KR20150064949A - New mollugin analogues and their antioxidant and antibacterial activities - Google Patents

Abstract

The present invention relates to a new mollugin analogue and medical use thereof and, more specifically to newly synthesized mollugin analogues having both antibacterial and antioxidant activities, which can be effectively used as a medicine for oxidation-related diseases or as an antibacterial agent.

Description

New mollugin analogs and their antioxidant and antibacterial activities.

The present invention relates to a novel molybdenum derivative and an antioxidant or antimicrobial composition containing the same.

The toxic substances related to oxygen are called reactive oxygen species (ROS). The types of ROS include superoxide, hydroxyl, peroxyl, alkoxyl, Free radicals such as hydroperoxyl and hydrogen peroxide, hypochlorous acid, ozone, singlet oxygen, peroxynitrite, And non-free radicals such as peroxynitrite.

Unsaturated fatty acids in the phospholipids constituting the biomembrane are initiated by the free radicals such as active oxygen species and proceed in a cascade. Therefore, the peroxidation reaction by free radical not only enhances the permeability of the cell membrane, but also induces overall cytotoxicity, thereby leading to aging phenomenon and various disease pathologies, thereby also involved in the carcinogenesis process. Radical action has a great influence on the progression of various chronic diseases such as atopic diseases, cancer, hypertension, myocardial infarction, arteriosclerosis, rheumatism, cataract, and Parkinson's disease (Bioorg. Med. Cehm. Lett , 14, 5859-5861, 2004) and may serve as a factor to weaken the immune system function (Int. J. Vitam. Nutr. Res., 65, 117-120, 1995).

Therefore, antioxidative evaluation of alternative substances to prevent oxidative damage has been actively studied. Antioxidants are used not to remove or absorb oxygen, but to react with free radicals to minimize the loss of certain vitamins and essential amino acids, or to retard or prevent rancidity of preserved products. Synthetic antioxidants commonly used in foods or pharmaceuticals include butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate (PG), tertiary butyl hydro- Quinone (TBHQ, Tertiarybutyl hydroquinone). However, when they are administered to experimental animals at a high concentration, it is known that hepatic hypertrophy is induced or carcinogenic.

As a result, many studies have been carried out in anticipation of developing a safe and economical natural antioxidant with high antioxidant effect (Larson RA, Phytochemistry, 27, 969-978, 1988).

On the other hand, molurin and 3,4-dihydroimolugine are separated from Rubia cordifolia, a medicinal plant used in China and India, and dried roots and rhizomes are used medicinally for diseases such as arthritis and menstrual irregularities come. Synthesis methods such as electron cyclization in relation to the synthesis of the molargin and 3,4-dihydro-morpholine have been reported in various papers.

Therefore, there is a need to synthesize a novel morpholine derivative as an antioxidant for the treatment of an oxidation-related disease and to analyze the various physiological activities thereof and use it as a pharmaceutical agent or the like.

Korean Patent No. 1322664

It is an object of the present invention to provide a novel molybdenum derivative and a medical use thereof.

In order to achieve the above object, the present invention provides a molygene derivative represented by formula (1)

[Chemical Formula 1]

In Formula 1, when X is hydroxy, R ¹ and R ² are each C1 to C4 alkyl; and when X is methoxy, R ¹ and R ² are each - (CH ₂ ) ₂ CH═C (CH _{3 ) 2, - (CH 2)} 3 CH (CH 3) 2, X is -O (CH _{2) 2} Ph, if the R ¹ and R ² are a C1 to C4 alkyl, each - CH ₂ = C (CH ₂₎ (CH ₃ ) ₂ , - (CH ₂ ) ₃ CH (CH ₃ ) ₂ , and the solid line with the dotted line (---) may represent a single bond or a double bond.

The present invention also provides a morpholine derivative represented by formula (2): < EMI ID =

(2)

In the above formula (2), a solid line accompanied by a dotted line (-) may represent a single bond or a double bond.

The present invention also provides an antioxidant composition for prevention or treatment of an oxidation-related disease selected from skin aging, skin pigmentation, wrinkles, psoriasis and eczema.

The present invention also provides an antimicrobial composition containing the above-mentioned molar derivative as an active ingredient.

According to the present invention, newly synthesized mulligene derivatives have antioxidative activity and antimicrobial activity, and thus can be usefully used as a therapeutic agent for an oxidation-related disease or an antimicrobial agent.

Hereinafter, the present invention will be described in more detail with reference to an embodiment.

The present invention provides a morpholine derivative represented by formula (1): < EMI ID =

[Chemical Formula 1]

In Formula 1, when X is hydroxy, R ¹ and R ² are each C1 to C4 alkyl; and when X is methoxy, R ¹ and R ² are each - (CH ₂ ) ₂ CH═C (CH _{3 ) 2, - (CH 2)} 3 CH (CH 3) 2, X is -O (CH _{2) 2} Ph, if the R ¹ and R ² are a C1 to C4 alkyl, each - CH ₂ = C (CH ₂₎ (CH ₃ ) ₂ , - (CH ₂ ) ₃ CH (CH ₃ ) ₂ , and the solid line with the dotted line (---) may represent a single bond or a double bond.

