KR101386068B1 - Novel 4-Ｏ-Methylhonokiol Derivatives and Composition for Treating Inflammatory Disease Comprising the Same as Active Ingredient - Google Patents

Abstract

The present invention provides a novel methylmonoquiol derivative and a composition for treating, preventing or ameliorating an inflammatory disease containing the same as an active ingredient. The methyl honokiol derivative of the present invention exhibits 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 and health functional food of various inflammatory diseases.

Description

TECHNICAL FIELD The present invention relates to novel 4-O-methylmonoquinol derivatives and their use as an effective ingredient for the treatment of inflammatory diseases. The novel 4-O-

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

4-O-methylhornokiol is a generic term for 3 ', 5-diallyl-4'-methoxybiphenyl-2-ol and has recently been isolated from Magnolia species, (1), (2) and (3). Korean Patent No. 10-932962, Korean Patent Publication No. 2009-94916, and Korean Patent Publication No. 2008-104760 disclose 4-O-methyl hornokiol extracted from the stem and leaves of Magnolia officinalis Rehd. Et Wils It is disclosed that the composition can be used for treatment of amyloid-related diseases, prevention of hair loss, promotion of hair growth, and skin whitening.

To date, the bark of roots and stems of Magnolia species have been used as traditional medicines for the treatment of various diseases and the main biologically active compounds belonging to Magnolia are honokiol, magnolol and obovatol, (2). These compounds are known as biphenyl-neo-lignan compounds. Interestingly, 4-O-methylhornokiol has a higher anti-inflammatory activity than honokiol and various other monocarboxylic analogs, with an IC50 value for COX-2 of 0.06 μM (3). In addition, 4-O-methyl-honokiol has recently been shown to exhibit neuroprotective and memory-enhancing activity (4). The chemical structure of the 4-O-methylhornokiol is 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-methylhornokiol, the synthesis of homologs, hornokiol and obovatol has been reported, while the synthesis of derivatives of this compound has not yet been reported in the art (3 , 5), and the various activities of the derivatives have not been reported.

Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.

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 methylmonochiol derivative.

It is still another object of the present invention to provide a composition for treating an inflammatory disease comprising the novel methylmonoquiol 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, there is provided a methylnonochiol derivative compound represented by the following general formula (1), (2) or (3)

이고, Wherein 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 selected from the group consisting of 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;

Wherein 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 C ₃ -C ₈ heterocycloalkyl, wherein n is an integer from 0 to 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.

The term "alkyl" in the above formulas (1), (2) and (3) of the present invention means a straight or branched saturated aliphatic hydrocarbon group of the specified carbon number. For example, "C ₁ -C ₃ alkyl" include an isopropyl group, as well as a group of straight-chain n- propyl, "C ₁ -C ₄ alkyl" is an n- butyl, isobutyl and t- butyl .

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

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

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

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

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

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

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

The term "aryl" means an aromatic hydrocarbon group. For example, a "C ₆ -C ₁₀ aryl" group includes 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 "arylalkyl" means an alkyl group in which at least one of the hydrogen atoms of the alkyl group has been replaced 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, Methyl, and the like.

According to another aspect of the present invention, there is provided a pharmaceutical composition for the treatment or prevention of an inflammatory disease comprising, as an active ingredient, a methylhydroquinol derivative represented by the above Chemical Formulas 1, 2 or 3.

According to another aspect of the present invention, there is provided a functional food composition for improving inflammatory diseases, comprising the methylnonochiol derivative represented by the above Chemical Formulas 1, 2 or 3 as an active ingredient.

The methylmonoquiol derivative of the present invention has excellent anti-inflammatory activity by inhibiting the activity of COX-2 (Cyclooxigenase-2) as demonstrated in the specific example of the present invention described below. Thus, the methylmonoquiol derivatives of the present invention can be used as active ingredients for the treatment, prevention or amelioration of inflammatory diseases.

