WO2019194583A1 - 3-phenyl-2,8-dihydropyrano[2,3-f]chromene derivative and pharmaceutical composition comprising same - Google Patents

Abstract

The present invention may provide a 3-phenyl-2,8-dihydropyrano[2,3-f] chromene derivative with excellent prophylactic and therapeutic effects on metabolic syndromes including obesity and diabetes, and a pharmaceutical composition comprising same.

Description

3-phenyl-2,8-dihydropyrano [2,3-F] chromen derivative and pharmaceutical composition comprising the same

This specification claims the benefit of the filing date of Korean Patent Application No. 10-2018-0038895 filed with the Korea Patent Office on April 3, 2018, the entire contents of which are included in the present invention.

The present invention relates to 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivatives and pharmaceutical compositions comprising the same.

There are more than 20 billion fat cells in the human body, and when the supply of energy to the human body is much higher than the demand for energy, it is stored as triglycerides in the fat cells in the human body, and free fatty acids and glucose when the energy is depleted. It is decomposed into an energy source. About 30 to 40% of modern people have obesity caused by the accumulation of excessive energy due to the imbalance of this process, and appears as a phenomenon that the size of fat cells increases or increases.

Obesity is caused by energy imbalance when excessive nutrition is consumed compared to energy consumption for a long period of time, thereby increasing the incidence of diabetes, fatty liver, dyslipidemia, sexual dysfunction, arthritis, cardiovascular disease, sleep apnea, etc. It is known to cause gallstones and some cancers. For this reason, the World Health Organization (WHO) defines obesity as a cause of various metabolic diseases (adult diseases), obesity is a cause of diabetes, and diabetic patients develop obesity due to insulin resistance, etc. Obesity and diabetes are basically diseases that affect each other.

Metabolic syndrome is a conceptualization of a group of cardiovascular diseases and the risk factors for type 2 diabetes as a disease group. This concept can be used to explain insulin resistance and various complicated and diverse metabolic abnormalities and clinical aspects. It is a syndrome that increases risk factors such as obesity, diabetes, fatty liver, and hypertriglyceridemia. Refer. Thus, the presence of metabolic syndrome increases the risk of developing cardiovascular disease or type 2 diabetes.

Insulin resistance refers to a phenomenon in which the intracellular supply of glucose performed by insulin does not normally occur even though insulin is normally secreted in the body. Glucose in the blood does not enter the cell shows high blood sugar symptoms, the cells do not function due to the lack of glucose, and eventually the symptoms of metabolic syndrome.

This diabetic condition is called type 2 diabetes (insulin-independent diabetes: NIDDM) separately from type 1 diabetes (insulin dependent diabetes) resulting from insulin deficiency. For this reason, the most preferred method of treating type 2 diabetes is to improve insulin resistance and induce insulin to function normally. Nevertheless, therapeutic agents to improve insulin resistance have not been developed so far.

Most Type 2 diabetes treatments currently used or developed aim to increase insulin secretion to compensate for insulin function lost due to insulin resistance. However, increasing insulin secretion in our body not only causes obesity and inflammation, but also leads to various side effects such as an increase in the incidence of cancer. Thus, unless the insulin resistance problem is fundamentally improved, temporary blood sugar normalization can be expected. It only gets worse. For this reason, there is an urgent need for a type 2 diabetes drug that can improve insulin resistance and normalize blood sugar.

On the other hand, Patent Document 1 discloses that pyranochromenylphenol derivatives are effective for the prevention and treatment of metabolic syndrome including hyperlipidemia, fatty liver, abnormal glucose metabolism, diabetes and obesity, and have an anti-inflammatory effect.

(Prior art document)

(Patent literature)

1. Republic of Korea Patent Publication 10-2015-0075030

One embodiment of the present invention is to provide a 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative excellent in the prevention and treatment of metabolic syndrome including obesity and diabetes.

Another embodiment of the present invention is 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative having excellent efficacy in preventing and treating metabolic syndromes such as obesity, type 2 diabetes, hypertension, hyperlipidemia, and the like. It provides a pharmaceutical composition comprising a.

One embodiment of the present invention provides 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative of Formula I, a pharmaceutically acceptable salt thereof, or solvate thereof:

[Formula I]

In Chemical Formula I,

R ₁ is a hydrogen atom; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkyl group; Halogen atom; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkoxy group; A substituted or unsubstituted, straight or branched C ₁ -C ₄ thioalkyl group; Substituted or unsubstituted allyloxy group; Or a substituted or unsubstituted C ₆ -C ₁₂ aryloxy group;

R ₂ is a hydroxy group; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkyl group; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkoxy group; Or a substituted or unsubstituted allyloxy group;

R ₃ is a hydrogen atom, methyl, ethyl, methoxy or ethoxy;

R ₄ and R ₅ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group;

The dashed line is an optional double bond;

In the case of the substituted alkyl group, substituted alkoxy group, substituted thioalkyl group, substituted allyloxy group and substituted aryloxy group, the substituent is a halogen atom, straight or branched chain C ₁ -C ₅ alkyl group, straight or branched chain C ₁ -C ₅ An alkoxy group or a straight or branched C ₁ -C ₃ thioalkyl group.

Another embodiment of the present invention is a metabolism comprising 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative of formula I, a pharmaceutically acceptable salt thereof, or solvate thereof Provided are pharmaceutical compositions for the prevention or treatment of syndromes:

[Formula I]

In Chemical Formula I,

R ₁ is a hydrogen atom; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkyl group; Halogen atom; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkoxy group; A substituted or unsubstituted, straight or branched C ₁ -C ₄ thioalkyl group; Substituted or unsubstituted allyloxy group; Or a substituted or unsubstituted C ₆ -C ₁₂ aryloxy group;

R ₂ is a hydroxy group; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkyl group; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkoxy group; Or a substituted or unsubstituted allyloxy group;

R ₃ is a hydrogen atom, methyl, ethyl, methoxy or ethoxy;

R ₄ and R ₅ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group;

The dashed line is an optional double bond;

In the case of the substituted alkyl group, substituted alkoxy group, substituted thioalkyl group, substituted allyloxy group and substituted aryloxy group, the substituent is a halogen atom, a straight or branched C ₁ -C ₅ alkyl group, a straight or branched chain C ₁ -C ₅ An alkoxy group or a straight or branched C ₁ -C ₃ thioalkyl group.

According to one embodiment of the present invention, 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative is excellent in preventing and treating metabolic syndrome including obesity and diabetes.

1 is a graph showing the weight gain of the mouse according to the administration period of the compound II-1 prepared in Example 1 of the present invention.

Figure 2 is a graph showing the change in blood glucose of the mouse according to the elapsed time (min) after administration of the compounds prepared in Examples 1, 2 and 4 of the present invention.

Figure 3 is a graph showing the change in blood glucose of the mouse according to the time (week) after the administration of the compound prepared in Examples 1, 2 and 4 of the present invention.

Hereinafter, the present invention will be described in more detail.

All technical terms used in the present invention, unless defined otherwise, are used in the meaning as commonly understood by those skilled in the art in the related field of the present invention. In addition, although a preferred method or sample is described herein, similar or equivalent things are included in the scope of the present invention. The contents of all publications that are incorporated herein by reference are incorporated by reference in their entirety.

According to an exemplary embodiment of the present invention, 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative of formula (I), a pharmaceutically acceptable salt thereof, or solvate thereof is provided. do:

[Formula I]

In Chemical Formula I,

R ₁ is a hydrogen atom; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkyl group; Halogen atom; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkoxy group; A substituted or unsubstituted, straight or branched C ₁ -C ₄ thioalkyl group; Substituted or unsubstituted allyloxy group; Or a substituted or unsubstituted C ₆ -C ₁₂ aryloxy group;

R ₂ is a hydroxy group; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkyl group; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkoxy group; Or a substituted or unsubstituted allyloxy group;

R ₃ is a hydrogen atom, methyl, ethyl, methoxy or ethoxy;

R ₄ and R ₅ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group;

The dashed line is an optional double bond;

In the case of the substituted alkyl group, substituted alkoxy group, substituted thioalkyl group, substituted allyloxy group and substituted aryloxy group, the substituent is a halogen atom, straight or branched chain C ₁ -C ₅ alkyl group, straight or branched chain C ₁ -C ₅ An alkoxy group or a straight or branched C ₁ -C ₃ thioalkyl group.

The term "selective double bond" described above means that in some cases, it may be a single bond or a double bond.

According to one embodiment of the present invention, the 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative of Formula I is effective in preventing and treating metabolic syndrome including obesity and diabetes. great. That is, the 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative of Formula I has excellent anti-obesity efficacy. In addition, the 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative of Formula I is excellent in antidiabetic efficacy. In addition, the 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative of Formula I is excellent in anti-obesity and anti-diabetic efficacy.

According to an exemplary embodiment of the present invention, in Chemical Formula I, R ₁ is methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, n-pentyl, 2-methylbutyl, 3-methyl Butyl, 2-ethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, or 2-ethylbutyl; R ₂ is a hydroxy group; R ₃ is a hydrogen atom; R ₄ and R ₅ may each be methyl.

Further, according to an exemplary embodiment of the present invention, in the general formula (I), wherein R ₁ is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-methylpropoxy, n-pentyloxy , 2-methylbutoxy, 3-methylbutoxy, 2-ethylpropoxy, n-hexyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, or 2-ethylbutoxy ; R ₂ is a hydroxy group; R ₃ is a hydrogen atom; R ₄ and R ₅ may each be methyl.

According to an exemplary embodiment of the present invention, the 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative may be a compound of Formula II:

[Formula II]

In Chemical Formula II,

R ₁ is a hydrogen atom; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkyl group; Halogen atom; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkoxy group; A substituted or unsubstituted, straight or branched C ₁ -C ₄ thioalkyl group; Substituted or unsubstituted allyloxy group; Or a substituted or unsubstituted C ₆ -C ₁₂ aryloxy group;

R ₂ is a hydroxy group; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkyl group; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkoxy group; Or a substituted or unsubstituted allyloxy group;

R ₃ is a hydrogen atom, methyl, ethyl, methoxy or ethoxy;

R ₄ and R ₅ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group;

In the case of the substituted alkyl group, substituted alkoxy group, substituted thioalkyl group, substituted allyloxy group and substituted aryloxy group, the substituent is a halogen atom, straight or branched chain C ₁ -C ₅ alkyl group, straight or branched chain C ₁ -C ₅ An alkoxy group or a straight or branched C ₁ -C ₃ thioalkyl group.

According to an exemplary embodiment of the present invention, the 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative of Formula II may be any one of the following compounds:

<Compound II-1> <Compound II-2>

<Compound II-3> <Compound II-4>

<Compound II-5> <Compound II-6>

<Compound II-7> <Compound II-8>

<Compound II-9> <Compound II-10>

<Compound II-11> <Compound II-12>

<Compound II-13> <Compound II-14>

<Compound II-15> <Compound II-16>

<Compound II-17> <Compound II-18>

<Compound II-19> <Compound II-20>

<Compound II-21> <Compound II-22>

<Compound II-23> <Compound II-24>

<Compound II-25> <Compound II-26>

<Compound II-27> <Compound II-28>

<Compound II-29> <Compound II-30>

<Compound II-31> <Compound II-32>

<Compound II-33> <Compound II-34>

<Compound II-35> <Compound II-36>

<Compound II-37>

According to an exemplary embodiment of the present invention, the 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative of Formula II is excellent in preventing and treating diabetes due to its excellent glycemic control ability. Has an effect. In addition, the 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative of Formula II is excellent in the prevention and treatment of obesity.

According to an exemplary embodiment of the present invention, 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative of Chemical Formula II may be prepared through Scheme 1 below, The method for preparing 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative is not limited thereto.

Scheme 1

In the above formulas,

R ₁ is a hydrogen atom; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkyl group; Halogen atom; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkoxy group; A substituted or unsubstituted, straight or branched C ₁ -C ₄ thioalkyl group; Substituted or unsubstituted allyloxy group; Or a substituted or unsubstituted C ₆ -C ₁₂ aryloxy group;

R ₂ is a hydroxy group; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkyl group; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkoxy group; Or a substituted or unsubstituted allyloxy group;

R ₃ is a hydrogen atom, methyl, ethyl, methoxy or ethoxy;

R ₄ and R ₅ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group;

P is a substituted or unsubstituted allyl group; t-butyldimethylsilyl group (tert-butyldimethylsilyl, TBDMS); t-butyldiphenylsilyl group (tert-butyldiphenylsilyl, TBDPS); Methylphenylsilyl group; Trimethylphenylsilyl group; MeSO ₂ (methanesulfonyl); p-TsSO ₂ (p-toluenesulfonyl); Or a protecting group of trimethylphenylsulfonyl group; And

In the case of the substituted alkyl group, substituted alkoxy group, substituted thioalkyl group, substituted allyloxy group, substituted aryloxy group, substituted benzyl group and substituted allyl group, the substituent is a halogen atom, a straight chain or branched C ₁ -C ₅ alkyl group, a straight chain Or a branched C ₁ -C ₅ alkoxy group, a straight or branched C ₁ -C ₃ thioalkyl group or a nitro group.

According to an exemplary embodiment of the present invention, the coupling of the compound of Chemical Formula 1 and the compound of Chemical Formula 2 in Scheme 1 may be performed under basic conditions, and may be more preferably performed with a weak basic compound as a catalyst. have. In this case, an intermolecular aldol condensation can prevent the synthesis of unwanted compounds.

In addition, according to an exemplary embodiment of the present invention, the weak basic compound is sodium carbonate (Na ₂ CO ₃ ), lithium carbonate (Li ₂ CO ₃ ), potassium carbonate (K ₂ CO ₃ ), sodium bicarbonate (NaHCO ₃ ), Potassium hydrogen carbonate (KHCO ₃ ), triethylamine (triethylamine) and pyridine (pyridine) may be at least one selected from the group consisting of, potassium carbonate or sodium carbonate may be preferred.

According to an exemplary embodiment of the present invention, the step of reducing the compound of Formula 3 in Scheme 1 by selectively reducing only the formyl group (-COH) in a state in which the carbonyl group (-CO-) of the ketone is safely maintained The compound of can be prepared. The selective reduction is L-Selectride {Li [CH (CH ₃ ) CH ₂ CH ₃ ] ₃ BH}, N-Selectride {NaB [CH (CH ₃ ) C ₂ H ₅ ] ₃ H}, K-Selectride {K [ CH (CH ₃ ) CH ₂ CH ₃ ] ₃ BH} and LS-Selectride {LiB [CH (CH ₃ ) CH (CH ₃ ) ₂ ] ₃ H} by adding one or more reducing agents selected from the group consisting of. have. The reduction reaction is preferably made at -10 ° C or less, more preferably at -60 ° C or less, and most preferably at -78 ° C or less.

According to an exemplary embodiment of the present invention, the reaction for preparing the compound of Formula 5 by cyclizing the compound of Formula 4 in Scheme 1 is an intramolecular cyclization reaction, as shown in Scheme 2 below Dissolving the compound of 4 in acetonitrile (CH ₃ CN) and adding triphenylphosphonium bromide (Ph ₃ PHBr), concentrating the resultant and dissolving the concentrate, sodium It may consist of adding ethoxide (NaOEt).

Scheme 2

According to one embodiment of the present invention, the step of concentrating the resultant or dissolving the concentrate is preferably using ethanol.

Further, according to an exemplary embodiment of the present invention, when an allyl group or an analog thereof is used as the protecting group (P) of the hydroxy group in Scheme 1 or 2, tris (acetonitrile) cyclopentadienyl ruthenium as shown in Scheme 3 below (II) Hexafluorophosphate {tris (acetonitrile) cyclopentadienylruthenium (II) hexafluorophosphate} and quinaldic acid are used as a catalyst, and the deprotection process is carried out to obtain the compound of the above formula (II).