Examples of the molar derivative include 6-hydroxy-2,2-dimethyl-2H-benzo [h] chromene-5-carboxylate -5-carboxylic acid; 3-dihydro-2H-benzo [h] chromene-5-carboxylate [6-hydroxy-2,2- 4-dihydro-2H-benzo [h] chromene-5-carboxylic acid; Compound 4], methyl 6-hydroxy-2-methyl-2- (4-methylpent-3-en-1-yl) -2H- benzo [h] chromen- Methyl-2- (4-methylpent-3-en-1-yl) -2H-benzo [ Methylpentyl) -3,4-dihydro-2H-benzo [h] chromen-5-carboxylate [methyl 6-hydroxy-2- -2H-benzo [h] chromene-5-carboxylate; Phenethyl 6-hydroxy-2,2-dimethyl-2H-benzo [h] chromene-5-carboxylate [phenethyl 6-hydroxy- chromene-5-carboxylate; Compound 9], phenethyl 6-hydroxy-2,2-dimethyl-3,4-dihydro-2H-benzo [h] chromen- -3,4-dihydro-2H-benzo [h] chromene-5-carboxylate; Compound 10], phenethyl 6-hydroxy-2-methyl-2- (4-methylpent-3-en-1-yl) -2H- benzo [h] chromen- hydroxy-2-methyl-2- (4-methylpent-3-en-1-yl) -2H-benzo [h] chromene-5-carboxylate; Compound 11 and phenethyl 6-hydroxy-2-methyl-2- (4-methylpentyl) -3,4, -dihydro-2H- benzo [h] chromen- hydroxy-2-methyl-2- (4-methylpentyl) -3,4-dihydro-2H-benzo [h] chromene-5-carboxylate; Compound 12].

The present invention also provides a morpholine derivative represented by formula (2): < EMI ID =

(2)

In the above formula (2), a solid line accompanied by a dotted line (-) may represent a single bond or a double bond.

The above-mentioned molar derivatives include methyl 6-hydroxy-2-phenyl-4H-benzo [h] chromene-5-carboxylate [methyl 6-hydroxy- carboxylate; Compound 7] and methyl 6-hydroxy-2-phenyl-3,4-dihydro-2H-benzo [h] chromene- dihydro-2H-benzo [h] chromene-5-carboxylate; Compound 8].

The molargin derivative according to the present invention can be synthesized by the following reaction formula (1). Namely, molargin (1) was synthesized through reaction between 1,4-dihydroxy-2-naphthoate and 3-methyl-2-butenal using PhB (OH) ₂ / AcOH in refluxing toluene, Acetate can be hydrogenated under Pd / C to synthesize 3,4-dihydroimolugine (2). Compound 3 and Compound 4 can be synthesized through hydrolysis of the molargin (1) or 3,4-dihydromorpholine (2).

Compound 5 is synthesized through reaction between 1,4-dihydroxy-2-naphthoate and thiazol with PhB (OH) ₂ / AcOH in refluxing toluene, and Compound 5 is hydrogenated to synthesize Compound 6 . Further, Compound 7 was synthesized through reaction between 1,4-dihydroxy-2-naphthoate and trans-cinnamaldehyde using PhB (OH) ₂ / AcOH in refluxing toluene, and Compound 7 was hydrogenated to obtain Compound 8 Can be synthesized.

[Reaction Scheme 1]

Further, the molargin derivative according to the present invention can be synthesized by the following reaction formula (2). That is, Compound 9 and Compound 11 were respectively synthesized through reaction between 1,4-dihydroxy-2-naphthoate and 3-methyl 2-butenal or citalal using PhB (OH) 2 / AcOH in refluxing toluene Compound 9 and Compound 11 can be hydrogenated to synthesize Compound 10 and Compound 12, respectively.

[Reaction Scheme 2]

The morpholine derivative may be provided in the form of a pharmaceutically acceptable salt, wherein the pharmaceutically acceptable salt is an organic acid selected from the group consisting of oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid and benzoic acid, Hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid.

The present invention also provides an antioxidant composition for prevention or treatment of an oxidation-related disease selected from skin aging, skin pigmentation, wrinkles, psoriasis and eczema.

Examples of the morpholine derivatives having excellent antioxidative activity in the present invention include methyl 6-hydroxy-2-methyl-2- (4-methylpent-3-en-1-yl) -2H- benzo [h] 5-carboxylate: compound 5], methyl 6-hydroxy-2-methyl-2- Methyl-2- (4-methylpentyl) -3,4-dihydro-2H-benzo [h] chromen- methylpentyl) -3,4-dihydro-2H-benzo [h] chromene-5-carboxylate; Compound 6], methyl 6-hydroxy-2-phenyl-4H-benzo [h] chromene-5-carboxylate [methyl 6-hydroxy-2-phenyl-4H-benzo [h] chromene-5-carboxylate; Methyl 7-hydroxy-2-phenyl-3,4-dihydro-2H-benzo [h] chromene-5-carboxylate -2H-benzo [h] chromene-5-carboxylate; Compound 8], phenethyl 6-hydroxy-2,2-dimethyl-3,4-dihydro-2H-benzo [h] chromen- -3,4-dihydro-2H-benzo [h] chromene-5-carboxylate; Compound 10], phenethyl 6-hydroxy-2-methyl-2- (4-methylpent-3-en-1-yl) -2H- benzo [h] chromen- hydroxy-2-methyl-2- (4-methylpent-3-en-1-yl) -2H-benzo [h] chromene-5-carboxylate; Compound 11 and phenethyl 6-hydroxy-2-methyl-2- (4-methylpentyl) -3,4, -dihydro-2H- benzo [h] chromen- hydroxy-2-methyl-2- (4-methylpentyl) -3,4-dihydro-2H-benzo [h] chromene-5-carboxylate; Compound 12] and the like.

The present invention also provides an antimicrobial composition containing the above-mentioned molar derivative as an active ingredient.

The composition according to the present invention may be provided as a pharmaceutical composition or a health food.

The pharmaceutical composition may further comprise suitable carriers, excipients and diluents conventionally used in the manufacture of pharmaceutical compositions.

Examples of such carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Vaginal cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

The pharmaceutical compositions may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories and sterilized injection solutions according to conventional methods.

