KR20120086538A - Novel 4-o-methylhonokiol derivatives and composition for treating inflammatory disease comprising the same as active ingredient - Google Patents

Abstract

PURPOSE: A 4-O-methylhonokiol derivative is provided to have excellent anti-inflammation activity by restraining activation of cyclooxigenase-2, thereby capable of being used for medicines for treating various inflammations. CONSTITUTION: A 4-O-methylhonokiol derivative is in chemical formula 1, chemical formula 2, or chemical formula 3. In chemical formula 1, R1 is H, C1-7 alkyl, C2-7 alkenyl, -CO(CH2)nCH3, or -CO-NR5R6, R2 is H or halo, and R3 and R4 is respectively C1-7 alkyl, C2-7 alkenyl, C1-7 hydroxyalkyl, or C3-8 cycloalkyl, C3-8 heterocycloalkyl, or (C3-8 heterocycloalkyl)C1-7 alkyl. In chemical formula 2, R1 is C1-7 alkyl, C2-7 alkenyl, or halo, and R2 is C1-7 alkyl, C2-7 alkenyl, or C1-7 hydroxyalkyl. In chemical formula 3, R1 is C1-7 alkyl, or C2-7 alkenyl, and R2 is C1-7 alkyl, C2-7 alkenyl, C3-8 cycloalkyl, or (C3-8 cycloalkyl)C1-7 alkyl.

Description

Novel 4-O-Methylhonokiol Derivatives and Composition for Treating Inflammatory Disease Comprising the Same as Active Ingredient

The present invention relates to a novel 4-O-methyl honokiol derivative and a composition for treating inflammatory diseases comprising the same as an active ingredient.

4-O-methylhonokiol is a generic name for 3 ', 5-diallyl-4'-methoxybiphenyl-2-ol, recently isolated from Magnolia species and inhibited by cyclic oxygenase enzymes. Inflammatory effect, as well as memory impairment is reported to be very useful substance (1, 2). Meanwhile, Korean Patent Registration No. 10-932962, Korean Patent Publication No. 2009-94916, and Korean Patent Publication No. 2008-104760 disclose 4-O-methylhonokiol extracted from stems and leaves of Magnolia officinalis Rehd. Et Wils. It is disclosed that it can be used for the treatment of amyloid-related diseases, prevention of hair loss, promotion of hair growth, and skin whitening.

To date, the bark of the roots and stems of magnolia species has been used as a traditional medicine for the treatment of various diseases, and the main biologically active compounds belonging to magnolia are honokiol, magnolol and obovatol. Biphenyl-neolignan-based compounds such as (2). Interestingly, 4-O-methylhonokiol was found to have higher anti-inflammatory activity than honokiol or various other honokiol analogues, with an IC50 value of 0.06 μM for COX-2 (3). In addition, 4-O-methylhonokiol has recently been shown to exhibit neuroaffinity and memory enhancing activity (4). The chemical structural feature of 4-O-methylhonokiol is an asymmetric 5,3'-diallyl-biphenyl having a hydroxyl group at the C2 position of the A ring and a methoxy group at the C4 position of the B ring. However, despite the interesting biological activity of 4-O-methylhonokiol, the synthesis of isomers, honokiol and obovatol has been reported, whereas the synthesis of derivatives of this compound has not yet been reported in the art (3). , 5), various activities of the derivatives have not been reported.

Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of cited papers and patent documents are incorporated herein by reference in their entirety, and the level of the technical field to which the present invention belongs and the contents of the present invention are more clearly explained.

The present inventors earnestly researched to develop derivative compounds having more improved activity of methylhonokiol compounds known to have various physiological activities such as anti-inflammatory and anti-dementia efficacy. As a result, the present invention was completed by experimentally confirming that they have synthesized various derivatives of methyl honochiol and have anti-inflammatory activity that inhibits the activity of COX-2 (Cyclooxigenase-2).

Accordingly, an object of the present invention is to provide a novel methyl honokiol derivative.

Another object of the present invention to provide a composition for treating inflammatory diseases comprising the novel methyl honokiol derivative as an active ingredient.

The objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.

According to one aspect of the present invention, the present invention provides a methyl honokiol derivative compound represented by the following formula (1), (2) or (3).

이고, In Formula 1, R ₁ is H, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, -CO (CH ₂ ) _n CH ₃ , or

ego,

R ₂ is H, or halo;

R ₃ and R ₄ are each independently C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₁ -C ₇ hydroxyalkyl, or C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ heterocycloalkyl , (C ₃ -C ₈ heterocycloalkyl) C ₁ -C ₇ alkyl;

R ₅ and R ₆ are each independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ haloaryl, (C ₆ -C ₁₀ aryl ) C ₁ -C ₇ alkyl, -CH ₂ CO ₂ CH ₃ , -CH ₂ CONH ₂ , or linked to each other to form C ₃ -C ₈ heterocycloalkyl, wherein n is an integer from 0-4;

In Formula 2,

R ₁ is C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, or halo;

R ₂ is C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, or C ₁ -C ₇ hydroxyalkyl;

In Formula 3,

R ₁ is C ₁ -C ₇ alkyl, or C ₂ -C ₇ alkenyl;

R ₂ is C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₃ -C ₈ cycloalkyl, or (C ₃ -C ₈ cycloalkyl) C ₁ -C ₇ Alkyl.

,

,

,

,

,

, 또는

이고; R₂는 H, Br 또는 Cl이고; R₃ 및 R₄는 각각 독립적으로 C₁-C₅ 알킬, C₂-C₅ 알케닐,

, 또는 C₁-C₅ 히드록시알킬이고; 상기 화학식 2에서, R₁은 C₁-C₇ 알킬, C₂-C₇ 알케닐, 또는 Br이고; R₂는 C₁-C₇ 알킬, 또는 C₁-C₇ 히드록시알킬이고; 상기 화학식 3에서, R₁은 C₁-C₇ 알킬이고; R₂는 C₂-C₇ 알케닐, 또는

이다. According to a preferred embodiment of the present invention, in formula 1, R ₁ is H, C ₁ -C ₅ alkyl, C ₂ -C ₅ Alkenyl, -COCH ₃ ,

,

,

,

,

,

, or

ego; R ₂ is H, Br or Cl; R ₃ and R ₄ are each independently C ₁ -C ₅ alkyl, C ₂ -C ₅ Alkenyl,

Or C ₁ -C ₅ hydroxyalkyl; In Chemical Formula 2, R ₁ is C ₁ -C ₇ alkyl, C ₂ -C ₇ Alkenyl, or Br; R ₂ is C ₁ -C ₇ alkyl, or C ₁ -C ₇ hydroxyalkyl; In Formula 3, R ₁ is C ₁ -C ₇ alkyl; R ₂ is C ₂ -C ₇ Alkenyl, or

to be.

In the above formulas (1), (2) and (3), the term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group of the specified carbon number. For example, "C ₁ -C ₃ alkyl" includes not only straight n-propyl groups but also branched isopropyl groups, and "C ₁ -C ₄ alkyl" refers to n-butyl, isobutyl and t-butyl. Include.

The term "hydroxyalkyl" means an alkyl group wherein at least one hydrogen atom of the alkyl group as defined above is substituted with a hydroxy group.

The term "alkenyl" refers to a straight or branched chain unsaturated hydrocarbon group of the specified carbon number having at least one double bond, for example ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, t- Butenyl, n-pentenyl, n-hexenyl and the like.

The term "halo" means fluoro (F), chloro (Cl), bromo (Br) or iodo (I).

The term "cycloalkyl" refers to a non-aromatic saturated monocyclic, fused bicyclic or crosslinked polycyclic ring hydrocarbon group containing the specified number of ring carbon atoms. For example, "C ₃ -C ₆ cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The term "cycloalkyl alkyl" means an alkyl group wherein at least one hydrogen atom of the alkyl group as defined above is substituted with a cycloalkyl group.

The term "heterocycloalkyl" refers to cycloalkyl as defined above, wherein at least one of the designated ring carbon atoms is -O-, -N =, -NR-, -C (O)-, -S-, -S ( O)-or -S (O) ₂ -wherein R is hydrogen, C ₁ -C ₄ alkyl or nitrogen protecting group.

The term "heterocycloalkyl alkyl" means an alkyl group wherein at least one hydrogen atom of the alkyl group as defined above is substituted with a heterocycloalkyl group.

The term "aryl" refers to an aromatic hydrocarbon group. For example "C ₆ -C ₁₀ aryl" groups include phenyl, α-naphthyl, β-naphthyl, biphenyl and tetrahydronaphthyl.

The term "haloaryl" means an aryl group in which at least one of the hydrogen atoms of the aryl group is substituted with a halo group.