Scheme 3

According to an exemplary embodiment of the present invention, 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative represented by the following general formula (II ′) wherein R ₂ in the general formula (II) is a hydroxy group is represented by the following reaction formula: It may be prepared through 4, but the manufacturing method is not limited thereto.

Scheme 4

R ₁ , R ₃ , R ₄ , and R _{5 in} the chemical formula of Scheme ₄ may each be the same as R ₁ , R ₃ , R ₄ , and R _{5 in} the chemical formula of Scheme 1 above. In addition, P ₁ and P _{2 which} are protecting groups in the chemical formula of Scheme 4 may be independently the same as P of the chemical formula of Scheme 1. In addition, the coupling reaction, reduction reaction, cyclization reaction and deprotection reaction in the reaction scheme 4 is the same as the coupling reaction, reduction reaction, cyclization reaction and deprotection reaction of the reaction scheme 1.

In addition, according to an exemplary embodiment of the present invention, 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative of Formula II may be prepared through the following Scheme 5.

Scheme 5

In Formula 5, R ₁ , R ₃ , R ₄ , R _5, and P may be the same as R ₁ , R ₃ , R ₄ , R _5, and P of Formula ₁ , respectively. In addition, the coupling reaction in Scheme 5 is the same as the coupling reaction in Scheme 1.

According to the exemplary embodiment of the present invention, the compound of Chemical Formula 6 may be obtained by performing a cyclization process through benzoin condensation by adding a salt to the compound of Chemical Formula 3 in Scheme 5. Specifically, the salt is a thiazolium salt, triazolium salt or 6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazolium salt (6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazolium salt).

According to the exemplary embodiment of the present invention, the compound of Chemical Formula 7 may be synthesized through the reaction of reducing the carbonyl group in the compound of Chemical Formula 6 to the hydroxyl group in Scheme 5. Specifically, the reduction reaction may be made by adding lithium borohydride (LiBH ₄ ) or sodium borohydride (NaBH ₄ ).

According to an exemplary embodiment of the present invention, in the Scheme 5, the reductive removal reaction is preferably made in the presence of low valence titanium (LVT). Here, the low-atomic titanium refers to titanium tetrachloride (TiCl ₄ ) or titanium trichloride (TiCl ₃ ) and the like when first reacted with sufficient equivalents (2 to 3 equivalents) of zinc (Zn), magnesium (Mg), lithium (Li), and the like. It means a valence of 0 or monovalent titanium species.

In addition, the reductive removal reaction is a result of dissolving the compound of Formula 7 in tetrahydrofuran (THF) and then adding sodium borohydride (LiBH ₄ ) and refluxing zinc and titanium tetrachloride (TiCl ₄ ) Adding and refluxing.

According to an exemplary embodiment of the present invention, the 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative may be a compound of Formula III:

[Formula III]

In Chemical Formula III,

R ₁ is a hydrogen atom; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkyl group; Halogen atom; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkoxy group; A substituted or unsubstituted, straight or branched C ₁ -C ₄ thioalkyl group; Substituted or unsubstituted allyloxy group; Or a substituted or unsubstituted C ₆ -C ₁₂ aryloxy group;

R ₂ is a hydroxy group; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkyl group; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkoxy group; Or a substituted or unsubstituted allyloxy group;

R ₃ is a hydrogen atom, methyl, ethyl, methoxy or ethoxy;

R ₄ and R ₅ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group;

In the case of the substituted alkyl group, substituted alkoxy group, substituted thioalkyl group, substituted allyloxy group and substituted aryloxy group, the substituent is a halogen atom, straight or branched chain C ₁ -C ₅ alkyl group, straight or branched chain C ₁ -C ₅ An alkoxy group or a straight or branched C ₁ -C ₃ thioalkyl group.

According to an exemplary embodiment of the present invention, the 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative of Formula III may be any one of the following compounds:

<Compound III-1> <Compound III-2>

<Compound III-3> <Compound III-4>

<Compound III-5> <Compound III-6>

<Compound III-7> <Compound III-8>

<Compound III-9> <Compound III-10>

<Compound III-11> <Compound III-12>

<Compound III-13> <Compound III-14>

<Compound III-15> <Compound III-16>

<Compound III-17> <Compound III-18>

<Compound III-19> <Compound III-20>

<Compound III-21> <Compound III-22>

<Compound III-23> <Compound III-24>

<Compound III-25> <Compound III-26>

<Compound III-27> <Compound III-28>

<Compound III-29> <Compound III-30>

<Compound III-31> <Compound III-32>

<Compound III-33> <Compound III-34>

<Compound III-35> <Compound III-36>

<Compound III-37>

According to an exemplary embodiment of the present invention, the 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative of Formula III has excellent blood glucose control ability and is excellent in preventing and treating diabetes. Has an effect. In addition, the 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative of Formula III is excellent in the prevention and treatment of obesity.

According to an exemplary embodiment of the present invention, 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative of Formula III may be prepared through Scheme 6, but The method for preparing 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative is not limited thereto.

Scheme 6

In Formula 6, R ₁ , R ₂ , R ₃ , R _4, and R ₅ may be the same as R ₁ , R ₂ , R ₃ , R _4, and R ₅ of Formula ₁ , respectively. In addition, the protecting group (P) of the formula (2) is substituted or unsubstituted benzyl group, allyl group; t-butyldimethylsilyl group; t-butyldiphenylsilyl group; Methylphenylsilyl group; Trimethylphenylsilyl group; MeSO ₂ ; p-TsSO ₂ ; Or a trimethylphenylsulfonyl group, the protecting group (P ₁ ) of Formula 9 may be one of the above-described protecting groups, and may be different from the protecting group (P) of Formula (2). In addition, the coupling reaction, cyclization reaction and reductive removal reaction of Scheme 6 are the same as the coupling reaction, cyclization reaction and reductive removal reaction of Scheme 5.

According to an exemplary embodiment of the present invention, through the hydrogenation reaction (H ₂ , Pd / C) in Scheme 6, while reducing the carbon double bond of the dihydropyran ring in the compound of Formula 6, The protecting group (P) in the compound of 6 can be deprotected. In addition, by the method used in the art, by replacing the hydroxyl group of the formula (8) with the above-described protecting group, the formula (9) can be prepared. For example, K ₂ CO ₃ and allyl bromide (1-Bromo-1-propene) may be used to protect the hydroxyl group of the formula (8).

According to an exemplary embodiment of the present invention, by adding a lithium borohydride (LiBH ₄ ) or sodium borohydride (NaBH ₄ ), the compound of formula 10 may be prepared by reducing the carbonyl group in the compound of formula 9 with a hydroxyl group .

The pharmaceutically acceptable salt may be present as an acid addition salt in which the compound of Formula I forms a salt with the free acid. The compounds of formula (I) may form pharmaceutically acceptable acid addition salts according to conventional methods known in the art. The free acid may be an organic acid or an inorganic acid, and the inorganic acid may be hydrochloric acid, bromic acid, sulfuric acid, or phosphoric acid, and the organic acid may be citric acid, acetic acid, lactic acid, tartaric acid, or the like. ), Maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, galluxuronic acid, ambonic acid, Glutamic acid or aspartic acid, etc. can be used.

The pharmaceutically acceptable salt may be present as an inorganic salt of the compound of formula (I). The compounds of formula (I) may form pharmaceutically acceptable inorganic salts according to conventional methods known in the art. The inorganic salts include, but are not limited to, salts with aluminum, ammonium, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, or zinc, and ammonium, calcium, magnesium, potassium, or sodium salts are preferred. .

In addition, the compound of formula (I) according to the present invention may include not only pharmaceutically acceptable salts, but also all solvates including all salts and hydrates that may be prepared by conventional methods.

According to another embodiment of the present invention, 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative of formula (I), a pharmaceutically acceptable salt thereof, or solvate thereof Provided is a pharmaceutical composition for preventing or treating metabolic syndrome.

[Formula I]

In Chemical Formula I,

R ₁ is a hydrogen atom; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkyl group; Halogen atom; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkoxy group; A substituted or unsubstituted, straight or branched C ₁ -C ₄ thioalkyl group; Substituted or unsubstituted allyloxy group; Or a substituted or unsubstituted C ₆ -C ₁₂ aryloxy group;

R ₂ is a hydroxy group; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkyl group; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkoxy group; Or a substituted or unsubstituted allyloxy group;

R ₃ is a hydrogen atom, methyl, ethyl, methoxy or ethoxy;

R ₄ and R ₅ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group;

The dashed line is an optional double bond;

In the case of the substituted alkyl group, substituted alkoxy group, substituted thioalkyl group, substituted allyloxy group and substituted aryloxy group, the substituent is a halogen atom, straight or branched chain C ₁ -C ₅ alkyl group, straight or branched chain C ₁ -C ₅ An alkoxy group or a straight or branched C ₁ -C ₃ thioalkyl group.

According to an exemplary embodiment of the present invention, 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative of Formula I, a pharmaceutically acceptable salt thereof, or solvate thereof The pharmaceutical composition may be used for the prevention or treatment of metabolic syndrome including diabetes, obesity or complications thereof.

According to an exemplary embodiment of the present invention, in Chemical Formula I, R ₁ is methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, n-pentyl, 2-methylbutyl, 3-methyl Butyl, 2-ethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, or 2-ethylbutyl; R ₂ is a hydroxy group; R ₃ is a hydrogen atom; R ₄ and R ₅ may each be methyl.

Further, according to an exemplary embodiment of the present invention, in the general formula (I), wherein R ₁ is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-methylpropoxy, n-pentyloxy , 2-methylbutoxy, 3-methylbutoxy, 2-ethylpropoxy, n-hexyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, or 2-ethylbutoxy ; R ₂ is a hydroxy group; R ₃ is a hydrogen atom; R ₄ and R ₅ may each be methyl.

According to an exemplary embodiment of the present invention, the pharmaceutical composition comprising 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative of Formula I is chemically stable and prevents diabetes. And excellent effects in treatment. In addition, the pharmaceutical composition may have an excellent effect in the prevention and treatment of obesity.

According to an exemplary embodiment of the present invention, the 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative may be a compound of Formula II:

[Formula II]

In Chemical Formula II,

R ₁ is a hydrogen atom; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkyl group; Halogen atom; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkoxy group; A substituted or unsubstituted, straight or branched C ₁ -C ₄ thioalkyl group; Substituted or unsubstituted allyloxy group; Or a substituted or unsubstituted C ₆ -C ₁₂ aryloxy group;

R ₂ is a hydroxy group; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkyl group; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkoxy group; Or a substituted or unsubstituted allyloxy group;

R ₃ is a hydrogen atom, methyl, ethyl, methoxy or ethoxy;

R ₄ and R ₅ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group;

In the case of the substituted alkyl group, substituted alkoxy group, substituted thioalkyl group, substituted allyloxy group and substituted aryloxy group, the substituent is a halogen atom, straight or branched chain C ₁ -C ₅ alkyl group, straight or branched chain C ₁ -C ₅ An alkoxy group or a straight or branched C ₁ -C ₃ thioalkyl group.

According to an exemplary embodiment of the present invention, the 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative of Formula II may be any one of the following compounds:

<Compound II-1> <Compound II-2>

<Compound II-3> <Compound II-4>

<Compound II-5> <Compound II-6>

<Compound II-7> <Compound II-8>

<Compound II-9> <Compound II-10>

<Compound II-11> <Compound II-12>

<Compound II-13> <Compound II-14>

<Compound II-15> <Compound II-16>

<Compound II-17> <Compound II-18>

<Compound II-19> <Compound II-20>

<Compound II-21> <Compound II-22>

<Compound II-23> <Compound II-24>

<Compound II-25> <Compound II-26>

<Compound II-27> <Compound II-28>

<Compound II-29> <Compound II-30>

<Compound II-31> <Compound II-32>

<Compound II-33> <Compound II-34>

<Compound II-35> <Compound II-36>

<Compound II-37>

According to an exemplary embodiment of the present invention, the 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative may be a compound of Formula III:

[Formula III]

In Chemical Formula III,

R ₁ is a hydrogen atom; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkyl group; Halogen atom; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkoxy group; A substituted or unsubstituted, straight or branched C ₁ -C ₄ thioalkyl group; Substituted or unsubstituted allyloxy group; Or a substituted or unsubstituted C ₆ -C ₁₂ aryloxy group;

R ₂ is a hydroxy group; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkyl group; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkoxy group; Or a substituted or unsubstituted allyloxy group;

R ₃ is a hydrogen atom, methyl, ethyl, methoxy or ethoxy;

R ₄ and R ₅ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group;

In the case of the substituted alkyl group, substituted alkoxy group, substituted thioalkyl group, substituted allyloxy group and substituted aryloxy group, the substituent is a halogen atom, straight or branched chain C ₁ -C ₅ alkyl group, straight or branched chain C ₁ -C ₅ An alkoxy group or a straight or branched C ₁ -C ₃ thioalkyl group.

According to an exemplary embodiment of the present invention, the 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative of Formula III may be any one of the following compounds:

<Compound III-1> <Compound III-2>

<Compound III-3> <Compound III-4>

<Compound III-5> <Compound III-6>

<Compound III-7> <Compound III-8>

<Compound III-9> <Compound III-10>

<Compound III-11> <Compound III-12>

<Compound III-13> <Compound III-14>

<Compound III-15> <Compound III-16>

<Compound III-17> <Compound III-18>

<Compound III-19> <Compound III-20>

<Compound III-21> <Compound III-22>

<Compound III-23> <Compound III-24>

<Compound III-25> <Compound III-26>

<Compound III-27> <Compound III-28>

<Compound III-29> <Compound III-30>

<Compound III-31> <Compound III-32>

<Compound III-33> <Compound III-34>

<Compound III-35> <Compound III-36>

<Compound III-37>

The pharmaceutical composition may be formulated in conventional pharmaceutical formulations known in the art. The formulations may be formulated and administered in any of the formulations including, but not limited to, oral, injectable, suppository, transdermal, and non-administrative formulations, but preferably, oral formulations and injectables. Can be.

When formulated into each of the above formulations, it may be prepared by the addition of a pharmaceutically acceptable carrier necessary for the preparation of each formulation. The term "pharmaceutically acceptable carrier" is used herein to refer to any component except for the pharmaceutically active ingredient. "Pharmaceutically acceptable" means that it does not cause undesirable pharmacological changes by interacting with other constituents present in the composition (e.g., between carriers or between the pharmaceutically active ingredient and the carrier). It means nature. The choice of pharmaceutically acceptable carrier may depend on such factors as the carrier's effect on the nature, mode of administration, solubility and stability of the particular dosage form.

In one embodiment of the present invention, the pharmaceutically acceptable carrier included in the pharmaceutical composition for oral administration may be a diluent, a binder, a lubricant (or a lubricant), a disintegrant, a stabilizer, a dissolution aid, a sweetener, a colorant, a flavoring agent. It may be one or more selected from, but is not limited thereto.

Diluent refers to any excipient added to increase the volume of the composition to make it the appropriate size according to the formulation. The diluent may include starch (eg potato starch, corn starch, wheat starch, starch gelatinized starch), microcrystalline cellulose (eg low water microcrystalline cellulose), lactose (eg lactose monohydrate, Anhydrous lactose, spray lactose), glucose, sorbitol, mannitol, sucrose, alginate, alkaline earth metal salts, clay, polyethylene glycol and dicalcium phosphate, anhydrous calcium phosphate, silicon dioxide and the like may be used alone or as a mixture thereof. It is not limited. In the present invention, the excipient may be used in the range of 5% to 50% by weight based on the total amount of the pharmaceutical composition, and for example, 10% to 35% by weight based on the total amount of the composition for tableting and quality maintenance. have.