In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose sucrose), lactose, gelatin, and the like.

In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.

The amount of the molar derivative in the pharmaceutical composition may vary depending on the age, sex and body weight of the patient, but it may be 0.001 to 100 mg / kg, preferably 0.01 to 10 mg / kg, once to several times daily . The dosage may also be increased or decreased depending on the route of administration, degree of disease, sex, weight, age, and the like. Thus, the dosage amounts are not intended to limit the scope of the invention in any manner.

The pharmaceutical composition may be administered to mammals such as rats, mice, livestock, humans, and the like in a variety of routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine or intracerebroventricular injections.

The health food may be provided in the form of powder, granules, tablets, capsules, syrups or beverages. The health food may be used in combination with other food or food additives in addition to the active ingredient, Can be suitably used. The amount of the active ingredient to be mixed can be suitably determined according to its use purpose, for example, prevention, health or therapeutic treatment.

The effective dose of the compound contained in the health food may be used in accordance with the effective dose of the pharmaceutical composition, but may be less than the above range for the purpose of health and hygiene or long-term intake for the purpose of health control, Since the active ingredient has no problem in terms of safety, it can be used in an amount exceeding the above range.

There is no particular limitation on the type of the health food, and examples thereof include meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, Drinks, alcoholic beverages and vitamin complexes.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the present invention is not limited by these examples.

All experiments were carried out under nitrogen atmosphere. For the TLC analysis, pre-coated silica gel plates (Art. 5554) with fluorescence indicator from Merck are used. Flash column chromatography was performed using silica gel 9385 (Merck). And ¹ H NMR and ¹³ C NMR analyzes were recorded via a Bruker Model ARX (300 and 75 MHz) spectrometer in CDCl _3, DMSO- d ₆ , acetone- d ₆ as solvent chemical shifts. IR analysis was performed using a Jasco FTIR 5300 spectrometer. HRMS analysis was carried out through Korea Basic Science Research Institute.

Synthesis Example 1 Synthesis of alkyl 1,4-dioxo-1,4-dihydronaphthalene-2-carboxylate

Sodium bicarbonate (0.840 g, 10.0 mmol) and iodomethane (20 mL) were added to dimethylformamide (DMF, 20 mL) containing 1,4-dihydroxy-2-naphthoic acid (2.042 g, 1.419 g, 10.0 mmol) or (2-bromoethyl) benzene (1.851 g, 10.0 mmol) at room temperature to prepare alkyl 1,4-dioxo-1,4-dihydronaphthalene- Respectively. The reaction mixture was stirred at room temperature for 10 hours, and the reaction was stopped by addition of 1N HCl solution (30 mL). The obtained aqueous solution was extracted with ethyl acetate (40 mL X 3), dried over magnesium sulfate and concentrated under reduced pressure. Then purified by flash chromatography on silica gel using hexane / ethyl acetate (3: 1) to give methyl 1,4-dihydroxy-2-naphthoate and phenetyl 1,4-dihydroxy- Naphthoate, respectively.

1) Methyl 1,4-dihydroxy-2-naphthoate: brown solid, 2.07 g, 95% yield, melting point 198-199 DEG C;

^{1 H NMR (300 MHz, CDCl} 3) δ 11.45 (1H, s), 8.32 (1H, d, J = 8.4Hz), 8.15 (1H, d, J = 8.2Hz), 7.60-7.55 (1H, m) , 7.52-7.47 (1 H, m), 7.09 (1 H, s), 3.91 (3 H, s);

¹³ C NMR (75 MHz, CDCl ₃ ) δ 171.16, 154.25, 144.77, 129.47, 128.31, 125.81, 125.22, 123.42, 122.10, 104.49, 104.28, 52.01;

IR (KBr) 3387, 2953, 1647, 1599, 1516, 1478, 1441, 1356, 1298, 1256, 1150, 1100, 1073, 1026, 992, 847 cm ^-1 ;

HRMS (EI ⁺ ): m / z : calcd for C ₁₂ H ₁₀ O ₄ : 218.0579. Found: 218.0581.

2) phenethyl 1,4-dihydroxy-2-naphthoate: yellow solid, 2.31 g, 75% yield, melting point 156-157 ° C;

^{1 H NMR (300 MHz, CDCl} 3) δ 11.41 (s, 1H), 8.27 (d, J = 8.1Hz, 1H), 8.11 (d, J = 8.1Hz, 1H), 7.52 (dd, J = 8.1, 6.9Hz, 1H), 7.43 (dd , J = 8.1,6.9Hz, 1H), 7.28-7.12 (m, 5H), 7.05 (s, 1H), 4.47 (t, J = 6.9Hz, 2H), 3.00 ( t, J = 6.9 Hz, 2H);

¹³ C NMR (75 MHz, CDCl ₃ ) δ 170.66, 154.45, 144.66, 137.46, 129.51, 128.79, 128.45, 128.37, 126.48, 125.83, 125.25, 123.47, 122.10, 104.56, 104.40, 65.46, 34.89; IR (KBr): 3382, 3055, 2987, 2925, 1732, 1650, 1599, 1453, 1405, 1345, 1265, 1153, 1095, 1071, 895, 743 cm ^-1 ;

^{HRMS (EI +): m /} z: calcd for C 19 H 16 O 4: 308.1049. found: 308.1049.

≪ Example 1 > Synthesis of Mulligin (1) and Its Derivative Compound 5, 7, 9, 11 Synthesis

(10.0 mmol) of the alkyl 1,4-dioxo-1,4-dihydronaphthalene-2-carboxylate synthesized in Synthesis Example 1, 10.0 mmol of aldehyde, 10 mmol of phenylboronic acid and 10 mL ) Dissolved in anhydrous toluene (200 mL) was subjected to a reflux reaction under a nitrogen atmosphere for 8 hours under a Dean-Stark trap. The optimum product was identified through TCL monitoring. The mixture was cooled, then concentrated under reduced pressure and extracted with CH ₂ Cl ₂ (30 mL).

