KR20130083879A - Composition for treating dementia comprising 4-o-methylhonokiol derivatives as active ingredient - Google Patents

Abstract

PURPOSE: Component for dementia cure is provided to include methyl honokilo derivative to active ingredient so it can have a cohesion control effect on beta-amyloid [β-amyloid] and increasing activity of beta - secretase [β-secretase] and deterring effect of nerve cell of beta-amyloid [β-amyloid]. CONSTITUTION: Pharmaceutical composition for treatment or prevention of dementia comprises of methyl honokiol derivative which includes chemical formula 1 as active ingredient. Pharmaceutical composition for treatment or prevention of dementia includes pharmaceutically effective dose of methyl honokiol derivative represented by chemical formula 1, and chemical formula 2 or by chemical formula 3 and a carrier which is pharmaceutically allowed (b).

Description

Composition for Treating Dementia Comprising 4-O-Methylhonokiol Derivatives as Active Ingredient

The present invention relates to a composition for treating dementia comprising a novel 4-O-methylhonokiol derivative 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 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 have diligently researched to develop derivatives having more improved activity of methylhonokiol compounds known to have various physiological activities such as anti-inflammatory and anti-dementia efficacy. As a result, it succeeded in synthesizing novel methyl honokiol derivatives, and the synthesized derivatives inhibited beta-amyloid aggregation and beta-secretase activity and beta-amyloid (β- By inhibiting neuronal cell death by amyloid), the present invention was completed by experimentally confirming the excellent anti-dementia activity.

It is therefore an object of the present invention to provide a composition for the treatment, prevention or improvement of dementia comprising a 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 invention, the present invention provides a pharmaceutical composition for the treatment or prevention of dementia comprising a methyl honokiol derivative represented by the following formula (1), (2) or (3) as an active ingredient.

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.

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

,

,

,

,

,

, 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

인 것을 특징으로 하는 조성물을 제공한다. According to a preferred embodiment of the present invention, the present invention in the general 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 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

It provides a composition characterized in that.

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.

The methyl honokiol derivative of the present invention inhibits beta-amyloid aggregation, inhibits the activity of beta-secretase, as demonstrated in one specific embodiment of the present invention, It has an effect of inhibiting the death of neurons by beta-amyloid. Therefore, the methyl honokiol derivative of the present invention can be used for the treatment, prevention and improvement of dementia caused by beta amyloid (β-amyloid).

The present invention (a) a pharmaceutically effective amount of the methyl honokiol derivative represented by Formula 1, Formula 2 or Formula 3; And (b) provides a pharmaceutical composition for the treatment or prevention of dementia 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 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 dementia 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 (e.g., glucose, fructose, etc.); Disaccharides (e.g., maltose, sucrose, etc.); oligosaccharide; Polysaccharides (eg, dextrins, cyclodextrins, etc.); 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:

(Iii) The novel methyl honokiol derivatives of the present invention inhibit beta-amyloid aggregation, inhibit beta-secretase activity, and inhibit beta-amyloid activity. It has the effect of inhibiting the death of nerve cells.

(Ii) The methyl honokiol derivatives of the present invention can be used for the treatment, prevention and amelioration of dementia caused by beta amyloid (β-amyloid).

The present invention provides a composition for the treatment, prevention or improvement of dementia comprising a novel methyl honokiol derivative as an active ingredient. The methyl honokiol derivative of the present invention has the effect of inhibiting the aggregation of beta-amyloid (β-amyloid), beta-secretase activity, and beta-amyloid inhibiting neuronal cell death. Indicates. Therefore, the methyl honokiol derivative of the present invention can be developed as an active ingredient of a therapeutic agent for dementia diseases caused by beta amyloid and a functional food for improving dementia.

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

[Reaction 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 ).

Preparation 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 ).

Preparation Example 4 Preparation of Derivative 4

[Reaction 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. After stirring for 24 hours under reflux and distillation 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.

Preparation 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 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: Preparation of Isoxazole 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).

In summary, the derivative compounds of the present invention synthesized in the preparation example are 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 Inhibitory Effects of Beta-amyloid Aggregation

45 μl of PBS was added to the Black 96-microwell plate, 5 μl of 250 mM beta-amyloid solution was added thereto, and 2 μl of the test substance was added and allowed to react at room temperature for 1 hour. Subsequently, 150 μl of Thioflavine T dissolved in 50 mM glycine (pH 8.5) to 5 mM was added thereto, and fluorescence intensity was measured using a fluorescence spectrometer (Ex: 450 nm. EmL 480 nm). Thioflavin T is basically a yellow pigment and fluoresces with the fibrillated beta-amyloid, whereby the higher the fibrillation level of the beta-amyloid, the stronger the fluorescence. Methyl honochiol (5 μM) inhibited beta-amyloid aggregation by 43%, derivative 1 was 41%, derivative 4 was 40%, derivative 7 was 29%, derivative 8 was 44%, derivative 12 was 30%, derivative 13 Silver was 39%, derivative 14 was 24%, derivative 17 was 42%, derivative 20 was 16%, derivative 21 was suppressed 48%. Beta-amyloid coagulation inhibitory effect of each derivative is summarized in Table 4 below.