According to a preferred embodiment of the present invention, the inflammatory diseases are selected from the group consisting of atopic dermatitis, encephilitis, inflammatory bowel disease, chronic obstructive pulmonary disease, pulmonary hemorrhagic shock, pulmonary fibrosis, undifferentiated vertebral arthropathy, Type 2 diabetes, type 2 diabetes, rheumatoid arthritis, Reactive Arthritis, osteoarthritis, psoriasis, scleroderma, osteoporosis, atherosclerosis, inflammatory bowel disease, chronic inflammatory diseases caused by chronic viral or bacterial infections, inflammatory bowel disease, The present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and / or prophylaxis of inflammation, myocarditis, endocarditis, pericarditis, cystic fibrosis, Hashimoto's thyroiditis, Graves' disease, leprosy, syphilis, Lyme disease, Borreliosis, Lupus nephritis, systemic lupus erythematosus, macular degeneration, uveitis, irritable bowel syndrome, Crohn ' s disease, 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 methylnonochiol derivative represented by the general formula (1), (2) or (3) And (b) a pharmaceutically acceptable carrier. The pharmaceutical composition of the present invention may be in the form of a pharmaceutical composition for the treatment or prevention of inflammatory diseases.

The pharmaceutically acceptable carriers to be contained in the pharmaceutical composition of the present invention are those conventionally used in the formulation and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, But are not limited to, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. It is not. 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 amount 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 can be administered orally or parenterally, and when administered parenterally, it can be administered by intravenous injection, subcutaneous injection, muscle 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 required, and the like, and is not limited to a specific range of concentration.

The pharmaceutical composition of the present invention may be formulated into a unit dose form by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs. Or by intrusion 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 inflammatory diseases, which comprises the methylnonochiol derivative represented by the above Chemical Formulas (1), (2) or (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 it is made of a drink, a flavorant or a natural carbohydrate may be included as an additional ingredient in addition to the methylnonochiol derivative as an active ingredient. For example, natural carbohydrates include monosaccharides (e.g., glucose, fructose, etc.); Disaccharides (e.g., maltose, sucrose, etc.); oligosaccharide; Polysaccharides (e.g., dextrin, cyclodextrin and the like); And sugar alcohols (e.g., xylitol, sorbitol, erythritol, etc.). Natural flavoring agents (e.g., tau martin, stevia extract, etc.) and synthetic flavoring agents (e.g., saccharin, aspartame, etc.) may be used as flavorings.

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

(i) The present invention provides novel methylmonoquiol derivative compounds.

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

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

The present invention provides a novel methylmonoquiol derivative and a composition for treating, preventing or ameliorating an inflammatory disease containing the same as an active ingredient. The methylmonoquiol derivative of the present invention exhibits excellent anti-inflammatory activity by inhibiting the activity of COX-2 (Cyclooxigenase-2). Therefore, the methylmonoquiol derivative of the present invention can be developed as a therapeutic agent for various inflammatory diseases and an active ingredient of a 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 the ethanol solution of methylhornokiol and the pressure was reduced. After depressurization, reaction was carried out under a stream of H _{2 for} 1 hour. After completion of the reaction, the mixture was filtered through celite filter. Concentrated under reduced pressure and purified by flash column chromatography (EtOAc: Hexane = 1: 13) to obtain the product. 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 1H, Ar-H), 6.95 (d, 1H, J = 8.3 Hz, Ar-H), 6.89 (d, 1H, J = 7.9 Hz, Ar- , 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

[Reaction Scheme 2]

Methylene hydroquinone (1.0 eq) was dissolved in anhydrous DMF under nitrogen flow, potassium carbonate (3.0 eq) was added, and the mixture was stirred for 30 minutes. After 30 minutes, methyl iodide (3.0 eq) was added dropwise and reacted for 3 hours. Washed once with 1N HCl and extracted three times with ethyl acetate. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (EtOAc: Hexane = 1: 8) 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

Methylhydroquinol (1.0 eq) was dissolved in anhydrous DMF under a nitrogen stream, potassium carbonate (3.0 eq) was added, and the mixture was stirred 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

[Reaction Scheme 4]

Dimethylaminopyridine (0.2 eq), triethylamine (5.0 eq) and acetic anhydride (1.2 eq) were added to a methylene dichloride solution of methyl hornokiol (1.0 eq) and reacted 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-CH2CH 2 CH 3), 2.09 (s, 3H, Ar-OCOCH 3).