Binder refers to a material used to impart adhesion to powdery materials to facilitate compaction and improve flowability. The binder is starch, microcrystalline cellulose, highly dispersible silica, mannitol, lactose, polyethylene glycol, polyvinylpyrrolidone, cellulose derivatives (e.g., hydroxypropyl cellulose, hydroxypropyl cellulose, low substituted hydroxy) Propylcellulose), natural gums, synthetic gums, povidone, copovidone and gelatin may be one or more selected from, but is not limited thereto. In the present invention, the binder may be used in an amount of 2% by weight to 15% by weight based on the total amount of the pharmaceutical composition, and may be used, for example, in an amount of 1% by weight to 3% by weight, for tableting and quality maintenance.

Disintegrant refers to a substance that is added to facilitate the collapse or disintegration of a solid formulation after in vivo administration. The disintegrant is starch or modified starch such as sodium starch glycolate, corn starch, potato starch or starch gelatinized starch, clay such as bentonite, montmorillonite, veegum, microcrystalline cellulose, hydroxypropyl cellulose or Cellulose such as carboxymethyl cellulose, alginates such as sodium alginate or alginic acid, cross-linked cellulose such as croscarmellose sodium, gums such as guar gum, xanthan gum, cross-linked such as polyvinylpyrrolidone Effervescent agents such as polymers, sodium bicarbonate, citric acid may be used alone or in combination, but are not limited thereto. In the present invention, the disintegrant may be used in an amount of about 2 wt% to 15 wt% based on the total amount of the pharmaceutical composition, and for example, 4 wt% to 10 wt% for tableting and quality maintenance.

Glidant or lubricant refers to a material that performs the function of preventing the adhesion of powder to the compaction equipment and improving the flow of granules. The lubricant is hard silicic anhydride, talc, stearic acid, metal salt of stearic acid (such as magnesium salt or calcium salt), sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl bihenate, glyceryl mono Stearate or polyethylene glycol may be used alone or in combination, but is not limited thereto. In the present invention, the glidant may be used in an amount of 0.1% to 5% by weight based on the total amount of the pharmaceutical composition, for example, 1% to 3% by weight for tableting and quality maintenance.

The adsorbent may include, but is not limited to, hydrous silicon dioxide, hard silicic anhydride, colloidal silicon dioxide, magnesium metasilicate aluminate, microcrystalline cellulose, lactose, or crosslinked polyvinylpyrrolidone.

Stabilizers include antioxidants such as butylhydroxyanisole, butylhydroxytoluene, carotene, retinol, ascorbic acid, tocopherol, tocopherol polyethylene glycol succinic acid or propylgallate, cyclodextrin, carboxyethyl cyclodextrin, hydroxy Cyclic compounds of saccharides such as propyl cyclodextrin, sulfobutyl ether or cyclodextrin, organic acids such as phosphoric acid, lactic acid, acetic acid, citric acid, tartaric acid, succinic acid, maleic acid, fumaric acid, glycolic acid, propionic acid, gluconic acid or glucuronic acid It may be more than one species, but is not limited thereto.

Optionally, the pharmaceutical composition may include known additives to enhance taste and enhance palatability. For example, sweeteners such as sucralose, sucrose, fructose, erythritol, acesulfame potassium, sugar alcohols, honey, sorbitol or aspartame may be added to more effectively mask bitter taste and to ensure the stability and quality of the formulation. Can be maintained. In addition, citric acid, acidulants such as sodium citrate, natural flavors such as plum flavor, lemon flavor, pineapple flavor, herbal flavor, natural pigments such as natural fruit juice, chlorophyllin, flavonoids can be used.

The pharmaceutical composition for oral administration may be a solid preparation, a semisolid preparation or a liquid preparation for oral administration. Solid preparations for oral administration include, for example, tablets, pills, hard or soft capsules, powders, granules, granules, powders for reconstituting solutions or suspensions, lozenges, wafers, oral strips and dragees. And chewable gums, but are not limited thereto. Liquid preparations for oral administration include solutions, suspensions, emulsions, syrups, elixirs, spirits, fragrances, lemonades, extracts, precipitants, tinctures and pharmaceuticals. Semi-solid formulations include, but are not limited to, aerosols, creams, gels, and the like.

The pharmaceutical composition according to the present invention may be formulated as an injection, and when formulated as an injection, it may include a blood and isotonic non-toxic buffer as a diluent, for example, a phosphate buffer solution of pH 7.4. The pharmaceutical composition may include other diluents or additives in addition to the buffer solution.

The carriers and methods for the preparation of the formulations used in the above-mentioned formulations can be selected and prepared as is well known in the art and can be prepared, for example, according to the methods described in the latest edition of Remington's Pharmaceutical Science.

The dosage and timing of administration of the pharmaceutical composition according to the present invention may vary depending on the age, sex, condition, weight, route of administration, frequency of administration, and form of the subject. The daily dose is about 0.1 to 1000 mg / kg, preferably 1 to 100 mg / kg. The dosage may be appropriately increased or decreased depending on the type of disease, degree of cancer progression, route of administration, sex, age, weight, and the like.

In order to obtain the desired effect, the pharmaceutical composition according to the present invention may be administered in several divided doses so that the total daily dose is 0.1 to 1000 mg / kg as a compound as an active ingredient. The dosage may be appropriately increased or decreased depending on the type of disease to be treated or prevented, the extent of disease progression, administration route, sex, age, weight, health condition, and the like.

The pharmaceutical composition according to the present invention may contain the compound of formula I according to the present invention in an amount of about 0.0001 to 10% by weight, preferably 0.001 to 1% by weight, based on the total weight of the total composition.

Hereinafter, one or more embodiments will be described in more detail with reference to Examples. However, these examples are provided to illustrate one or more embodiments illustratively and the scope of the present invention is not limited to these examples.

Example 1: 4 -(8,8-dimethyl-2,8- Dihydropyrano [2,3- f ] Chrome -3-yl) benzene-1,3-diol {4- (8,8- dimethyl -2,8- dihydropyrano [2,3- f ] chromen -3- yl ) benzene-1,3- diol } (Compound II- 1)  synthesis

One- 1: 5 -(2- (2,4- Bisallyloxyphenyl )-2- Oxoethoxy ) -2,2-dimethyl-2 H - Chromen -6-carbaldehyde {5- (2- (2,4- bis (allyloxy) phenyl )-2- oxoethoxy ) -2,2- dimethyl -2H-chromene-6-carbaldehyde}

5-hydroxy-2,2-dimethyl -2 H - chromen-6-dehydrogenase Cavalli {5-hydroxy-2,2-dimethyl -2 H -chromene-6-carbaldehyde} 4.08 g (20.0 mmol) and 1- (2,4-bis (allyloxy) phenyl) -2-bromoethanone {1- (2,4-bis (allyloxy) phenyl) -2-bromoethanone} 6.20 g (20.0 mmol) was added to acetone (CH ₃ COCH ₃ ) Was dissolved in 20 ml, and then 2.76 g (20.0 mmol) of potassium carbonate (K ₂ CO ₃ ) was added thereto, and the mixture was stirred vigorously at room temperature for 12 hours. The reaction mixture was filtered to remove solids, then concentrated, and the concentrate was dissolved in 20 ml of ethyl acetate (CH ₃ COOC ₂ H ₅ ) again, washed with saturated brine, and then the organic solution layer was separated and sulfuric acid Dried over magnesium (MgSO ₄ ). After filtration to remove magnesium sulfate, the solution was concentrated and recrystallized with isopropyl alcohol (IPA), and 5- (2- (2,4-bisallyloxyphenyl) -2-oxoethoxy) -2 , 2-dimethyl-2H-chromen-6-carbaldehyde (5- (2- (2,4-bis (allyloxy) phenyl) -2-oxoethoxy) -2,2-dimethyl-2H-chromene-6-carbaldehyde } 7.46 g (16.3 mmol) were obtained (Yield: 81.4%).

¹ H-NMR (CDCl ₃ ): 10.285 (s, 1H), 8.044 (d, 1H, J = 8.8 Hz), 7.670 (d, 1H, J = 8.8 Hz), 6.734 (d, 1H, J = 10.0 Hz ), 6.666 (d, 1H, J = 8.4 Hz), 6.602 (dd, 1H, J = 8.4, 2.0 Hz), 6.452 (d, 1H, J = 2.0 Hz), 5.94-6.07 (m, 2H), 5.672 (d, 1H, J = 10.0 Hz), 5.26-5.45 (m, 4H), 5.210 (s, 2H), 4.56-4.60 (m, 4H) 1.459 (s, 6H).

¹³ C-NMR (CDCl ₃ ): 192.197, 188.798, 164.201, 160.142, 159.698, 158.858, 133.086, 132.238, 131.837, 130.328, 129.856, 122.594, 119.127, 118.378, 118.019, 116.418, 114.360, 113.310, 106.914, 866.744. , 69.588, 69.059, 28.064.

One- 2: 1 -(2,4- Bis (allyloxy) phenyl ) -2-((6- Hydroxymethyl ) -2,2-dimethyl-2H- Chromen -5-yl) oxy) ethanone {1- (2,4- bis (allyloxy) phenyl ) -2-((6- ( hydroxymethyl ) -2,2-dimethyl-2H-chromen-5-yl) oxy) ethanone}

5- (2- (2,4-bisallyloxyphenyl) -2-oxoethoxy) -2,2-dimethyl-2H-chromen-6-carbaldehyde obtained in Example 1-1 under a nitrogen atmosphere 7.46 g (16.3 mmol) was dissolved in 50 mL of tetrahydrofuran (THF), and then the solution was cooled to -78 ° C. Vigorously stirring the reaction solution, the L-Selectride ^® -THF 1.0 M solution, 10 ㎖ the reaction temperature in a maintained state to -78 ℃ was added slowly for 30 minutes. The reaction solution was further stirred at −78 ° C. for 30 minutes, and then stirred vigorously for 30 minutes while being slowly heated to room temperature. After the reaction solution was cooled to 0 ° C., 20 ml of concentrated brine was added slowly to terminate the reaction. The organic solution layer was separated, and the water layer was extracted once more using 20 ml of ethyl acetate and mixed with the organic solution layer. It was. The organic solution layer was dried over magnesium sulfate, and then concentrated by distillation under reduced pressure. The concentrate was separated by silica gel, and 1- (2,4-bis (allyloxy) phenyl) -2-((6-hydroxymethyl) -2,2-dimethyl-2H-chromen-5-yl) oxy 3.43 g (7.45 mmol) of ethanone were obtained (Yield: 74.5%).

¹ H-NMR (CDCl ₃ ): 8.048 (d, 1H, J = 8.4 Hz), 7.043 (d, 1H, J = 8.0 Hz), 6.602 (d, 1H, J = 10.0 Hz), 6.593 (dd, 1H , J = 8.4, 2.0Hz), 6.558 (d, 1H, J = 8.0Hz), 6.450 (d, 1H, J = 2.0Hz), 5.95 ~ 6.08 (m, 2H), 5.652 (d, 1H, J = 10.0 Hz), 5.27 to 5.62 (m, 4H), 5.216 (s, 2H), 4.631 (d, 2H, J = 6.8 Hz), 4.56 to 4.60 (m, 4H), 3.964 (t, 1H, J = 6.8 Hz), 1.430 (s, 6 H).

¹³ C-NMR (CDCl ₃ ): 194.330, 164.317, 160.321, 154.619, 153.784, 133.201, 132.202, 131.945, 130.248, 129.739, 126.183, 119.170, 118.384, 117.872, 117.699, 114.379, 111.991, 106.869, 99 75644. , 69.640, 69.049, 61.670, 27.446.

One- 3: 3 -(2,4- Bis (allyloxy) phenyl ) -8,8-dimethyl-2,8- Dihydropyrano [2,3- f ] Chrome  {3- (2,4- bis (allyloxy) phenyl ) -8,8- dimethyl -2,8- dihydropyrano [2,3- f ] chromene}

1- (2,4-bis (allyloxy) phenyl) -2-((6-hydroxymethyl) -2,2-dimethyl-2H-chromen-5-yl) obtained in Example 1-2 above 3.43 g (7.45 mmol) of oxy) ethanone was dissolved in 25 ml of acetonitrile (CH ₃ CN), and 2.81 g (8.20 mmo) of triphenylphosphine hydrobromide (Ph ₃ PHBr) was added little by little while stirring vigorously at room temperature. The prepared reaction solution was stirred vigorously at room temperature for 10 hours, concentrated by distillation under reduced pressure, and dissolved by adding 20 ml of ethanol to the concentrate, after which the solution was concentrated by distillation under reduced pressure and 20 ml of ethanol was added thereto. In the next step, 0.24 g (35 mmol) of sodium ethoxide (NaOEt) was added at room temperature with vigorous stirring, followed by stirring overnight at 35 ° C. to precipitate a solid. The solid was filtered and washed again with 20 ml of ethanol. The mixture was refluxed for 1 hour with stirring and further stirred for 1 hour while cooling to room temperature The resulting solid was filtered and the filtered solid was washed with cold ethanol at 0 ° C. The solid was thoroughly dried in vacuo 2.34 g (5.47 mmol) of 3- (2,4-bis (allyloxy) phenyl) -8,8-dimethyl-2,8-dihydropyrano [2,3- f ] chromen were obtained (Yield: 73.5%).

¹ H-NMR (CDCl ₃ ): 7.215 (d, 1H, J = 8.4 Hz), 6.823 (d, 1H, J = 8.0 Hz), 6.652 (d, 1H, J = 10.0 Hz), 6.47 to 6.52 (m , 3H), 6.372 (d, 1H, J = 8.0 Hz), 5.99 to 6.08 (m, 2H), 5.588 (d, 1H, J = 10.0 Hz), 5.427 (m, 1H, J = 10.8, 1.6 Hz) , 5.384 (m, 1H, J = 10.8, 1.6 Hz), 5.285 (m, 1H, J = 10.4, 1.6 Hz), 5.272 (m, 1H, J = 10.4, 1.6 Hz), 5.025 (s, 2H), 4.50-4.55 (m, 4H), 1.423 (s, 6H).

¹³ C-NMR (CDCl ₃ ): 159.446, 157.140, 153.358, 149.186, 133.079, 132.852, 129.281, 129.243, 128.742, 126.516, 121.552, 121.313, 117.848, 117.801, 116.945, 116.660, 109.557, 109.222,500. , 69.180, 68.947, 68.444, 27.811.