Sample compound Beta-amyloid aggregation (%) Control group 100 Methyl Honokiol 57  Derivative 1 59 Derivative 2 ND Derivative 3 ND Derivative 4 60 Derivative 5 ND Derivative 6 ND Derivative 7 71 Derivative 8 56 Derivative 11 ND Derivative 12 70 Derivative 13 61 Derivatives 14 76 Derivative 15 ND Derivative 16 ND Derivative 17 58 Derivative 18 ND Derivative 19 ND Derivative 20 84 Derivative 21 52

Experimental Example 2: inhibitory effect of beta-secretase activity

The inhibitory effect of the beta-secretase activity of the synthesize | combined methyl honokiol derivative compound was measured. To measure beta-secretase activity in the cortex and hippocampus of the mouse brain, a beta-secretase activity measurement kit (R & D systems, Wiesbaden, Germany) was used. 50 μl of tissue sample lysate was added to the Black 96-microwell plate, mixed with 50 μl of reaction buffer, and 5 μl of EDANS / DABCYL conjugated substrate was added as a reporter. After mixing gently, it was reacted at 37 ° C. for 1 hour. Since the reporter EDANS / DABCYL is fluorescence when cut by beta-secretase, the fluorescence intensity was measured at Ex / Em 355/510 nm using a fluorescence spectrometer. Beta-secretase activity was expressed per mg of protein using a fluorescence unit as a fluorometric reaction. Methyl honochiol (5 μM) inhibited beta-secretase activity by 43%, derivative 1 was 37%, derivative 4 was 35%, derivative 7 was 29%, derivative 8 was 64%, derivative 12 was 46%, Derivative 13 was 52%, derivative 14 was 36%, derivative 17 was 54%, derivative 20 was 62%, derivative 21 was 58% inhibited. Beta-secretase activity inhibitory effect of each derivative is summarized in Table 5 below.

Sample compound Beta-secretase inhibition (%) Control group 100 Methyl Honokiol 57 Derivative 1 63 Derivative 2 ND Derivative 3 ND Derivative 4 65 Derivative 5 ND Derivative 6 ND Derivative 7 71 Derivative 8 64 Derivative 11 ND Derivative 12 54 Derivative 13 48 Derivatives 14 64 Derivative 15 ND Derivative 16 ND Derivative 17 54 Derivative 18 ND Derivative 19 ND Derivative 20 62 Derivative 21 58

Experimental Example 3: Inhibitory effect of beta-amyloid on neuronal cell death

The effect of inhibiting the death of neurons by beta-amyloid of the synthesized methyl honokiol derivative compounds was measured. When the confluency of the cells reaches 70-80% or more, divide 200 μl of 1 × 10 ⁴ cells into a 96-well plate and incubate for 24 hours in a 37 ° C., 5% CO ₂ incubator. Discarded medium was discarded and 200 μM H ₂ O ₂ or 10 μM beta-amyloid was added to each well. After incubation for 24 hours, the morphology of the cells was observed under an optical microscope (OLYMPUS) or cell death was measured by Lactate dehydrogenase (LDH) release assay. When tetrazolium salt was added to LDH released during cell necrosis, a reduced form of formazan was formed. The absorbance was measured at 492 nm. H ₂ O ₂ killed 51% of the neurons, and treatment with H ₂ O ₂ and methyl honochiol simultaneously resulted in 30% cell death, and methyl honokiol had 21% neuronal cell death protection. Derivative 1 protects 10%, derivative 2 2%, derivative 3 17%, derivative 4 10%, derivative 7 13%, derivative 8 8%, derivative 12 8%, derivative 13 14% There was. However, derivative 5, derivative 6, derivative 11, derivative 15, and derivative 16-21 had no protective effect. Treatment with beta-amyloid killed 57% of neurons. Treatment with beta-amyloid and methylhonokiol resulted in 40% cell death. . Experiments in the same manner as described above, derivative 1 is 18%, derivative 3 is 6%, derivative 4 is 15%, derivative 7 is 11%, derivative 8 is 9%, derivative 12 is 8%, derivative 13 is 4%, derivative 14 had a protective effect of 16%, derivative 17 of 5%, derivative 20 of 16%, and derivative 21 of 19%. The cytoprotective effect of each derivative is summarized in Table 6 below.

Sample compound Induced by H ₂ O ₂ treatment
Apoptosis (% survival) Induced by beta-amyloid
Apoptosis (% survival) Control group 100 100 H ₂ O ₂ treatment group: 49 Beta-amyloid treatment group: 43 Methyl Honokiol 70 60 Derivative 1 59 61 Derivative 2 51 ND Derivative 3 66 49 Derivative 4 59 58 Derivative 5 37 ND Derivative 6 32 ND Derivative 7 62 54 Derivative 8 57 52 Derivative 11 48 ND Derivative 12 57 51 Derivative 13 63 47 Derivatives 14 66 59 Derivative 15 28 ND Derivative 16 31 ND Derivative 17 49 48 Derivative 18 35 ND Derivative 19 34 ND Derivative 20 51 59 Derivative 21 49 62

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.

Claims (3)

A pharmaceutical composition for the treatment or prophylaxis of dementia comprising a methyl honokiol derivative represented by Formula 1 as an active ingredient.
[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.
Functional food composition for improvement of dementia comprising a methyl honokiol derivative represented by the formula (1) as an active ingredient.
[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.
According to claim 1 or 2, 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.