Preparation Example 5: Preparation of derivative 5

[Reaction Scheme 5]

Methylhornokiol (1.0 eq) was dissolved in anhydrous THF under a nitrogen stream, and isopropyl magnesium chloride (2.0 M solution in diethyl ether, 1.2 eq) was added at -78 ° C. The mixture was stirred at -78 占 폚 for 30 minutes and further stirred at room temperature for 10 minutes. After stirring for 10 minutes, DBDMH (0.8 eq) was added and reacted for 2 hours. After completion of the reaction, the reaction mixture was washed with aqueous NH ₄ Cl and extracted three times with ethyl acetate. The extract was concentrated under reduced pressure and purified by flash column chromatography (EtOAc: Hexane = 1: 15) to obtain the 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 methylene-choline (1.0 eq) in anhydrous methylene dichloride, Lt; / RTI > The mixture was extracted three times with ethyl acetate, 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)? 7.33 (dd, 1H, J = 8.3, 2.2 Hz, Ar-H), 7.30 (ds, 1H, J = 2.2 Hz, Ar- , 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]

Methylhornokiol (1.0 eq) was dissolved in anhydrous THF under a nitrogen stream, and isopropylmagnesium chloride (2.0 M solution in diethyl ether, 1.2 eq) was added at -78 ° C. The mixture was stirred at -78 占 폚 for 30 minutes and further stirred at room temperature for 10 minutes. After stirring for 10 minutes, DCDMH (0.8 eq) was added and reacted for 2 hours. After completion of the reaction, the reaction mixture was washed with aqueous NH ₄ Cl and extracted three times with ethyl acetate. The extract was concentrated under reduced pressure and purified by flash column chromatography (EtOAc: Hexane = 1: 10) to obtain the product. The yield was 30%, 17 mg. ¹ H NMR (CDCl ₃ , 500 MHz)? 7.36 (dd, IH, J = 8.4, 2.3 Hz, Ar-H), 7.29 (ds, IH, J = 2.3 Hz, Ar- , 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. Thereafter, the mixture was stirred at room temperature for 2 hours. After stirring, an excess amount of 3N NaOH and H ₂ O ₂ was added at 10 ° C, followed by reaction at 70 ° C for 2 hours. The mixture was extracted three times with ether, concentrated under reduced pressure, and purified by flash column chromatography (EtOAc: Hexane = 1: 1) to obtain the 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 (M, 2H, Ar-H), 7.06-7.02 (m, 4H, Ar-H), 6.95 (d, 2H, J = 8.3 Hz, Ar- 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 _{-CH 2 CH 2 CH 2 OH)} .

Production Example 9: Preparation of derivative 9

[Reaction Scheme 9]

BH ₃ -THF (15.0 eq) was added dropwise to anhydrous THF over an ice bath, and methylnonochiol dissolved in THF was slowly added over 5 minutes. Thereafter, the mixture was stirred at room temperature for 2 hours. After stirring, 3N NaOH and H ₂ O ₂ were added in excess at 10 ° C, and the mixture was reacted at 70 ° C for 2 hours. The mixture was extracted three times with ether, concentrated under reduced pressure, and purified by flash column chromatography (EtOAc: Hexane = 1: 1) to obtain the product. The yield was 45%, 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 , 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).