The term "aryl alkyl" means an alkyl group wherein at least one of the hydrogen atoms of the alkyl group is substituted with an aryl group as defined above. For example (C ₆ -C ₁₄ aryl) C ₁ -C ₄ alkyl is benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-naphthylmethyl, 2-naphthyl Methyl and the like.

According to another aspect of the invention, the present invention provides a pharmaceutical composition for the treatment or prevention of inflammatory diseases comprising a methyl honokiol derivative represented by the formula (1), (2) or (3) as an active ingredient.

According to another aspect of the present invention, the present invention provides a functional food composition for improving an inflammatory disease comprising a methyl honokiol derivative represented by Formula 1, Formula 2 or Formula 3 as an active ingredient.

The methyl honokiol derivative of the present invention has excellent anti-inflammatory activity by inhibiting the activity of COX-2 (Cyclooxigenase-2), as demonstrated in one specific example of the present invention. Therefore, the methyl honokiol derivative of the present invention can be used as an active ingredient for the treatment, prevention or amelioration of inflammatory diseases.

According to a preferred embodiment of the present invention, the inflammatory disease is atopic dermatitis, encephilitis, inflammatory enteritis, chronic obstructive pulmonary disease, pulmonary pulmonary shock, pulmonary fibrosis, undifferentiated spondyloarthropathy, undifferentiated arthrosis, arthritis, Inflammatory osteolysis, chronic inflammatory diseases caused by chronic viral or bacterial infections, colitis, inflammatory bowel disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, reactive arthritis, osteoarthritis, psoriasis, scleroderma, osteoporosis, atherosclerosis Sclerosis, myocarditis, endocarditis, pericarditis, cystic fibrosis, Hashimoto's thyroiditis, Graves' disease, leprosy, syphilis, Lyme disease, Borreliosis, neuro-borelia, tuberculosis, Sarcoidosis, lupus, disc Lupus erythematosus, lupus erythematosus, lupus nephritis, systemic lupus erythematosus, macular degeneration, uveitis, irritable bowel syndrome, Croce's disease, shogranosis Including the military, fibromyalgia, chronic fatigue syndrome, chronic fatigue immune dysfunction syndrome, myalgia encephalomyelitis, amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, autism spectrum disorders, attention deficit disorder and attention deficit hyperactivity disorder, etc.

The pharmaceutical composition of the present invention comprises (a) a pharmaceutically effective amount of a methyl honokiol derivative represented by Formula 1, Formula 2 or Formula 3; And (b) it may be provided in the form of a pharmaceutical composition for the treatment or prevention of inflammatory diseases comprising a pharmaceutically acceptable carrier.

Pharmaceutically acceptable carriers included in the pharmaceutical compositions of the present invention are those commonly used in the preparation, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, Calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oils It doesn't happen. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington ' s Pharmaceutical Sciences (19th ed., 1995).

The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate, . On the other hand, the oral dosage of the pharmaceutical composition of the present invention is preferably 0.001-100 mg / kg (body weight) per day. The pharmaceutical composition of the present invention may be administered orally or parenterally, and when administered parenterally, may be administered by intravenous infusion, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, or the like. In the pharmaceutical composition of the present invention, the route of administration is preferably determined depending on the type of disease to which it is applied. The concentration of the active ingredient in the pharmaceutical composition of the present invention can be determined in consideration of the purpose of treatment, the condition of the patient, the period of time, etc., and is not limited to a specific range of concentration.

The pharmaceutical compositions of the present invention may be prepared in unit dosage form by formulating with a pharmaceutically acceptable carrier and / or excipient according to methods which can be easily carried out by those skilled in the art. Or may be prepared by incorporating into a multi-dose container. The formulations may be in the form of solutions, suspensions or emulsions in oils or aqueous media, or in the form of excipients, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents.

The present invention provides a functional food composition for improving an inflammatory disease comprising a methyl honokiol derivative represented by Formula 1, Formula 2, or Formula 3 as an active ingredient.

The functional food composition of the present invention includes components that are ordinarily added during the manufacture of food, and includes, for example, proteins, carbohydrates, fats, nutrients, and seasonings. For example, when prepared with a drink, a flavoring agent or a natural carbohydrate may be included as an additional component in addition to the methyl honokiol derivative as an active ingredient. For example, natural carbohydrates include monosaccharides (eg, glucose, fructose, etc.); Disaccharides (eg maltose, sucrose, etc.); oligosaccharide; Polysaccharides (eg, dextrins, cyclodextrins, etc.); And sugar alcohols (eg, xylitol, sorbitol, erythritol, and the like). As the flavoring agent, natural flavoring agents (e.g., taumartin, stevia extract, etc.) and synthetic flavoring agents (e.g., saccharin, aspartame, etc.) can be used.

The features and advantages of the present invention are summarized as follows:

(i) The present invention provides novel methyl honokiol derivative compounds.

(Ii) The novel methyl honokiol derivatives of the present invention exhibited anti-inflammatory activity by inhibiting the activity of COX-2 in RAW 264.7 macrophages.

(Iii) The novel methyl honokiol derivatives of the present invention can be developed as drugs for the treatment or prevention of inflammatory diseases.

The present invention provides a novel methyl honokiol derivative and a composition for the treatment, prevention or improvement of inflammatory diseases comprising the same as an active ingredient. The methyl honokiol derivative of the present invention exhibits very excellent anti-inflammatory activity by inhibiting the activity of COX-2 (Cyclooxigenase-2). Therefore, the methyl honokiol derivative of the present invention can be developed as an active ingredient of a therapeutic agent for various inflammatory diseases and health functional food for improving inflammatory diseases.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example

Preparation Example 1 Preparation of Derivative 1

[Reaction Scheme 1]

Pd / C was added to an ethanol solution of methylhonokiol, and the pressure was reduced. After the pressure reduction, the reaction was carried out under H ₂ air flow for 1 hour. After completion of the reaction, a celite filtration was performed. Concentration under reduced pressure and the product was purified by flash column chromatography (EtOAc: Hexane = 1: 13). The yield was 98%, 30 mg. ¹ H NMR (CDCl ₃ , 500 MHz) δ 7.27 (dd, 1H, J = 8.3, 2.3 Hz, Ar-H), 7.23 (ds, 1H, J = 2.2 Hz, Ar-H), 7.05-7.03 (m , 2H, Ar-H), 6.95 (d, 1H, J = 8.3 Hz, Ar-H), 6.89 (d, 1H, J = 7.9 Hz, Ar-H), 5.16 (s, 1H, Ar-OH) , 3.87 (s, 3H, Ar-OCH ₃ ), 2.64 (t, 2H, J = 7.5 Hz, Ar-CH ₂ CH ₂ CH ₃ ), 2.55 (t, 2H, J = 7.5 Hz, Ar-CH ₂ CH ₂ CH ₃ ), 1.68-1.61 (m, 4H, Ar—CH ₂ CH ₂ CH ₃ ), 0.99-0.94 (m, 6H, Ar—CH ₂ CH ₂ CH ₃ ).

Preparation Example 2 Preparation of Derivative 2

Scheme 2

After dissolving methyl honokiol (1.0 eq) in anhydrous DMF under a nitrogen stream, potassium carbonate (3.0 eq) was added thereto and stirred for 30 minutes. After 30 minutes, methyl iodine (3.0 eq) was added dropwise and reacted for 3 hours. Washed once with 1N HCl and extracted three times with ethyl acetate. After concentration under reduced pressure, flash column chromatography (EtOAc: Hexane = 1: 8) was purified to obtain a product. The yield was 98%, 51 mg. ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.37 (dd, 1H, J = 8.3, 2.2 Hz, Ar-H), 7.31 (ds, 1H, J = 2.2 Hz, Ar-H), 7.12 (ds, 1H , J = 2.1 Hz, Ar-H), 7.10 (dd, 1H, J = 8.2, 2.3 Hz, Ar-H), 6.90 (d, 2H, J = 8.3 Hz, Ar-H), 6.08-5.93 (m , 2H, Ar-CH ₂ CHCH ₂ ), 5.12-5.02 (m, 4H, Ar-CH ₂ CHCH ₂ ), 3.86 (s, 3H, Ar-OCH ₃ ), 3.79 (s, 3H, Ar-OCH ₃ ) , 3.43 (d, 2H, J = 6.6 Hz, Ar-CH ₂ CHCH ₂ ), 3.37 (d, 2H, J = 6.7 Hz, Ar-CH ₂ CHCH ₂ ).