One- 4: 4 -(8,8-dimethyl-2,8- Dihydropyrano [2,3- f ] Chrome -3-yl) benzene-1,3- Dior  {4- (8,8-dimethyl-2,8-dihydropyrano [2,3- f ] chromen-3-yl) benzene-1,3-diol}

1 g of 3- (2,4-bis (allyloxy) phenyl) -8,8-dimethyl-2,8-dihydropyrano [2,3- f ] chromen obtained in Example 1-3 2.48 mmol) is dissolved in 30 ml of methanol, followed by 87 mg of tris (acetonitrile) cyclopentadienylruthenium (II) hexafluorophosphate} and 35 mg of quinaldic acid. After the addition, the mixture was heated to 65 ° C., stirred vigorously for 6 hours, concentrated by distillation under reduced pressure, and column separation. Then, recrystallized using 10 ml of chloroform, 4- (8,8-dimethyl-2,8-dihydropyrano [2,3- f ] chromen-3-yl) benzene-1,3-diol 0.71 g (22.0 mmol) was obtained. (Yield: 88.8%)

¹ H-NMR (DMSO-d6): 9.627 (s, 1H), 9.412 (s, 1H), 7.020 (d, 1H, J = 8.4 Hz), 6.860 (d, 1H, J = 8.0 Hz), 6.569 ( s, 1H), 6.539 (d, 1H, J = 10.0 Hz), 6.332 (s, 1H), 6.319 (d, 1H, J = 8.4 Hz), 6.245 (d, 1H, J = 8.0 Hz), 5.702 ( d, 1H, J = 10.0 Hz), 4.983 (s, 2H), 1.302 (s, 6H)

¹³ C-NMR (DMSO-d6): 158.90, 156.213, 152.459, 148.244, 129.874, 128.983, 128.747, 126.422, 119.221, 116.886, 115.985, 115.952, 108.845, 108.800, 106.847, 102.794, 75.807, 67.829, 27.456

Example  2: 4- (8,8-dimethyl-2,8-dihydropyrano [2,3- f ] Chromen-3-yl) -2-methylbenzene-1,3-diol {4- (8,8-dimethyl-2,8-dihydropyrano [2,3- f ] chromen-3-yl) -2-methylbenzene-1,3-diol} (Compound II- 2)  synthesis

2- 1: 5 -(2- (2,4- Bisallyloxy -3- Methylphenyl )-2- Oxoethoxy ) -2,2-dimethyl-2H- Chromen -6-carbaldehyde {5- (2- (2,4- bis ( allyloxy ) -3- methylphenyl )-2- oxoethoxy ) -2,2-dimethyl-2H-chromene-6-carbaldehyde}

In Example 1-1, 1- (2,4-bis (allyloxy) -3-methylphenyl) -2-bromoee instead of 1- (2,4-bis (allyloxy) phenyl) -2-bromoethanone 5- (2- (2,4-bisallyloxy-3-methylphenyl) -2-oxoethoxy) -2,2- using the same method except that 1.56 g (5.32 mmol) of tan temperature was used 3 g (6.69 mmol) of dimethyl-2H-chromen-6-carbaldehyde were obtained.

¹ H-NMR (DMSO-d6): 10.251 (s, 1H), 7.645 (d, 1H, J = 8.8 Hz), 7.562 (d, 1H, J = 8.8 Hz), 6.908 (d, 1H, J = 8.8 Hz), 6.697 (d, 1H, J = 8.8 Hz), 6.688 (d, 1H, J = 10.0 Hz), 5.84-6.09 (m, 2H), 5.866 (d, 1H, J = 10.0 Hz), 5.406 ( m, H), 5.345 (m, 1H), 5.316 (s, 2H), 5.273 (m, 1H), 5.183 (m, 1H), 4.653 (m, 2H), 4.313 (m, 2H), 2.082 (s , 3H), 1.412 (s, 6H).

¹³ C-NMR (DMSO-d6): 193.924, 188.828, 161.130, 159.043, 158.265, 157.399, 133.206, 133.170, 131.025, 129.428, 128.564, 122.579, 122.411, 119.726, 117.854, 117.419, 115.831, 114.831, 2.8.109. 79.918, 77.382, 68.701, 27.613, 9.195.

2- 2: 3 -(2,4- Vis ( Allyloxy ) -3- Methylphenyl ) -3-hydroxy-8,8-dimethyl-2,3- Dihydropyrano [2,3- f ] Chrome -4 (8H) -one {3- (2,4- bis ( allyloxy ) -3- methylphenyl ) -3-hydroxy-8,8-dimethyl-2,3-dihydropyrano [2,3- f ] chromen-4 (8H) -one}

6,7-dihydro-2-pentafluorophenyl -5 H - pyrrolo [2,1- c] -1,2,4- triazolo imidazolium tetrafluoro borate in {6,7-Dihydro-2-pentafluorophenyl- 0.075 g (0.206 mmol) of 5 H- pyrrolo [2,1- c ] -1,2,4-triazolium tetrafluoroborate} was dissolved in 10 ml of tetrahydrofuran (THF), followed by 0.018 g (0.177 triethylamine). mmol) was added and stirred at room temperature for 10 minutes. 5- (2- (2,4-bisallyloxy-3-methylphenyl) -2-oxoethoxy) -2,2-dimethyl-2H-chromen-6- obtained in the above solution and Example 2-1 A solution of 3 g (6.69 mmol) of carbaldehyde dissolved in 10 mL of THF was mixed and then refluxed with stirring for 15 h. The reaction solution was cooled in an ice bath with vigorous stirring for 1 hour, and the resulting solid was filtered, and the filtered solid was washed thoroughly with THF cooled to 0 ° C. The washed solid was subjected to 3- (2,4-bis (allyloxy) -3-methylphenyl) -3-hydroxy-8,8-dimethyl-2,3-dihydropyrano [2,3- under vacuum conditions. f ] 2.75 g (6.13 mmol) of chromen-4 (8H) -one were obtained (Yield: 91.7%).

¹ H-NMR (CDCl ₃ ): 7.744 (d, 1H, J = 8.8 Hz), 7.090 (d, 1H, J = 8.4 Hz), 6.548 (d, 1H, J = 10.0 Hz), 6.532 (d, 1H , J = 8.4Hz), 6.494 (d, 1H, J = 8.8Hz), 5.98 ~ 6.07 (m, 2H), 5.538 (d, 1H, J = 10.0Hz), 5.406 (dd, 1H, J = 12.8, 1.6 Hz), 5.363 (dd, 1H, J = 12.8, 1.6 Hz), 5.258 (dd, 1H, J = 10.8, 1.2 Hz), 5.196 (dd, 1H, J = 10.4, 1.2 Hz), 5.151 (d, 1H, J = 11.2 Hz, 4.493 (d, 2H, J = 5.2 Hz), 4.452 (dd, 1H, J = 12.0, 5.2 Hz), 4.247 (d, 1H, J = 11.2 Hz), 4.240 (dd, 1H, J = 12.0, 5.2 Hz, 4.065 (s, 1H), 2.149 (s, 3H), 1.434 (s, 3H), 1.419 (s, 3H).

¹³ C-NMR (CDCl ₃ ): 192.945, 159.624, 158.261, 157.589, 156.700, 133.753, 133.236, 128.592, 128.577, 125.558, 124.195, 120.843, 117.116, 117.004, 115.685, 113.454, 111.430, 109.125,106.755, 77.309. , 74.212,73.853, 68.876, 28.301, 28.256, 9.992.

2- 3: 3 -(2,4- Vis ( Allyloxy ) -3- Methylphenyl ) -8,8-dimethyl-2,8- Dihydropyrano [2,3- f ] Chrome  {3- (2,4- bis ( allyloxy ) -3- methylphenyl ) -8,8- dimethyl -2,8-dihydropyrano [2,3- f ] chromene}

3- (2,4-bis (allyloxy) -3-methylphenyl) -3-hydroxy-8,8-dimethyl-2,3-dihydropyrano [2,3] obtained in Example 2-2. f ) 2.75 g (6.13 mmol) of chromen-4 (8H) -one were dissolved in 15 mL of THF, followed by rinsing for 1 hour by adding 17 mL (1.0 M) of a lithium borohydride (LiBH ₄ ) -THF solution. It was refluxed with stirring. After the reaction solution was cooled to room temperature, 10 ml of concentrated brine was added to terminate the reaction, and the organic layer was separated. The water layer was extracted once more using 15 mL of THF and then mixed with the organic layer and thoroughly dried with a sufficient amount of magnesium sulfate. The clear solution from which magnesium sulfate was removed was concentrated under reduced pressure by distillation under reduced pressure.

Into a separate reaction vessel, 1.83 g (27.99 mmol) of powdered zinc (Zn) and 20 ml of THF were stirred vigorously, and 2.65 g (13.97 mmol) of titanium tetrachloride (TiCl ₄ ) was stirred at room temperature during stirring. The reaction mixture was refluxed for 1 hour by slow addition over time and then cooled to room temperature.

The THF solution concentrated in the 15 mL portion of the low valence titanium reaction mixture {Ti (0)} prepared by the above method was slowly added at room temperature for 30 minutes, and then stirred vigorously for 5 hours. Thereafter, 50 ml of water was slowly added to the reaction solution to terminate the reaction. Then, 100 ml of methylene chloride (CH ₂ Cl ₂ ) was extracted three times. The combined organic layers were combined, dried over a sufficient amount of magnesium sulfate, and the clear solution from which magnesium sulfate was removed was concentrated by distillation under reduced pressure. 20 mL of ethanol was added to the concentrate, and the mixture was refluxed with vigorous stirring for 1 hour, and then stirred at room temperature for 1 hour. The resulting solid was filtered off and the filtered solid was washed with ethanol at 0 ° C. and then thoroughly dried in vacuo to afford 3- (2,4-bis (allyloxy) -3-methylphenyl) -8,8-dimethyl 1.2 g (2.88 mmol) of -2,8-dihydropyrano [2,3- f ] chromen were obtained (Yield: 56.5%).

¹ H-NMR (CDCl ₃ ): 7.085 (d, 1H, J = 8.4 Hz), 6.827 (d, 1H, J = 8.4 Hz), 6.660 (d, 1H, J = 10.0 Hz), 6.628 (d, 1H , J = 8.4 Hz), 6.554 (s, 1H), 6.380 (d, 1H, J = 8.4 Hz), 5.99-6.11 (m, 2H), 5.593 (d, 1H, J = 10.0 Hz), 5.435 (m , 1H, J = 15.6, 1.6 Hz), 5.350 (m, 1H, J = 15.6, 1.6 Hz), 5.285 (m, 1H, J = 10.4, 1.6 Hz), 5.200 (m, 1H, J = 10.4, 1.6 Hz), 5.031 (s, 2H), 4.545 (m, 2H), 4.262 (m, 2H), 2.188 (s, 3H), 1.430 (s, 6H).

¹³ C-NMR (CDCl ₃ ): 157.435, 155.623, 153.493, 149.206, 133.722, 133.339, 129.322, 128.803, 126.529, 126.119, 125.208, 121.783, 120.622, 117.537, 117.116, 116.792, 116.614, 109.595, 109.218. 76.101. , 73.760, 69.001, 68.298, 27.866, 9.239.

2- 4: 4 -(8,8-dimethyl-2,8- Dihydropyrano [2,3- f ] Chrome -3-yl) -2-methylbenzene-1,3-diol {4- (8,8- dimethyl -2,8- dihydropyrano [2,3- f ] chromen -3- yl ) -2-methylbenzene-1,3-diol}

Using the same method as in Example 1-4, 3- (2,4-bis (allyloxy) -3-methylphenyl) -8,8-dimethyl-2,8- obtained in Example 2-3. dihydro-pyrano [2,3- f] by the reaction of chromene 1.2 g (2.88 mmol) 4- ( 8,8- dimethyl-2,8-dihydro-pyrano [2,3- f] chromen -3 0.47 g (1.40 mmol) of 2-yl) -2-methylbenzene-1,3-diol was obtained. (Yield: 48%)

¹ H-NMR (CDCl ₃ ): 9.658 (s, 1H), 9.447 (s, 1H), 6.888 (d, 1H, J = 8.4 Hz), 6.826 (d, 1H, J = 8.4 Hz), 6.657 (d , 1H, J = 10.0 Hz), 6.502 (s, 1H), 393 (d, 1H, J = 8.4 Hz), 6.386 (d, 1H, J = 8.4 Hz), 5.612 (d, 1H, J = 10.0 Hz ), 5.539 (s, 1H), 5.026 (s, 1H), 4.946 (s, 2H), 2.180 (s, 3H), 1.432 (s, 6H).

¹³ C-NMR (CDCl ₃ ): 154.348, 153.910, 152.010, 148.763, 129.649, 126.969, 126.642, 125.301, 122.820, 117.257, 116.350, 115.705, 110.695, 109.734, 109.511, 107.437, 76.281, 68.510, 27.826, 8.2.83.

Example 3: 2 - Chloro -4- (8,8-dimethyl-2,8- Dihydropyrano [2,3- f ] Chrome -3-yl) benzene-1,3-diol {2- chloro -4- (8,8- dimethyl -2,8- dihydropyrano [2,3- f ] chromen -3-yl) benzene-1,3-diol} (Compound II- 26)  synthesis

3- 1: 5 -(2- (2,4- Vis ( Allyloxy ) -3- Chlorophenyl )-2- Oxoethoxy ) -2,2-dimethyl-2H-chromen-6-carbaldehyde {5- (2- (2,4- bis ( allyloxy ) -3- chlorophenyl )-2- oxoethoxy ) -2,2-dimethyl-2H-chromene-6-carbaldehyde}

In Example 1-1, 1- (2,4-bis (allyloxy) -3-chlorophenyl) -2- instead of 1- (2,4-bis (allyloxy) phenyl) -2-bromoethanone 5- (2- (2,4-bis (allyloxy) -3-chlorophenyl) -2-oxoethoxy) using the same method except that 41.2 g (0.119 mol) of bromoethanone was used 50.2 g (0.107 mol) of -2,2-dimethyl-2H-chromen-6-carbaldehyde were obtained. (Yield: 89.9%)

¹ H-NMR (CDCl ₃ ): 10.231 (s, 1H), 7.813 (d, 1H, J = 8.8 Hz), 7.652 (d, 1H, J = 8.8 Hz), 6.828 (d, 1H, J = 8.8 Hz ), 6.689 (d, 1H, J = 10.0 Hz), 6.673 (d, 1H, J = 8.8 Hz), 5.95-6.11 (m, 2H), 5.683 (d, 1H, J = 10.0 Hz), 5.488 (m , H, J = 16.8, 1.6 Hz), 5.358 (m, 1H, J = 12.4, 1.2 Hz), 5.356 (m, 1H, J = 16.8, 1.6 Hz), 5.245 (m, 1H, J = 12.4, 1.2 Hz), 5.236 (s, 2H), 4.688 (m, 2H, J = 5.2, 1.6 Hz), 4.557 (m, 6.0, 1.2 Hz), 1.460 (s, 6H).

¹³ C-NMR (CDCl ₃ ): 193.143, 188.665, 159.692, 159.284, 158.117, 155.916, 132.000, 131.620, 130.599, 130.534, 129.396, 124.060, 122.535, 119.697, 118.546, 117.256, 116.155, 114.293, 113.442 393. , 75.259, 69.973, 28.121.

3- 2: 3 -(2,4- Vis ( Allyloxy ) -3- Chlorophenyl ) -3-hydroxy-8,8-dimethyl-2,3- Dihydropyrano [2,3- f ] Chrome -4 (8H) -one {3- (2,4- bis ( allyloxy ) -3- chlorophenyl ) -3-hydroxy-8,8-dimethyl-2,3-dihydropyrano [2,3- f ] chromen-4 (8H) -one}

5- (2- (2,4-bis (allyloxy) -3-chlorophenyl) -2-oxoethoxy) obtained in Example 3-1 using the same method as in Example 2-2. 5- (2,2-bis (allyloxy) -3-chlorophenyl) -3-hydroxy-8 by reacting 50.2 g (0.107 mol) of -2,2-dimethyl-2H-chromen-6-carbaldehyde 33.5 g (0.071 mol) of, 8-dimethyl-2,3-dihydropyrano [2,3- f ] chromen-4 (8H) -one were obtained. (Yield: 66.7%)

¹ H-NMR (CDCl ₃ ): 7.744 (d, 1H, J = 8.8 Hz), 7.165 (d, 1H, J = 8.4 Hz), 6.606 (d, 1H, J = 8.8 Hz), 6.539 (d, 1H , J = 10.0 Hz), 6.505 (d, 1H, J = 8.4 Hz), 6.027 (m, 2H), 5.553 (d, 1H, J = 10.0 Hz), 5.448 (dd, 1H, J = 17.2, 0.8 Hz ), 5.356 (dd, 1H, J = 17.2, 0.8 Hz), 5.298 (dd, 1H, J = 10.4, 0.8 Hz), 5.194 (dd, 1H, J = 10.4, 0.8 Hz), 5.097 (d, 1H, J = 11.6 Hz), 4.680 (dd, 1H, J = 11.6, 5.6 Hz), 4.567 (d, 2H, J = 5.2 Hz), 4.428 (dd, 1H, J = 11.6, 5.6 Hz), 4.229 (d, 1H, J = 11.6 Hz), 4.052 (s, 1H), 1.436 (s, 3H), 1.431 (s, 3H).