Production Example 10: Preparation of derivative 10

[Reaction Scheme 10]

Methylhornokiol (1.0 eq) was dissolved in anhydrous DMF under a nitrogen stream, potassium carbonate (3.0 eq) was added, and the mixture was stirred for 30 minutes. After stirring for 30 minutes, allylbromide (3.0 eq) was added dropwise and reacted for 3 hours. Washed with 1N HCl and extracted three times with ethyl acetate. The extract was concentrated under reduced pressure and purified by flash column chromatography (EtOAc: Hexane = 1: 20) to obtain the product. The yield was 98%, 56 mg. ¹ H NMR (CDCl ₃ , 500 MHz)? 7.39 (dd, IH, J = 8.3, 2.3 Hz, Ar-H), 7.37 (ds, IH, J = 2.0 Hz, Ar- , 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]

K ₂ CO ₃ (55 mg, 0.40 mmol) and 3,3-dimethylallyl bromide (47 mg, 0.32 mmol) were added to an acetone solution (1 mL) of methylhydroquinol (56 mg, 0.20 mmol). The mixture was refluxed for 5 hours, concentrated under reduced pressure, diluted with ethyl acetate and washed with water. Then washed with brine (brine) dried over MgSO _4, filtered, evaporated under reduced pressure. Column chromatography (ethyl acetate: n-Hexane = 1: 10) was conducted 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, , 39.4, 34.2, 25.6, 18.1.

Preparation Example 12: Preparation of derivative 12

[Reaction Scheme 12]

A Grubbs catalyst (4 mg, mmol) was added to a sealed tube containing methylmonochiol (28 mg, 0.1 mmol), 2-methyl-2-butene (1.2 mL) and dichloromethane . 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), 2H, J = 7.3 Hz), 1.88 (m, 12H); 5.49 (m, 2H), 4.02 (s, 3H), 3.51 (d, 2H, J = 7.3 Hz). ^{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

[Reaction 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 at room temperature for 2 hours, allylamine (20 mg, 0.35 mmol) was added. After stirring at room temperature for 12 h, it was diluted with dichloromethane and washed with saturated NH ₄ Cl and water. Then washed with brine (brine), dried over MgSO _4, filtered, evaporated 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 3H), 3.74 (t, 2H, J = 5.8) 3.37 (d, 4H, J = 6.3), 5.77 (m, .

Production Example 14: Preparation of derivative 14

[Reaction Scheme 14]

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, N-benzylmethylamine (36 mg, 0.3 mmol) was added. After stirring at room temperature for 12 h, it was diluted with dichloromethane and washed with saturated NH ₄ Cl and water. After washing with brine (brine) was distilled under reduced pressure after dried over MgSO ₄ and filtered. Column chromatography (ethyl acetate: n-Hexane = 1: 3) was conducted to obtain a product. The yield was 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).

Production 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 for 2 h at room temperature, morpholine (26 mg, 0.3 mmol) was added. After stirring at room temperature for 12 hours, it was diluted with dichloromethane and washed with saturated NH ₄ Cl and water. Washed with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. The product was obtained by column chromatography (ethyl acetate: n-hexane = 1: 2). 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).

Production Example 16: Preparation of derivative 16

[Reaction Scheme 16]

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, benzylamine (32 mg, 0.3 mmol) was added. After stirring at room temperature for 12 hours, it was diluted with dichloromethane and washed with saturated NH ₄ Cl and water. After then washed with brine (brine) dried over MgSO _4, filtered, it evaporated under reduced pressure. Column chromatography (ethyl acetate: n-Hexane = 1: 4) was conducted to obtain a 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).

Production Example 17: Preparation of derivative 17

[Reaction Scheme 17]

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, glycine methyl ester (14 mg, 3.0 mmol) was added. After stirring at room temperature for 12 hours, it was diluted with dichloromethane and washed with saturated NH ₄ Cl and water. Then washed with brine (brine) dried over MgSO _4, filtered, evaporated under reduced pressure. The product was obtained by column chromatography (ethyl acetate: n-hexane = 1: 2). 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 18: Preparation of derivative 18

[Reaction Scheme 18]

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, glycinamide (22 mg, 0.3 mmol) was added. After stirring at room temperature for 12 hours, it was diluted with dichloromethane and washed with saturated NH ₄ Cl and water. After then washed with brine (brine) dried over MgSO _4, filtered, it evaporated under reduced pressure. The residue was subjected to column chromatography (ethyl acetate: n-hexane = 1: 2) to obtain a 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).