Manufacturing example  3: Preparation of Derivative 3

Scheme 3

Methyl honokiol (1.0 eq) was dissolved in anhydrous DMF under a nitrogen stream, and potassium carbonate (3.0 eq) was added thereto, followed by stirring for 30 minutes. After 30 minutes, 2-bromopropane (1.5 eq) was added dropwise and reacted for 4 hours. Washed once with 1N HCl and extracted three times with ethyl acetate. After concentration under reduced pressure, the product was purified by flash column chromatography (EtOAc: Hexane = 1: 25). The yield was 60%, 21 mg. ¹ H NMR (CDCl ₃ , 500 MHz) δ 7.40 (ds, 1H, J = 2.2 Hz, Ar-H), 7.37 (dd, 1H, J = 8.4, 2.3 Hz, Ar-H), 7.13 (ds, 1H , J = 2.3 Hz, Ar-H), 7.04 (dd, 1H, J = 8.3, 2.3 Hz, Ar-H), 6.89 (d, 1H, J = 8.3 Hz, Ar-H), 6.88 (d, 1H , J = 8.4 Hz, Ar-H), 6.07-5.94 (m, 2H, Ar-CH ₂ CHCH ₂ ), 5.11-5.03 (m, 4H, Ar-CH ₂ CHCH ₂ ), 4.41-4.33 (m, 1H , Ar-OCH (CH ₃ ) ₂ ), 3.86 (s, 3H, Ar-OCH ₃ ), 3.42 (d, 2H, J = 6.7 Hz, Ar-CH ₂ CHCH ₂ ), 3.36 (d, 2H, J = 6.7 Hz, Ar—CH ₂ CHCH ₂ ), 1.23 (d, 6H, J = 6 Hz, Ar—OCH (CH ₃ ) ₂ ).

Manufacturing example  4: Preparation of Derivative 4

Scheme 4

Dimethyl amino pyridine (0.2 eq), triethylamine (5.0 eq) and acetic anhydride (1.2 eq) were added to a methylene dichloride solution of methyl honokiol (1.0 eq) at room temperature. . After stirring for 20 minutes, the reaction was terminated and neutralized with sodium bicarbonate (NaHCO ₃ ). Then, the mixture was extracted three times with ethyl acetate, concentrated under reduced pressure, and purified by flash column chromatography (EtOAc: Hexane = 1: 10) to obtain a product. The yield was 93%, 54 mg. ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.24 (dd, 1H, J = 8.3, 2.2 Hz, Ar-H), 7.21 (ds, 1H, J = 2.2 Hz, Ar-H), 7.20 (ds, 1H , J = 2.1 Hz, Ar-H), 7.14 (dd, 1H, J = 8.2, 2.2 Hz, Ar-H), 7.02 (d, 1H, J = 8.2 Hz, Ar-H), 6.89 (d, 1H , J = 8.3 Hz, Ar-H), 6.06-5.93 (m, 2H, Ar-CH ₂ CHCH ₂ ), 5.14-5.02 (m, 4H, Ar-CH ₂ CHCH ₂ ), 3.86 (s, 3H, Ar -OCH ₃ ), 3.42-3.39 (m, 4H, Ar-CH ₂ CH ₂ CH ₃ ), 2.09 (s, 3H, Ar-OCOCH ₃ ).

Preparation Example 5 Preparation of Derivative 5

Scheme 5

Methyl honokiol (1.0 eq) was dissolved in anhydrous THF under a nitrogen stream, and then isopropyl magnesium chloride (2.0 M solution in diethyl ether, 1.2 eq) was added at -78 ° C. The mixture was stirred at -78 ° C for 30 minutes and then further stirred at room temperature for about 10 minutes. After stirring for 10 minutes, DBDMH (0.8 eq) was added, followed by reaction for 2 hours. After completion of the reaction, the mixture was washed with aqueous NH ₄ Cl and extracted three times with ethyl acetate. After extraction, the mixture was concentrated under reduced pressure and purified by flash column chromatography (EtOAc: Hexane = 1: 15) to obtain a product. The yield was 64%, 41 mg. ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.34 (dd, 1H, J = 8.4, 2.3 Hz, Ar-H), 7.28 (ds, 1H, J = 2.2 Hz, Ar-H), 7.26 (ds, 1H , J = 2.1 Hz, Ar-H), 7.02 (ds, 1H, J = 2.0 Hz, Ar-H), 6.93 (d, 1H, J = 8.4 Hz, Ar-H), 6.07-5.89 (m, 2H , Ar-CH ₂ CHCH ₂ ), 5.55 (s, 1H, Ar-OH), 5.13-5.03 (m, 4H, Ar-CH ₂ CHCH ₂ ), 3.87 (s, 3H, Ar-OCH ₃ ), 3.43 ( d, 2H, J = 6.6 Hz, Ar-CH ₂ CHCH ₂ ), 3.32 (d, 2H, J = 6.8 Hz, Ar-CH ₂ CHCH ₂ ).

Preparation Example 6 Preparation of Derivative 6

[Reaction Scheme 6]

Meta-chloroperoxybenzoic acid (3 eq) and NaHCO ₃ (5.0 eq) were added to a solution of methyl honokiol (1.0 eq) in anhydrous methylene dichloride, followed by 1 at room temperature. Stir for days. After extraction three times with ethyl acetate and concentrated under reduced pressure and purified by flash column chromatography (EtOAc: Hexane = 1: 2) to obtain the product. The yield was 53%, 30 mg. ¹ H NMR (CDCl ₃ , 500 MHz) δ 7.33 (dd, 1H, J = 8.3, 2.2 Hz, Ar-H), 7.30 (ds, 1H, J = 2.2 Hz, Ar-H), 7.12-7.09 (m , 2H, Ar-H), 6.97 (d, 1H, J = 8.4 Hz, Ar-H), 6.91 (d, 1H, J = 8.0 Hz, Ar-H).

Preparation Example 7 Preparation of Derivative 7

[Reaction Scheme 7]

Methyl honokiol (1.0 eq) was dissolved in anhydrous THF under a nitrogen stream, and then isopropyl magnesium chloride (2.0 M solution in diethyl ether, 1.2 eq) was added at -78 ° C. The mixture was stirred at -78 ° C for 30 minutes and then further stirred at room temperature for about 10 minutes. After stirring for 10 minutes, DCDMH (0.8 eq) was added, followed by reaction for 2 hours. After completion of the reaction, the mixture was washed with aqueous NH ₄ Cl and extracted three times with ethyl acetate. After extraction, the mixture was concentrated under reduced pressure and purified by flash column chromatography (EtOAc: Hexane = 1: 10) to obtain a product. The yield was 30% and 17 mg. ¹ H NMR (CDCl ₃ , 500 MHz) δ 7.36 (dd, 1H, J = 8.4, 2.3 Hz, Ar-H), 7.29 (ds, 1H, J = 2.3 Hz, Ar-H), 7.11 (ds, 1H , J = 2.1 Hz, Ar-H), 6.99 (ds, 1H, J = 2.1 Hz, Ar-H), 6.93 (d, 1H, J = 8.5 Hz, Ar-H), 6.05-5.89 (m, 2H , Ar-CH ₂ CHCH ₂ ), 5.56 (s, 1H, Ar-OH), 5.12-5.03 (m, 4H, Ar-CH ₂ CHCH ₂ ), 3.87 (s, 3H, Ar-OCH ₃ ), 3.42 ( d, 2H, J = 6.6 Hz, Ar-CH ₂ CHCH ₂ ), 3.32 (d, 2H, J = 6.7 Hz, Ar-CH ₂ CHCH ₂ ).

Preparation Example 8 Preparation of Derivative 8

[Reaction Scheme 8]

BH ₃ -THF (15 eq) was added dropwise to anhydrous THF on an ice bath, and methylhonokol dissolved in THF was added slowly over 5 minutes. Then stirred at room temperature for 2 hours. After stirring, an excess of 3N NaOH and H ₂ O ₂ was added at 10 ° C., and the mixture was reacted at 70 ° C. for 2 hours. Extraction with ether three times, followed by concentration under reduced pressure, and purification by flash column chromatography (EtOAc: Hexane = 1: 1) yielded a product. The yield was 36%, 77 mg. ¹ H NMR (CDCl ₃ , 500 MHz) δ 7.29-7.27 (m, 2H, Ar-H), 7.24 (ds, 1H, J = 2.2 Hz, Ar-H), 7.22 (ds, 1H, J = 2.3 Hz , Ar-H), 7.06-7.02 (m, 4H, Ar-H), 6.95 (d, 2H, J = 8.3 Hz, Ar-H), 6.91-6.88 (m, 2H, Ar-H), 6.04- 5.93 (m, 2H, Ar-CH ₂ CHCH ₂ ), 5.18 (s, 2H, Ar-OH), 5.11-5.03 (m, 4H, Ar-CH ₂ CHCH ₂ ), 3.88 (s, 3H, Ar-OCH ₃ ), 3.87 (s, 3H, Ar-OCH ₃ ), 3.69 (t, 2H, J = 6.5 Hz, Ar-CH ₂ CH ₂ CH ₂ OH), 3.64 (t, 2H, J = 6.2 Hz, Ar- CH ₂ CH ₂ CH ₂ OH), 3.42 (d, 2H, J = 6.7 Hz, Ar-CH ₂ CHCH ₂ ), 3.35 (d, 2H, J = 6.8 Hz, Ar-CH ₂ CHCH ₂ ), 2.76 (t , 2H, J = 7.3 Hz, Ar-CH ₂ CH ₂ CH ₂ OH), 2.66 (t, 2H, J = 7.5 Hz, Ar-CH ₂ CH ₂ CH ₂ OH), 1.91-1.85 (m, 4H, Ar -CH ₂ CH ₂ CH ₂ OH).