The resulting extract was washed successively with H ₂ O (30 mL), NaHCO ₃ (50 mL) and brine (30 mL) and dried over sodium sulfate. The solvent was evaporated and the remaining product was purified by flash chromatography on silica gel using nucleic acid / ethyl acetate (5: 1) to give morulin (1).

Compound 5 was subjected to a reflux reaction for 7 hours in the presence of methyl 1,4-dihydroxy-2-naphthoate and citral in the presence of phenylboronic acid / glacial acetic acid [PhB (OH) ₂ / AcOH] Methyl 1,4-dihydroxy-2-naphthoate and trans-cinnamaldehyde were dissolved in PhB (OH) ₂ / AcOH and refluxed for 8 hours. Compounds 9 and 11 were obtained by reacting phenethyl 1,4-dihydroxy-2-naphthoate with 3-methyl-2-butenal or citral, and the other procedures were the same as those of the preceding molar synthesis Do.

1) Mulligin: yellow solid, 2.59 g, 91% yield, melting point: 129-130 C;

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 12.15 (1H, s), 8.35 (1H, d, J = 8.4Hz), 8.15 (1H, d, J = 8.2Hz), 7.63-7.57 (1H, m), (1H, m), 7.09 (1H, d, J = 10.0Hz), 5.65 (1H, d, J = 10.0Hz), 4.0 (3H, s), 1.47 (6H, s);

_{^{13 C NMR (75MHz, CDCl 3}} ) δ 172.5, 156.4, 141.6, 129.3, 129.1, 128.9, 126.3, 125.1, 124.0, 122.3, 121.9, 112.5, 102.2, 74.6, 52.3, 28.6; IR (KBr) 2972, 1651, 1582, 1451, 1362, 1343, 1248, 1194, 1163, 1132, 1098, 1013, 957, 889, 806, 770 cm ^-1 ;

^{HRMS (EI +): m /} z: calcd for C 17 H 16 O 4: 284.1049. Found: 284.1051.

2) Compound 5: yellow liquid, 3.24 g, 92% yield;

^{1 H NMR (300 MHz, CDCl} 3) δ 12.21 (1H, s), 8.38 (1H, d, J = 8.4Hz), 8.19 (1H, d, J = 8.4Hz), 7.61 (1H, t, J = 8.1Hz), 7.50 (1H, dd , J = 8.4,6.9Hz), 7.14 (1H, d, J = 9.9Hz), 5.65 (1H, d, J = 10.2Hz), 5.13 (1H, t, J = M), 1.66 (3H, s), 1.56 (3H, s), 1.47 (3H, s);

_{^{13 C NMR (75MHz, CDCl 3}} ) δ 172.42, 156.34, 141.43, 131.61, 129.23, 128.83, 128.08, 126.17, 124.99, 124.08, 123.95, 122.52, 121.81, 112.36, 102.13, 76.75, 52.20, 39.79, 25.61, 24.67, 22.47, 17.51;

IR (neat) 2968, 2922, 1733, 1651, 1579, 1442, 1363, 1332, 1236, 1101, 1013, 808, 771 cm ^-1 ;

^{HRMS (EI +): m /} z: calcd for C 22 H 24 O 4: 352.1675. Found: 352.1675.

3) Compound 7: brown solid, 2.92 g, 88% yield, melting point 108-109 DEG C;

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 12.49 (1H, s), 8.36 (1H, d, J = 8.4Hz), 8.24 (1H, d, J = 8.4Hz), 7.74 (2H, t, J = 7.2 Hz), 7.65 (1H, t , J = 8.1Hz), 7.48 (1H, dd, J = 8.1,7.2Hz), 7.44-7.32 (3H, m), 5.49 (1H, t, J = 3.9Hz), 3.93 (3H, s), 3.83 (2H, d, J = 3.9 Hz);

¹³ C NMR (75 MHz, CDCl ₃ ) δ 172.78, 158.68, 147.54, 139.45, 134.29, 129.76, 128.33, 128.21, 128.05, 125.97, 124.25, 123.89, 121.16, 111.62, 104.05, 96.40, 52.2025.75;

IR (KBr) 3069, 2953, 1734, 1651, 1590, 1444, 1337, 1238, 1166, 1097, 762 cm < ^{-1 &} gt ;;

^{HRMS (EI +): m /} z: calcd for C 21 H 16 O 4: 332.1049. Found: 332.1048.

4) Compound 9: yellow solid, 3.18 g, 85% yield, melting point 89-90 캜;

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 12.06 (s, 1H), 8.25 (d, J = 8.1Hz, 1H), 8.05 (d, J = 8.4Hz, 1H), 7.48 (dd, J = 8.1,7.2 Hz, 1H), 7.37 (dd , J = 8.1,7.2Hz, 1H), 7.24-7.09 (m, 5H), 6.78 (d, J = 9.9Hz, 1H), 5.44 (d, J = 10.2Hz, 1H ), 4.53 (t, J = 6.9 Hz, 2H), 3.00 (t, J = 6.9 Hz, 2H), 1.37 (s, 6H);

¹³ C NMR (75 MHz, CDCl ₃ ) δ 171.92, 156.43, 141.43, 137.54, 129.23, 128.93, 128.89, 128.54, 128.39, 126.70, 126.18, 124.97, 123.93, 122.43, 121.82, 112.61, 102.21, 74.53, 66.31, 34.91, 26.76;

IR (KBr): 3289, 3067, 3030, 2974, 2928, 1736, 1646, 1578, 1497, 1439, 1392, 1358, 1325, 1238, 1166, 1046, 1011, 808, 770, 744 cm ^-1 ;

HRMS (EI ⁺ ): m / z calcd for C ₂₄ H ₂₂ O ₄ : 374.1518. Found: 374.1518.