Production Example 19: Preparation of derivative 19

Scheme 19

4-fluorophenyl chloroformate (52 mg, 0.3 mmol) was added to a dichloromethane solution (1 mL) of methylhydroquinol (42 mg, 0.15 mmol) and pyridine mmol). After stirring at room temperature for 12 hours, it was diluted with dichloromethane and washed with saturated NH ₄ Cl and water. Then washed with brine (brine) dried over MgSO _4, filtered, evaporated under reduced pressure. Column chromatography (ethyl acetate: n-Hexane = 1: 5) was conducted to obtain a 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), 2H), 5.25 (m, 4H), 3.93 (s, 3H), 3.53 (d, 2H, J = 6.3), 3.49 (d, 2H, J = 6.8).

Production Example 20: Preparation of derivative 20

[Reaction Scheme 20]

Step 1: Production of aldoxime compound

To pyridine (5 mL) and dichloromethane solution (50 mL) of 5-bromo-2-anisaldehyde (2.15 g, 10 mmol) was added hydroxylamine hydrochloride hydrochloride (764 mg, 11 mmol). After refluxing for 12 hours, the mixture was cooled to room temperature, and a slight amount of solvent was concentrated under reduced pressure to about half. It was poured into ice water and the resulting solid was filtered to give a yellow solid.

Step 2: Production of isoxazole compound

[Method A]

NCS (58 mg, 0.44 mmol) was added to a chloroform solution (1 mL) of aldoxime (92 mg, 0.4 mmol) at 0 占 폚. After stirring at room temperature for 3 hours, pentyne (40 mg, 0.6 mmol) and triethylamine (0.11 mL, 0.8 mmol) were added. The mixture was slowly heated from room temperature to 50 DEG C, stirred for 12 hours, and concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water. Washed with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. The product was purified by column chromatography (ethyl acetate: n-hexane = 1: 10) to give the product of isoxazole in a yield of 75 mg (63%).

[Method B]

NCS (58 mg, 0.44 mmol) was added to a chloroform solution (1 mL) of aldoxime (92 mg, 0.4 mmol) at 0 占 폚. After stirring for 3 hours at room temperature, the reaction solution was poured into ice water. Extracted with ethyl acetate and dried over MgSO ₄ and concentrated under reduced pressure. It was placed in a flask for use in the next reaction, and pentyne (40 mg, 0.6 mmol) and triethylamine (0.11 mL, 0.8 mmol) were added. The mixture was gradually heated from room temperature to 50 DEG C, stirred for 12 hours, and concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water. Washed with brine (brine) dried over MgSO ₄ and evaporated under reduced pressure after the filter. 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) was added to a DMF solution (1 mL) of the isoxazole compound (46 mg, 0.16 mmol) obtained in Step 2 and allyltributyltin (103 mg, mg, 7.8 [mu] mol). After stirring for 5 hours at < RTI ID = 0.0 > 90 C < / RTI > Diluted with ethyl acetate and washed twice with water. Washed with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. Column chromatography (ethyl acetate: n-Hexane = 1: 10) was conducted to obtain the product in a yield of 30 mg, 71%. ^{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 (T, 2H, J = 7.3), 1.82 (m, 2H), 3.87 (d, 2H, J = (m, 2H), 1.04 (t, 3H, J = 7.3).

Step 5: Preparation of the derivative 1 compound

Boron tribromide (1.0 M solution in dichloromethane, 680 [mu] L, 0.68 mmol) was slowly added to a dichloromethane solution (2 mL) of the allyl compound obtained in Step 4 (70 mg, 0.27 mmol) . After stirring for 1 hour, the temperature was slowly raised to room temperature. The reaction was terminated by adding methanol, stirred at room temperature for 30 minutes, diluted with dichloromethane and washed with water. Washed with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. Column chromatography (ethyl acetate: n-hexane = 1: 15) was conducted to obtain the final product in a yield of 40 mg, 61%. ^{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 2H, J = 6.8) 2.81 (t, 2H, J = 7.3) 1.84 (m, 2H) ), 1.05 (t, 3H, J = 7.3).