Preparation Example 9 Preparation of Derivative 9

Scheme 9

BH ₃ -THF (15.0 eq) was added dropwise to anhydrous THF in an ice bath, and methylhonokol dissolved in THF was added slowly over 5 minutes. Then stirred at room temperature for 2 hours. After stirring, an excess of 3N NaOH and H ₂ O ₂ was added at 10 ° C., and the mixture was reacted at 70 ° C. for 2 hours. Extraction with ether three times and concentration under reduced pressure were purified by flash column chromatography (EtOAc: Hexane = 1: 1) to obtain a product. The yield was 45% and 103 mg. ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.28 (dd, 1H, J = 8.3, 2.3 Hz, Ar-H), 7.24 (ds, 1H, J = 2.2 Hz, Ar-H), 7.06-7.04 (m , 2H, Ar-H), 6.95 (d, 1H, J = 8.3 Hz, Ar-H), 6.88 (d, 1H, J = 8.2 Hz, Ar-H), 3.88 (s, 3H, Ar-OCH3) , 3.69 (t, 2H, J = 6.4 Hz, Ar-CH ₂ CH ₂ CH ₂ OH), 3.64 (t, 2H, J = 6.2 Hz, Ar-CH ₂ CH ₂ CH ₂ OH), 2.77 (t, 2H , J = 7.3 Hz, Ar-CH ₂ CH ₂ CH ₂ OH), 2.67 (t, 2H, J = 7.4 Hz, Ar-CH ₂ CH ₂ CH ₂ OH), 1.92-1.84 (m, 4H, Ar-CH ₂ CH ₂ CH ₂ OH).

Preparation Example 10 Preparation of Derivative 10

[Reaction Scheme 10]

Under nitrogen stream, methyl honokiol (1.0 eq) was dissolved in anhydrous DMF, and then potassium carbonate (3.0 eq) was added thereto, followed by stirring for 30 minutes. After stirring for 30 minutes, allylbromide (3.0 eq) was added dropwise and reacted for 3 hours. After washing with 1N HCl and extracted three times with ethyl acetate. After extraction, the mixture was concentrated under reduced pressure and purified by flash column chromatography (EtOAc: Hexane = 1: 20) to obtain a product. The yield was 98%, 56 mg. ¹ H NMR (CDCl ₃ , 500 MHz) δ 7.39 (dd, 1H, J = 8.3, 2.3 Hz, Ar-H), 7.37 (ds, 1H, J = 2.0 Hz, Ar-H), 7.13 (ds, 1H , J = 2.3 Hz, Ar-H), 7.06 (dd, 1H, J = 8.2, 2.2 Hz, Ar-H), 6.89 (d, 1H, J = 8.3 Hz, Ar-H), 6.88 (d, 1H , J = 8.3 Hz, Ar-H), 6.06-5.93 (m, 3H, Ar-CHCH ₂ ), 5.35-5.30 (m, 1H, Ar-OCH ₂ CHCH ₂ ), 5.20-5.17 (m, 1H, Ar -OCH ₂ CHCH ₂ ), 5.10-5.01 (m, 4H, Ar-CH ₂ CHCH ₂ ), 4.51-4.49 (m, 2H, Ar-OCH ₂ CHCH ₂ ), 3.86 (s, 3H, Ar-OCH ₃ ) , 3.42 (d, 2H, J = 6.7 Hz, Ar-CH ₂ CHCH ₂ ), 3.36 (d, 2H, J = 6.7 Hz, Ar-CH ₂ CHCH ₂ ).

Preparation Example 11 Preparation of Derivative 11

[Reaction Scheme 11]

To acetone solution (1 mL) of methyl honochiol (56 mg, 0.20 mmol) was added K ₂ CO ₃ (55 mg, 0.40 mmol) and 3,3-dimethylallylbromide (47 mg, 0.32 mmol). The mixture was refluxed for 5 hours, concentrated under reduced pressure, diluted with ethyl acetate and washed with water. After washing with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. Column chromatography (ethyl acetate: n-Hexane = 1: 10) was carried out to obtain a product. The yield was 60 mg, 86%. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.40 (m, 2H), 7.15 (d, 1H, J = 2.4 Hz), 7.09 (dd, 1H, J = 8.3 and 2.4 Hz), 6.93 (m, 2H ), 6.05 (m, 2H), 5.45 (t, 1H, J = 2.3 Hz), 5.08 (m, 4H), 4.50 (d, 2H, J = 2.3 Hz), 3.87 (s, 3H), 3.44 (d , 2H, J = 6.3), 3.39 (d, 2H, J = 6.8), 1.81 (s, 3H), 1.75 (s, 3H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 156.2, 154.1, 137.8, 137.0, 136.6, 132.3, 131.1 130.88, 130.84, 130.7, 128.1, 127.77, 127.72, 120.3, 115.4, 115.2, 113.3, 109.8, 65.7, 55.4 , 39.4, 34.2, 25.6, 18.1.

Preparation Example 12 Preparation of Derivative 12

[Reaction Scheme 12]

A 2nd Grubbs catalyst (4 mg, mmol) was placed in a sealed tube containing methylhonocyol (28 mg, 0.1 mmol), 2-methyl-2-butene (1.2 mL), dichloromethane (0.5 mL). Put in. The mixture was stirred at reflux for 24 hours, and then distilled under reduced pressure. The product was purified by column chromatography (ethyl acetate: n-Hexane = 1: 9). The yield was 32 mg, 95%. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.41 (m, 2H), 7.19 (m, 2H), 7.10 (d, 1H, J = 8.2 Hz), 7.04 (d, 1H, J = 7.8 Hz), 5.49 (m, 2H), 4.02 (s, 3H), 3.51 (d, 2H, J = 7.3 Hz), 3.45 (d, 2H, J = 7.3 Hz), 1.88 (m, 12H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 157.0, 150.5, 133.8, 132.9, 132.2, 131.1, 129.9, 129.8, 128.9, 128.3, 127.8, 127.4, 123.5, 121.9, 115.3, 110.7, 55.4, 33.4, 28.4, 25.8, 25.7, 17.7.

Manufacturing example  13: Preparation of Derivative 13

Scheme 13

Triphosgene (89 mg, 0.3 mmol) was added to a dichloromethane solution (1 mL) of methylnonochiol (42 mg, 0.15 mmol) and pyridine (80 mg, 1 mmol). After stirring for 2 hours at room temperature, allylamine (20 mg, 0.35 mmol) was added thereto. After stirring for 12 hours at room temperature, it was diluted with dichloromethane and washed with saturated NH ₄ Cl and water. After washing with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. The product was obtained under column chromatography (ethyl acetate: n-Hexane = 1: 6). The yield was 35 mg, 65%. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.22 (m, 2H), 7.13 (S, 1H), 7.07 (m, 2H), 6.85 (d, 1H, J = 8.7 Hz), 6.01 (m, 2H ), 5.77 (m, 1H), 5.09 (m, 6H), 4.87 (b, 1H), 3.81 (S, 3H), 3.74 (t, 2H, J = 5.8) 3.37 (d, 4H, J = 6.3) .

Preparation Example 14 Preparation of Derivative 14

[Reaction Scheme 14]

Triphosgene (89 mg, 0.3 mmol) was added to a dichloromethane solution (1 mL) of methylhonokiol (42 mg, 0.15 mmol) and pyridine (80 mg, 1 mmol). After stirring for 2 hours at room temperature, N-benzylmethylamine (36 mg, 0.3 mmol) was added thereto. After stirring for 12 hours at room temperature, it was diluted with dichloromethane and washed with saturated NH ₄ Cl and water. After washing with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. Column chromatography (ethyl acetate: n-Hexane = 1: 3) was carried out to obtain the product. Yield 38 mg, 59%. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.23 (m, 5H), 7.13 (m, 3H), 7.00 (m, 2H), 6.80 (m, 1H), 5.99 (m, 2H), 5.09 (m , 4H), 4.41 and 4.35 (S6, 2H), (S6, 2H), 3.82 (S, 3H), 3.38 (m, 4H), 2.79 (S, 3H).

