ represent a methyl group; R ₃ is Represents; Wherein R ₄ is a halogen atom, —O (CH ₂ ) _k CH ₃ , —O (CH ₂ ) _k OH, —O (CH ₂ ) _k O (CO) CH ₃ , or —O (CH ₂ ) CO ₂ R ₆ is represented; R ₅ represents a methyl group; R ₆ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; X represents C = 0; n represents 0, and k and m represent 0 or an integer of 1 to 10, respectively. A pharmaceutical composition useful as a brain metabolic inhibitor, characterized in that it contains a quinone compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof. [Formula 1] In Formula 1, R ₁ , R ₂ , R ₃ , X and n are as defined in claim 1, respectively. The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition is used as a therapeutic agent for neurodegenerative diseases. The intermediate represented by the following formula (3), characterized in that it is used to prepare a compound represented by the formula (1). [Formula 1] In the above formula, R ₁ , R ₂ , R ₃ , X and n are as defined in claim 1, respectively.