Production Example 21: Preparation of derivative 21

[Reaction Scheme 21]

To a dichloromethane solution (2 mL) of the isoxazole bromide compound (30 mg, 0.10 mmol) obtained in the above Step 2 of Preparation Example 2 was added boron tribromide (1.0 M solution in dichloromethane, 30 μL, 0.30 mmol) was slowly added at -78 < 0 > C. After stirring for 1 hour, the temperature was slowly raised to room temperature. The reaction was terminated by adding methanol, stirred at room temperature for 30 minutes, diluted with dichloromethane and washed with water. Washed with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. Column chromatography (ethyl acetate: n-hexane = 1: 15) was conducted to obtain the product in a yield of 18 mg, 64%. ^{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 22: Preparation of derivative 22

[Reaction Scheme 22]

Step 1: Isoxazol ( isoxazole ) Preparation of compound

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

Step 2: Preparation of allyl compound

To the DMF solution (1 mL) of the isoxazole compound (80 mg, 0.3 mmol) obtained in the above step 1 and allyltributyltin (148 mg, 0.45 mmol) was added tetrakis (triphenylphosphine) palladium 17 mg, 15 μmol) was added. After stirring for 5 hours at < RTI ID = 0.0 > 90 C < / RTI > Diluted with ethyl acetate and washed twice with water. 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 the product in a yield of 60 mg (82%). ^{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), 2H), 3.81 (s, 3H), 3.37 (d, 2H, J = 6.3 Hz), 6.75 (s, 1H), 6.00 (m,

Step 3: Preparation of the derivative 22 compound

Boron tribromide (1.0 M solution in dichloromethane, 88 μL, 0.88 mmol) was added to a dichloromethane solution (2 mL) of the allyl compound (55 mg, 0.22 mmol) 0.0 > 78 C. < / RTI > After stirring for 1 hour, the temperature was slowly raised to room temperature. The reaction was terminated by the addition of methanol, stirred at room temperature for 30 minutes, diluted with dichloromethane and washed with water. Washed with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. The residue was subjected to column chromatography (ethyl acetate: n-hexane = 1: 2) to obtain the final product in a yield of 35 mg and 69%. ¹ H-NMR (400 MHz, CDCl ₃ ) 隆 9.32 (s, 1H), 7.27 (d, 1H, J = 1.9 Hz), 7.18 (dd, 1H, J = 8.8 and 2.4 Hz) , 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).

Production 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 for 12 hours at room temperature, NaHSO ₃ aqueous solution was added to terminate the reaction. The mixture was extracted with ether, washed with water and brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The following reaction was used without purification.

Step 1-2 :

Triethylamine (2.8 mL, 20 mmol) and acetic anhydride (1.4 mL, 15 mmol) were added to a dichloromethane (20 mL) solution of 2-bromo-4-propylphenol It was a week. After stirring for 2 hours at room temperature, diluted with dichloromethane and washed with water. Washed with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. Column chromatography (ethyl acetate: n-Hexane = 1: 12) was conducted to obtain intermediate compound (a) (2.2 g, 86% for step 2).

Step 2: Preparation of intermediate compounds (b) and (c)

Step 2-1 :

Bis (triphenylphosphine) palladium (II) was added to a triethylamine solution (12 mL) of the intermediate compound (a) (1.26 g, 4.9 mmol) obtained in the above step 1 and ethynyltrimethylsilane (727 mg, dichloride (172 mg, 0.25 mmol) and CuI (48 mg, 0.25 mmol). After stirring for 5 hours at 80 < 0 > C, the mixture 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 :

An aqueous solution (1 mL) of Cs ₂ CO ₃ (60 mg, 0.18 mmol) was added to an acetonitrile solution (5 mL) of the product (506 mg, 1.85 mmol) obtained in the above step 2-1. The mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure, diluted with ethyl acetate and washed with water. Washed with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. (B) (220 mg, 59%) and an intermediate compound (c) (74 mg, 25%) were obtained by column chromatography (diethyl ether: n-Hexane = 1:10). ^{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)