Preparation Example 15 Preparation of Derivative 15

[Reaction Scheme 15]

Triphosgene (89 mg, 0.3 mmol) was added to a dichloromethane solution (1 mL) of methylnonochiol (42 mg, 0.15 mmol) and pyridine (80 mg, 1 mmol). After stirring at room temperature for 2 hours, morpholine (26 mg, 0.3 mmol) was added. After stirring for 12 hours at room temperature, it was diluted with dichloromethane and washed with saturated NH ₄ Cl and water. After washing with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. Column chromatography (ethyl acetate: n-Hexane = 1: 2) was carried out to obtain the product. The yield was 40 mg, 68%. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.40 (m, 5H), 7.04 (d, 1H, J = 8.2), 6.20 (m, 2H), 5.28 (m, 4H), 4.01 (S, 3H) , 3.76 (m, 4H), 3.59 (m, 4H), 3.56 (d, 4H, J = 6.3).

Preparation Example 16 Preparation of Derivative 16

[Reaction Scheme 16]

Triphosgene (89 mg, 0.3 mmol) was added to a dichloromethane solution (1 mL) of methyl honochiol (42 mg, 0.15 mmol) and pyridine (80 mg, 1 mmol). After stirring for 2 hours at room temperature benzylamine (32 mg, 0.3 mmol) was added. After stirring for 12 hours at room temperature, it was diluted with dichloromethane and washed with saturated NH ₄ Cl and water. After washing with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. Column chromatography (ethyl acetate: n-Hexane = 1: 4) was carried out to obtain the product. The yield was 50 mg, 81%. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.30 (m, 6H), 7.13 (S, 1H), 7.11 (m, 4H), 6.80 (d, 1H, J = 8.2), 5.98 (m, 2H) , 5.12 (m, 4H), 4.29 (d, 2H, J = 6.3), 3.81 (S, 3H), 3.37 (d, 2H, J = 6.8), 3.33 (d, 2H, J = 6.3).

Preparation Example 17 Preparation of Derivative 17

[Reaction Scheme 17]

Triphosgene (89 mg, 0.3 mmol) was added to a dichloromethane solution (1 mL) of methyl honochiol (42 mg, 0.15 mmol) and pyridine (80 mg, 1 mmol). After stirring for 2 hours at room temperature, glycine methyl ester (glycine methyl ester) (14 mg, 3.0 mmol) was added thereto. After stirring for 12 hours at room temperature, it was diluted with dichloromethane and washed with saturated NH ₄ Cl and water. After washing with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. Column chromatography (ethyl acetate: n-Hexane = 1: 2) was carried out to obtain the product. The yield was 26 mg, 44%. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.23-7.06 (m, 5H), 6.85 (d, 1H, J = 8.7 Hz), 5.99-(m, 2H), 5.35 (bt, 1H, J = 5.2 ), 5.09 (m, 4H), 3.91 (d, 2H, J = 5.3), 3.8 (S, 3H), 3.70 (S, 3H), 3.36 (d, 4H, J = 6.3).

Preparation Example 18 Preparation of Derivative 18

[Reaction Scheme 18]

Triphosgene (89 mg, 0.3 mmol) was added to a dichloromethane solution (1 mL) of methyl honochiol (42 mg, 0.15 mmol) and pyridine (80 mg, 1 mmol). After stirring for 2 hours at room temperature, glycineamide (22 mg, 0.3 mmol) was added thereto. After stirring for 12 hours at room temperature, it was diluted with dichloromethane and washed with saturated NH ₄ Cl and water. After washing with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. Column chromatography (ethyl acetate: n-Hexane = 1: 2) was carried out to obtain the product. The yield was 32 mg, 57%. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.22 (m, 5H), 6.91 (d, 1H, J = 8.3), 6.03 (m, 2H), 5.19 (t, 1H, J = 5.5), 5.14- 5.03 (m, 4H), 4.08 d, 2H, J = 5.8 Hz, 3.85 (S, 3H), 3.42 (d, 4H, J = 5.8).

Preparation Example 19 Preparation of Derivative 19

Scheme 19

Difluoromethane (42 mL, 42 mg, 0.15 mmol) and pyridine (80 mg, 1 mmol) in 4-chlorophenyl chloroformate (52 mg, 0.3) at 0 ° C. mmol) was added. After stirring for 12 hours at room temperature, it was diluted with dichloromethane and washed with saturated NH ₄ Cl and water. After washing with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. Column chromatography (ethyl acetate: n-Hexane = 1: 5) was carried out to obtain the product. The yield was 35 mg, 59%. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.37 (m, 5H), 7.09 (m, 2H), 6.99 (d, 1H, J = 8.3) 6.95 (bS, 1H), 6.14 (m, 2H), 5.25 (m, 4H), 3.93 (S, 3H), 3.53 (d, 2H, J = 6.3), 3.49 (d, 2H, J = 6.8).

Preparation Example 20 Preparation of Derivative 20

[Reaction Scheme 20]

Step 1: Generation of Aldoxime Compound

5-bromo-2-anisaldehyde (2.15 g, 10 mmol) in pyridine (5 mL) and dichloromethane solution (50 mL) in hydroxylamine hydrochloride hydrochloride) (764 mg, 11 mmol) was added. After refluxing for 12 hours, it was cooled to room temperature and the solvent was concentrated under reduced pressure to about half. The solid formed by pouring into ice water was filtered to obtain a yellow solid.

Step 2: Generation of isoxazole compound

[Method A]

To a solution of aldoforme (92 mg, 0.4 mmol) in chloroform (1 mL) was added NCS (58 mg, 0.44 mmol) at 0 ° C. After stirring for 3 hours at room temperature, the reaction proceeded, and then pentyne (40 mg, 0.6 mmol) and triethylamine (0.11 mL, 0.8 mmol) were added. The mixture was slowly heated to room temperature to 50 ° C., stirred for 12 hours, and concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water. After washing with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. Column chromatography (ethyl acetate: n-Hexane = 1: 10) was carried out to obtain the product of isoxazole compound in 75 mg, 63% yield.

[Method B]

NCS (58 mg, 0.44 mmol) was added to a solution of aldoforme (92 mg, 0.4 mmol) in chloroform (1 mL) at 0 ° C. After stirring for 3 hours at room temperature, after confirming that the reaction proceeded, the reaction solution was poured into ice water. Extracted with ethyl acetate, dried over MgSO ₄ and concentrated under reduced pressure. Immediately into the flask for use in the next reaction was added pentyne (40 mg, 0.6 mmol) and triethylamine (0.11 mL, 0.8 mmol). The mixture was slowly heated from room temperature to 50 ° C., stirred for 12 hours, and concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water. After washing with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. Column chromatography (ethyl acetate: n-Hexane = 1: 10) was conducted to obtain a product.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.97 (d, 1H, J = 2.4), 7.44 (dd, 1H, J = 8.8 and 2.9), 8.83 (d, 1H, J = 8.8), 6.43 (S , 1H), 3.84 (S, 3H), 2.75 (t, 2H, J = 7.8), 1.79 (m, 2H), 1.00 (t, 3H, J = 7.8).

Step 3: Preparation of Allyl Compound

Tetrakis (triphenylphosphine) palladium (0) (10) in a DMF solution (1 mL) of isoxazole compound (46 mg, 0.16 mmol) and allyltributyltin (103 mg, 0.31 mmol) obtained in step 2 mg, 7.8 μmol) was added. Stir at 90 ° C. for 5 hours and then cool to room temperature. Diluted with ethyl acetate and washed twice with water. After washing with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. Column chromatography (ethyl acetate: n-Hexane = 1: 10) was carried out to obtain the product in 30 mg, 71% yield. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.70 (d, 1H, J = 2.6), 7.22 (dd, 1H, J = 2.4 and 8.2), 6,93 (d, 1H, J = 8.8), 6.47 (S, 1H), 6.01 (m, 1H), 5.10 (m, 2H), 3.87 (S, 3H), 3.37 (d, 2H, J = 6.3), 2.78 (t, 2H, J = 7.3), 1.82 (m, 2H), 1.04 (t, 3H, J = 7.3).

Step 5: Preparation of Derivative 1 Compound

To a dichloromethane solution (2 mL) of the allyl compound (70 mg, 0.27 mmol) obtained in step 4 was slowly added boron tribromide (1.0 M solution in dichloromethane, 680 μL, 0.68 mmol) at -78 ° C. Added. After stirring for 1 hour, the temperature was slowly raised to room temperature. Methanol was added to terminate the reaction. The mixture was stirred at room temperature for 30 minutes, diluted with dichloromethane, and washed with water. After washing with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. Column chromatography (ethyl acetate: n-Hexane = 1: 15) was carried out to obtain a final product in 40 mg, 61% yield. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.47 (bS, 1H), 7.27 (d, 1H, J = 1.9), 7.16 (dd, 1H, J = 8.3 and 2.4), 7.01 (d, 1H, J = 8.3), 6.4 (S, 1H), 6.01 (m, 1H), 5.10 (m, 2H), 3.37 (d, 2H, J = 6.8) 2.81 (t, 2H, J = 7.3) 1.84 (m, 2H ), 1.05 (t, 3H, J = 7.3).