5) Compound 11: Yellow liquid, 3.89 g, 88% yield.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 12.29 (s, 1H), 8.45 (d, J = 8.1Hz, 1H), 8.27 (d, J = 8.1Hz, 1H), 7.65 (t, J = 7.5Hz, 1H), 7.54 (dd, J = 7.8,7.2Hz, 1H), 7.45-7.29 (m, 5H), 7.01 (d, J = 9.9Hz, 1H), 5.61 (d, J = 10.2Hz, 1H), 5.21 (t, J = 6.9Hz, 1H), 4.68 (t, J = 6.9Hz, 2H), 3.15 (t, J = 6.9Hz, 2H), 2.32-2.41 (m, 2H), 1.92-1.86 (m , 2H), 1.75 (s, 3H), 1.65 (s, 3H), 1.54 (s, 3H);

¹³ C NMR (75 MHz, CDCl ₃ ) δ 171.81, 156.30, 141.30, 137.45, 131.44, 129.12, 128.82, 128.73, 128.44, 127.60, 126.59, 126.04, 124.92, 124.10, 123.89, 122.65, 121.71, 112.43, 102.14, 66.20, 39.68, 34.80, 25.57, 24.60, 22.42, 17.45;

IR (neat): 3287, 3064 , 3029, 2969, 2923, 1723, 1647, 1579, 1496, 1443, 1388, 1361, 1323, 1234, 1180, 1101, 1011, 905, 809, 770, 743, 700 cm - ¹ ;

HRMS (EI ⁺ ): m / z : calcd for C ₂₉ H ₃₀ O ₄ : 442.2144. Found: 442.2144.

Example 2 Synthesis of 3,4-dihydroxymorphine (2) and Compounds 6, 8, 10 and 12

To a Parr bottle containing 10% ethyl acetate (20 mL) dissolved in a molar (1) or molybdenum derivative 5, 7, 9, 11 (1 mmol) synthesized in Example 1 was added 10% Pd / C (30 mg) was added and shaken under H ₂ (20 psi) for 5 hours. The solvent was removed and the remaining oil-soluble residue was purified by column chromatography on silica gel using hexane / ethyl acetate (15: 1) to give hydrolyzed 3,4-dihydroxymorphine (2) Compound 8 was obtained by transferring a double bond through catalytic hydrogenation of Compound 7. Compound 10 and compound 12 were obtained by adding hydrogen and an excess amount of Pd / C to each of Compound 9 and Compound 11, , ≪ / RTI > 4-dihydroxy-morpholine.

1) 3,4-Dihydroxymorphine: yellow solid, 275 mg, 96%. Melting point (M.p.) 98-99 C;

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 12.23 (1H, s), 8.37 (1H, d, J = 8.1Hz), 8.18 (1H, d, J = 8.1Hz), 7.60 (1H, t, J = 8.1 Hz), 7.49 (1H, dd , J = 8.1,6.9Hz), 3.97 (3H, s), 3.04 (2H, t, J = 6.9Hz), 1.82 (2H, t, J = 6.9Hz), 1.40 ( 6H, s);

_{^{13 C NMR (75MHz, CDCl 3}} ) δ 172.97, 156.16, 141.43, 129.40, 128.99, 125.58, 124.26, 123.67, 121.51, 111.51, 105.11, 72.91, 51.97, 33.12, 26.41, 23.26;

IR (KBr) 2975, 1649, 1589, 1445, 1383, 1339, 1236, 1123, 1098, 997, 804, 770 cm ^-1 ;

^{HRMS (EI +): m /} z: calcd for C 17 H 18 O 4: 286.1205. Found: 286.1202.

2) Compound 6: Yellow liquid, 349 mg, 98% yield.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 12.23 (1H, s), 8.37 (1H, d, J = 8.4Hz), 8.18 (1H, d, J = 8.4Hz), 7.60 (1H, dd, J = 7.8 , 7.5 Hz), 7.49 (1H, dd, J = 8.1,7.2Hz), 3.97 (3H, s), 3.05 (2H, t, J = 6.9Hz), 1.85-1.80 (2H, m), 1.61-1.58 (2H, m), 1.56-1.45 (2H, m), 1.35 (3H, s), 1.26-1.17 , s);

¹³ C NMR (75 MHz, CDCl ₃ ) δ 172.97, 156.11, 141.33, 129.47, 128.99, 125.55, 124.36, 124.27, 123.68, 121.48, 111.74, 105.12, 74.94, 51.96, 39.65, 39.39, 31.57, 27.82, 23.37, 2260, 21.33, IR (neat) 3071, 2949, 2869, 1734, 1651, 1589, 1445, 1380, 1336, 1237, 1170, 1101, 997, 770 cm ^-1 ;

^{HRMS (EI +): m /} z: calcd for C 22 H 28 O 4: 356.1988. Found: 356.1988.