¹³ C-NMR (CDCl ₃ ): 192.126, 159.862, 157.589, 155.669, 154.610, 133.353, 132.350, 128.736, 128.631, 126.260, 125.898, 117.976, 117.700, 115.516, 113.212, 111.622, 109.150, 108.149,77.738, 74.216 , 73.790, 69.739, 28.299.

3- 3: 3 -(2,4- Vis ( Allyloxy ) -3- Chlorophenyl ) -8,8-dimethyl-2,8- Dihydropyrano [2,3- f ] Chrome  {3- (2,4- bis ( allyloxy ) -3- chlorophenyl ) -8,8- dimethyl -2,8-dihydropyrano [2,3- f ] chromene}

3- (2,4-bis (allyloxy) -3-chlorophenyl) -3-hydroxy-8,8- obtained in Example 3-2 using the same method as in Example 2-3. 3- (2,4-bis (allyloxy) -3- by reacting 33.5 g (0.071 mol) of dimethyl-2,3-dihydropyrano [2,3- f ] chromen-4 (8H) -one 10 g (0.022 mol) of chlorophenyl) -8,8-dimethyl-2,8-dihydropyrano [2,3- f ] chromen was obtained. (Yield: 32.1%)

¹ H-NMR (CDCl ₃ ): 7.144 (d, 1H, J = 8.4 Hz), 6.838 (d, 1H, J = 8.0 Hz), 6.721 (d, 1H, J = 8.4 Hz), 6.653 (d, 1H , J = 10.0 Hz), 6.576 (t, 1H, J = 1.2 Hz), 6.389 (d, 1H, J = 8.0 Hz), 6.01-6.11 (m, 2H), 5.603 (d, 1H, J = 10.0 Hz ), 5.479 (m, 1H, J = 17.2, 1.6 Hz), 5.350 (m, 1H, J = 15.6, 1.6 Hz), 5.327 (m, 1H, J = 9.6, 1.6 Hz), 5.220 (m, 1H, J = 10.4, 1.2 Hz), 5.019 (d, 2H, J = 1.2 Hz), 4.625 (m, 2H, J = 5.2, 1.6 Hz), 4.414 (m, 2H, J = 5.6, 1.2 Hz), 1.433 ( s, 6H).

¹³ C-NMR (CDCl ₃ ): 154.827, 153.835, 153.607, 149.272, 133.191, 132.470, 129.437, 127.462, 126.809, 126.763, 126.641, 122.920, 118.471, 118.020, 117.759, 116.508, 116.450, 109.6359.1 109.388, 109.388, 109.388. , 74.134, 69.905, 68.055, 27.900.

3- 4: 2 - Chloro -4- (8,8-dimethyl-2,8- Dihydropyrano [2,3- f ] Chrome -3-yl) benzene-1,3-diol {2- chloro -4- (8,8- dimethyl -2,8- dihydropyrano [2,3- f ] chromen -3-yl) benzene-1,3-diol}

Using the same method as in Example 1-3, 3- (2,4-bis (allyloxy) -3-chlorophenyl) -8,8-dimethyl-2,8 obtained in Example 3-3 2-chloro-4- (8,8-dimethyl-2,8-dihydropyrano [2,3- f ) by reacting 10 g (0.022 mol) of dihydropyrano [2,3- f ] chromen ] Chromen-3-yl) benzene-1,3-diol 5.5g (0.015mol) was obtained (Yield: 67%)

¹ H-NMR (CDCl ₃ ): 7.074 (d, 1H, J = 8.4 Hz), 6.824 (d, 1H, J = 8.0 Hz), 6.645 (d, 1H, J = 10.0 Hz), 6.617 (d, 1H , J = 8.4 Hz), 6.559 (s, 1H), 6.387 (d, 1H, J = 8.0 Hz), 5.601 (d, 1H, J = 10.0 Hz), 5.022 (s, 1H), 1.429 (s, 6H ).

¹³ C-NMR (CDCl ₃ ): 153.789, 151.390, 149.289, 149.044, 129.497, 127.047, 126.788, 122.807, 118.815, 116.481, 116.270, 109.665, 109.483, 108.153, 107.716, 76.236, 67.958, 27.826.

Example 4: 4 -(5,8,8- Trimethyl -2,8- Dihydropyrano [2,3- f ] Chrome -3-yl) benzene-1,3-diol {4- (5,8,8- trimethyl -2,8- dihydropyrano [2,3- f ] chromen -3- yl benzene-1,3-diol} (Compound II- 27)  synthesis

4- 1: 5 -(2- (2,4- Bis (allyloxy) phenyl )-2- Oxoethoxy ) -2,2,7- Trimethyl -2H- Chromen -6-carbaldehyde {5- (2- (2,4- bis (allyloxy) phenyl )-2- oxoethoxy ), 2,2,7-trimethyl-2H-chromene-6-carbaldehyde}

In Example 1-1, 5-hydroxy-2,2,7-trimethyl-2H-chromen-6-carbal instead of 5-hydroxy-2,2-dimethyl-2H-chromen-6-carbaldehyde 5- (2- (2,4-bis (allyloxy) phenyl) -2-oxoethoxy) -2,2,7 using the same method except that 0.6 g (2.74 mmol) of dehydration was used 0.65 g (1.45 mmol) of -trimethyl-2H-chromen-6-carbaldehyde was obtained. (Yield: 52.7%)

¹ H-NMR (CDCl ₃ ): 10.495 (s, 1H), 8.047 (d, 1H, J = 8.4 Hz), 6.655 (d, 1H, J = 10.0 Hz), 6.601 (dd, 1H, J = 8.4, 2.4Hz), 6.468 (s, 1H), 6.449 (d, 1H, J = 2.4Hz), 5.92 ~ 6.07 (m, 2H), 5.626 (d, 1H, J = 10.0Hz), 5.26 ~ 5.45 (m, 4H), 5.145 (s, 2H), 4.56-4.60 (m, 4H) 2.555 (s, 3H), 1.444 (s, 6H).

¹³ C-NMR (CDCl ₃ ): 192.012, 190.810, 164.176, 160.517, 160.112, 158.203, 143.516, 133.085, 132.226, 131.837, 129.714, 120.945, 119.000, 118.364, 117.990, 116.277, 115.912, 112.288, 106.897, 99.743. , 69.546, 69.041, 28.060, 21.835.

4- 2: 1 -(2,4- Bis (allyloxy) phenyl ) -2- (6- Hydroxymethyl ) -2,2,7- Trimethyl -2H-chromen-5-yl) oxy) ethanone {1- (2,4- bis (allyloxy) phenyl ) -2-((6- ( hydroxymethyl ) -2,2,7-trimethyl-2H-chromen-5-yl) oxy) ethenone}

5- (2- (2,4-bis (allyloxy) phenyl) -2-oxoethoxy) -2,2, obtained in Example 4-1 using the same method as in Example 1-2 above 1- (2,4-bis (allyloxy) phenyl) -2- (6-hydroxymethyl) -2,2 by reacting 0.65 g (1.45 mmol) of 7-trimethyl-2H-chromen-6-carbaldehyde 0.45 g (0.99 mmol) of 7, trimethyl-2H-chromen-5-yl) oxy) ethanone were obtained. (Yield: 68.9%)

¹ H-NMR (CDCl ₃ ): 8.034 (d, 1H, J = 8.4 Hz), 6.588 (dd, 1H, J = 8.4, 2.4 Hz), 6.548 (d, 1H, J = 10.0 Hz), 6.460 (s , 1H), 6.445 (d, 1H, J = 2.4 Hz), 5.98 to 6.09 (m, 2H), 5.582 (d, 1H, J = 10.0 Hz), 5.27 to 5.62 (m, 4H), 5.208 (s, 2H), 4.724 (b, 2H), 4.56-4.60 (m, 4H), 3.65 (b, 1H), 2.350 (s, 3H), 1.413 (s, 6H).

¹³ C-NMR (CDCl ₃ ): 194.479, 164.263, 160.291, 154.946, 153.118, 139.001, 133.202, 132.240, 132.014, 129.149, 124.568, 119.124, 118.403, 117.803, 114.027, 111.804, 106.836, 99.706, 80.882. 75. , 69.065, 56.913, 27.505, 19.436.

4- 3: 3 -(2,4- Bis (allyloxy) phenyl ) -5,8,8- Trimethyl -2,8- Dihydropyrano [2,3- f ] Chrome  {3- (2,4- bis (allyloxy) phenyl ) -5,8,8- trimethyl -2,8- dihydropyrano [2,3- f ] chromene}

1- (2,4-bis (allyloxy) phenyl) -2- (6-hydroxymethyl) -2,2, obtained in Example 4-2 using the same method as in Example 1-3. 0.4-g (0.99 mmol) of 7-trimethyl-2H-chromen-5-yl) oxy) ethanone was reacted to 3- (2,4-bis (allyloxy) phenyl) -5,8,8-trimethyl- 0.13 g (0.31 mmol) of 2,8-dihydropyrano [2,3- f ] chromen were obtained. (Yield: 31.2%)

¹ H-NMR (CDCl ₃ ): 7.242 (d, 1H, J = 8.0 Hz), 6.664 (s, 1H), 6.626 (d, 1H, J = 10.0 Hz), 6.511 (d, 1H, J = 8.0 Hz ), 6.489 (s, 1H), 6.263 (s, 1H), 5.99-6.10 (m, 2H), 5.529 (d, 1H, J = 10.0 Hz), 5.431 (d, 1H, J = 11.2 Hz), 5.388 (d, 1H, J = 11.2 Hz), 5.301 (d, 1H, J = 11.6 Hz), 5.272 (d, 1H, J = 11.6 Hz), 4.964 (s, 2H), 4.50 to 4.55 (m, 4H) , 2.258 (s, 3 H), 1.413 (s, 6 H).

¹³ C-NMR (CDCl ₃ ): 159.421, 157.138, 149.410, 134.858, 133.097, 132.850, 129.206, 128.309, 128.264, 121.730, 118.985, 117.849, 116.781, 115.606, 110.848, 107.573, 105.866, 100.458, 76.0118.9 69.177 , 68.033, 27.851, 18.771.

4- 4: 4 -(5,8,8- Trimethyl -2,8- Dihydropyrano [2,3- f ] Chrome -3-yl) benzene-1,3-diol {4- (5,8,8- trimethyl -2,8- dihydropyrano [2,3- f ] chromen -3- yl Synthesis of benzene-1,3-diol}

3- (2,4-bis (allyloxy) phenyl) -5,8,8-trimethyl-2,8-dihydro obtained in Example 4-3 using the same method as in Example 1-3. pyrano [2,3- f] chromene 0.13g (0.31 mmol) to afford 4 (5,8,8- trimethyl-2,8-dihydro-pyrano [2,3- f] chromen -3 reaction 20 mg (0.059 mmol) of benzene-1,3-diol were obtained. (Yield: 19.0%)

¹ H-NMR (DMSO-d6): 9.658 (s, 1H), 9.447 (s, 1H), 7.019 (d, 1H, J = 8.4 Hz), 6.696 (s, 1H), 6.549 (d, 1H, J = 10.0 Hz), 6.374 (d, 1H, J = 2.4 Hz), 6.294 (dd, 1H, J = 8.4, 2.4 Hz), 6.266 (s, 1H), 5.674 (d, 1H, J = 10.0 Hz), 4.950 (s, 2H), 2.243 (s, 3H), 1.380 (s, 6H).

¹³ C-NMR (DMSO-d6): 158.210, 156.191, 151.934, 148.533, 134.300, 128.928, 128.844, 116.605, 116.523, 116.175, 115.483, 110.516, 106.915, 106.875, 102.760, 75.773, 67.449, 27.483, 18.420.

Example  5 to Example  12

Using the same method as in Example 1, 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative represented by Chemical Formula II was prepared, and in Examples 5 to 12, H-NMR data and C-NMR data of the 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative represented by Formula II are shown in Table 1 below.

number Chemical structure ¹ H-NMR, ¹³ C-NMR (CDCl ₃ , δ) Example 5

(화합물 Ⅱ-30)

(Compound II-30) ¹ H-NMR (DMSO-d6): 9.843 (s, 1H), 7.223 (d, 1H, J = 7.2 Hz), 6.744 (s, 1H), 6.551 (d, 1H, J = 10.0 Hz), 6.467 ( s, 1H), 6.442 (d, 1H, J = 7.2 Hz), 6.273 (s, 1H), 5.681 (d, 1H, J = 10.0 Hz), 4.964 (s, 2H), 4.002 (q, 2H, J = 6.8 Hz), 2.249 (s, 3H), 1.383 (s, 6H), 1.347 (t, 3H, J = 6.8 Hz). ¹³ C-NMR (DMSO-d6): 159.216, 156.196, 152.101, 148.635, 134.515, 128.996, 128.909, 128.539, 118.025, 117.312, 116.168, 115.412, 110.605, 106.955, 105.539, 101.906, 75.848, 67.361, 62.971, 27.512 14.710. Example 6

(Compound II-31) ¹ H-NMR (DMSO-d6): 9.842 (s, 1H), 7.221 (d, 1H, J = 8.0 Hz), 6.748 (s, 1H), 6.554 (d, 1H, J = 10.0 Hz), 6.460 ( s, 1H), 6.449 (d, 1H, J = 8.0 Hz), 6.274 (s, 1H), 5.675 (d, 1H, J = 10.0 Hz), 4.969 (s, 2H), 3.900 (t, 2H, J = 6.8 Hz), 2.251 (s, 3H), 1.745 (m, 2H), 1.383 (s, 6H), 1.000 (t, 3H, J = 7.2 Hz). ¹³ C-NMR (DMSO-d6): 159.377, 156.201, 152.110, 148.641, 134.503, 128.972, 128.897, 128.543, 118.034, 117.297, 116.177, 115.415, 110.603, 106.964, 105.564, 101.970, 75.838, 68.881, 67.373, 27.73 22.078, 10.455. Example 7

(Compound II-32) ¹ H-NMR (DMSO-d6): 9.843 (s, 1H), 7.223 (d, 1H, J = 7.2 Hz), 6.744 (s, 1H), 6.551 (d, 1H, J = 10.0 Hz), 6.467 ( s, 1H), 6.442 (d, 1H, J = 7.2 Hz), 6.273 (s, 1H), 5.681 (d, 1H, J = 10.0 Hz), 4.964 (s, 2H), 4.002 (q, 2H, J = 6.8 Hz), 2.249 (s, 3H), 1.383 (s, 6H), 1.347 (t, 3H, J = 6.8 Hz). ¹³ C-NMR (DMSO-d6): 159.216, 156.196, 152.101, 148.635, 134.515, 128.996, 128.909, 128.539, 118.025, 117.312, 116.168, 115.412, 110.605, 106.955, 105.539, 101.906, 75.848, 67.361, 62.971, 27.512 14.710. Example 8

