HK1227863A1 - Pyranochromenyl phenol derivative, and pharmaceutical composition for treating metabolic syndrome or inflammatory disease - Google Patents

Abstract

The present invention discloses a pyran okra fiber isocresol derivative, its pharmaceutically acceptable salt, or its solvate. And, disclose a pharmaceutical composition comprising them for the prevention or treatment of metabolic syndrome or inflammatory diseases. This can effectively treat or prevent metabolic syndrome or inflammatory diseases, and its chemical properties are stable.

Description

Pyranookra celloisocresol derivative and pharmaceutical composition for treating metabolic syndrome or inflammatory disease

Technical Field

The present invention relates to a novel pyranookra fibroisocresol derivative compound that is effective for preventing or treating metabolic syndrome or inflammatory diseases and use of the compound for preventing or treating metabolic syndrome.

Background

There are more than 200 billion fat cells in a human body, and in the case where the energy supply of the human body is much larger than the energy demand, energy is stored in the fat cells as neutral fat, and then, in the case where the energy is exhausted, is decomposed into free fatty acids and glucose to be used as an energy source.

Obesity, which 30% to 40% of modern people have, occurs in the case of excessive energy storage due to imbalance of the above process, and is a phenomenon in which the size of fat cells becomes large or the number thereof increases. Recently, with economic development, improvement of living standard, improvement of sanitary environment, frequent intake of fast food and change of diet life mainly for meat have resulted in excessive heat energy storage in the body. This change in dietary life of modern people coupled with the decrease in caloric expenditure from exercise deficiency has induced a rapid increase in the obese population. Such obesity is highly correlated with metabolic syndrome, so that it is used to diagnose metabolic syndrome.

Metabolic syndrome (metabolic syndrome) is a concept conceptualizing a phenomenon in which risk factors of various cardiovascular diseases and type ii diabetes form a cluster with each other into one disease. This is a useful concept that can be generalized to account for insulin resistance and its associated complex and diverse metabolic disorders and clinical features, and refers to the syndrome of increased risk factors such as obesity, diabetes, fatty liver and hypertriglyceridemia. Thus, in the case of metabolic syndrome, the risk of cardiovascular disease or type ii diabetes is also increased. According to ATPIII of american NECP (National Cholesterol education program) published in 2001, metabolic syndrome can be judged when a patient exhibits more than 3 of the following risk factors: abdominal obesity with waist circumference of 40 inches (102 cm) in men and 35 inches (88 cm) in women; triglycerides (triglycerides) above 150 mg/dL; HDL cholesterol is 40mg/dL for male and below 50mg/dL for female; the blood pressure is above 130/85 mmHg; fasting plasma glucose (fastingglucose) is above 110 mg/dL.

Insulin resistance refers to a phenomenon in which, even if insulin is normally secreted in the body, the intracellular glucose supply action performed by insulin is not normally exerted, which is manifested in that glucose in blood cannot enter into cells to cause hyperglycemia symptoms, and cells cannot perform normal functions due to insufficient glucose to finally cause metabolic syndrome symptoms. The resulting diabetic symptoms are called type II diabetes (T2DM, non-insulin dependent diabetes mellitus: NIDDM) and are thus distinguished from type 1 diabetes (insulin dependent diabetes mellitus) which is caused by insulin deficiency. Therefore, the most preferred method of treating type ii diabetes is to improve insulin resistance so that insulin functions normally. Even in this case, almost no therapeutic agent for improving insulin resistance has been developed at present. Most of the second-type diabetes therapeutic agents currently in use or under development aim to further increase the amount of insulin secretion and supplement the insulin function lost by insulin resistance. However, if the insulin secretion amount in our body increases, obesity, inflammation and the like are obviously induced, and various side effects such as an increase in the incidence of cancer are accompanied, so if the problem of insulin resistance cannot be fundamentally improved, although a temporary normalization of blood glucose can be expected, health gradually deteriorates. Therefore, the current situation is that the social demand for a second type diabetes therapeutic agent capable of improving insulin resistance and normalizing blood glucose is increasing.

In addition, patent document 1 discloses the use of glabridin (glabridin) for preventing or treating metabolic syndrome including hyperlipidemia, fatty liver, abnormal glucose metabolism, diabetes, and obesity.

Glabridin is known to be effective in the prevention and treatment of hyperlipidemia, fatty liver, abnormal carbohydrate metabolism, diabetes, metabolic syndrome of obesity, anti-inflammatory action, anticancer action, and the like, but it has been difficult to develop a product using glabridin due to low chemical stability (low chemical stability) such that it is easily decomposed by sunlight, humidity, acidity, alkalinity, oxygen, heat, and the like (non-patent document 1).

According to the results of the present studies, leptin resistance and insulin resistance are important causes among the causes of obesity and type ii diabetes (T2DM), respectively, but a representative inventive mechanism causing these resistances is that signaling (signaling) processes in leptin receptor (leptin receptor) and Insulin Receptor (IR) cause problems, and these are closely linked to PTP1B (protein tyrosine phosphatase 1B; protein tyrosine phosphatase 1B) (non-patent document 2).

By virtue of the fact that the signaling processes of the most important hormones in our body, namely leptin (a signaling substance promoting food intake and energy expenditure) and insulin (a signaling substance promoting synthesis of lipids for carbohydrate absorption), are both related to PTP1B (protein tyrosine phosphatase 1B), which are related to energy storage, PTP1B is sufficiently spotlighted as the most important therapeutic target for obesity and diabetes. Also, in fact, after 2000 years when the mechanism of action on PTP1B was clearly determined, PTP1B has attracted the most attention as a pharmacological mechanism for treating type ii diabetes and cancer. That is, PTP1B inhibitors capable of arbitrarily controlling the activity of PTP1B are highly likely to be developed as therapeutic agents for obesity and type ii diabetes in which the activity of leptin and insulin is normalized by improving the resistance to leptin and insulin (non-patent documents 3 and 4).

According to the findings revealed by the results of various studies, PTP1B has been found to be closely related to various inflammatory diseases, cardiac diseases, Endoplasmic Reticulum Stress (Endoplasmic Reticulum Stress) diseases, breast cancer, prostate cancer, and the like, in addition to obesity and diabetes. As described above, PTP1B has attracted attention as an important fundamental therapeutic target for treating various chronic diseases that are generally recognized as adult diseases, as it is found that PTP1B is directly or indirectly associated with these diseases. Therefore, PTP1B is also referred to as the most basic and fundamental cause among causes forming various adult diseases (non-patent document 5).

[ Prior art documents ]

[ patent document ]

(patent document 1) International patent publication WO07/058480

[ non-patent document ]

Non-patent document 1, m.ao, Natural Product Communication 5(2010), 1907 to 1912.

(non-patent document 2) d.popov; biochem Biophys Res Commun.410(2011), 377-381.

(non-patent document 3) a.p.combs; med. chem.53(2010), 2333-2344.

(non-patent document 4) t.o.johnson, j.ermolieff, m.jirousek; nature Reviews1(2002), 696-709.

(non-patent document 5) m.feldhammer, n.uetani, d.miranda-Saavedra, m.l.tremblay; crit, rev, biochem, mol, biol.48(2013) 430-445.

Disclosure of Invention

Technical problem

The present invention aims to provide a novel pyranookra fiber isocresol derivative which has excellent anti-obesity, anti-diabetic and anti-inflammatory effects, is effective for the treatment of hyperlipidemia and the like, and is chemically stable under normal atmospheric conditions including oxygen and acidic or alkaline conditions.

It is also an object of the present invention to provide a pharmaceutical composition for preventing or treating metabolic syndrome or inflammatory diseases.

Technical scheme

In order to achieve the above object, according to an aspect of the present invention, there is provided a compound of the following formula (I), a pharmacologically acceptable (or "pharmacologically acceptable") salt thereof, or a solvate thereof.

[ chemical formula 1]

The meaning of each symbol in the above formula is as follows:

R¹is a hydrogen atom, a methyl group, a methoxy group or a halogen atom.

R²Is a hydrogen atom; substituted or unsubstituted, straight-chain or branched C₁-C₆An alkyl group; a halogen atom; substituted or unsubstituted, straight-chain or branched C₁-C₆An alkoxy group; or substituted or unsubstituted, straight or branched C₁-C₄A thioalkyl group.

R³And R⁴Each independently is a hydrogen atom or C₁-C₂An alkyl group.

For the substituted alkyl, substituted alkoxy and substituted thioalkyl groups, the substituent is a straight or branched chain C₁-C₅Alkyl, halogen, straight or branched C₁-C₅Alkoxy or straight or branched C₁-C₃A thioalkyl group.

According to another aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating metabolic syndrome or inflammatory diseases, comprising a compound of formula (I') as described below, a pharmacologically acceptable salt thereof, or a solvate thereof.

The meaning of each symbol in the above formula is as follows:

R¹is a hydrogen atom, a methyl group, a methoxy group or a halogen atom.

R²Is a hydrogen atom; a hydroxyl group; substituted or unsubstituted, straight-chain or branched C₁-C₆An alkyl group; a halogen atom; substituted or unsubstituted, straight-chain or branched C₁-C₆An alkoxy group; or substituted or unsubstituted, straight or branched C₁-C₄A thioalkyl group.

R³And R⁴Each independently is a hydrogen atom or C₁-C₂An alkyl group.

For the substituted alkyl, substituted alkoxy and substituted thioalkyl groups, the substituent is a straight or branched chain C₁-C₅Alkyl, halogen, straight or branched C₁-C₅Alkoxy, or straight or branched C₁-C₃A thioalkyl group.

Advantageous effects

The pharmaceutical composition comprising the pyrookra fiber isocresol derivative according to an embodiment of the present invention is effective and chemically stable in the treatment or prevention of metabolic syndrome or inflammatory diseases.