3) Compound 8: yellow solid, 327 mg, 98% yield, melting point 131-132 [deg.] C;

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 12.19 (1H, s), 8.21 (1H, d, J = 8.1Hz), 8.00 (1H, d, J = 8.1Hz), 7.38 (1H, dd, J = 8.1 , 6.9Hz), 7.32-7.14 (6H, m), 4.79 (1H, d, J = 9.9Hz), 3.70 (3H, s), 2.88-2.66 (2H, m), 2.02-1.98 (1H, m) , 1.80-1.72 (1H, m), 1.61-1.58 (2H, m), 1.56-1.45 (2H, m), 1.35 (3H, s), 1.26-1.17 , 0.88 (3H, s);

¹³ C NMR (75 MHz, CDCl ₃ ) δ 172.67, 156.56, 142.56, 141.87, 129.06, 128.77, 128.32, 127.49, 125.73, 125.57, 124.04, 123.63, 121.33, 112.84, 104.85, 76.27, 51.84, 30.21, 25.67;

IR (KBr) 3055, 2952, 2867, 1726, 1645, 1589, 1444, 1382, 1333, 1240, 1170, 1097, 997, 763, 743, 702, 649 cm ^-1 ;

^{HRMS (EI +): m /} z: calcd for C 21 H 18 O 4: 334.1205. Found: 334.1205.

4) Compound 10: yellow solid, 361 mg, 96%. Melting point 74-75 DEG C;

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 12.13 (s, 1H), 8.26 (d, J = 8.1Hz, 1H), 8.07 (d, J = 8.4Hz, 1H), 7.49 (dd, J = 8.1,6.9 Hz, 1H), 7.39 (dd , J = 8.4,6.9Hz, 1H), 7.27-7.16 (m, 5H), 4.57 (t, J = 6.9Hz, 2H), 3.04 (t, J = 6.9Hz, 2H ), 2.71 (t, J = 6.9 Hz, 2H), 1.61 (t, J = 6.9 Hz, 2H), 1.28 (s, 6H);

_{^{13 C NMR (75MHz, CDCl 3}} ) δ 172.52, 156.27, 141.36, 137.65, 129.39, 129.02, 128.84, 128.56, 126.70, 125.59, 124.25, 123.68, 121.49, 111.71, 105.16, 72.91, 65.98, 34.95, 33.10, 26.41, 23.24;

IR (KBr): 3395, 3067, 3028, 2970, 2935, 1736, 1642, 1587, 1445, 1387, 1327, 1235, 1174, 1123, 1097, 989, 807, 770, 700 cm ^-1 ;

HRMS (EI ⁺ ): m / z calcd for C ₂₄ H ₂₄ O ₄ : 376.1675; found: 376.1675.

5) Compound 12: yellow liquid, 437 mg, 98% yield.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 12.13 (s, 1H), 8.24 (d, J = 8.1Hz, 1H), 8.04 (d, J = 8.1Hz, 1H), 7.45 (dd, J = 8.4,6.9 (T, J = 6.9 Hz, 2H), 2.98 (t, J = 6.9 Hz, 2H), 7.34 (dd, J = 7.2, 6.9 Hz, 1H), 7.25-7.08 ), 2.66 (t, J = 6.9 Hz, 2H), 1.61-1.32 (m, 8H), 1.19 (s, 3H), 1.15-1.05 3H);

¹³ C NMR (75 MHz, CDCl ₃ ) δ 172.48, 156.23, 141.21, 137.64, 129.44, 128.96, 128.78, 128.50, 126.64, 125.50, 124.25, 123.67, 121.45, 111.92, 105.12, 74.88, 65.91, 39.57, 39.39, 31.49, 27.81, 23.39, 22.91, 22.61, 22.57, 21.31; IR (neat): 3272, 3066, 3028, 2948, 2870, 1723, 1642, 1588, 1496, 1445, 1386, 1323, 1235, 1172, 1099, 988, 806, 769, 743, 700, 649 cm ^-1 ;

HRMS (EI ⁺ ): m / z calcd for C ₂₉ H ₃₄ O ₄ : 446.2457; found: 446.2457.

Example 3 Synthesis of Compound 3 and Compound 4

(284 mg, 1.0 mmol) or 3,4-dihydromorpholine (286 mg, 1.0 mmol) was added to DMSO (4 mL) in which KOH (168 mg, 3.0 mmol) was dissolved. The reaction mixture was heated at 60 < 0 > C for 8 hours and the reaction was quenched by the addition of 1N HCl (10 mL) solution. The solution was extracted with ethyl acetate (15 mL X 3), washed with water, . After concentration under reduced pressure, compounds 3 and 4 were purified by silica gel flash chromatography (hexane / ethyl acetate = 9: 1).

1) Compound 3: Yellow solid, 205 mg, 76%. Melting point 102-103 占 폚;

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 14.04 (1H, s), 10.53 (1H, s), 8.18 (1H, d, J = 8.1Hz), 8.16 (1H, d, J = 7.2Hz), 7.54 ( 1H, dd, J = 8.1,7.2Hz) , 7.36 (1H, dd, J = 8.1,7.2Hz), 6.79 (1H, d, J = 10.2Hz), 5.66 (1H, d, J = 9.9Hz), 1.54 (6 H, s); _{^{13 CNMR (75MHz, CDCl 3)}} δ 190.74, 163.47, 157.21, 133.64, 129.53, 127.84, 123.91, 123.31, 120.22, 118.35, 115.65, 106.48, 106.19, 79.14, 28.45; IR (KBr) 3068, 2976, 2929, 1735 , 1639, 1449, 1363, 1303, 1245, 1142, 1022, 771, 673 cm < ^{-1 &} gt ;; ^{HRMS (EI +): m /} z: calcd for C 16 H 14 O 4: 270.0892. Found: 270.0893.