Preparation Example 21 Preparation of Derivative 21

Scheme 21

To dichloromethane solution (2 mL) of the isoxazole bromide compound (30 mg, 0.10 mmol) obtained by step 2 of Preparation Example 2, boron tribromide (1.0 M solution in dichloromethane, 30 μL, 0.30 mmol) was slowly added at -78 ° C. After stirring for 1 hour, the temperature was slowly raised to room temperature. Methanol was added to terminate the reaction. The mixture was stirred at room temperature for 30 minutes, diluted with dichloromethane, and washed with water. After washing with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. Column chromatography (ethyl acetate: n-Hexane = 1: 15) was carried out to obtain the product in 18 mg, 64% yield. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.63 (S, 1H), 7.58 (d, 1H, J = 2.4), 7.41 (dd, 1H, J = 2.4 and 8.7), 6.97 (d, 1H, J = 8.8), 6.37 (S, 3H), 2.82 (t, 2H, J = 7.8), 1.8 (m, 2H), 1.05 (t, 3H, J = 7.3).

Preparation Example 22 Preparation of Derivative 22

[Reaction Scheme 22]

Step 1: Isoxazole ( isoxazole ) Preparation of Compound

NCS (120 mg, 0.9 mmol) was added to a chloroform solution (2 mL) of the product aldoxime compound (164 mg, 0.76 mmol) of step 1 of Preparation Example 20 at 0 ° C. After stirring for 3 hours at room temperature, after confirming that the reaction proceeded, the reaction solution was poured into ice water. Extracted with ethyl acetate, dried over MgSO ₄ and concentrated under reduced pressure to give chlorooxime (chlorooxime). Chlorooxime was placed in the flask for use in the next reaction and propargyl alcohol (84 mg, 1.5 mmol) and triethylamine (264 μL, 1.9 mmol) were added. The mixture was slowly heated to 50 ° C. at room temperature, stirred for 12 hours, and concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water. After washing with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. Column chromatography (ethyl acetate: n-Hexane = 1: 2) was carried out to obtain the product in 90 mg, 44% yield.

Step 2: Preparation of Allyl Compound

Tetrakis (triphenylphosphine) palladium (0) (1 mL) in a DMF solution (1 mL) of isoxazole compound (80 mg, 0.3 mmol) and allyltributyltin (148 mg, 0.45 mmol) obtained in step 1 was obtained. 17 mg, 15 μmol) was added. Stir at 90 ° C. for 5 hours and then cool to room temperature. Diluted with ethyl acetate and washed twice with water. After washing with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. Column chromatography (ethyl acetate: n-Hexane = 1: 2) was carried out to obtain the product in 60 mg, 82% yield. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.69 (d, 1H, J = 1.9 Hz), 7.24 (dd, 1H, J = 8.8 and 2.4 Hz), 6.94 (d, 1H, J = 8.8 Hz), 6.75 (s, 1H), 6.00 (m, 1H), 5.10 (m, 2H), 4.81 (bs, 2H), 3.81 (s, 3H), 3.37 (d, 2H, J = 6.3 Hz).

Step 3: Preparation of Derivative 22 Compound

To a dichloromethane solution (2 mL) of the allyl compound (55 mg, 0.22 mmol) obtained in step 2 was added boron tribromide (1.0 M solution in dichloromethane, 88 μL, 0.88 mmol). Add slowly at 78 ° C. After stirring for 1 hour, the temperature was slowly raised to room temperature. Methanol was added to terminate the reaction, stirred for 30 minutes at room temperature, diluted with dichloromethane and washed with water. After washing with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. Column chromatography (ethyl acetate: n-Hexane = 1: 2) was carried out to obtain a final product of 35 mg, 69% yield. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.32 (s, 1H), 7.27 (d, 1H, J = 1.9 Hz), 7.18 (dd, 1H, J = 8.8 and 2.4 Hz), 7.01 (d, 1H , J = 8.3 Hz), 6.66 (s, 1H), 6.00 (m, 1H), 5.10 (m, 2H), 4.84 (s, 2H), 3.36 (d, 2H, J = 6.8 Hz), 2.37 (bs , 1H).

Preparation Example 23 Preparation of Derivative 23

[Reaction Scheme 23]

Step 1: Preparation of Intermediate Compound (a)

Step 1-1 :

Bromine (10 mg, 7.8 μmol) was slowly added to a chloroform solution (13 mL) of 4-propylphenol (1.36 g, 10 mmol) at room temperature. After stirring at room temperature for 12 hours, the reaction was terminated by adding an aqueous NaHSO ₃ solution. Extracted with ether, washed with water and brine, dried over MgSO ₄ , filtered and distilled under reduced pressure and concentrated. Used for the next reaction without purification.

Step 1-2 :

To a solution of dichloromethane (20 mL) in 2-bromo-4-propylphenol (ca 2.15 g, 10 mmol) was added triethylamine (2.8 mL, 20 mmol) and acetic anhydride (1.4 mL, 15 mmol) at 0 ° C. Stock price After stirring for 2 hours at room temperature, it was diluted with dichloromethane and washed with water. After washing with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. Column chromatography (ethyl acetate: n-Hexane = 1: 12) was carried out to obtain an intermediate compound (a) (2.2 g, 86% for 2 steps).

Step 2: Preparation of Intermediate Compounds (b) and (c)

Step 2-1 :

Bis (triphenylphosphine) palladium (II) in a triethylamine solution (12 mL) of the intermediate compound (a) obtained in step 1 (1.26 g, 4.9 mmol) and ethynyltrimethylsilane (727 mg, 7.4 mmol). Dichloride (172 mg, 0.25 mmol) and CuI (48 mg, 0.25 mmol) were added. After stirring at 80 ° C. for 5 hours, it was cooled to room temperature. After distillation under reduced pressure, the residue was subjected to column chromatography (diethylether: n-Hexane = 1: 15) to obtain a product (1.09 g, 81%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.31 (d, 1H, J = 1.9 Hz), 7.14 (m, 1H), 7.02 (d, 1H, J = 8.3 Hz), 2.57 (dd, 2H, J = 15 and 7.8 Hz), 2.31 (s, 3H), 1.65 (m, 2H), 0.96 (dd, 3H, J = 15 and 6.8 Hz), 0.23 (s, 9H).

Step 2-2 :

To an acetonitrile solution (5 mL) of the product (506 mg, 1.85 mmol) obtained in step 2-1 was added an aqueous solution of Cs ₂ CO ₃ (60 mg, 0.18 mmol) (1 mL). The mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure, diluted with ethyl acetate and washed with water. After washing with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. Column chromatography (diethyl ether: n-Hexane = 1: 10) was carried out to obtain an intermediate compound (b) (220 mg, 59%) and an intermediate compound (c) (74 mg, 25%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.41 (d, 1H, J = 1.9 Hz), 7.12 (dd, 1H, J = 4.4 and 1.9 Hz), 6.97 (d, 1H, J = 8.2 Hz), 2.57 (dd, 2H, J = 15 and 7.8 Hz), 2.34 (s, 3H), 1.63 (m, 2H), 0.96 (dd, 3H, J = 15 and 6.8 Hz).

Step 3: Preparation of Intermediate Compound (d)

A solution of DMSO (2 mL) of allyl bromide (145 mg, 1.2 mmol) and sodium azide (78 mg, 1.2 mmol) was added to a sealed tube and stirred at room temperature for 12 hours. Sodium ascorbate (25 mg, 0.1 mmol), an aqueous solution of copper sulfate (CuSO ₄ ) (16 mg, 0.05 mmol) (0.5 mL) and the intermediate compound (b) (200 mg, 1 mmol) were added 1 Stir at room temperature for hours, and stir at 70 ° C. for 12 hours. To terminate the reaction, the reaction solution was poured into cold 1N-NH ₄ OH aqueous solution (to prevent explosion when drying residual CuN ₃ ). Extracted with ethyl acetate, washed with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. Column chromatography (ethyl acetate: n-Hexane = 1: 2) was carried out to obtain an intermediate compound (d) (148 mg, 62%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.88 (d, 1H, J = 1.9 Hz), 7.73 (s, 1H), 7.18 (dd, 1H, J = 8.2 and 2.4 Hz), 7.07 (d, 1H , J = 8.3 Hz), 6.09 (m, 1H), 5.39 (d, 1H, J = 10.2 Hz), 5.35 (d, 1H, J = 17.0 Hz), 5.03 (d, 2H, J = 6.3 Hz), 2.64 (t, 2H, J = 7.8 Hz), 2.3 (s, 3H), 1.72 (m, 2H), 0.97 (t, 3H, J = 7.3 Hz).