(Compound II-33) ¹ H-NMR (DMSO-d6): 9.842 (s, 1H), 7.221 (d, 1H, J = 8.0 Hz), 6.748 (s, 1H), 6.554 (d, 1H, J = 10.0 Hz), 6.460 ( s, 1H), 6.449 (d, 1H, J = 8.0 Hz), 6.274 (s, 1H), 5.675 (d, 1H, J = 10.0 Hz), 4.969 (s, 2H), 3.900 (t, 2H, J = 6.8 Hz), 2.251 (s, 3H), 1.745 (m, 2H), 1.383 (s, 6H), 1.000 (t, 3H, J = 7.2 Hz). ¹³ C-NMR (DMSO-d6): 159.377, 156.201, 152.110, 148.641, 134.503, 128.972, 128.897, 128.543, 118.034, 117.297, 116.177, 115.415, 110.603, 106.964, 105.564, 101.970, 75.838, 68.881, 67.373, 27.73 22.078, 10.455. Example 9

(Compound II-34) ¹ H-NMR (CDCl ₃ ): 7.099 (d, 1H, J = 8.0 Hz), 6.816 (d, 1H, J = 8.0 Hz), 6.778 (d, 1H, J = 8.0 Hz), 6.720 (s, 1H ), 6.645 (d, 1H, J = 10.0 Hz), 6.572 (s, 1H), 6.385 (d, 1H, J = 8.0 Hz), 5.605 (d, 1H, J = 10.0 Hz), 5.303 (s, 1H ), 5.011 (s, 2H), 2.599 (q, 2H, 7.6 Hz), 1.430 (s, 6H), 1.223 (t, 3H, J = 7.6 Hz). ¹³ C-NMR (CDCl ₃ ): 153.858, 152.814, 148.945, 145.788, 130.077, 128.040, 126.799, 126.739, 122.945, 122.213, 120.460, 116.432, 115.975, 115.319, 109.689, 109.453, 76.224, 68.260, 28.488, 27.815, 15.282 . Example 10

(Compound II-35) ¹ H-NMR (DMSO-d6): 9.589, 7.133 (d, 1H, J = 8.0 Hz), 6.882 (d, 1H, J = 8.0 Hz), 6.772 (d, 1H, J = 2.4 Hz), 6.643 ( dd, 1H, J = 8.0, 2.4 Hz, 6.542 (d, 1H, J = 10.0 Hz), 6.336 (d, 1H, J = 8.0 Hz), 5.740 (d, 1H, J = 10.0 Hz), 5.019 ( s, 2H), 2.459 (t, 2H, 7.2 Hz), 1.533 (m, 2H) 1.359 (s, 6H), 0.868 (t, 3H, J = 7.2 Hz). ¹³ C-NMR (DMSO-d6): 154.956, 152.793, 148.475, 143.132, 129.941, 128.833, 127.899, 126.753, 122.161, 120.756, 119.534, 116.679, 115.906, 115.692, 108.963, 108.859, 75.912, 67.693, 37.000 23.904, 13.701. Example 11

(Compound II-36) ¹ H-NMR (CDCl ₃ ): 7.087 (d, 1H, J = 8.0 Hz), 6.816 (d, 1H, J = 8.0 Hz), 6.758 (dd, 1H, J = 8.0, 1.6 Hz), 6.704 (d , 1H, J = 1.6 Hz, 6.646 (d, 1H, J = 10.0 Hz), 6.574 (t, 1H, J = 1.2 Hz), 6.385 (d, 1H, J = 8.0 Hz), 5.606 (d, 1H , J = 10.0 Hz), 5.314 (b, 1H), 5.010 (d, 2H, J = 1.2 Hz), 2.558 (t, 2H, J = 7.6 Hz), 1.592 (m, 2H), 1.442 (s, 6H ), 1.385 (m, 2H), 0.945 (t, 3H, J = 6.0 Hz). ¹³ C-NMR (CDCl ₃ ): 154.945, 152.770, 148.979, 144.487, 129.529, 127.937, 127.004, 126.743, 122.967, 122.188, 121.039, 116.459, 115.980, 115.875, 109.702, 109.467, 77.203, 76.220, 32.926, 29.702, 29.702, 29.702. , 22.690, 13.929. Example 12

(Compound II-37) ¹ H-NMR (DMSO-d6): 7.070 (d, 1H, J = 8.4 Hz), 6.807 (d, 1H, J = 8.4 Hz), 6.640 (d, 1H, J = 10.0 Hz), 6.528 (s, 1H), 6.513 (dd, 1H, J = 8.4, 2.4 Hz), 6.468 (d, 1H, J = 2.4 Hz), 6.383 (d, 1H, J = 8.4 Hz), 6.037 (m, 1H), 5.608 ( d, 1H, J = 10.0 Hz), 5.469 (s, 1H), 5.407 (m, 1H, J = 17.2, 2.8, 1.2 Hz), 5.291 (m, 1H, J = 10.4, 1.2 Hz), 4.978 (s , 2H), 4.511 (m, 2H, J = 5.2, 1.2 Hz), 1.430 (s, 6H). ¹³ C-NMR (DMSO-d6): 159.345, 153.970, 153.835, 148.836, 132.988, 128.776, 126.651, 122.581, 117.837, 117.700, 116.410, 115.914, 109.697, 109.471, 107.463, 102.488, 76.234, 68.875, 68.331.

Example 13: 4 -(8,8-dimethyl-2,8,9,10- Tetrahydropyrano [2,3- f ] Chrome -3-yl) benzene-1,3-diol {4- (8,8- dimethyl -2,8,9,10- tetrahydropyrano [2,3- f ] chromen -3-yl) benzene-1,3-diol} (Compound III- 1) of  synthesis)

13- 1: 3 -( Benzyloxy ) -4- (2-((6- Formyl -2,2-dimethyl-2H- Chromen -5 days) Oxy ) Acetyl) phenyl 2,4,6- Trimethylbenzenesulfonate  {3- ( benzyloxy ) -4- (2-((6- formyl -2,2-dimethyl-2H-chromen-5-yl) oxy) acetyl) phenyl 2,4,6- trimethylbenzenesulfonate } Manufacturing

3- (benzyloxy) -4- (2-bromoacetyl) phenyl 2,4,6 instead of 1- (2,4-bis (allyloxy) phenyl) -2-bromoethanone in Example 1-1 3- (benzyloxy) -4- (2-((6-formyl-2,2-dimethyl-2H-) using the same method except that 133.5 g (0.265 mol) of trimethylbenzenesulfonate was used. 82.6 g (0.131 mol) of chromen-5-yl) oxy) acetyl) phenyl 2,4,6-trimethylbenzenesulfonate was obtained (Yield: 49.6%).

¹ H-NMR (CDCl ₃ ): 10.085 (s, 1H), 7.914 (d, 1H, J = 8.8 Hz), 7.596 (d, 1H, J = 8.8 Hz), 7.26-7.32 (m, 5H), 6.989 (s, 2H), 6.813 (d, 1H, J = 2.0 Hz), 6.636 (d, 1H, J = 8.8 Hz), 6.540 (dd, 1H, J = 8.8, 2.0 Hz), 6.535 (d, 1H, J = 10.0 Hz), 5.574 (d, 1H, J = 10.0 Hz), 5.079 (s, 2H), 4.986 (s, 2H), 2.557 (s, 6H), 2.329 (s, 3H), 1.409 (s, 6H).

¹³ C-NMR (CDCl ₃ ): 192.772, 188.435, 159.612, 159.183, 158.038, 154.157, 144.331, 140.420, 134.526, 132.448, 131.905, 130.521, 130.412, 130.244, 128.787, 127.839, 123.220, 122.421, 115.952. , 113.325, 107.413, 81.715, 77.404, 71.445, 28.129, 22.734, 21.109.

13- 2: 3 -( Benzyloxy ) -4- (3-hydroxy-8,8-dimethyl-4-oxo-2,3,4,8- Tetrahydropyrano [2,3- f ] Chrome -3-yl) phenyl 2,4,6- Trimethylbenzenesulfonate  {3- (benzyloxy) -4- (3-hydroxy-8,8-dimethyl-4-oxo-2,3,4,8-tetrahydropyrano [2,3- f ] chromen-3-yl) phenyl 2,4,6- trimethylbenzenesulfonate } Manufacturing

3- (benzyloxy) -4- (2-((6-formyl-2,2-dimethyl-2H-chromen-) obtained in Example 13-1 using the same method as in Example 2-2. 5-yl) oxy) acetyl) phenyl 2,4,6-trimethylbenzenesulfonate 82.6 g (0.131 mol) is reacted to 3- (benzyloxy) -4- (3-hydroxy-8,8-dimethyl-4 72.6 g (0.116 mol) of -oxo-2,3,4,8-tetrahydropyrano [2,3- f ] chromen-3-yl) phenyl 2,4,6-trimethylbenzenesulfonate were obtained. (Yield: 89.2%)

¹ H-NMR (CDCl ₃ ): ¹ H-NMR (CDCl ₃ ): 7.618 (d, 1H, J = 8.8 Hz), 7.457 (d, 1H, J = 8.4 Hz), 7.18-7.26 (m, 5H), 6.970 (s, 2H), 6.636 (d, 1H, J = 2.0 Hz), 6.556 (d, 1H, J = 10.0 Hz), 6.518 (dd, 1H, J = 8.8, 2.0 Hz), 6.425 (d, 1H, J = 8.4 Hz), 5.569 (d, 1H, J = 10.0 Hz), 4.838 (s, 2H), 4.820 (d, 1H, J = 12.0 Hz), 4.238 (d, 1H, J = 12.0 Hz), 3.511 (s, 1H), 2.543 (s, 6H), 2.323 (s, 3H), 1.452 (s, 3H), 1.436 (s, 3H).

¹³ C-NMR (CDCl ₃ ): ¹³ C-NMR (CDCl ₃ ): 189.937, 159.572, 156.977, 156.266, 150.407, 143.897, 140.439, 135.291, 131.771, 130.626, 128.826, 128.787, 128.635, 128.453, 128.055, 127.369, 126.056, 115.611, 114.137, 113.322, 111.618, 109.139, 107.382, 77.603, 77.203, 74.212, 73.698, 70.959, 28.257, 28.183, 22.675, 21.089.

13- 3: 3 -Hydroxy-4- (3-hydroxy-8,8-dimethyl-4-oxo-2,3,4,8,9,10- Hexahydropyrano [2,3- f ] Chrome -3-yl) phenyl 2,4,6- Trimethylbenzenesulfonate  {3-hydroxy-4- (3-hydroxy-8,8-dimethyl-4-oxo-2,3,4,8,9,10-hexahydropyrano [2,3- f ] chromen-3-yl) phenyl 2,4,6- trimethylbenzenesulfonate } Manufacturing

3- (benzyloxy) -4- (3-hydroxy-8,8-dimethyl-4-oxo-2,3,4,8-tetrahydropyrano [2,3] obtained in Example 13-2. f ) 72.6 g (0.116 mol) of chroman-3-yl) phenyl 2,4,6-trimethylbenzenesulfonate was dissolved in 300 ml of THF, followed by the addition of 2.1 g of Pd / C at 2 atmospheres of hydrogen at room temperature. Agitation was stirred for 24 hours. The reaction was removed from the solid by column and then recrystallized with 500 ml of ethyl acetate (EthylAcetate) to give 3-hydroxy-4- (3-hydroxy-8,8-dimethyl-4-oxo-2,3,4, 48.3 g (0.089 mol) of 8,9,10-hexahydropyrano [2,3- f ] chromen-3-yl) phenyl 2,4,6-trimethylbenzenesulfonate were obtained. (Yield: 78%)

¹ H-NMR (CDCl ₃ ): 8.434 (b, 1H), 7.738 (d, 1H, J = 8.8 Hz), 6.951 (s, 2H), 6.760 (d, 1H, J = 8.8 Hz), 6.569 (d , 1H, J = 2.4 Hz, 6.554 (d, 1H, J = 8.8 Hz), 6.407 (dd, 1H, J = 8.8, 2.4 Hz), 4.807 (d, 1H, J = 11.2 Hz), 4.521 (s , 1H), 4.339 (d, 1H, J = 11.2 Hz), 2.605 (m, 2H), 2.550 (s, 6H), 2.307 (s, 3H), 1.782 (m, 2H), 1.359 (s, 3H) , 1.351 (s, 3 H).

¹³ C-NMR (CDCl ₃ ): 190.919, 162.291, 161.380, 157.453, 150.566, 143.839, 140.236, 131.834, 131.797, 127.358, 126.458, 122.219, 113.397, 112.077, 111.729, 109.357, 76.279, 74.006, 73.306, 31.448896 , 26.591, 22.659, 21.092, 16.258.

13- 4: 3 -( Allyloxy ) -4- (3-hydroxy-8,8-dimethyl-4-oxo-2,3,4,8,9,10- Hexahydropyrano [2,3- f ] Chrome -3-yl) phenyl 2,4,6-trimethylbenzenesulfonate {3- (allyloxy) -4- (3-hydroxy-8,8-dimethyl-4-oxo-2,3,4,8,9, 10-hexahydropyrano [2,3- f ] chromen-3-yl) phenyl 2,4,6- trimethylbenzenesulfonate } Manufacturing

3-hydroxy-4- (3-hydroxy-8,8-dimethyl-4-oxo-2,3,4,8,9,10-hexahydropyrano [2] obtained in Example 13-3 above. , 3- f] chromen-3-yl) phenyl, 6-trimethyl benzene sulfonate was dissolved 48.3g (0.089mol) in acetone (acetone) 600 ㎖ then, potassium carbonate (K ₂ CO to the solution ₃ ) 20 g (0.145 mol) was added, and 18.4 g (0.152 mol) of 3-Bromo-1-propene was slowly added dropwise, followed by vigorous reflux for 18 hours, Stirred. The reaction product was filtered to remove solids, and then concentrated. Then, 300 ml of methylene chloride and 300 ml of water were added thereto, shaken. The layers were separated, the methylene chloride layer was taken, the solvent was concentrated, and then, 300 ml of hexane was added. Recrystallization to give 3- (allyloxy) -4- (3-hydroxy-8,8-dimethyl-4-oxo-2,3,4,8,9,10-hexahydropyrano [2,3- f ] 47.6 g (0.082 mol) of chromen-3-yl) phenyl 2,4,6-trimethylbenzenesulfonate were obtained. (Yield: 91.8%)

¹ H-NMR (CDCl ₃ ): 7.685 (d, 1H, J = 8.8 Hz), 7.403 (d, 1H, J = 8.4 Hz), 6.970 (s, 2H), 6.551 (d, 1H, J = 2.0 Hz ), 6.497 (d, 1H, J = 8.4 Hz), 6.496 (d, 1H, J = 8.8 Hz), 5.71 to 5.81 (m, 1H), 5.201 (dd, 1H, J = 1.6, 17.2 Hz), 5.136 (dd, 1H, J = 1.2, 10.8 Hz), 4.874 (d, 1H, J = 11.8 Hz), 4.331 (m, 1H), 4.263 (d, 1H, J = 11.8 Hz), 3.581 (s, 1H) , 2.629 (t, 2H, J = 6.8 Hz), 2.550 (s, 6H), 2.318 (s, 3H), 1.782 (t, 2H, J = 6.8 Hz), 1.349 (s, 3H), 1.332 (s, 3H).