2) Compound 4: white solid, 196 mg, 72%. Melting point 165-166 DEG C;

_{^{1 H NMR (300MHz, CDCl 3}} ) δ 14.18 (s, 1H), 10.51 (s, 1H), 8.23 (d, J = 8.4Hz, 1H), 8.18 (d, J = 8.4Hz, 1H), 7.52 ( dd, J = 8.1,7.2,1H), 7.35 (dd, J = 8.1,7.2Hz, 1H), 2.89 (t, J = 6.6Hz, 2H), 1.85 (t, J = 6.6Hz, 2H), 1.31 (s, 6 H);

¹³ C NMR (75 MHz, CDCl ₃ ) δ 190.37, 166.84, 159.71, 132.88, 128.88, 123.66, 123.61, 120.84, 117.96, 113.69, 106.15, 72.60, 41.00, 29.77, 16.24; IR (KBr): 3380, 3055, 2980, 2931, 1693, 1619, 1582, 1429, 1392, 1368, 1327, 1264, 1020, 897, 743, 713 cm- ¹ ;

^{HRMS (EI +): m /} z: calcd for C 16 H 16 O 4: 272.1049; found: 272.1051.

<Experimental Example 1> Antioxidative activity analysis of molurin, 3,4-dihydromolgin and its derivatives

1. Analysis of DPPH radical scavenging activity

The antioxidative activities of the above synthesized compounds were evaluated by measuring 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging activity ( Food Chem . 2009, 113 , 1202). The DPPH methanol solution exhibits a deep purple color and strongly absorbs the 517 nm wavelength. In the presence of antioxidants, the absorption decreases and turns into a yellow solution, which is based on the inverse relationship between the concentration of DPPH remaining and the anti-radical activity of the antioxidant.

The synthesized Compounds 1 to 12 were treated with a DPPH methanol solution at the concentrations shown in Table 1, and the degree of discoloration of the purple color of the DPPH methanol solution was measured by absorbance at 517 nm. At this time, inhibition of free radical generation (I%) of DPPH was calculated by the following equation.

Inhibition rate (%) = [(A _control -A _sample ) / A _control ] X100

At this time, the absorbance of DPPH 517 nm was measured by a UV-vis spectrometer, the A _control was the absorbance of the DPPH solution, and the A _sample was the absorbance of the synthesized compound.

The antioxidant activity of each compound was expressed as IC ₅₀ (micromolar concentration required to inhibit radical formation of 50% DPPH).

As a result, compounds 1, 2, 5, 6, 8, 10, 11 and 12 exhibited better antioxidative effect than the compounds 3, 4, 7 and 9 as shown in Table 1 below and 3,4- 2) had an IC ₅₀ of 0.15 ㎍ / mL which was better than the IC ₅₀ value of 2.13 ㎍ / mL of the control, 3,5-di-tert-4-butylhydroxytoluene (BHT).

Compound No. Inhibition by concentration (㎍ / mL)
IC ₅₀ / mL 10 25 50 75 100 One 75.74 + 0.17 79.09 ± 0.26 84.54 ± 1.21 88.89 ± 0.75 93.03 + - 1.08 0.20 + - 0.87 2 77.03 + - 0.43 79.70 ± 0.67 81.44 ± 1.09 89.19 ± 0.87 95.62 + 0.47 0.15 + - 0.45 3 48.78 ± 0.20 59.43 + - 0.30 61.40 ± 0.25 67.01 + - 0.31 71.91 + 0.21  11.48 ± 1.02 4 49.81 ± 0.31 57.53 + - 0.29 58.53 ± 1.20 63.77 + - 0.71 72.15 + 0.26  11.22 + - 0.87 5 58.01 + - 0.20 65.17 + - 0.25 74.15 + 0.30 79.04 + - 0.37 81.92 + 0.25 0.34 + 0.62 6 59.50 ± 0.15 66.31 ± 0.29 78.36 ± 1.00 81.41 + 0.15 83.28 ± 0.31 0.30 0.93 7 54.80 ± 0.24 59.36 ± 0.65 68.74 + 0.16 74.31 + - 0.23 78.68 + - 0.84 1.99 ± 1.08 8 59.04 + - 0.34 66.19 ± 0.23 76.25 + - 0.56 78.09 + - 0.76 81.88 ± 0.76 0.37 ± 0.91 9 49.52 ± 0.30 58.60 ± 1.05 65.30 ± 1.40 70.70 +/- 1.75 73.92 + 1.65  10.71 ± 0.26 10 60.31 + - 0.20 68.79 + - 0.30 75.47 ± 0.25 86.82 ± 0.20 87.98 + - 1.15 0.29 0.74 11 57.50 + - 0.60 64.80 ± 0.55 72.90 + - 0.70 76.50 ± 1.28 82.20 ± 1.15 0.35 + 0.85 12 59.20 ± 1.30 69.40 +/- 1.41 73.60 ± 1.85 78.01 + - 1.80 83.50 ± 1.55 0.33 ± 0.69 BHT 53.90 + - 0.35 61.40 ± 0.32 61.40 ± 0.56 67.90 + - 0.73 74.80 ± 0.77 2.13 + - 0.61

2. Investigation of antibacterial activity in vitro

E. coli strains to determine the antibacterial activity of the compounds 1 to 12 (E.coli, KCTC-1924) and Muller-Hinton agar medium to confirm that Staphylococcus aureus (S.aureus, KCTC-1916) inhibit the growth of The agar-disc diffusion method was used.

Each compound was dissolved in DMSO at a concentration of 100 μg / mL, and each strain was divided into pre-inoculated agar medium and 100 μg / mL of antibiotic ciprofloxacin was used as a control. Each plate was incubated at 37 ° C for 24 hours and the diameter of the growth inhibited portion was measured and recorded.

As a result, Compounds 3, 5, 7, 10 and 12 exhibited strong bactericidal growth inhibition activity in the E. coli growth inhibition region of 20-21 mm as shown in Table 2 below. Compounds 4, 6, 9 and 11 exhibited intermediate or weakest Compounds 1, 4, 5, 10, and 11 exhibited strong activity against Staphylococci, while compounds 1, 4, 5, 10, and 11 showed moderate (18-20 mm), and the other compounds showed weak antibacterial activity.