Drawings

FIG. 1 is a graph showing the results of PTP1B inhibition experiments for a pyrano-okra fiber metacresol (pyranochromenoyl phenol) derivative according to the present invention.

FIG. 2a is a photomicrograph (at 100X magnification) of H & E (hematoxylin and eosin) stained liver tissues of mice extracted by a dissection examination after final elimination after 6 weeks of administration of Compound 16 of the present invention. Figure 2b is a photomicrograph of a control group not administered compound 16.

FIG. 3a is a photomicrograph (200X magnification) of H & E (hematoxin and eosin; hematoxylin and eosin) stained liver tissues of mice extracted by a dissection after 6 weeks of administration of Compound 16 of the present invention after final elimination. Figure 3b is a photomicrograph of a control group not administered compound 16.

Fig. 4a is a photomicrograph (at 100-fold magnification) of liver tissue of mice, which was extracted by dissection after final elimination after 6 weeks of administration of compound 16 of the present invention, stained with lipid droplet-coated protein antibody (perilipin antibody). Figure 4b is a photomicrograph of a control group not administered compound 16.

Fig. 5a is a photomicrograph (200-fold magnification) of a lipid droplet-coated protein antibody (perilipin antibody) stained rat liver tissue extracted by a dissection after final elimination after 6 weeks of administration of compound 16 of the present invention. Figure 5b is a photomicrograph of a control group not administered compound 16.

Fig. 6 is a graph showing the results of an anti-inflammatory efficacy confirmation experiment of the iso-cresol derivatives of okra fiber according to the present invention.

Fig. 7 is a graph showing the stability of the pyrano-okra fiber isocresol derivative according to the present invention in an acidic solution.

Fig. 8 is a graph showing the stability of the pyrano-okra fiber isocresol derivative according to the present invention in an alkaline solution.

Detailed Description

The present invention will be described in more detail below.

All technical terms used in the present invention are used without other definitions in the meaning equivalent to those understood by practitioners having basic knowledge in the relevant fields of the present invention. Also, the scope of the present invention includes the preferred methods or samples described, as well as concepts similar or equivalent thereto. The entire contents of all publications cited as references in the present specification are incorporated herein by reference.

The pyranookra fiber isocresol (pyranochromenyl phenol) derivative according to an aspect of the present invention may be represented by formula 1 below.

[ chemical formula 1]

In the formula, the meanings of the respective symbols are as follows:

R¹is a hydrogen atom, a methyl group, a methoxy group or a halogen atom.

R²Is a hydrogen atom; substituted or unsubstituted straight or branched C₁-C₆An alkyl group; a halogen atom; substituted or unsubstituted straight or branched C₁-C₆An alkoxy group; or substituted or unsubstituted, linear or branched C₁-C₄A thioalkyl group.

R³And R⁴Each independently is a hydrogen atom or C₁-C₂An alkyl group.

For the substituted alkyl, substituted alkoxy and substituted thioalkyl groups, the substituents are halogen atoms, straight or branched C₁-C₅Alkyl, straight or branched C₁-C₅Alkoxy or straight or branched C₁-C₃A thioalkyl group.

The pyranookra fiber isocresol derivative according to an embodiment of the present invention has a superior effect in preventing or treating metabolic syndrome such as obesity, diabetes, hyperlipidemia, fatty liver, or inflammatory diseases, as well as a superior effect in chemical stability, compared to glabridin.

According to an embodiment of the present invention, in the formula (I), R is¹May be a hydrogen atom, R²Can be methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, 2-methoxyethyl, trifluoromethyl, fluorine, chlorine, bromine, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, n-pentoxy, methoxymethoxy, etc.

According to another embodiment of the invention, in said formula (I), in said R¹In the case of a halogen atom, it may be fluorine, chlorine or bromine.

According to another embodiment of the present invention, the compound of formula (I) may be 1 or more of the following compounds.

The compounds of formula (I) form salts with the free acids, and the pharmacologically useful salts may thus be present in the form of acid addition salts. The compounds of formula (I) may be formed into pharmaceutically acceptable acid addition salts by conventional methods well known in the art. The free acid may be an organic acid or an inorganic acid, the inorganic acid may be hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, or the like, and the organic acid may be citric acid (citric acid), acetic acid, lactic acid, tartaric acid (tartariac acid), maleic acid, fumaric acid (fumaric acid), formic acid, propionic acid (propionic acid), oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, galacturonic acid, pamoic acid, glutamic acid, aspartic acid, or the like.

The pharmacologically acceptable salts may be present as inorganic salts of the compounds of formula (I). The compounds of formula (I) may be formed into pharmaceutically acceptable inorganic salts by conventional methods well known in the art. The inorganic salt includes salts of aluminum, ammonium, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, zinc, or zinc, but is not limited thereto, and ammonium, calcium, or sodium salts are preferable.

Also, the compound of formula (I) according to the present invention includes not only pharmacologically useful salts but also all salts which can be produced by a conventional method and solvates including hydrates.

The method for producing the compound of formula (I) is not particularly limited, but may be a method for synthesizing (±) -glabridin (bull. korean chem. soc. 2007) (a method developed by the present inventors)28)481 to 484).

[ reaction formula 1]

In the reaction formula, OBz is benzoyloxy, Me is methyl, R₁、R₂As described above, P denotes a protecting group (protecting group) such as benzyl, methoxymethyl, trialkylsilyl, etc., DEAD denotes diethylAn azodicarboxylate. Wherein, in case P is benzyl, the deprotection process can be simultaneously performed during the additional reaction of hydrogen without arranging a special deprotection process.

It is obvious to those having basic knowledge in the field of organic chemistry that the compound of formula (I) can be produced by changing the substituents according to the production method of the above reaction formula 1 and the following examples. Although an example of the method for producing the compound of formula (I) is described in the present specification, a person having basic knowledge in the field of organic chemistry can produce the compound of formula (I) by a method different from the method described in the present specification by appropriately changing the starting materials, the reaction route, and the reaction conditions.

The pharmaceutical composition for preventing and treating metabolic syndrome diseases or treating inflammatory diseases according to another aspect of the present invention comprises: a compound represented by the following formula (I'), a pharmacologically acceptable salt thereof or a solvate thereof.

In the formula, the meanings of the respective symbols are as follows:

R¹is a hydrogen atom, a methyl group, a methoxy group or a halogen atom.

R²Is a hydrogen atom; a hydroxyl group; substituted or unsubstituted straight or branched C₁-C₆An alkyl group; a halogen atom; substituted or unsubstituted straight or branched C₁-C₆An alkoxy group; or substituted or unsubstituted, linear or branched C₁-C₄A thioalkyl group.

R³And R⁴Each independently is a hydrogen atom or C₁-C₂An alkyl group.

For the substituted alkyl, substituted alkoxy, and substituted thioalkyl groups, the substituent isStraight or branched C₁-C₅Alkyl, halogen, straight or branched C₁-C₅Alkoxy or straight or branched C₁-C₃A thioalkyl group.

According to an embodiment of the present invention, in the formula (I'), the R¹May be a hydrogen atom, R²Can be hydrogen atom, hydroxyl, substituted or unsubstituted straight chain or branched chain C₁-C₅Alkyl, straight or branched C₁-C₅Alkoxy, or straight or branched C₁-C₄A thioalkyl group.

According to another embodiment of the invention, in said formula (I'), said R¹May be a hydrogen atom, R²Can be methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, 2-methoxyethyl, trifluoromethyl, fluorine, chlorine, bromine, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, n-pentoxy, methoxymethoxy, etc.

According to a further embodiment of the invention, in said formula (I'), in said R¹In the case of a halogen atom, it may be fluorine, chlorine or bromine.

According to still another embodiment of the present invention, the compound of formula (I') may be 1 or more of the following compounds.

The metabolic syndrome may be one or more of obesity, diabetes, hyperlipidemia, and fatty liver. And, the diabetes may be type ii diabetes (T2 DM).

Also, the metabolic syndrome may be a complex disease of type ii diabetes and obesity.

In the present specification, "metabolic syndrome" refers to a disease that increases the risk of metabolic syndrome, and includes, for example, diseases with increased risk factors such as hypertriglyceridemia, fatty liver, diabetes, and obesity, but is not limited thereto.

The pharmaceutical composition according to an embodiment of the present invention is preferably used for preventing or treating the above-mentioned type II diabetes and obesity complex diseases.

And, the inflammatory disease may be rheumatoid arthritis; degenerative arthritis; and inflammatory diseases caused by asthma, allergy, diabetes or myocardial infarction.

The pharmaceutical composition may be formulated into conventional pharmaceutical preparations well known in the art. The preparation includes oral preparation, injection, suppository, transdermal preparation and nasal administration preparation, but can also be formulated into any preparation for administration, preferably into oral preparation and injection.

When formulated into the respective formulations, they can be manufactured by adding pharmaceutically acceptable carriers required in the formulation of the respective formulations. In the present specification, the term "pharmacologically acceptable carrier" is used for any constituent ingredient other than the pharmaceutically active ingredient. "pharmaceutically acceptable" refers to the property of not interacting with other constituent components present in the composition (e.g., the interaction of carriers with each other or between a pharmaceutically active ingredient and a carrier) to cause a pharmaceutically undesirable change. The choice of the pharmaceutically acceptable carrier may vary depending on such factors as the nature of the formulation to be administered, the mode of administration, the solubility and stability of the carrier.

In one embodiment, the pharmaceutically acceptable carrier included in the pharmaceutical composition for oral administration may be one or more selected from diluents, binders, glidants (or lubricants), disintegrants, stabilizers, dissolution aids, sweeteners, colorants, and flavors, but is not limited thereto.