¹³ C-NMR (CDCl ₃ ): 190.364, 160.743, 160.173, 156.383, 150.290, 143.894, 140.429, 131.910, 131.765, 130.597, 128.599, 126.686, 126.310, 118.081, 114.099, 112.499, 112.176, 108.928, 107.598, 75.619, 73.989 , 73.592, 69.800, 31.663, 26.928, 26.503, 22.679, 21.063, 16.461.

13- 5: 3 -( Allyloxy ) -4- (8,8-dimethyl-2,8,9,10- Tetrahydropyrano [2,3- f ] Chrome -3-yl) phenyl 2,4,6- Trimethylbenzenesulfonate  {3- ( allyloxy ) -4- (8,8- dimethyl -2,8,9,10-tetrahydropyrano [2,3- f ] chromen-3-yl) phenyl 2,4,6-trimethylbenzenesulfonate}

3- (allyloxy) -4- (3-hydroxy-8,8-dimethyl-4-oxo-2,3, obtained in Example 13-4 using the same method as in Example 2-3 above 4 (8,9,10-hexahydropyrano [2,3- f ] chromen-3-yl) phenyl 2,4,6-trimethylbenzenesulfonate 47.6 g (0.082 mol) is reacted to react 3- (allyl Oxy) -4- (8,8-dimethyl-2,8,9,10-tetrahydropyrano [2,3- f ] chromen-3-yl) phenyl 2,4,6-trimethylbenzenesulfonate 28.3 g (0.052 mol) was obtained. (Yield: 63%)

¹ H-NMR (CDCl ₃ ): 7.166 (d, 1H, J = 8.4 Hz), 6.993 (s, 2H), 6.835 (d, 1H, J = 8.4 Hz), 6.533 (d, 1H, J = 2.0 Hz ), 6.531 (s, 1H), 6.496 (dd, 1H, J = 2.0, 8.4 Hz), 6.383 (d, 1H, J = 8.4 Hz), 5.89-5.99 (m, 1H), 5.333 (dd, 1H, J = 1.6, 17.2 Hz), 5.253 (dd, 1H, J = 1.6, 10.4 Hz), 4.978 (s, 1H), 4.387 (m, 2H), 2.660 (t, 2H, J = 6.8 Hz), 2.584 ( s, 6H), 2.334 (s, 3H), 1.780 (t, 2H, J = 6.8 Hz), 1.328 (s, 6H).

¹³ C-NMR (CDCl ₃ ): 156.532, 155.059, 151.969, 149.435, 143.855, 140.475, 132.233, 131.748, 130.631, 128.979, 127.259, 126.825, 125.296, 123.562, 118.180, 115.139, 114.247, 110.121, 109.121, 106.795. , 69.923, 68.006, 32.065, 26.674, 22.761, 21.075, 16.912.

13-6: 3- (allyloxy) -4- (8,8-dimethyl-2,8,9,10-tetrahydropyrano [2,3- f ] Chromen-3-yl) phenol {3- (allyloxy) -4- (8,8-dimethyl-2,8,9,10-tetrahydropyrano [2,3- f ] chromen-3-yl) phenol}

3- (allyloxy) -4- (8,8-dimethyl-2,8,9,10-tetrahydropyrano [2,3- f ] chromen-3-yl) obtained in Example 13-5 28.3 g (0.052 mol) of phenyl 2,4,6-trimethylbenzenesulfonate was dissolved in 200 ml of ethanol (Ethanol), and 80 ml of 1 N NaOH was added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated and dissolved in 200 ml of methylene chloride, 80 ml of aqueous ammonium chloride solution was added thereto, followed by neutralization by stirring. After separation of the layers, the reaction mixture was concentrated and recrystallized using 80 ml of hexane. 10.8 g (0.029 mol) of allyloxy) -4- (8,8-dimethyl-2,8,9,10-tetrahydropyrano [2,3- f ] chromen-3-yl) phenol were obtained. (Yield: 57.8%)

¹ H-NMR (DMSO-d6): 9.647 (s, 1H), 7.139 (d, 1H, J = 8.4 Hz), 6.876 (d, 1H, J = 8.4 Hz), 6.554 (s, 2H), 6.468 ( d, 1H, J = 2.0 Hz, 6.425 (dd, 1H, J = 2.0, 8.4 Hz), 6.328 (d, 1H, J = 8.4 Hz), 6.03-6.14 (m, 1H), 5.431 (dd, 1H , J = 1.6, 17.2 Hz), 5.299 (dd, 1H, J = 1.6, 10.4 Hz), 4.967 (s, 1H), 4.564 (d, 2H, J = 2.0 Hz), 2.599 (t, 2H, J = 6.8 Hz), 1.763 (t, 2H, J = 6.8 Hz), 1.294 (s, 6H).

¹³ C-NMR (DMSO-d6): 158.468, 156.873, 154.032, 151.047, 133.592, 128.972, 127.787, 124.855, 120.504, 118.274, 117.388, 115.189, 109.511, 108.561, 107.700, 100.405, 73.922, 68.530, 67.875, 31.433, 67.875 26.395, 16.574.

13- 7: 4 -(8,8-dimethyl-2,8,9,10- Tetrahydropyrano [2,3- f ] Chrome -3-yl) benzene-1,3-diol {4- (8,8- dimethyl -2,8,9,10- tetrahydropyrano [2,3- f ] chromen -3-yl) benzene-1,3-diol} (Compound III- 1) of  Produce

Using the same method as in Example 1-4, 3- (allyloxy) -4- (8,8-dimethyl-2,8,9,10-tetrahydropyrano [ Reaction of 8 g (0.022 mol) of 2,3- f ] chromen-3-yl) phenol to react 4- (8,8-dimethyl-2,8,9,10-tetrahydropyrano [2,3- f ] Chromen-3-yl) benzene-1,3-diol {4- (8,8-dimethyl-2,8,9,10-tetrahydropyrano [2,3- f ] chromen-3-yl) benzene-1 5.06 g (0.015 mol) of 3-diol were obtained.

^{1 1} H-NMR (DMSO-d6): 9.576 (s, 1H), 9.375 (s, 1H), 7.017 (d, 1H, J = 8.4 Hz), 6.819 (d, 1H, J = 8.4 Hz), 6.551 ( s, 1H), 6.336 (d, 1H, J = 2.4 Hz), 6.273 (d, 1H, J = 8.4 Hz), 6.241 (dd, 1H, J = 2.4, 8.4 Hz), 4.973 (s, 2H), 2.558 (t, 2H, J = 6.8 Hz), 1.719 (t, 2H, J = 6.8 Hz), 1.251 (s, 6H).

¹³ C-NMR (DMSO-d6): 158.036, 156.156, 153.837, 150.920, 128.672, 128.113, 124.723, 119.513, 116.213, 115.309, 109.383, 108.478, 106.794, 102.794, 73.852, 67.702, 31.472, 26.399, 16.578.

Example  14 to Example  16

Using the same method as in Example 13, 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative represented by Chemical Formula III was prepared. In Examples 14 to 16, H-NMR data and C-NMR data of the 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative represented by Formula III are shown in Table 2 below.

number Chemical structure ¹ H-NMR, ¹³ C-NMR (CDCl ₃ , δ) Example 14

(화합물 Ⅲ-30)

(Compound III-30) ¹ H-NMR (CDCl ₃ ): 7.068 (d, 1H, J = 8.4 Hz), 6.825 (d, 1H, J = 8.4 Hz), 6.543 (s, 1H), 6.497 (dd, 1H, J = 2.4, 8.4 Hz), 6.461 (d, 1H, J = 2.4 Hz), 6.397 (d, 1H, J = 8.4 Hz), 5.0434 (s, 1H), 4.986 (s, 2H), 4.015 (q, 2H, J = 7.2 Hz), 2.676 (t, 2H, J = 6.8 Hz), 1.796 (t, 2H, J = 6.8 Hz), 1.411 (t, 3H, J = 7.2 Hz), 1.341 (s, 6H). ¹³ C-NMR (CDCl ₃ ): 159.657, 155.106, 153.958, 151.415, 128.702, 125.829, 125.106, 122.771, 117.452, 114.449, 110.146, 109.272, 107.291, 102.068, 74.338, 68.351, 63.547, 32.071, 26.676, 16.911, 14.754 . Example 15

(Compound III-31) ¹ H-NMR (CDCl ₃ ): .062 (d, 1H, J = 8.4 Hz), 6.813 (d, 1H, J = 8.4 Hz), 6.531 (s, 1H), 6.489 (dd, 1H, J = 2.4 , 8.4 Hz), 6.447 (d, 1H, J = 2.4 Hz), 6.389 (d, 1H, J = 8.4 Hz), 5.537 (s, 1H), 4.981 (s, 2H), 3.884 (t, 2H, J = 6.8 Hz), 2.666 (t, 2H, J = 6.8 Hz), 1.74-1.96 (m, 4H), 1.331 (s, 6H), 1.020 (t, 3H, J = 7.2 Hz). ¹³ C-NMR (CDCl ₃ ): 159.829, 155.021, 153.989, 151.390, 128.716, 125.980, 125.092, 122.652, 117.476, 114.538, 110.127, 109.257, 107.274, 102.180, 74.344, 69.592, 68.332, 32.062, 26.658, 22.471, 16.902 , 10.465. Example 16

(Compound III-32) ¹ H-NMR (CDCl ₃ ): 9.590 (s, 1H), 7.100 (d, 1H, J = 8.4 Hz), 6.828 (d, 1H, J = 8.4 Hz), 6.669 (d, 1H, J = 1.6 Hz ), 6.628 (dd, 1H, J = 1.6, 8.4 Hz), 6.621 (s, 1H), 6.264 (d, 1H, J = 8.4 Hz), 4.980 (s, 2H), 2.47 to 2.58 (m, 4H) , 1.700 (t, 2H, J = 6.8 Hz), 1.230 (s, 6H), 1.121 (t, 3H, J = 7.2 Hz).

Experimental Example  1: Compound II- Of 1 (Example 1) Anti-obesity  Effect experiment

The anti-obesity effect of the compound II- 1 prepared in Example 1 was tested as follows.

Specifically, DIO (diet induced obesity) mice (Jackson Lab., USA), in which 5 to 6 week old C57BL / 6J mice were bred with high fat feed for 12 weeks or longer, were used. Compound II- 1 prepared in the control group and Example 1 was accurately weighed according to the dosage and placed in a 50 ml Falcon tube and added with an excipient (10% LM 2125 CS MCT solution) stored at room temperature, followed by vortex It was dissolved by stirring with a mixer. After sonication for about 10 minutes, and prepared to a prescribed concentration to prepare a stock solution (stock solution). After adding 0.5% MC aqueous solution as excipient to the prepared stock solution, lightly stirred with a vortex mixer, homogenized with homogenizer (PT-1600E, Kinematica, Switzerland) at 30,000 rpm for 3 minutes, and sonicated for 30 minutes. The final concentration was prepared. The prepared samples were administered to oral gavage once daily for 6 weeks using a disposable plastic syringe with a zonde for oral administration. The DIO mice were fed with high fat feed and weighed once a week for 4 weeks.

 The anti-obesity effect was calculated according to Equation 1 based on the measured data, and the results are shown in Table 3 below.

[Equation 1]

% Weight gain = {(weight after compound administration)-(weight before compound administration)} / (weight before compound administration) Х100

Experimental group Control group (DIO mouse) Example 1 Treatment Group (Compound II-1) Dose (mg / kg) 0 100mg / kg Week 0 1 week 2 weeks 3 weeks 4 Weeks Week 0 1 week 2 weeks 3 weeks 4 Weeks weight 40.2 39.5 41.4 43.5 44.8 39.7 36.4 34.9 34.7 34.2 Standard error 2.1 2.0 2.0 2.0 1.9 1.9 1.4 1.5 1.6 1.7 Number of individuals 5 5 Weight gain (%) 11.4% -13.9%

1 is a graph showing the weight gain of the mouse according to the administration period of the compound II-1 prepared in Example 1 of the present invention. Referring to Table 3 and Figure 1, when administering the compound II-1 prepared in Example 1 of the present invention, it was confirmed that the weight of the DIO mouse is reduced over time. On the other hand, the DIO control mice were confirmed to increase in weight over time. That is, the compound II-1 prepared in Example 1 of the present invention is excellent in the effect of inhibiting weight gain, it can be seen that the anti-obesity activity is excellent.

Experimental Example  2: compound II-1 ( Example  1), Compound II-2 ( Example  2), Compound II-27 (Example 4) Antidiabetic  Effect experiment

The antidiabetic effect of Compound II-1, Compound II-2 and Compound II-27 prepared in the above Examples was tested as follows.

Specifically, five-week-old C57BLKS / J- db / db male mice (Central Experimental Animal, South Korea) were purchased and purified for 2 weeks before being used for this experiment. A 50 ml tube was weighed (CP423S, Sartorius, Germany) according to the dosage for each of Compound II-1 prepared in Example 1, Compound II-2 prepared in Example 2 and Compound II-27 prepared in Example 4 And excipients (10% LM 2125 CS MCT solution) stored at room temperature were added and then stirred by vortex mixer to dissolve. After sonication for about 10 minutes, and prepared to a prescribed concentration to prepare a stock solution (stock solution). After adding 0.5% MC aqueous solution as excipient to the prepared stock solution, lightly stirred with a vortex mixer, homogenized with homogenizer (PT-1600E, Kinematica, Switzerland) at 30,000 rpm for 3 minutes, and sonicated for 30 minutes. It was prepared at a prescribed concentration. The prepared samples were administered to oral gavage once daily for 8 weeks using a disposable plastic syringe with a zonde for oral administration.

C57BLKS / J- db / db mice were bred as described above, fasting the mice for 14 to 16 hours on day 55 after administration, and then glucose (Lot No: SLBM9269V, Sigma-Aldrich, USA) at a dose of 2 g / kg Oral administration was performed by glucose tolerance test. Specifically, blood was collected from the tail vein a total of 7 times before glucose administration, 15 minutes after administration, 30 minutes after administration, 60 minutes after administration, 120 minutes after administration, 180 minutes after administration, and 240 minutes after administration. Then, blood glucose is measured by using two blood glucose meters (AGM-4000, Allmedicus Inc., Korea), and the average blood sugar, standard deviation, and standard error are calculated using the respective blood glucose measurements, and the results are shown in Table 4 below. Shown in

group Blood sugar (mg / dl) AUC (mg / dl / min) Minutes after glucose administration 0 15 30 60 120 180 240 Negative control group (0 mg / kg) Mean 514 778 797 761 714 644 566 2770 Standard Deviation (S.D.) 111 49 27 65 57 57 50 Standard error (S.E.) 42 18 10 24 22 22 19 41 Number of samples 7 7 7 7 7 7 7 7 Example 1 (150 mg / kg) Average 167 293 288 204 166 130 122 712 Standard Deviation 41 90 80 47 40 32 33 Standard error 14 30 27 16 13 11 11 53 Number of samples 9 9 9 9 9 9 9 9 Example 2 (150 mg / kg) Average 295 549 569 476 432 296 243 1595 Standard Deviation 90 133 165 155 167 120 123 Standard error 40 59 74 69 75 54 55 240 Number of samples 5 5 5 5 5 5 5 5 Example 4 (150 mg / kg) Average 181 275 247 193 161 122 92 659 Standard Deviation 61 121 120 84 86 84 30 Standard error 28 54 53 38 38 38 13 144 Number of samples 5 5 5 5 5 5 5 5

In addition, the blood concentration-time curve area (AUC) with respect to the blood glucose level at each measurement point was calculated and shown in FIG. 2.