DMSO (2 mL) solution of allyl bromide (145 mg, 1.2 mmol) and sodium azide (78 mg, 1.2 mmol) was placed in a sealed tube and stirred at room temperature for 12 hours. An aqueous solution (0.5 mL) of sodium ascorbate (25 mg, 0.1 mmol), copper sulfate (CuSO ₄ ) (16 mg, 0.05 mmol) and the intermediate compound (b) (200 mg, 1 mmol) Lt; 0 > C for 12 h, and stirred at 70 < 0 > C for 12 h. The reaction solution to terminate the reaction and poured into cold 1N-NH ₄ OH solution (conducted in order to prevent dryness of the residual blast CuN _3). Extracted with ethyl acetate, washed with brine, dried over MgSO ₄ , filtered and then distilled under reduced pressure. The intermediate compound (d) was obtained by subjecting to column chromatography (ethyl acetate: n-Hexane = 1: 2) (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 the 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). Stir at 50 < 0 > C for 2 h, concentrate under reduced pressure, dilute with ethyl acetate and wash with water. Washed 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 the 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 2H, J = 7.8 Hz), 6.98 (d, 1H, J = 8.3 Hz), 6.12 (m, 1H), 5.44-5.36 (m, 2H), 5.06-5.04 , 1.66-1.57 (m, 2H), 0.95 (t, 3H, J = 7.3 Hz). ¹³ C-NMR (100 MHz, CDCl ₃ ) 隆 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 24: Preparation of derivative 24

[Reaction Scheme 24]

DMSO (1 mL) solution of (bromomethyl) cyclobutane (90 mg, 0.6 mmol) and sodium azide (40 mg, 0.6 mmol) was placed in a sealed tube, The mixture was stirred at room temperature. An aqueous solution (0.5 mL) of sodium ascorbate (13 mg, 0.05 mmol), copper sulfate (CuSO ₄ ) (8 mg, 0.03 mmol) and an alkyne compound (100 mg, 0.5 mmol) Lt; 0 > C, and stirred at 70 [deg.] C for 12 hours. The reaction solution to terminate the reaction and poured into cold 1N-NH ₄ OH solution (conducted in order to prevent dryness of the residual blast CuN _3). Extracted with ethyl acetate, washed with brine, dried over MgSO ₄ , filtered and then distilled under reduced pressure. It was placed in a flask for use in the next reaction, and methanol (1 mL) and K ₂ CO ₃ (15 mg, 0.1 mmol) were added. Stir at 50 < 0 > C for 2 h, concentrate under reduced pressure, dilute with ethyl acetate and wash with water. Washed with brine, dried over MgSO ₄ , filtered and distilled under reduced pressure. Column chromatography (ethyl acetate: n-Hexane = 1: 1) was conducted to obtain the final product in a yield of 90 mg (67%). ^{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 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 substituted with hydrogen gas. The mixture was stirred at room temperature for 5 hours, filtered through celite, and distilled under reduced pressure. The residue was subjected to column chromatography (ethyl acetate: n-hexane = 1: 2) to obtain the final product in a yield of 30 mg and 85%. ^{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 compounds of the present invention synthesized in the above examples are summarized as follows.

[Chemical 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

(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: Test method for measuring the anti-inflammatory effect of methylnonochiol 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. Analysis of NO production

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

NO, and mitogen analysis, the remaining medium was discarded, 200 ml of fresh medium was added, and the mixture was stabilized for 1 hour. MTT reagent was added so as to be 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. Then, the absorbance was measured at 550 nm.