Diluent (diluent) refers to any excipient added to increase the volume of the composition to form an appropriate size. The diluent may use starch (e.g., potato starch, corn starch, wheat starch, pregelatinized starch), microcrystalline cellulose (e.g., low-hydrated microcrystalline cellulose), lactose (e.g., lactose monohydrate, anhydrous lactose, spray lactose), glucose, sorbitol, mannitol, sucrose, alginate, alkaline earth metal salt, clay, polyethylene glycol, dicalcium carbonate, anhydrous dicalcium phosphate, silicon dioxide, etc., as a monomer or a mixture, but is not limited thereto. In the present invention, the excipient may be used in a range of 5 to 50% by weight relative to the total amount of the composition, and for formulation and quality maintenance, for example, 10 to 35% by weight relative to the total amount of the composition may be used.

The binder (binder) refers to a substance used for imparting tackiness to a powdery substance to make adhesion easier and improve fluidity. The binder may be one or more selected from starch, microcrystalline cellulose, highly dispersible silicon dioxide, mannitol, lactose, polyethylene glycol, polyvinylpyrrolidone, cellulose derivatives (e.g., hydroxypropylmethylcellulose, hydroxypropylcellulose having a low substitution degree), natural gums, synthetic gums, povidone, copovidone, and gelatin, but is not limited thereto. In the present invention, the binder may be used in a range of 2 to 15 wt% with respect to the total amount of the composition, and for formulation and quality maintenance, for example, 1 to 3 wt% may be taken with respect to the total amount of the composition.

A disintegrant (disintegrant) refers to a substance added to facilitate the collapse or disintegration of a solid preparation after in vivo administration. The disintegrating agent may be used by using one or a mixture of more of starch such as sodium starch glycolate, corn starch, potato starch, pregelatinized starch, modified starch, bentonite, montmorillonite, magnesium aluminum silicate (veegum), cellulose such as clay (clay), microcrystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, alginic acid such as sodium alginate or alginic acid, crosslinked cellulose such as sodium croscarmellose (croscarmellose), gum such as guar gum or xanthan gum, crosslinked polymer such as crospovidone, and effervescent agent such as sodium bicarbonate or citric acid, but is not limited thereto. In the present invention, the disintegrant may be used in a range of 2 to 15% by weight relative to the total amount of the pharmaceutical composition, for example, 4 to 10% by weight relative to the total amount of the composition.

A glidant (glidant) or lubricant (lubricant) refers to a substance that functions to prevent powder from sticking to the compression equipment and to improve flow. The slip agent may be used using one or a mixture of two or more of hard anhydrous silicic acid, talc, stearic acid, metal stearate (magnesium salt, calcium salt, etc.), sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monostearate, and polyethylene glycol, but is not limited thereto. In the present invention, the lubricant may be used in a range of 0.1 to 5% by weight relative to the total amount of the pharmaceutical composition, for example, 1 to 3% by weight may be taken relative to the total amount of the composition for formulation and quality maintenance.

The adsorbent (adsorbant) may be used using one or a mixture of more of hydrated silica, hard anhydrous silicic acid, colloidal silica, magnesium aluminate silicate, microcrystalline cellulose, lactose, or crosslinked polyvinylpyrrolidone, but is not limited thereto.

The stabilizer (stabilizer) can be selected from antioxidant such as butyl hydroxy anisole, butyl hydroxy toluene, carotene, retinol, ascorbic acid, tocopherol polyethylene glycol succinic acid, or propyl gallic acid; sugar cyclic compounds such as cyclodextrin, carboxyethyl cyclodextrin, hydroxypropyl cyclodextrin, sulfobutyl ether, and cyclodextrin; one or more 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, and glucuronic acid, but not limited thereto.

Optionally, well-known additives for enhancing aesthetics and palatability may be included. For example, sweeteners such as sucralose, sucrose, fructose, erythritol, acesulfame potassium, sugar alcohols, honey, sorbitol, or aspartame may be used to more effectively mask the bitter taste and maintain the stability and quality of the formulation. Also, acidulants such as citric acid, sodium citrate, etc.; natural spices such as plum, lemon, pineapple, and vanilla; natural fruit juice, chlorophyllin, flavonoid, etc.

The pharmaceutical composition for oral administration may be a solid preparation, a semi-solid preparation or a liquid preparation for oral administration. Solid preparations for oral administration include, but are not limited to, tablets, pills, hard or soft capsules, powders, granules, powders for reconstituting solutions or suspensions, troches, wafers, oral strip dragees (dragees), and chewing gums (chewable gum). Liquid formulations for oral administration include: solutions, suspensions, emulsions, syrups, elixirs, alcoholic preparations, aromatic water, lemon water, extracts, precipitants, tinctures and oily preparations. Semisolid formulations include, but are not limited to, aerosols, creams, gels, and the like.

The pharmaceutical composition according to the present invention may be formulated into an injection, and in the case of being formulated into an injection, may include a non-toxic buffer solution isotonic with blood as a diluent, for example, a phosphate buffer solution of ph7.4, etc. The pharmaceutical composition may include other diluents or additives in addition to the buffer solution.

The carriers used in the mentioned preparations and the preparation method of the preparations can be selected and manufactured according to techniques well known in the art, for example, according to the method described in Remington's Pharmaceutical Science (Remington's Pharmaceutical Science) latest edition.

The dosage and administration period of the pharmaceutical composition of the present invention may vary depending on the age, sex, disease type, condition, body weight, route of administration, frequency of administration, and form of the drug to be administered. The daily dose is 0.1-1000 mg/kg, and preferably 1-100 mg/kg. The dose can be increased or decreased as appropriate depending on the type of disease, the degree of cancer progression, the route of administration, sex, age, body weight, and the like.

In order to obtain the effect of preventing and treating metabolic syndrome, diabetes and obesity, the pharmaceutical composition of the present invention may be administered in any number of divided doses so that the total daily dose of the active ingredient compounds based on an adult is 0.1 to 1000 mg/kg. The dose can be increased or decreased as appropriate depending on the type of disease to be treated or prevented, the degree of progression of the disease, the route of administration, sex, age, body weight, health condition, and the like.

For the pharmaceutical composition according to the present invention, the compound of formula (I') according to the present invention may be contained in an amount of 0.0001 to 10% by weight, preferably 0.001 to 1% by weight, based on the total weight.

The present invention will be described in more detail below with reference to the following examples and experimental examples. It is only intended to aid in the understanding of the present invention and it is not intended to limit the scope of the present invention in any sense.

The reagents used in the production examples and examples were, unless otherwise indicated, of reagent grade purchased from Sigma Aldrich (Sigma-Aldrich).

Production example 1: preparation of glabridin

Commercially available glabridin is obtained by extracting glycyrrhiza (Licorice) and refining to a content level of 40% and refining by silica gel column chromatography to obtain pure glabridin.

Production example 2: production of Compound 1

Glabridin obtained in production example 1 is prepared in accordance with the literature (Archives of pharmaceutical research)32(2009)647 to 654) carrying out a hydrogenation reaction (H)₂Pd/C) to give 3",4" -dihydroglabridin (compound 1).

Production example 3: synthesis of 6-formyl-2, 2-dimethyl-2H-benzopyran-5-benzoic acid

According to [ Tetrahedron, 57(2001) ]5335-5338]Method (2) 5-hydroxy-2, 2-dimethyl-2H-benzopyran-6-carbaldehyde was prepared in 20ml of CH₂Cl₂After melting 2.04g (10.mmol), the mixture was stirred at room temperature for 5 hours while adding 1ml of TEA and 1.54g (11.0mmol) of benzoyl chloride. Thereto was added 10ml NaHCO₃After the aqueous solution was saturated and stirred for another 10 minutes, an aqueous layer and an organic layer were separated. 10ml of CH were used₂Cl₂The separated aqueous layer was re-extracted, and then mixed with the organic layer and MgSO₄Treated, then filtered and concentrated. The solid concentrated by the above method was recrystallized using isopropyl alcohol (IPA) to obtain pure 6-formyl-2, 2-dimethyl-2H-benzopyran-5-benzoic acid (8.1 mmol).

¹H-NMR(CDCl₃):9.92(s,1H),8.25(m,2H),7.71(d,1H),7.68(m,1H),7.55(t,2H),6.83(d,1H),6.38(d,1H),5.69(d,1H),1.49(s,6H)。

Production example 4: synthesis of methyl (2-methoxymethoxyphenyl) acetate

After 3.04g (20.0mmol) of 2-hydroxyphenylacetic acid was melted in 20ml of methanol, 1.0ml of concentrated sulfuric acid was added. After the reaction solution was allowed to flow through the column for 10 hours, the reaction solution was distilled under reduced pressure and concentrated. The concentrate was subjected to column chromatography to give 2.78g (16.7mmol) of methyl (2-hydroxyphenyl) acetate. This was melted again in 20ml of acetone and 2.8g (20.0mmol) of K were added₂CO₃Then, 2.40g (30.0mmol) of chloromethyl methyl ether (chloromethyl methyl ether) was added while vigorously stirring at room temperature for 30 minutes, followed by vigorous stirring overnight. Then, the reaction solution was filtered to remove solid components, the filtrate was distilled under reduced pressure and concentrated, and then silicon was usedThe concentrated solution was purified by gel column chromatography to obtain 2.56g (12.3mmol) of methyl (2-methoxymethoxybenzene) acetate.