Compound No.
Diameter of Growth Restraint Area (mm) E. coli
Gram-negative S. aureus
Gram - positive One 15 18 2 13 30 3 21 38 4 19 18 5 21 18 6 18 20 7 20 15 8 14 28 9 17 15 10 20 18 11 19 20 12 21 14 Ciprofloxacin 30 35

While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereby. something to do. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.

Claims (8)

The molar derivative represented by the formula (1)
[Chemical Formula 1]

In Formula 1, when X is hydroxy, R ¹ and R ² are each C1 to C4 alkyl; and when X is methoxy, R ¹ and R ² are each - (CH ₂ ) ₂ CH═C (CH _{3 ) 2, - (CH 2)} 3 CH (CH 3) 2, X is -O (CH _{2) 2} Ph, if the R ¹ and R ² are a C1 to C4 alkyl, each - CH ₂ = C (CH ₂₎ (CH ₃ ) ₂ , - (CH ₂ ) ₃ CH (CH ₃ ) ₂ , and the solid line with the dotted line (---) indicates a single bond or a double bond. The method of claim 1, wherein the molar derivative is selected from the group consisting of 6-hydroxy-2,2-dimethyl-2H-benzo [h] [h] chromene-5-carboxylic acid; 3-dihydro-2H-benzo [h] chromene-5-carboxylate [6-hydroxy-2,2- 4-dihydro-2H-benzo [h] chromene-5-carboxylic acid; Compound 4], methyl 6-hydroxy-2-methyl-2- (4-methylpent-3-en-1-yl) -2H- benzo [h] chromen- Methyl-2- (4-methylpent-3-en-1-yl) -2H-benzo [ Methylpentyl) -3,4-dihydro-2H-benzo [h] chromen-5-carboxylate [methyl 6-hydroxy-2- -2H-benzo [h] chromene-5-carboxylate; Phenethyl 6-hydroxy-2,2-dimethyl-2H-benzo [h] chromene-5-carboxylate [phenethyl 6-hydroxy- chromene-5-carboxylate; Compound 9], phenethyl 6-hydroxy-2,2-dimethyl-3,4-dihydro-2H-benzo [h] chromen- -3,4-dihydro-2H-benzo [h] chromene-5-carboxylate; Compound 10], phenethyl 6-hydroxy-2-methyl-2- (4-methylpent-3-en-1-yl) -2H- benzo [h] chromen- hydroxy-2-methyl-2- (4-methylpent-3-en-1-yl) -2H-benzo [h] chromene-5-carboxylate; Compound 11 and phenethyl 6-hydroxy-2-methyl-2- (4-methylpentyl) -3,4, -dihydro-2H- benzo [h] chromen- hydroxy-2-methyl-2- (4-methylpentyl) -3,4-dihydro-2H-benzo [h] chromene-5-carboxylate; Compound [12]. &Lt; / RTI &gt; The molargin derivative represented by the formula (2)
(2)

In the formula (2), a solid line accompanied by a dotted line (-) indicates a single bond or a double bond. The method of claim 3, wherein the molar derivative is methyl 6-hydroxy-2-phenyl-4H-benzo [h] chromene- chromene-5-carboxylate; Compound 7] and methyl 6-hydroxy-2-phenyl-3,4-dihydro-2H-benzo [h] chromene- dihydro-2H-benzo [h] chromene-5-carboxylate; Lt; RTI ID = 0.0 &gt; 8]. &Lt; / RTI &gt; An antioxidant composition for preventing or treating an oxidative disease selected from skin aging, skin pigmentation, wrinkles, psoriasis, and eczema, which comprises the molargin derivative of any one of claims 1 to 4 as an active ingredient. 6. The process of claim 5 wherein the molar derivative is selected from the group consisting of methyl 6-hydroxy-2-methyl-2- (4-methylpent-3-en-1-yl) -2H-benzo [h] chromen- 5-carboxylate: compound 5], methyl 6-hydroxy-2-methyl-2- -Methyl-2- (4-methylpentyl) -3,4-dihydro-2H-benzo [h] chromen- -3,4-dihydro-2H-benzo [h] chromene-5-carboxylate; Compound 6], methyl 6-hydroxy-2-phenyl-4H-benzo [h] chromene-5-carboxylate [methyl 6-hydroxy-2-phenyl-4H-benzo [h] chromene-5-carboxylate; Methyl 7-hydroxy-2-phenyl-3,4-dihydro-2H-benzo [h] chromene-5-carboxylate -2H-benzo [h] chromene-5-carboxylate; Compound 8], phenethyl 6-hydroxy-2,2-dimethyl-3,4-dihydro-2H-benzo [h] chromen- -3,4-dihydro-2H-benzo [h] chromene-5-carboxylate; Compound 10], phenethyl 6-hydroxy-2-methyl-2- (4-methylpent-3-en-1-yl) -2H- benzo [h] chromen- hydroxy-2-methyl-2- (4-methylpent-3-en-1-yl) -2H-benzo [h] chromene-5-carboxylate; Compound 11 and phenethyl 6-hydroxy-2-methyl-2- (4-methylpentyl) -3,4, -dihydro-2H- benzo [h] chromen- hydroxy-2-methyl-2- (4-methylpentyl) -3,4-dihydro-2H-benzo [h] chromene-5-carboxylate; Compound 12]. &Lt; RTI ID = 0.0 &gt; 11. &lt; / RTI &gt; An antimicrobial composition comprising the molar derivative as claimed in any one of claims 1 to 4 as an active ingredient. 8. The antimicrobial composition according to claim 7, wherein the molybdenum derivative has an antibacterial effect on a bacterium selected from E. coli or Staphylococcus.