Step 4: Preparation of Derivative 23 Compound

To a methanol solution (1 mL) of intermediate compound (d) (18 mg, 0.06 mmol) was added K ₂ CO ₃ (20 mg, 0.15 mmol). The mixture was stirred at 50 ° C. for 2 hours, concentrated under reduced pressure, diluted with ethyl acetate and washed with water. After washing with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. Column chromatography (ethyl acetate: n-Hexane = 1: 1) was carried out to obtain a final product in a yield of 10 mg, 68%. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 10.6 (bs, 1H), 7.84 (s, 1H), 7.20 (d, 1H, J = 2.0 Hz), 7.06 (dd, 1H, J = 2.4 and 8.3 Hz ), 6.98 (d, 1H, J = 8.3 Hz), 6.12 (m, 1H), 5.44-5.36 (m, 2H), 5.06-5.04 (m, 2H), 2.54 (t, 2H, J = 7.8 Hz) , 1.66-1.57 (m, 2H), 0.95 (t, 3H, J = 7.3 Hz). ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 142.8, 137.1, 122.5, 119.7, 118.9, 114.4, 109.7, 107.5, 106.4, 102.4, 42.0, 26.1, 13.7, 27.3.

Preparation Example 24 Preparation of Derivative 24

Scheme 24

A solution of DMSO (1 mL) of (Bromomethyl) cyclobutane (90 mg, 0.6 mmol) and sodium azide (40 mg, 0.6 mmol) was placed in a sealed tube for 12 hours. Stir at room temperature. An aqueous solution of sodium ascorbate (13 mg, 0.05 mmol), copper sulfate (CuSO ₄ ) (8 mg, 0.03 mmol) (0.5 mL) and an alkyne compound (100 mg, 0.5 mmol) was added thereto for 1 hour. Was stirred at room temperature for 12 hours at 70 ° C. To terminate the reaction, the reaction solution was poured into cold 1N-NH ₄ OH aqueous solution (to prevent explosion when drying residual CuN ₃ ). Extracted with ethyl acetate, washed with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. Immediately into the flask for use in the next reaction was added methanol (1 mL) and K ₂ CO ₃ (15 mg, 0.1 mmol). The mixture was stirred at 50 ° C. for 2 hours, concentrated under reduced pressure, diluted with ethyl acetate and washed with water. After washing with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. Column chromatography (ethyl acetate: n-Hexane = 1: 1) was carried out to obtain a final product in 90 mg, 67% yield. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 10.6 (bs, 1H), 7.78 (s, 1H), 7.20 (d, 1H, J = 2.4 Hz), 7.05 (dd, 1H, J = 2.4 and 8.3 Hz ), 6.97 (d, 1H, J = 8.3 Hz), 4.44 (d, 2H, J = 7.8 Hz), 2.93 (m, 1H), 2.55 (m, 2H), 2.17-2.10 (m, 2H), 2.04 -1.81 (m, 4H), 1.66-1.56 (m, 2H), 0.95 (t, 3H, J = 7.3 Hz).

Preparation Example 25 Preparation of Derivative 25

[Reaction Scheme 25]

A methanol solution (2 mL) of an allyl compound (35 mg, 0.15 mmol) and palladium carbon (10% Pd / C) (15 mg) was replaced with hydrogen gas after depressurization. After stirring at room temperature for 5 hours, the mixture was filtered through celite and distilled under reduced pressure. Column chromatography (ethyl acetate: n-Hexane = 1: 2) was carried out to obtain a final product of 30 mg, 85% yield. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.27 (s, 1H), 7.25 (s, 1H), 7.16 (m, 1H), 6.99 (d, 1H, J = 8.2 Hz), 6.66 (s, 1H ), 4.83 (s, 2H), 2.57 (m, 2H), 2.32 (bs, 1H), 1.64 (m, 2H), 0.95 (t, 3H, J = 7.3 Hz).

The derivative compound of the present invention synthesized in the above embodiment is as follows.

[Formula 1]

derivative R1 R2 R3 R4 One -H -H -CH ₂ CH ₂ CH ₃ -CH ₂ CH ₂ CH ₃ 2 -CH ₃ -H -CH ₂ CH = CH ₂ -CH ₂ CH = CH ₂ 3 -CH (CH ₃ ) ₂ -H -CH ₂ CH = CH ₂ -CH ₂ CH = CH ₂ 4 -COCH ₃ -H -CH ₂ CH = CH ₂ -CH ₂ CH = CH ₂ 5 -H -Br -CH ₂ CH = CH ₂ -CH ₂ CH = CH ₂ 6 -H -H

7 -H -Cl -CH ₂ CH = CH ₂ -CH ₂ CH = CH ₂ 8 -H -H -CH ₂ CH = CH ₂ ; -CH ₂ CH ₂ CH ₂ OH -CH ₂ CH ₂ CH ₂ OH; -CH ₂ CH = CH ₂ 9 -H -H -CH ₂ CH ₂ CH ₂ OH -CH ₂ CH ₂ CH ₂ OH 10 -CH ₂ CH = CH ₂ -H -CH ₂ CH = CH ₂ -CH ₂ CH = CH ₂ 11 _{-CH 2 CH = C (CH 3} ) 2 -H -CH ₂ CH = CH ₂ -CH ₂ CH = CH ₂ 12 -H -H _{-CH 2 CH = C (CH 3} ) 2 _{-CH 2 CH = C (CH 3} ) 2 13

-H -CH ₂ CH = CH ₂ -CH ₂ CH = CH ₂ 14

-H -CH ₂ CH = CH ₂ -CH ₂ CH = CH ₂ 15

-H -CH ₂ CH = CH ₂ -CH ₂ CH = CH ₂ 16

-H -CH ₂ CH = CH ₂ -CH ₂ CH = CH ₂ 17

-H -CH ₂ CH = CH ₂ -CH ₂ CH = CH ₂ 18

-H -CH ₂ CH = CH ₂ -CH ₂ CH = CH ₂ 19

-H -CH ₂ CH = CH ₂ -CH ₂ CH = CH ₂

[Formula 2]

derivative R1 R2 20 -CH ₂ CH = CH ₂ -CH ₂ CH ₂ CH ₃ 21 -Br -CH ₂ CH ₂ CH ₃ 22 -CH ₂ CH = CH ₂ -CH ₂ OH 25 -CH ₂ CH ₂ CH ₃ -CH ₂ OH

(3)

derivative R1 R2 23 -CH ₂ CH ₂ CH ₃ -CH ₂ CH = CH ₂ 24 -CH ₂ CH ₂ CH ₃

Experimental Example 1 Experimental Method for Measuring Anti-inflammatory Effect of Methyl Honokiol Derivatives

1-1. RAW 264.7 Macrophage Culture

RAW 264.7 macrophages were cultured in DMEM medium containing 10% FBS in mouse macrophages.

1-2. NO production analysis

RAW 264.7 macrophages, dendritic cells were diluted in DMEM medium containing 10% FBS and aliquoted at 96 × plate at 5 × 10 ⁵ cells / ml. LPS and samples of 1 mg / ㎖ were treated by concentration. After the sample was incubated for 24 hours, 100 ml of the supernatant was added to 100 ml of a grease reagent (griess A: griess B = 1: 1), reacted for 10 minutes at room temperature, and absorbed at 540 nm. The amount of NO produced was quantified by the measurement.

1-3. MTT analysis

After proceeding with NO, Mitogen analysis, the remaining medium was discarded and a new medium was added 200 ml and stabilized for 1 hour. MTT reagent was added to 0.5 mg / ml and then cultured in a 37 ° C. incubator. When 70% of the cells formed crystals, all of the medium was removed and 100 ml of DMSO was added to dissolve the crystals. The absorbance was then measured at 550 nm.

1-4. COX-2 enzyme inhibition assay

To proceed with enzyme analysis, prepare a background tube with COX-2 inactive, a 100% initial active tube with maximum reactivity, and a COX-2 inhibitor tube with a sample. It was. In the background tube, 10 μl of COX-2 enzyme was inactivated at 100 ° C. for 3 minutes, and then 970 μl reaction buffer and 10 μl of heme were added thereto. 100% initial activity tube (initial activity tube) 970 μl of reaction buffer, 10 μl of heme (heme), 10 μl of COX-2 was added. The COX-2 inhibitor tube was filled with 950 μl reaction buffer, 10 μl heme, 10 μl COX-2 and 20 μl sample. The three tubes were reacted for 10 minutes in a 37 ° C. water bath, 10 μl of arachidonic acid was added, followed by vortex and 2 minutes in a 37 ° C. water bath. Then, 50 µl of 1M HCl was added to stop the reaction. 100 µl of stannous chloride solution was added thereto, followed by vortexing, and the reaction was performed at room temperature for 5 minutes. Samples were prepared, 50 μl of the sample, tracer, and antiserum of the three tubes were placed in a well and allowed to react at room temperature for 18 hours. After the reaction, the reaction was washed five times, and 200 μl of Ellman's regent was added to each well, darkened, and reacted. When the absorbance value of the reference value is between 0.3 and 0.8 at 412 nm, the value was measured and analyzed.