¹H-NMR(CDCl₃):7.239(t,1H,J＝8.0Hz),7.201(d,1H,J＝8.0Hz),7.099(d,1H,J＝8.0Hz),6.973(t,1H,J＝8.0Hz),5.191(s,2H),3.687(s,3H),3.666(s,2H),3.459(s,3H)。

Production example 5: synthesis of methyl (2-benzyloxy-4-methylphenyl) acetate

In 30ml of CH₂Cl₂After 3.01g (20.0mmol) of 2'-hydroxy-4' -methylacetophenone (2'-hydroxy-4' -methylacetophenone) was melted, 5ml of a 15% aqueous NaOH solution and 1.0g of tetrabutylammonium bromide (tetrabutylammonium bromide) were added. The reaction solution was vigorously stirred while adding 3.42g (20.0mmole) of benzyl bromide, and then vigorously stirred overnight to effect a flow reversal. The reaction solutions were separated from each other using 20ml of CH₂Cl₂After one extraction, carrying CH₂Cl₂The layers were concentrated by distillation under reduced pressure. The concentrate was subjected to chromatography to give 3.89g (16.2mmol) of 2 '-benzyloxy-4' -methylacetophenone. After completely melting the mixture in 20ml of formaldehyde, 3ml of HClO was added to the solution₄And uniformly stirring at normal temperature. Then, 7.33g (16.5mmol) of thallium nitrate (Tl (NO) was gradually added thereto while vigorously stirring at room temperature for 30 minutes the reaction solution prepared by the above-mentioned method₃)₃·3H₂O), and then stirred at room temperature for another 1 hour. Then, 30ml of NaHCO was added to the reaction solution₃Saturated aqueous solution, followed by vacuum distillation to remove MeOH. 20ml of CH was added to the reaction solution₂Cl₂The organic layer was extracted and concentrated, and the concentrate was subjected to chromatography to give 3.70g (13.7mmol) of methyl (2-benzyloxy-4-methylphenyl) acetate.

¹H-NMR(CDCl₃):7.28～7.45(m,5H),7.088(d,1H,J＝8.0Hz),6.767(s,1H)6.761(d,1H,J＝8.0Hz),5.065(s,2H),3.644(s,2H),3.625(s,3H),2.334(s,3H)。

Production example 6: (2-benzyloxy-4-ethylphenyl) acetic acid methyl esterSynthesis of esters

In 150ml of CH₂Cl₂12.2g (100.0mmole) of 3-ethylphenol were melted and stirred, while 15ml of triethylamine were slowly added over 1 hour. 11.2g (220.0mmole) of anhydrous acetic acid (acetic anhydride) was slowly added to the ice bath for 1 hour, and then stirred vigorously for 2 hours. After 200ml of saturated brine was slowly added to the reaction mixture, the mixture was vigorously stirred for 10 minutes, and then the organic layer was separated, distilled under reduced pressure, and concentrated. 16.7g (110.0mmole) of anhydrous AlCl were added to specially prepared bottles₃Thereafter, the concentrated solution prepared in the above was slowly dropped while vigorously stirring with a mechanical stirrer (mechanical stirrer), and then vigorously stirring and heating were continued to 165 ℃ and then maintained in this state for 1 hour. After the reaction mixture was cooled to normal temperature, 500ml of saturated brine was slowly added to dissolve the reaction mixture in water to completely release. When the solid in the solution melted and completely disappeared, 500ml of CH was used₂Cl₂Extraction is carried out. The organic layer was concentrated by separation and thawed again in 150ml of CH₂Cl₂Then, 25ml of a 15% NaOH aqueous solution and 3.0g of tetrabutylammonium bromide (tetrabutylammonium bromide) were added. While the reaction solution was vigorously stirred, 18.82g (110.0mmole) of benzyl bromide (benzyl bromide) was added thereto, and the mixture was vigorously stirred overnight to conduct inversion. The reaction solutions were separated from each other and 50ml of CH was used₂Cl₂After extracting the water layer once, carrying CH₂Cl₂The layers were distilled together under reduced pressure and concentrated. The concentrate was distilled under high vacuum (155-160 ℃ C./0.01 mmHg) to obtain 18.70g (73.6mmol) of 2 '-benzyloxy-4' -ethylacetophenone. After fully dissolving the resulting solution in 10ml of methanol, 15ml of HClO was added to the solution₄And mixed at normal temperature. While vigorously stirring the reaction solution prepared by the above method at room temperature, 33.33g (75.0mmol) of Tl (NO) was slowly added over 60 minutes₃)₃·3H₂After O, the mixture was stirred again at room temperature for 5 hours. Then, vacuum distillation was performed to remove MeOH. 80ml of CH was added to the reaction mixture₂Cl₂Extracting the organic layer, concentrating, and refining the concentrated solution by silica gel column chromatographyThus, 17.86g (62.8mmol) of methyl (2-benzyloxy-4-ethylphenyl) acetate was obtained.

¹H-NMR(CDCl₃):7.28～7.45(m,5H),7.116(d,1H,J＝8.0Hz),6.787(m,2H),5.078(s,2H),3.649(s,2H),3.627(s,3H),2.630(q,2H,J＝8.0Hz),1.228(t,3H,J＝8.0Hz)。

Production example 7: synthesis of methyl (2-benzyloxy-4-propylphenyl) acetate

Methyl (2-benzyloxy-4-propylphenyl) acetate was obtained in the same manner as in production example 6 above, except that 15.22g (100 mmoles) of 3-propylphenol was used in place of 3-ethylphenol.

¹H-NMR(CDCl₃):7.28～7.45(m,5H),7.109(d,1H,J＝8.0Hz),6.764(d,1H,J＝8.0Hz)6.763(s,1H),5.073(s,2H),3.650(s,2H),3.627(s,3H),2.561(t,2H,J＝4.0Hz),1.628(m,2H),0.936(t,3H,J＝7.6Hz)。

Production example 8: synthesis of methyl (2-benzyloxy-4-butylphenyl) acetate

Methyl (2-benzyloxy-4-butylphenyl) acetate was obtained in the same manner as in production example 6 above, except that 3-butylphenol was used instead of 3-ethylphenol.

¹H-NMR(CDCl₃):7.30～7.43(m,5H),7.110(d,1H,J＝8.0Hz),6.768(d,1H,J＝8.0Hz),6.766(s,1H),5.079(s,2H),3.653(s,2H),3.632(s,3H),2.589(t,2H,J＝8.0Hz),1.588(m,2H),1.348(m,2H),0.925(t,3H,J＝7.4Hz)。

Production example 9: synthesis of methyl (2-benzyloxy-4, 5-dimethylphenyl) acetate

Methyl (2-benzyloxy-4, 5-dimethylphenyl) acetate was obtained by the same method as in production example 6 above, except that 3, 4-dimethylphenol was used instead of 3-ethylphenol.

¹H-NMR(CDCl₃):7.28～7.46(m,5H),7.007(s,1H),6.785(s,1H)5.083(s,2H),3.670(s,3H),2.272(s,3H),2.228(s,3H)。

Production example 10: synthesis of methyl (2-benzyloxy-4-methoxyphenyl) acetate

In 30ml of CH₂Cl₂After 4.9g (21.7mmol) of 2'-hydroxy-4' -methoxyacetophenone was melted, 5ml of a 15% NaOH aqueous solution and 1.0g of tetrabutylammonium bromide (tetrabutylammonium bromide) were added. While the reaction solution was vigorously stirred, 3.42g (20.0mmole) of benzyl bromide (benzylbromide) was added, and the mixture was vigorously stirred overnight while being changed to a stream. The reaction solutions were separated from each other and 20ml of CH was used₂Cl₂After extracting the water layer once, carrying CH₂Cl₂The layers were distilled together under reduced pressure and concentrated. The concentrate was purified by column chromatography to give 4.27g (15.8mmol) of 2 '-benzyloxy-4' -methoxyacetophenone. This was mixed again with 1.76g (20.0mmol) of morpholine (morpholinone) and 1.5g of sulfur, and the mixture was vigorously stirred at 160 ℃ overnight. After the reaction mixture was cooled to room temperature, 4.24g (11.4mmol) of 2- (2-benzyloxy) -4-methoxyphenyl) -1-morpholinoethanethione was obtained as it was by silica gel column chromatography. After adding the solution to 30ml of a NaOH saturated ethanol solution, the solution was changed over for 8 hours, and then concentrated hydrochloric acid was slowly added thereto to lower the pH to 1 or less while cooling the solution to 0 ℃. Then, it was distilled under reduced pressure to use 30ml of CH₂Cl₂And 20ml of water to melt the concentrated solid, and then the solid was separated again. Using a CH of 30m₂Cl₂After the aqueous layer was extracted again, they were concentrated together. After 20ml of formaldehyde was added to the concentrated solid and melted, the mixture was refluxed for 10 hours with 1ml of concentrated sulfuric acid added. The reaction solution was dissolved in 30m CH₂Cl₂Then, the residue was washed with brine, concentrated and purified by silica gel column chromatography to give methyl (2-benzyloxy-4-methoxyphenyl) acetate.

¹H-NMR(CDCl₃):7.27～7.43(m,5H),7.100(d,1H,J＝8.0Hz),6.511(d,1H,J＝2.0Hz),6.461(dd,1H,J＝8.0,2.0Hz),5.040(s,2H),3.763(s,3H),3.619(s,3H),3.605(s,2H)。

Production example 11: (2-benzyloxy-4-ethoxy)Phenyl) acetic acid methyl ester synthesis

Methyl (2-benzyloxy-4-ethoxyphenyl) acetate was obtained by the same method as that of preparation example 10 above, except that 2'-hydroxy-4' -ethoxyacetophenone was used instead of 2'-hydroxy-4' -methoxyacetophenone.

¹H-NMR(CDCl₃):7.28～7.45(m,5H),7.117(d,1H,J＝8.0Hz),6.546(d,1H,J＝2.4Hz)6.483(dd,1H,J＝8.0,2.4Hz),5.073(s,2H),4.028(q,2H,J＝6.8Hz),3.653(s,3H),3.635(s,2H),1.421(t,3H,J＝7.8Hz)。

Production example 12: synthesis of methyl (2-benzyloxy-4-propoxyphenyl) acetate

Methyl (2-benzyloxy-4-propoxyphenyl) acetate was obtained by the same method as that of the above production example 11, except that 2'-hydroxy-4' -propoxylacetophenone was used instead of 2'-hydroxy-4' -methoxyacetophenone.