Figure 2 is a graph showing the change in blood glucose of the mouse according to the elapsed time (min) after administration of the compounds prepared in Examples 1, 2 and 4 of the present invention. Specifically, FIG. 2 shows the blood glucose levels of the mice according to the elapsed time (min) after the administration of the compound performed in the mice 55 days after the administration of the compound prepared in Examples 1, 2 and 4 It is a change.

Referring to Table 4 and Figure 2, in the case of the mouse continuously administered the compound prepared in Example 1, Example 2 and Example 4 of the present invention, it was confirmed that the blood sugar is lower than the negative control (negative control) mice It was. In addition, as time passes after the administration of the compound, it was confirmed that the blood sugar level of the mouse is effectively reduced. In other words, Compounds II-1, Compounds II-2, and Compounds II-27 prepared in Examples of the present invention are excellent in lowering blood sugar and excellent in antidiabetic activity.

Experimental Example  3: Antidiabetic  Comparison of efficacy

Using the same method as Experimental Example 2, the C57BLKS / J- db / db mice were treated with a negative control group, Compound II-1, Compound II-2, and Compound II-27, respectively, once daily for 8 weeks, followed by four hours of fasting once a week. The antidiabetic effect was confirmed by measuring fasting blood glucose change, and the results of blood glucose measurement of db / db mice are shown in Table 5 and FIG. 3.

group Fasting Blood Sugar (mg / dl / min) Week 0 1 week 2 weeks 3 weeks 4 Weeks 5 Weeks 6 Weeks Week 7 8 Weeks Negative control group (0 mg / kg) Average 322 335 480 526 543 487 521 536 589 Standard error 22 22 52 26 26 15 24 24 32 Number of samples 7 7 7 7 7 7 7 7 7 Example 1 (150 mg / kg) Average 319 197 174 223 175 211 152 147 135 Standard error 19 19 9 21 19 26 14 13 13 Number of samples 9 9 9 9 9 9 9 9 9 Example 2 (150 mg / kg) Average 319 276 323 318 275 362 369 353 384 Standard error 34 56 58 65 55 64 72 61 93 Number of samples 5 5 5 5 5 5 5 5 5 Example 4 (150 mg / kg) Average 319 177 185 249 197 197 142 148 141 Standard error 20 30 37 57 75 52 33 41 40 Number of samples 5 5 5 5 5 5 5 5 5

Figure 3 is a graph showing the change in blood glucose of the mouse according to the administration period (week) of the compound prepared in Examples 1, 2 and 4 of the present invention.

Referring to Table 5 and Figure 3, it was confirmed that the blood glucose of the mice administered the compounds prepared in Examples 1, 2 and 3 of the present invention is lower than the negative control mouse blood glucose throughout the administration period. That is, it can be seen that the compound II-1, the compound II-2, and the compound II-27 prepared in the embodiment of the present invention are excellent in lowering blood sugar. In addition, in the case of the compound II-1 prepared in Example 1 and the compound II-27 prepared in Example 4 of the present invention, it was confirmed that the effect of lowering blood sugar was very excellent as the period elapsed. That is, it can be seen that the 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative having better antidiabetic effect can be prepared by appropriately adjusting the substituent in the compound II.

As described above, it can be confirmed that the 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative according to the present invention has excellent anti-diabetic and anti-obesity effects.

So far I looked at the center of the preferred embodiment for the present invention. Those skilled in the art will appreciate that the present invention can be implemented in a modified form without departing from the essential features of the present invention. Therefore, the disclosed embodiments should be considered in descriptive sense only and not for purposes of limitation. The scope of the present invention is shown in the claims rather than the foregoing description, and all differences within the scope will be construed as being included in the present invention.

Claims (15)

3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative of formula (I), a pharmaceutically acceptable salt thereof, or solvate thereof: [Formula I]

In Chemical Formula I, R ₁ is a hydrogen atom; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkyl group; Halogen atom; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkoxy group; A substituted or unsubstituted, straight or branched C ₁ -C ₄ thioalkyl group; Substituted or unsubstituted allyloxy group; Or a substituted or unsubstituted C ₆ -C ₁₂ aryloxy group; R ₂ is a hydroxy group; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkyl group; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkoxy group; Or a substituted or unsubstituted allyloxy group; R ₃ is a hydrogen atom, methyl, ethyl, methoxy or ethoxy; R ₄ and R ₅ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group; The dashed line is an optional double bond; In the case of the substituted alkyl group, substituted alkoxy group, substituted thioalkyl group, substituted allyloxy group and substituted aryloxy group, the substituent is a halogen atom, straight or branched chain C ₁ -C ₅ alkyl group, straight or branched chain C ₁ -C ₅ An alkoxy group or a straight or branched C ₁ -C ₃ thioalkyl group. The method of claim 1, R ₁ is methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 2-ethylpropyl, n-hexyl, 2-methyl Pentyl, 3-methylpentyl, 4-methylpentyl, or 2-ethylbutyl; R ₂ is a hydroxy group; R ₃ is a hydrogen atom; And R ₄ and R ₅ are methyl, respectively, 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative, a pharmaceutically acceptable salt thereof, or solvate thereof. The method of claim 1, R ₁ is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-methylpropoxy, n-pentyloxy, 2-methylbutoxy, 3-methylbutoxy, 2-ethyl Propoxy, n-hexyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, or 2-ethylbutoxy; R ₂ is a hydroxy group; R ₃ is a hydrogen atom; And R ₄ and R ₅ are methyl, respectively, 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative, a pharmaceutically acceptable salt thereof, or solvate thereof. The method of claim 1, The 3-phenyl-2,8-dihydro-pyrano [2,3- f] chroman, 3-phenyl-2,8-dihydro-pyrano chromene derivative is a compound of the formula Ⅱ [2,3- f] chroman Men derivatives, pharmaceutically acceptable salts thereof, or solvates thereof: [Formula II]

In Chemical Formula II, R ₁ is a hydrogen atom; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkyl group; Halogen atom; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkoxy group; A substituted or unsubstituted, straight or branched C ₁ -C ₄ thioalkyl group; Substituted or unsubstituted allyloxy group; Or a substituted or unsubstituted C ₆ -C ₁₂ aryloxy group; R ₂ is a hydroxy group; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkyl group; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkoxy group; Or a substituted or unsubstituted allyloxy group; R ₃ is a hydrogen atom, methyl, ethyl, methoxy or ethoxy; R ₄ and R ₅ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group; In the case of the substituted alkyl group, substituted alkoxy group, substituted thioalkyl group, substituted allyloxy group and substituted aryloxy group, the substituent is a halogen atom, straight or branched chain C ₁ -C ₅ alkyl group, straight or branched chain C ₁ -C ₅ An alkoxy group or a straight or branched C ₁ -C ₃ thioalkyl group. The method of claim 4, wherein The compound of formula II is 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative, a pharmaceutically acceptable salt thereof, or solvate thereof, which is any one of the following compounds:

<Compound II-1> <Compound II-2>

<Compound II-3> <Compound II-4>

<Compound II-5> <Compound II-6>

<Compound II-7> <Compound II-8>

<Compound II-9> <Compound II-10>

<Compound II-11> <Compound II-12>

<Compound II-13> <Compound II-14>

<Compound II-15> <Compound II-16>

<Compound II-17> <Compound II-18>

<Compound II-19> <Compound II-20>

<Compound II-21> <Compound II-22>

<Compound II-23> <Compound II-24>

<Compound II-25> <Compound II-26>

<Compound II-27> <Compound II-28>

<Compound II-29> <Compound II-30>

<Compound II-31> <Compound II-32>

<Compound II-33> <Compound II-34>

<Compound II-35> <Compound II-36>

<Compound II-37>. The method of claim 1, The 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative is 3-phenyl-2,8-dihydropyrano [2,3- f ] chrom, which is a compound represented by Formula III Men derivatives, pharmaceutically acceptable salts thereof, or solvates thereof: [Formula III]

In Chemical Formula III, R ₁ is a hydrogen atom; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkyl group; Halogen atom; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkoxy group; A substituted or unsubstituted, straight or branched C ₁ -C ₄ thioalkyl group; Substituted or unsubstituted allyloxy group; Or a substituted or unsubstituted C ₆ -C ₁₂ aryloxy group; R ₂ is a hydroxy group; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkyl group; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkoxy group; Or a substituted or unsubstituted allyloxy group; R ₃ is a hydrogen atom, methyl, ethyl, methoxy or ethoxy; R ₄ and R ₅ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group; In the case of the substituted alkyl group, substituted alkoxy group, substituted thioalkyl group, substituted allyloxy group and substituted aryloxy group, the substituent is a halogen atom, straight or branched chain C ₁ -C ₅ alkyl group, straight or branched chain C ₁ -C ₅ An alkoxy group or a straight or branched C ₁ -C ₃ thioalkyl group. The method of claim 6, The compound of formula III is 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative, a pharmaceutically acceptable salt thereof, or solvate thereof, which is any one of the following compounds:

<Compound III-1> <Compound III-2>

<Compound III-3> <Compound III-4>

<Compound III-5> <Compound III-6>

<Compound III-7> <Compound III-8>

<Compound III-9> <Compound III-10>

<Compound III-11> <Compound III-12>

<Compound III-13> <Compound III-14>

<Compound III-15> <Compound III-16>

<Compound III-17> <Compound III-18>

<Compound III-19> <Compound III-20>

<Compound III-21> <Compound III-22>

<Compound III-23> <Compound III-24>

<Compound III-25> <Compound III-26>

<Compound III-27> <Compound III-28>

<Compound III-29> <Compound III-30>

<Compound III-31> <Compound III-32>

<Compound III-33> <Compound III-34>

<Compound III-35> <Compound III-36>

<Compound III-37>. A pharmaceutical for the prevention or treatment of metabolic syndrome comprising 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative of formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof Composition: [Formula I]

In Chemical Formula I, R ₁ is a hydrogen atom; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkyl group; Halogen atom; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkoxy group; A substituted or unsubstituted, straight or branched C ₁ -C ₄ thioalkyl group; Substituted or unsubstituted allyloxy group; Or a substituted or unsubstituted C ₆ -C ₁₂ aryloxy group; R ₂ is a hydroxy group; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkyl group; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkoxy group; Or a substituted or unsubstituted allyloxy group; R ₃ is a hydrogen atom, methyl, ethyl, methoxy or ethoxy; R ₄ and R ₅ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group; The dashed line is an optional double bond; In the case of the substituted alkyl group, substituted alkoxy group, substituted thioalkyl group, substituted allyloxy group and substituted aryloxy group, the substituent is a halogen atom, straight or branched chain C ₁ -C ₅ alkyl group, straight or branched chain C ₁ -C ₅ An alkoxy group or a straight or branched C ₁ -C ₃ thioalkyl group. The method of claim 8, R ₁ is methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 2-ethylpropyl, n-hexyl, 2-methyl Pentyl, 3-methylpentyl, 4-methylpentyl, or 2-ethylbutyl; R ₂ is a hydroxy group; R ₃ is a hydrogen atom; And R ₄ and R ₅ is methyl, respectively. A pharmaceutical composition for preventing or treating metabolic syndrome. The method of claim 8, R ₁ is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-methylpropoxy, n-pentyloxy, 2-methylbutoxy, 3-methylbutoxy, 2-ethyl Propoxy, n-hexyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, or 2-ethylbutoxy; R ₂ is a hydroxy group; R ₃ is a hydrogen atom; And R ₄ and R ₅ is methyl, respectively. A pharmaceutical composition for preventing or treating metabolic syndrome. The method of claim 8, The 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative is a pharmaceutical composition for preventing or treating metabolic syndrome, which is a compound of Formula II: [Formula II]

In Chemical Formula II, R ₁ is a hydrogen atom; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkyl group; Halogen atom; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkoxy group; A substituted or unsubstituted, straight or branched C ₁ -C ₄ thioalkyl group; Substituted or unsubstituted allyloxy group; Or a substituted or unsubstituted C ₆ -C ₁₂ aryloxy group; R ₂ is a hydroxy group; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkyl group; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkoxy group; Or a substituted or unsubstituted allyloxy group; R ₃ is a hydrogen atom, methyl, ethyl, methoxy or ethoxy; R ₄ and R ₅ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group; In the case of the substituted alkyl group, substituted alkoxy group, substituted thioalkyl group, substituted allyloxy group and substituted aryloxy group, the substituent is a halogen atom, straight or branched chain C ₁ -C ₅ alkyl group, straight or branched chain C ₁ -C ₅ An alkoxy group or a straight or branched C ₁ -C ₃ thioalkyl group. The method of claim 11, The compound of Formula II is any one of the following compounds for the prevention or treatment of metabolic syndrome pharmaceutical composition:

<Compound II-1> <Compound II-2>

<Compound II-3> <Compound II-4>

<Compound II-5> <Compound II-6>

<Compound II-7> <Compound II-8>

<Compound II-9> <Compound II-10>

<Compound II-11> <Compound II-12>

<Compound II-13> <Compound II-14>

<Compound II-15> <Compound II-16>

<Compound II-17> <Compound II-18>

<Compound II-19> <Compound II-20>

<Compound II-21> <Compound II-22>

<Compound II-23> <Compound II-24>

<Compound II-25> <Compound II-26>

<Compound II-27> <Compound II-28>

<Compound II-29> <Compound II-30>

<Compound II-31> <Compound II-32>

<Compound II-33> <Compound II-34>

<Compound II-35> <Compound II-36>

<Compound II-37>. The method of claim 8, The 3-phenyl-2,8-dihydropyrano [2,3- f ] chromen derivative is a pharmaceutical composition for preventing or treating metabolic syndrome, which is a compound of Formula III: [Formula III]

In Chemical Formula III, R ₁ is a hydrogen atom; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkyl group; Halogen atom; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkoxy group; A substituted or unsubstituted, straight or branched C ₁ -C ₄ thioalkyl group; Substituted or unsubstituted allyloxy group; Or a substituted or unsubstituted C ₆ -C ₁₂ aryloxy group; R ₂ is a hydroxy group; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkyl group; A substituted or unsubstituted, straight or branched C ₁ -C ₆ alkoxy group; Or a substituted or unsubstituted allyloxy group; R ₃ is a hydrogen atom, methyl, ethyl, methoxy or ethoxy; R ₄ and R ₅ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group; In the case of the substituted alkyl group, substituted alkoxy group, substituted thioalkyl group, substituted allyloxy group and substituted aryloxy group, the substituent is a halogen atom, straight or branched chain C ₁ -C ₅ alkyl group, straight or branched chain C ₁ -C ₅ An alkoxy group or a straight or branched C ₁ -C ₃ thioalkyl group. The method of claim 13, A pharmaceutical composition for preventing or treating metabolic syndrome, wherein the compound of Formula III is any one of the following compounds:

<Compound III-1> <Compound III-2>

<Compound III-3> <Compound III-4>

<Compound III-5> <Compound III-6>

<Compound III-7> <Compound III-8>

<Compound III-9> <Compound III-10>

<Compound III-11> <Compound III-12>

<Compound III-13> <Compound III-14>

<Compound III-15> <Compound III-16>

<Compound III-17> <Compound III-18>

<Compound III-19> <Compound III-20>

<Compound III-21> <Compound III-22>

<Compound III-23> <Compound III-24>

<Compound III-25> <Compound III-26>

<Compound III-27> <Compound III-28>

<Compound III-29> <Compound III-30>

<Compound III-31> <Compound III-32>

<Compound III-33> <Compound III-34>

<Compound III-35> <Compound III-36>

<Compound III-37>. The method of claim 8, The metabolic syndrome is a pharmaceutical composition for the prevention or treatment of metabolic syndrome, including obesity, type 2 diabetes, hypertension, hyperlipidemia or their complications.

Images