1-5. Inhibition of PGF1a Production in RAW 264.7 Cells

RAW 264.7 macrophages, dendritic cells were diluted with DMEM medium containing 10% FBS and aliquoted at 1 × 10 ⁶ cells / ml in 96 well plates. LPS and samples of 1 mg / ㎖ were treated by concentration. After the sample was incubated for 24 hours, the supernatant was recovered and used for the experiment. 50 μl of supernatant, tracer, and antiserum was added to each well, followed by reaction at 4 ° C for 18 hours. After the reaction, the reaction was washed five times, and 200 μl of Ellman's regent was added to each well, darkened, and reacted. When the absorbance value of the reference value is between 0.3 and 1.0 at 412 nm, the value was measured and analyzed.

Experimental Example  2: Methyl Honokiol  Results of Determination of Anti-inflammatory Effect of Derivatives

The methyl honokiol derivative of the present invention showed cytotoxicity with an IC ₅₀ of 20-100 μM. In addition, it has a similar IC ₅₀ value, inhibiting the NO production of macrophage (macrophage). This means that the derivatives are cytotoxic to macrophages but do not inhibit NO production at low concentrations (see Table 4). However, very low concentrations without cytotoxicity inhibited the activity of COX-2 (cycolooxygenase-2). When the derivatives were treated with cells at a concentration of 100 nM, the production of PGF1a was shown to be 20-60% inhibition (see Table 5). In addition, when the derivative was directly treated with COX-2 enzyme at a concentration of 100 nM, the inhibition rate was 20-70%. This shows that the methyl honokiol derivatives of the present invention have a COX-2 inhibitory effect, which means that there is a possibility of development as an anti-inflammatory drug in the future.

compound Cytotoxicity (μM, IC ₅₀ ) NO generation (μM, IC ₅₀ ) Methyl Honokiol 27 18 Derivative 1 13 11 Derivative 2 > 100 40 Derivative 3 > 100 78 Derivative 4 29 24 Derivative 5 33 28 Derivative 6 64 24 Derivative 7 81 40 Derivative 8 53 41 Derivative 11 > 100 > 100 Derivative 12 15 13 Derivative 13 > 100 > 100 Derivatives 14 44 33 Derivative 15 62 29 Derivative 16 > 100 > 100 Derivative 17 74 62 Derivative 19 35 30 Derivative 20 63 61 Derivative 21 81 63 Derivative 22 > 50 > 50 Derivative 23 > 50 > 50 Derivative 24 33 > 50 Derivative 25 36 > 50

compound PGF1α
(% Inhibition at 0.1 μM) COX-2 enzyme
(% Inhibition at 0.1 μM) Methyl Honokiol 43 57 Derivative 1 55 46 Derivative 2 48 46 Derivative 3 24 23 Derivative 4 45 39 Derivative 5 54 52 Derivative 6 51 58 Derivative 7 48 - Derivative 8 61 - Derivative 11 20 44 Derivative 12 40 41 Derivative 13 41 48 Derivatives 14 37 63 Derivative 15 41 44 Derivative 16 53 65 Derivative 17 29 74 Derivative 19 61 54 Derivative 20 50 35 Derivative 21 54 39 Derivative 22 29 22 Derivative 23 47 29 Derivative 24 43 Derivative 25 60

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Thus, the substantial scope of the present invention will be defined by the appended claims and equivalents thereof.

references

1. Rao, K. V .; Davis T. L. Plant Med. 1982, 45, 57-59.

2. (a) Lee, Y. K .; Yuk, D. Y .; Kim, T. I .; Kim, Y. H .; Kim, K. T .; Kim, K. H .; Lee, B. J .; Nam, S.-Y .; Hong, J. T. J. Nat. Med. 2009, 63, 274-282. (b) Sch ㆌ hly, W .; Khan, S. I .; Fischer, N. H. Inflammopharmacology 2009, 17, 106-110. (c) Oh, J. H .; Kang, L. L .; Ban, J. O .; Kim, Y. H .; Kim, K. H .; Han, S. B .; Hong, J. T. Chem. Biol. Interact. 2009, 180, 506-514. (d) Lee, Y. K .; Choi, I. S .; Kim, Y. H .; Kim, K. H .; Nam, S. Y .; Yun, Y. W .; Lee, M. S .; Oh, K. W .; Hong, J. T. Neurochem. Res. 2009, 34, 2251-2260. (e) Lee, J. W .; Lee, Y. K .; Lee, B. J .; Nam, S. Y .; Lee, S. I .; Kim, Y. H .; Kim, K. H .; Oh, K. W .; Hong, J. T. Pharmacol. Biochem. Behav. 2010, 95, 31-40. (f) Lee, Y. K .; Choi, I. S .; Ban, J. O .; Lee, H. J .; Lee, U. S .; Han, S. B .; Jung, J.-K .; Kim, Y. H .; Kim, K. H .; Oh, K. W .; Hong, J. T. J. Nutr. Biochem. 2010, 21, in press.

3. (a) Maruyama, Y .; Kuribara, H. CNS Drug Rev. 2000, 6, 35-44. (b) Fukuyama, Y .; Otoshi, Y .; Miyoshi, K .; Nakamura, K .; Kodama, M .; Nagasawa, M .; Hasegawa, T .; Okazaki, H .; Sugawara, H. Tetrahedron 1992, 48, 377-392. (c) Chen, C. M .; Liu, Y.C. Tetrahedron Lett. 2009, 50, 1151-1152 and references cited therein.

4. Schuhly, W .; H ㆌ fner, A .; Pferschy-Wenzig, E. M .; Prettner, E .; Adams, M .; Bodensieck, A .; Kunert, O .; Oluwemimo, A .; Haslinger, E .; Bauer, R. Bioorg. Med. Chem. 2009, 17, 4459.

5. (a) Tekeya, T .; Okubo, T .; Tobinaga, S. Chem. Pharm. Bull. 1986, 34, 2066-2070. (b) Kwak, J.-H .; In, J.-K .; Lee, M.-S .; Choi, E.-H .; Lee, H .; Hong, J. T .; Yun, Y. P .; Lee, S. J .; Seo, S.-Y .; Suh, Y.-G .; Jung, J.-K. Arch. Pharm. Res. 2008, 31, 1559-1563.

Claims (4)

Methyl honokiol derivative compounds represented by the following formula (1), (2) or (3).
[Formula 1]

In Formula 1, R ₁ is H, C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, -CO (CH ₂ ) _n CH ₃ , or

ego,
R ₂ is H, or halo;
R ₃ and R ₄ are each independently C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₁ -C ₇ hydroxyalkyl, or C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ heterocycloalkyl , (C ₃ -C ₈ heterocycloalkyl) C ₁ -C ₇ alkyl;
R ₅ and R ₆ are each independently H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ haloaryl, (C ₆ -C ₁₀ aryl ) C ₁ -C ₇ alkyl, -CH ₂ CO ₂ CH ₃ , -CH ₂ CONH ₂ , or linked to each other to form C ₃ -C ₈ heterocycloalkyl, wherein n is an integer from 0-4;
(2)

In Formula 2, R ₁ is C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, or halo; R ₂ is C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, or C ₁ -C ₇ hydroxyalkyl;
(3)

In Formula 3, R ₁ is C ₁ -C ₇ alkyl, or C ₂ -C ₇ alkenyl; R ₂ is C ₁ -C ₇ alkyl, C ₂ -C ₇ alkenyl, C ₃ -C ₈ cycloalkyl, or (C ₃ -C ₈ cycloalkyl) C ₁ -C ₇ alkyl.
According to claim 1, wherein in Formula 1, R ₁ is H, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, -COCH ₃ ,

,

,

,

,

,

, or

ego; R ₂ is H, Br or Cl; R ₃ and R ₄ are each independently C ₁ -C ₅ alkyl, C ₂ -C ₅ Alkenyl,

Or C ₁ -C ₅ hydroxyalkyl; In Chemical Formula 2, R ₁ is C ₁ -C ₇ alkyl, C ₂ -C ₇ Alkenyl, or Br; R ₂ is C ₁ -C ₇ alkyl, or C ₁ -C ₇ hydroxyalkyl; In Formula 3, R ₁ is C ₁ -C ₇ alkyl; R ₂ is C ₂ -C ₇ Alkenyl, or

The compound characterized by the above-mentioned.
A pharmaceutical composition for the treatment or prophylaxis of inflammatory diseases comprising the methyl honokiol derivative compound according to claim 1 or 2 as an active ingredient.
Functional food composition for improving inflammatory disease comprising the methyl honokiol derivative compound of claim 1 or claim 2 as an active ingredient.