¹H-NMR(CDCl₃):7.28～7.45(m,5H),7.098(d,1H,J＝8.0Hz),6.538(d,1H,J＝2.4Hz)6.469(dd,1H,J＝8.0,2.4Hz),5.055(s,2H),3.898(t,2H,J＝6.4Hz),3.632(s,3H),3.616(s,2H),1.795(m,2H),1.033(t,3H,J＝6.8Hz)。

Production example 13: synthesis of methyl (2-benzyloxy-4-butoxyphenyl) acetate

Methyl (2-benzyloxy-4-butoxyphenyl) acetate was obtained by the same method as in production example 11 above, except that 2'-hydroxy-4' -butoxyacetophenone was used instead of 2'-hydroxy-4' -methoxyacetophenone.

¹H-NMR(CDCl₃):7.28～7.45(m,5H),7.083(d,1H,J＝8.0Hz),6.518(d,1H,J＝2.0Hz)6.456(dd,1H,J＝8.0,2.0Hz),5.040(s,2H),3.925(t,2H,J＝6.4Hz),3.618(s,3H),3.602(s,2H),1.746(m,2H),1.475(m,2H),0.975(t,3H,J＝7.2Hz)。

Production example 14: synthesis of 6-formyl-2, 2-diethyl-2H-benzopyran-5-benzoic acid

In the process for synthesizing 5-hydroxy-2, 2-dimethyl-2H-benzopyran-6-carbaldehyde, 6-formyl-2, 2-diethyl-2H-benzopyran-5-benzoic acid was obtained in the same manner as in production example 3, except that 3-ethyl-2-pentenol (3-ethylpent-2-enal) was used instead of 3-methylbutenal (3-methylbutenal), based on the method of reference [ Tetrahedron, 57(2001), 5335 to 5338] referred to in production example 3.

¹H-NMR(CDCl₃):9.893(s,1H),8.251(m,2H),7.688(d,1H,J＝8.4Hz),7.686(m,1H),7.551(t,2H,J＝7.2Hz),6.813(d,1H,J＝8.4Hz),6.496(d,1H,J＝10.2Hz),5.544(d,1H,J＝10.2Hz),1.804(m,2H),1.657(m,2H),0.949(t,6H)。

Compounds 2 to 23 were produced according to the following reaction formulae.

The order of the hydrogenation reaction and the deprotection process may be changed as necessary. Also, in the case where the protecting group is benzyl or substituted benzyl, the hydrogenation reaction and the process of deprotecting may be carried out simultaneously, and thus there is no need to distinguish a specific process.

Example 1: 3- (2-hydroxyphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f]Benzopyrazine Synthesis of pyran (Compound 2)

(1)2- (2- (methoxymethoxy) phenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) Production of methyl acrylate

The 3-neck round-bottom flask was cooled to-78 ℃ using a dry ice-acetone bath under a nitrogen atmosphere. After adding 45ml of a 1.0M solution of Lithium Diisopropylamide (LDA) in THF, a solution of 6.30g (30.0mmol) of methyl (2-methoxymethoxyphenyl) acetate prepared in production example 4 in 100ml of THF was slowly added over 30 minutes, and then stirred for another 30 minutes.

To the reaction solution was added the following solution slowly over 30 minutes and stirred for another 30 minutes, and 9.24g (30.0mmol) of a solution of 5-benzoyl-2, 2-dimethyl-6-formyl-2H-1-benzopyran prepared in preparation example 3 was dissolved in 20ml of THF solution. After the round bottom flask was removed from the dry ice-acetone bath, heating was performed to slowly raise the temperature of the reaction solution to 0 ℃. In this state, 100ml of brine was added to the reaction solution, followed by vigorous stirring at room temperature for 30 minutes. After separating the organic layer, the aqueous layer was extracted again with 100ml of ethyl acetate. The organic layer extracted from ethyl acetate by the above method and the organic layer separated above were combined and dried over anhydrous sodium sulfate, and then concentrated by distillation under reduced pressure. This concentrated solution was purified by silica gel column chromatography to obtain 5.16g (13.02mmol) of methyl2- (2- (methoxymethoxy) phenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate (Yield: 43%).

¹H-NMR(CDCl₃):8.007(s,1H),7.293(td,1H,J＝8.0,1.6Hz),7.170(d,1H,J＝8.0Hz),7.035(dd,1H,J＝7.6,1.6Hz),6.940(t,1H,J＝7.6Hz),6.605(d,1H,J＝10.0Hz),6.603(d,1H,J＝8.8Hz),6.147(d,1H,J＝8.8Hz),6.136(s,1H),5.536(d,1H,J＝10.0Hz),5.113(s,2H),3.757(s,3H),3.377(s,3H),1.376(s,6H)。

¹³C-NMR(CDCl₃):168.902,155,066,154.906,150.589,135.977,131.065,130.067,129.723,128.882,128.364,125.824,122.271,116.345,114.951,114.730,109.460,109.101,94.793,76.144,55.986,52.340,27.834。

(2)2- (2- (methoxymethoxy) phenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) Production of propane-1-ol

3.96g (10.0mmol) of methyl2- (2- (methoxymethoxy) phenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate obtained in the above (1) was melted in 20ml of THF, and 60ml of LiBH was added₄After 1.0M THF solution, 5 streams were obtainedAnd (4) hours. After the reaction solution was cooled in an ice bath, 50ml of 1N HCl was slowly added, followed by 100ml of CH₂Cl₂And (4) extracting. The organic layer was dried over anhydrous magnesium sulfate and then concentrated by distillation under reduced pressure. The concentrated solution was purified by silica gel column chromatography to obtain 2.42g (6.53mmol) of 2- (2- (methoxymethoxy) phenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propane (Yield: 65%).

¹H-NMR(CDCl₃):7.621(b,1H),7.366(td,1H,J＝8.0,1.6Hz),7.228(d,1H,J＝8.0Hz),7.160(dd,1H,J＝7.6,1.6Hz),7.036(t,1H,J＝7.6Hz),6.773(d,1H,J＝10.0Hz),6.739(d,1H,J＝8.0Hz),6.333(d,1H,J＝8.0Hz),5.583(d,1H,J＝10.0Hz),5.245(s,2H),3.866(dd,1H,J＝10.8,4.0Hz),3.810(dd,1H,J＝10.8,2.8Hz),3.494(s,3H),3.398(m,1H),3.070(dd,1H,J＝14.4,10.4Hz),2.741(dd,1H,J＝14.4,4.0Hz),1.433(s,3H),1.420(s,3H)。

¹³C-NMR(CDCl₃):154.418,152.473,150.851,131.444,130.606,128.825,128.015,127.881,122.053,117.835,117.451,114.135,110.286,108.500,94.599,75.540,63.321,56.333,41.798,30.759,27.802,27.585。

(3)3- (2- (methoxymethoxy) phenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f]Benzopyrazine Production of pyran {2'- (methoxymethoxy) -4' -deoxyglabridin }, and pharmaceutical composition containing the same

After melting 1.31g (3.53mmol) of 2- (2- (methoxymethoxy) phenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propan-1-ol obtained in said (2) in 10ml of THF, 0.995g (3.80mmol) of triphenylphosphine (Ph) was added₃P) was followed by heating, thereby slowly inverting THF. This state was maintained and 3.8ml of a 1.0M toluene solution of diethyl azodicarboxylate (DEAD) was slowly added thereto, followed by vigorous stirring for one hour. The reaction mixture was cooled to room temperature, concentrated by distillation under reduced pressure, and purified by silica gel column chromatography to give 1.14g (3.24mmol) of 3- (2- (methoxymethoxy) phenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f ]]Benzopyran (Yield: 92%).

¹H-NMR(CDCl₃):7.231(td,1H,J＝7.2,1.6Hz),7.13～7.17(m,2H),7.010(td,1H,J＝7.2,0.8Hz),6.847(d,1H,J＝8.0Hz),6.677(d,1H,J＝10.0Hz),6.396(d,1H,J＝8.0Hz),5.578(d,1H,J＝10.0Hz),5.235(s,2H),4.408(ddd,1H,J＝10.4,2.4,1.2Hz),4.058(t,1H,J＝10.4Hz),3.702(m,1H),3.491(s,3H),3.015(dd,1H,J＝15.2,11.2Hz),2.881(ddd,1H,J＝15.2,3.6,1.6Hz),1.447(s,3H),1.426(s,3H)。

¹³C-NMR(CDCl₃):155.027,151.925,149.737,130.100,129.161,128.933,127.885,127.229,121.987,116.912,114.337,114.066,109.896,108.692,94.419,75.557,70.069,56.135,32.114,30.721,27.798,27.511。

(4)3- (2- (hydroxy) phenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2, 3-f)]Production of benzopyran

After 7.05g (20.0mmol) of 3- (2- (methoxymethoxy) phenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f ] benzopyran obtained in the above-mentioned (3) was melted in 80ml of isopropyl alcohol, 0.3ml of concentrated hydrochloric acid was added and stirred at ordinary temperature for 5 hours. The reaction solution was concentrated by distillation under the reduced pressure, and the solution was purified by silica gel column chromatography to obtain 2.82g (9.16mol) of 3- (2- (hydroxy) phenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f ] benzopyran (Yield: 46%).