1-4. COX-2 enzyme inhibition assay

To conduct the enzyme analysis, a background tube in which COX-2 is inactive, a 100% initial active tube with maximum reactivity, and a COX-2 inhibitor tube containing the sample are prepared Respectively. In the background tube, 10 μl of COX-2 enzyme was inactivated for 3 minutes at 100 ° C., and then 970 μl reaction buffer and 10 μl heme were added. The 100% initial activity tube was loaded with 970 μl of the reaction buffer, 10 μl of heme, and 10 μl of COX-2. COX-2 inhibitor tubes were loaded with 950 μl reaction buffer, 10 μl heme, 10 μl COX-2 and 20 μl samples. These three tubes were reacted in a 37 ° C water bath for 10 minutes, and then 10 μl of arachidonic acid was added, followed by vortexing for 2 minutes in a 37 ° C water bath. Then, 50 μl of 1 M HCl was added to stop the reaction, and 100 μl of a stannous chloride solution was added thereto, followed by vortexing, followed by reaction at room temperature for 5 minutes. Samples were prepared, and 50 μl of each of the above-mentioned three tubes, tracer and antiserum was added to the wells and reacted at room temperature for 18 hours. After the reaction was completed, the wells were washed five times, and 200 μl of Ellman's regent was added to each well, followed by darkening and reacting. 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. Inhibitory effect of PGF1a on 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 incubation for 24 h, the supernatant was collected 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 completion of the reaction, the wells were washed five times, and 200 μl of Ellman's regent was added to each well, followed by darkening and reacting. 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: Methylhornokiol  Results of Determination of Anti-inflammatory Effect of Derivatives

The methylmonoquiol derivatives of the present invention exhibited cytotoxicity with an IC ₅₀ of 20-100 μM. It also inhibited the NO production of macrophages with similar IC ₅₀ values. This means that the derivatives show cytotoxicity to macrophages but not at low concentrations (see Table 4). However, COX-2 (cyclooxygenase-2) was inhibited at very low concentrations without cytotoxicity. When the derivatives were treated with cells at a concentration of 100 nM and the production of PGF1a was measured, the degree of inhibition was 20-60% (see Table 5). In addition, when COX-2 enzyme was directly treated with a concentration of 100 nM, the inhibition was 20-70%. This suggests that the methylnonochiol derivatives of the present invention have an inhibitory effect on COX-2, which means that there is a potential for development of anti-inflammatory drugs in the future.

compound Cytotoxicity (μM, IC ₅₀ ) NO production (μM, IC ₅₀ ) Methylhornokiol 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 The derivative 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 The derivative 22 > 50 > 50 Derivative 23 > 50 > 50 The derivative 24 33 > 50 Derivative 25 36 > 50

compound PGF1α
(% Inhibition at 0.1 [mu] M) COX-2 enzyme
(% Inhibition at 0.1 [mu] M) Methylhornokiol 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 The derivative 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 The derivative 22 29 22 Derivative 23 47 29 The 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. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

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) Schiffly, 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.

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Claims (4)

A compound represented by the following formula (2) or (3).
(2)

In Chemical Formula 2, R ₁ is C ₁ -C ₅ alkyl or C ₂ -C ₅ alkenyl, R ₂ is C ₁ -C ₅ alkyl, or C ₁ -C ₅ hydroxyalkyl, provided that R ₁ and Except that both R ₂ are C ₁ -C ₅ alkyl;
(3)

In Formula 3, R ₁ is C ₁ -C ₅ alkyl, R ₂ is C ₂ -C ₅ alkenyl, C ₃ -C ₈ cycloalkyl, or (C ₃ -C ₈ cycloalkyl) C ₁ -C ₅ Alkyl.
The compound of claim 1, wherein in Formula 2, R ₁ is C ₁ -C ₃ alkyl or C ₂ -C ₃ alkenyl, R ₂ is C ₁ -C ₃ alkyl or C ₁ -C ₃ hydroxyalkyl, Provided that R ₁ and R ₂ are both C ₁ -C ₃ alkyl;
In Chemical Formula 3, R ₁ is C ₁ -C ₃ alkyl, R ₂ is C ₂ -C ₃ alkenyl, or

≪ / RTI >
A pharmaceutical composition for the treatment or prophylaxis of inflammatory diseases comprising the compound of claim 1 or 2 as an active ingredient.
Functional food composition for improving inflammatory disease comprising the compound of claim 1 or claim 2 as an active ingredient.