¹H-NMR(CDCl₃):7.11～7.16(m,2H),6.933(dt,1H,J＝7.6,1.2Hz),6.848(d,1H,J＝8.4Hz),6.759(dd,1H,J＝8.0,0.8Hz),6.676(d,1H,J＝10.0Hz),6.398(d,1H,J＝8.4Hz),5.578(d,1H,J＝10.0Hz),5.059(s,1H),4.434(ddd,1H,J＝10.4,3.2,2.0Hz),4.087(t,1H,J＝10.4Hz),3.607(m,1H),3.037(dd,1H,J＝15.2,10.8Hz),2.904(ddd,1H,J＝15.2,5.2,1.6Hz),1.449(s,3H),1.431(s,3H)。

¹³C-NMR(CDCl₃):153.405,151.802,149.721,129.190,128.943,127.792,127.617,127.557,121.128,116.934,115.417,114.335,109.935,108.720,75.659,69.781,32.202,30.388,27.732,27.490。

(5)3- (2-hydroxyphenyl) -8, 8-dimethyl-2, 3,48,9, 10-hexahydropyran [2,3-f ]]Process for preparation of benzopyransManufacture of

2.82g (9.16mol) of 3- (2- (hydroxy) phenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f ] benzopyran obtained in the above (4) was put in a 100ml pressure vessel, 20ml of ethanol was added and sufficiently dissolved, and then vigorously stirred under 2 atm hydrogen for 15 hours in a state of mixing 100mg of 10% PD/C. The reaction mixture was filtered to remove the catalyst, and then concentrated by distillation under reduced pressure, followed by purification by silica gel column chromatography to obtain 2.78g (8.97mmol) of 3- (2-hydroxyphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ] benzopyran (compound 2) (Yield 98%).

¹H-NMR(CDCl₃):7.218(t,1H,J＝7.6Hz),6.842(d,1H,8.4Hz),6.813(d,1H,7.6Hz),6.751(dd,1H,J＝7.6,2.0Hz),6.652(d,1H,J＝2.0Hz),6.419(d,1H,J＝8.4Hz),5.330(s,1H),4.366(ddd,1H,J＝10.4,3.6,0.4Hz),3.936(t,1H,J＝10.4Hz),3.128(m,1H),2.903(d,2H,J＝8.4Hz),2.667(m,2H),1.794(t,2H,J＝7.2Hz),1.361(s,3H),1.338(s,3H)。

¹³C-NMR(CDCl₃):155.875,152.714,151.978,143.459,129.903,127.478,119.797,114.227,113.953,112.644,109.480,109.428,74.053,70.774,38.666,32.296,32.034,26.880,26.222,17.116。

Example 2: 3- (2-hydroxy-4-methylphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ]] Synthesis of benzopyran (Compound 3)

(1)2- (2-benzyloxy-4-methylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propane Production of methyl enoate

While maintaining the atmosphere under a nitrogen atmosphere, 45ml of a 1.0MLDA THF solution was added to a 3-neck round-bottom flask, and then cooled by a-78 ℃ dry ice-acetone bath. After 8.10g (30.0mmol) of methyl (2-benzyloxy-4-methylphenyl) acetate { (methyl2-benzyloxy-4-methylphenyl) acetate } produced in production example 5 was dissolved in 150ml of THF, it was slowly added to the previously prepared 1.0M LDA THF solution over 30 minutes, and stirred again for 30 minutes. 9.24g (30.0mmol) of 5-benzoyl-2, 2-dimethyl-6-formyl-2H-1-benzopyran prepared in preparation 3 was dissolved in 20ml of THF, and then slowly added to the reaction solution prepared above over 30 minutes, followed by stirring for another 30 minutes. The round-bottomed flask was separated from the dry ice-acetone bath and left to stand, whereby the reaction solution was gradually heated to 0 ℃. In this state, 100ml of brine was added, and then stirred vigorously at room temperature for 30 minutes. After separating the organic layer, the aqueous layer was extracted again with 200ml of ethyl acetate. The organic layer extracted with ethyl acetate by the above method was combined with the previously separated organic layer, dried over anhydrous magnesium sulfate, and then concentrated by distillation under reduced pressure. This concentrated solution was purified by silica gel column chromatography to give 5.79g (12.70mmol) of methyl2- (2-benzyloxy-4-methylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate (Yield: 42.3%).

¹H-NMR(CDCl₃):7.879(s,1H),7.26～7.36(m,5H),6.932(d,1H,J＝7.6Hz),6.806(s,1H),6.712(d,1H,J＝7.6Hz),6.680(d,1H,J＝8.4Hz),6.585(d,1H,J＝10.0Hz),6.183(d,1H,J＝8.4Hz),5.701(s,1H),5.533(d,1H,J＝10.0Hz),5.037(s,2H),3.696(s,3H),2.345(s,3H),1.392(s,6H)。

¹³C-NMR(CDCl₃):168.893,156,193,154.704,150.259,139.893,136.992,135.674,130.963,130.160,128.842,128.721,127.668,126.965,122.024,121.948,116.543,114.971,113.332,109.470,109.040,76.115,70.023,52.253,27.872,21.790。

(2)2- (2-benzyloxy-4-methylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propane Production of alk-1-ols

4.56g (10.0mmol) of methyl2- (2-benzyloxy-4-methylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate obtained in the above (1) was melted in 20ml of THF, and 60ml of LiBH was added₄After 1.0M THF solution, the flow was reversed for 5 hours. After cooling the reaction mixture in an ice bath, the reaction mixture was slowly cooled50ml of 1N HCl was added followed by 100ml of CH₂Cl₂And (4) extracting. The organic layer was dried over anhydrous magnesium sulfate, concentrated by distillation under reduced pressure, and purified by silica gel column chromatography to give 2.35g (5.47mmol) of 2- (2-benzyloxy-4-methylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propan-1-ol (Yield: 54.7%).

¹H-NMR(CDCl₃):7.687(b,1H),7.33～7.43(m,5H),7.158(d,1H,J＝7.6Hz),6.845(s,1H),6.807(d,1H,J＝7.6Hz),6.737(d,1H,J＝10.0Hz),6.707(d,1H,J＝8.0Hz),6.309(d,1H,J＝8.0Hz),5.562(d,1H,J＝10.0Hz),5.105(s,2H),3.845(dd,1H,J＝10.8,3.6Hz),3.737(dd,1H,J＝10.8,2.8Hz),3.323(m,1H),3.118(dd,1H,J＝14.0,10.4Hz),2.702(dd,1H,J＝14.0,4.0Hz),2.360(s,3H),1.431(s,3H),1.410(s,3H)。

¹³C-NMR(CDCl₃):155.793,152.415,150.979,137.841,136.457,130.688,128.734,128.596,128.429,128.333,128.231,127.633,121.824,118.070,117.591,113.116,110.289,108.436,75.478,70.517,63.463,42.569,30.581,27.910,27.575,21.394。

(3)3- (2-benzyloxy-4-methylphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2, 3-f)]Benzopyrans Manufacture of

After melting 1.57g (3.65mmol) of 2- (2-benzyloxy-4-methylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propan-1-ol obtained in the (2) in 10ml of THF, 0.995g (3.80mmol) of triphenylphosphine (Ph)₃P) was followed by heating, thereby slowly inverting THF. This state was maintained and 3.9ml of a 1.0M toluene solution of diethyl azodicarboxylate (DEAD) was slowly added thereto, followed by vigorous stirring for one hour. The reaction mixture was cooled to room temperature, concentrated by distillation under reduced pressure, and purified by silica gel column chromatography to give 1.31g (3.17mmol) of 3- (2-benzyloxy-4-methylphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f ]]Benzopyran (Yield: 86.8%).

¹H-NMR(CDCl₃):7.32～7.45(m,5H),7.052(d,1H,J＝7.2Hz),6.838(d,1H,J＝8.0Hz),6.811(s,1H),6.796(d,1H,J＝7.2Hz),6.666(d,1H,J＝10.0Hz),6.384(d,1H,J＝8.0Hz),5.567(d,1H,J＝10.0Hz),5.116(s,2H),4.394(ddd,1H,J＝10.0,3.2,2.0Hz),4.059(t,1H,J＝10.0Hz),3.717(m,1H),2.991(dd,1H,J＝14.0,6.8Hz),2.894(dd,1H,J＝14.0,5.2Hz),2.348(s,3H),1.446(s,3H),1.432(s,3H)。

¹³C-NMR(CDCl₃):156.291,151.838,149.853,137.757,137.128,129.167,128.775,128.592,127.814,127.112,126.958,121.666,116.989,114.446,112.924,109.849,108.577,75.527,70.115,70.065,31.587,30.704,27.784,27.594,21.426。

(4)3- (2-hydroxy-4-methylphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ]]Benzo (b) is Production of pyrans

After 4.12g (10.0mol) of 3- (2-benzyloxy-4-methylphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f ] benzopyran obtained in the above (3) was put in a 100ml pressure vessel, 50ml of ethanol was added and sufficiently dissolved, and then vigorously stirred under hydrogen at 5 atm for 25 hours in a state of being mixed with 150mg of 5% PD/C. The reaction solution was filtered to remove the catalyst, and then concentrated by distillation under the reduced pressure, followed by chromatography on silica gel to obtain 2.67g (8.23mmol) of 3- (2-hydroxy-4-methylphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ] benzopyran (compound 3) (Yield ═ 82%).

¹H-NMR(CDCl₃):7.017(d,1H,J＝8.0Hz),6.850(d,1H,J＝7.6Hz),6.755(dd,1H,J＝7.6,0.4Hz),6.593(d,1H,J＝0.4Hz),6.407(d,1H,J＝8.0Hz),4.931(s,1H),4.422(ddd,1H,J＝10.4,3.6,2.0Hz),4.058(t,1H,J＝10.4Hz),3.556(m,1H),3.044(dd,1H,J＝15.6,11.2Hz),2.890(ddd,1H,J＝15.6,5.2,2.0Hz),2.657(m,2H,J＝6.8,2.4Hz),2.294(s,3H),1.809(t,2H,J＝6.8Hz),1.351(s,3H),1.337(s,3H)。

¹³C-NMR(CDCl₃):153.271,152.801,152.130,137.818,127.458,127.414,124.618,121.826,116.214,112.830,109.315,109.274,73.743,69.904,32.337,32.050,30.577,26.807,26.408,20.920,17.132。

Example 3: 3- (2-hydroxy-4-ethylphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ]] Synthesis of benzopyran (Compound 4)

(1)2- (2-benzyloxy-4-ethylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propane Production of methyl enoate

Methyl2- (2-benzyloxy-4-ethylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate was obtained in the same manner as in example 2(1) above, except that methyl 2-benzyloxy-4-ethylphenylacetate prepared in preparation example 6 was used instead of methyl (2-benzyloxy-4-methylphenyl) acetate.

¹H-NMR(CDCl₃):7.889(s,1H),7.26～7.36(m,5H),6.957(d,1H,J＝7.6Hz),6.882(s,1H),6.740(d,1H,J＝7.6Hz),6.657(d,1H,J＝8.4Hz),6.589(d,1H,J＝10.0Hz),6.170(d,1H,J＝8.4Hz),5.789(s,1H),5.534(d,1H,J＝10.0Hz),5.045(s,2H),3.696(s,3H),2.645(q,2H,J＝7.6Hz),1.391(s,6H),1.233(t,3H,J＝7.6Hz)。

¹³C-NMR(CDCl₃):168.965,156,246,154.681,150.298,146.182,137.036,135.651,131.006,130.842,130.202,128.874,128.272,127.674,126.938,122.123,120.702,116.555,115.022,112.147,109.477,109.025,76.132,70.033,52.294,28.988,27.880,15.164。

(2)2- (2-benzyloxy-4-ethylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propane Production of alk-1-ols

Except that methyl2- (2-benzyloxy-4-ethylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate obtained in the above (1) was used in place of methyl2- (2-benzyloxy-4-methylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate, 2- (2-benzyloxy-4-ethylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propan-1-ol was obtained by the same method as in example 2(2) above.

¹H-NMR(CDCl₃):7.33～7.45(m,5H),7.198(d,1H,J＝7.6Hz),6.875(s,1H),6.841(d,1H,J＝7.6Hz),6.749(d,1H,J＝10.0Hz),6.717(d,1H,J＝8.0Hz),6.321(d,1H,J＝8.0Hz),5.568(d,1H,J＝10.0Hz),5.125(s,2H),3.852(dd,1H,J＝10.8,3.6Hz),3.733(dd,1H,J＝10.8,2.8Hz),3.328(m,1H),3.132(dd,1H,J＝14.0,10.4Hz),2.712(dd,1H,J＝14.0,4.0Hz),2.662(q,2H,J＝4.4Hz),1.441(s,3H),1.417(s,3H),1.263(t,3H,J＝4.4Hz)。

¹³C-NMR(CDCl₃):155.799,152.370,150.984,144.227,136.439,130.670,128.711,128.653,128.578,128.355,128.217,127.661,120.499,118.115,117.587,111.897,110.281,108.412,75.465,70.476,63.352,42.565,30.497,28.755,27.899,27.538,15.477。

(3)3- (2-benzyloxy-4-ethylphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f]Benzopyrans Manufacture of

With the exception of using 2- (2-benzyloxy-4-ethylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propan-1-ol obtained in the above-mentioned (2) in place of 2- (2-benzyloxy-4-methylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propan-1-ol, 3- (2-benzyloxy-4-ethylphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f ] benzopyran.

¹H-NMR(CDCl₃):7.32～7.45(m,5H),7.081(d,1H,J＝8.0Hz),6.82～6.86(m,3H),6.663(d,1H,J＝10.0Hz),6.384(d,1H,J＝8.0Hz),5.568(d,1H,J＝10.0Hz),5.128(s,2H),4.402(m,1H),4.062(t,1H,J＝10.4Hz),3.724(m,1H),2.997(dd,1H,J＝15.6,10.2Hz),2.890(dd,1H,J＝15.6,3.2Hz),2.642(q,2H,J＝6.8Hz),1.446(s,3H),1.431(s,3H),1.246(t,3H,J＝6.8Hz)。

¹³C-NMR(CDCl₃):156.322,151.802,149.827,144.159,137.124,129.167,128.791,128.578,127.807,127.150,127.069,120.340,116.970,114.463,111.727,109.835,108.551,75.526,70.103,70.036,31.571,30.686,28.799,27.772,27.566,15.474。

(4)3- (2-hydroxy-4-ethylphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ]]Benzo (b) is Production of pyrans

3- (2-hydroxy-4-ethylphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f ] benzopyran (Compound 4) was obtained by the same procedure as in example 2(4) above, except that 3- (2-benzyloxy-4-ethylphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f ] benzopyran obtained from said (3) was used instead of 3- (2-benzyloxy-4-methylphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ] benzopyran (Compound 4).

¹H-NMR(CDCl₃):7.054(d,1H,J＝8.0Hz),6.860(d,1H,J＝8.0Hz),6.789(d,1H,J＝8.0Hz),6.616(s,1H),6.421(d,1H,J＝8.0Hz),5.097(s,1H),4.443(m,1H),4.069(t,1H,J＝10.4Hz),3.567(m,1H),3.059(dd,1H,J＝15.6,11.2Hz),2.901(m,1H),2.596(q,2H,J＝6.8Hz),1.802(t,2H,J＝6.8Hz),1.809(t,2H,J＝6.8Hz),1.362(s,3H),1.347(s,3H),1.231(t,3H,J＝6.8Hz)。

¹³C-NMR(CDCl₃):153.373,152.716,152.102,144.205,127.472,127.415,124.773,120.499,114.963,112.898,109.310,109.248,73.795,69.897,32.308,32.054,30.532,28.276,26.784,26.374,17.120,15.308。

Example 4: 3- (2-hydroxy-4-propylphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ]] Synthesis of benzopyran (Compound 5)

(1)2- (2-benzyloxy-4-propylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propane Production of methyl enoate

Methyl2- (2-benzyloxy-4-propylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate was obtained in the same manner as in example 2(1) except that methyl (2-benzyloxy-4-propylphenyl) acetate prepared in production example 7 was used instead of methyl (2-benzyloxy-4-methylphenyl) acetate.

¹H-NMR(CDCl₃):7.902(s,1H),7.26～7.36(m,5H),6.952(d,1H,J＝7.6Hz),6.803(s,1H),6.719(d,1H,J＝7.6Hz),6.636(d,1H,J＝8.8Hz),6.589(d,1H,J＝10.0Hz),6.156(d,1H,J＝8.8Hz),5.835(s,1H),5.531(d,1H,J＝10.0Hz),5.041(s,2H),3.699(s,3H),2.578(t,2H,J＝7.2Hz),1.641(m,2H,J＝7.2Hz),1.392(s,6H),0.920(t,3H,J＝7.2Hz)。

¹³C-NMR(CDCl₃):169.056,156,132,154.677,150.477,144.567,137.010,135.689,130.894,130.144,128.652,128.542,128.368,127.617,126.983,122.191,121.353,116.536,115.058,112.732,109.488,108.916,76.091,69.985,52.257,38.120,27.833,24.166,13.678。

(2)2- (2-benzyloxy-4-propylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propane Production of alk-1-ols

Except that methyl2- (2-benzyloxy-4-propylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate obtained in the above (1) was used in place of methyl2- (2-benzyloxy-4-methylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate, 2- (2-benzyloxy-4-propylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propan-1-ol was obtained by the same method as in example 2(2) above.

¹H-NMR(CDCl₃):7.721(s,1H),7.33～7.45(m,5H),7.189(d,1H,J＝8.0Hz),6.859(s,1H),6.824(d,1H,J＝8.0Hz),6.761(d,1H,J＝10.0Hz),6.715(d,1H,J＝8.4Hz),6.329(d,1H,J＝8.4Hz),5.575(d,1H,J＝10.0Hz),5.126(s,2H),3.858(m,1H),3.743(m,1H),3.339(m,1H),3.132(dd,1H,J＝14.0,10.4Hz),2.728(dd,1H,J＝14.0,4.4Hz),2.605(t,2H,J＝7.6Hz),1.676(m,2H,J＝7.6Hz),1.450(s,3H),1.429(s,3H),0.982(t,3H,J＝7.2Hz)。

¹³C-NMR(CDCl₃):155.670,152.304,150.940,142.630,136.425,130.674,128.675,128.583,128.564,128.192,128.173,127.629,121.125,118.119,117.563,112.389,110.255,108.386,75.452,70.407,63.289,42.432,37.925,30.462,27.859,27.512,24.455,13.840。

(3)3- (2-benzyloxy-4-propylphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2, 3-f)]Benzopyrans Manufacture of

With the exception of using 2- (2-benzyloxy-4-propylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propan-1-ol obtained in the above-mentioned (2) in place of 2- (2-benzyloxy-4-methylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propan-1-ol, 3- (2-benzyloxy-4-propylphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f ] benzopyran.

¹H-NMR(CDCl₃):7.32～7.47(m,5H),7.088(d,1H,J＝8.0Hz),6.869(d,1H,J＝8.0Hz),8.833(s,1H),6.820(d,1H,J＝8.0Hz),6.695(d,1H,J＝10.4Hz),6.409(d,1H,J＝8.0Hz),5.589(d,1H,J＝10.4Hz),5.142(s,2H),4.421(m,1H),4.079(t,1H,J＝10.4Hz),3.743(m,1H),3.008(dd,1H,J＝15.6,11.2Hz),2.914(m,1H,J＝15.6,3.2Hz),2.595(t,2H,J＝7.2Hz),1.668(m,2H,J＝7.2Hz),1.469(s,3H),1.454(s,3H),0.980(t,3H,J＝7.2Hz)。

¹³C-NMR(CDCl₃):156.250,151.832,149.850,142.593,137.148,129.164,128.756,128.563,127.790,127.144,127.031,127.031,121.034,116.993,114.471,112.342,109.836,108.556,75.509,70.122,70.070,38.008,31.627,30.718,27.785,27.583,24.437,13.858。

(4)3- (2-hydroxy-4-propylphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ]]Benzo (b) is Production of pyrans

3- (2-hydroxy-4-propylphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f ] benzopyran (Compound 5) was obtained by the same procedure as in example 2(4) above, except that 3- (2-benzyloxy-4-propylphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f ] benzopyran obtained in the above (3) was used instead of 3- (2-benzyloxy-4-methylphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ] benzopyran (Compound 5).

¹H-NMR(CDCl₃):7.029(d,1H,J＝8.0Hz),6.842(d,1H,J＝8.0Hz),6.755(d,1H,J＝8.0Hz),6.597(s,1H),6.390(d,1H,J＝8.4Hz),4.804(s,1H),4.423(m,1H,J＝10.4,2.4Hz),4.046(t,1H,J＝10.4Hz),3.537(m,1H),3.042(dd,1H,J＝15.6,11.2Hz),2.886(m,1H),2.652(m,2H),2.518(t,2H,J＝7.6Hz),1.781(t,2H,J＝6.8Hz),1.612(m,2H,J＝7.2Hz),1.338(s,3H),1.323(s,3H),0.947(t,3H,J＝7.2Hz)。

¹³C-NMR(CDCl₃):153.296,152.802,152.143,142.679,127.463,127.331,124.838,121.188,115.572,112.888,109.322,109.286,73.749,69.933,37.502,32.366,32.149,30.605,26.809,26.411,24.276,17.141,13.846。

Example 5: 3- (2-hydroxy-4-isopropylphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3- f]Synthesis of benzopyran (Compound 6)

By carrying out the same series of procedures as in example 2 above except that methyl (2-benzyloxy-4-isopropyl-phenyl) acetate was used instead of methyl (2-benzyloxy-4-methylphenyl) acetate, 3- (2-hydroxy-4-isopropyl-phenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ] benzopyran (Compound 6) was obtained.

¹H-NMR(CDCl₃):7.058(d,1H,J＝8.0Hz),6.853(d,1H,J＝8.0Hz),6.812(dd,1H,J＝8.0,1.2Hz),6.641(d,1H,J＝1.2Hz),6.408(d,1H,J＝8.0Hz),4.973(s,1H),4.444(m,1H,J＝10.4,3.2,2.0Hz),4.060(t,1H,J＝10.4Hz),3.552(m,1H),3.056(dd,1H,J＝15.6,11.2Hz),2.892(m,1H,J＝15.6,5.2,1.6Hz),2.859(m,1H,J＝6.8Hz),2.668(m,2H),1.794(t,2H,J＝6.8Hz),1.352(s,3H),1.337(s,3H),1.235(d,6H,J＝6.8Hz)。

¹³C-NMR(CDCl₃):153.331,152.780,152.123,148.947,127.471,127.408,124.870,119.166,113.559,112.857,109.310,109.268,73.751,69.902,33.597,32.334,32.124,30.566,26.813,26.395,23.853,17.139。

Example 6: 3- (2-hydroxy-4-butyl) phenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3- f]Synthesis of benzopyran (Compound 7)

(1)2- (2-benzyloxy-4-butylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propane Production of methyl enoate

Methyl2- (2-benzyloxy-4-butylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate was obtained in the same manner as in example 2(1) above, except that methyl (2-benzyloxy-4-butylphenyl) acetate was used instead of methyl (2-benzyloxy-4-methylphenyl) acetate, which was prepared in production example 8.

¹H-NMR(CDCl₃):7.879(s,1H),7.26～7.36(m,5H),6.934(d,1H,J＝7.6Hz),6.791(s,1H),6.711(d,1H,J＝7.6Hz),6.631(d,1H,J＝8.8Hz),6.572(d,1H,J＝10.0Hz),6.151(d,1H,J＝8.8Hz),5.835(s,1H),5.525(d,1H,J＝10.0Hz),5.026(s,2H),3.692(s,3H),2.585(t,2H,J＝7.2Hz),1.579(m,2H),1.381(s,6H),1.325(m,2H),0.909(t,3H,J＝7.2Hz)。

¹³C-NMR(CDCl₃):169.031,156,107,154.715,150.380,144.868,136.989,135.667,130.929,130.174,128.689,128.451,128.387,127.656,127.037,122.061,121.309,116.561,114.980,112.704,109.546,108.977,76.146,70.034,52.285,35.796,33.226,27.857,22.300,14.054。

(2)2- (2-benzyloxy-4-butylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propane Production of alk-1-ols

Except that methyl2- (2-benzyloxy-4-butylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate obtained in the above-mentioned (1) was used in place of methyl2- (2-benzyloxy-4-methylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate, 2- (2-benzyloxy-4-butylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propan-1-ol was obtained in the same manner as in example 2(2) above.

¹H-NMR(CDCl₃):7.422(b,1H),7.33～7.45(m,5H),7.161(d,1H,J＝8.0Hz),6.827(s,1H),6.797(d,1H,J＝8.0Hz),6.723(d,1H,J＝10.0Hz),6.697(d,1H,J＝8.4Hz),6.296(d,1H,J＝8.4Hz),5.547(d,1H,J＝10.0Hz),5.101(s,2H),3.837(m,1H),3.718(m,1H),3.295(m,1H),3.107(dd,1H,J＝14.0,10.4Hz),2.689(dd,1H,J＝14.0,4.4Hz),2.591(t,2H,J＝7.6Hz),1.588(m,2H,J＝7.6Hz),1.417(s,3H),1.394(s,3H),1.350(m,2H),0.930(t,3H,J＝7.2Hz)。

¹³C-NMR(CDCl₃):155.716,152.389,151.010,142.936,136.424,130.671,128.723,128.581,128.275,128.231,127.680,121.140,118.095,117.604,112.428,110.294,108.422,75.476,70.476,63.366,42.697,35.576,33.545,30.468,27.915,27.551,22.360,13.952。

(3)3- (2-benzyloxy-4-butylphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f]Benzopyrans Manufacture of

With the exception of using 2- (2-benzyloxy-4-butylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propan-1-ol obtained in the above-mentioned (2) in place of 2- (2-benzyloxy-4-methylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propan-1-ol, 3- (2-benzyloxy-4-butylphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f ] benzopyran.

¹H-NMR(CDCl₃):7.32～7.45(m,5H),7.064(d,1H,J＝8.0Hz),6.837(d,1H,J＝8.0Hz),8.808(s,1H),6.798(d,1H,J＝8.0Hz),6.667(d,1H,J＝10.4Hz),6.381(d,1H,J＝8.0Hz),5.567(d,1H,J＝10.4Hz),5.124(s,2H),4.402(m,1H),4.057(t,1H,J＝10.4Hz),3.728(m,1H),2.996(dd,1H,J＝15.6,11.2Hz),2.885(m,1H,J＝15.6,3.2Hz),2.595(t,2H,J＝7.2Hz),1.599(m,2H,J＝7.2Hz),1.446(s,3H),1.431(s,3H),1.380(m,2H),0.941(t,3H,J＝7.2Hz)。

¹³C-NMR(CDCl₃):156.222,151.797,149.827,142.813,137.127,129.165,128.773,128.563,127.787,127.146,127.060,127.028,120.952,116.973,114.480,112.247,109.829,108.540,75.517,70.112,70.017,35.609,33.538,31.573,30.693,27.772,27.561,22.368,13.948。

(4)3- (2-hydroxy-4-butylphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ]]Benzo (b) is Production of pyrans

3- (2-hydroxy-4-butylphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f ] benzopyran (compound 7) was obtained in the same manner as in example 2(4) above, except that 3- (2-benzyloxy-4-butylphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f ] benzopyran obtained in the above-mentioned (3) was used instead of 3- (2-benzyloxy-4-methylphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ] benzopyran (compound 7).

¹H-NMR(CDCl₃):7.033(d,1H,J＝8.0Hz),6.851(d,1H,J＝8.0Hz),6.761(d,1H,J＝8.0Hz),6.596(s,1H),6.407(d,1H,J＝8.4Hz),4.904(s,1H),4.434(m,1H,J＝10.4,2.4Hz),4.056(t,1H,J＝10.4Hz),3.538(m,1H),3.051(dd,1H,J＝15.6,11.2Hz),2.892(m,1H),2.667(m,2H),2.546(t,2H,J＝7.6Hz),1.792(t,2H,J＝6.8Hz),1.599(m,2H,J＝7.2Hz),1.375(m,2H),1.351(s,3H),1.336(s,3H),0.939(t,3H,J＝7.2Hz)。

¹³C-NMR(CDCl₃):153.256,152.765,152.114,142.906,127.463,127.331,124.724,121.142,115.492,112.866,109.302,109.253,73.751,69.910,35.084,33.380,32.321,32.085,30.565,26.805,26.387,22.351,17.131,13.932。

Example 7: 3- (2-hydroxy-4-n-pentylphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3- f]Synthesis of benzopyran (Compound 8)

3- (2-hydroxy-4-n-pentylphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ] benzopyran (Compound 8) was obtained by the same procedure as in example 2 above, except that methyl (2-benzyloxy-4-n-pentylphenyl) acetate was used instead of methyl (2-benzyloxy-4-methylphenyl) acetate.

¹H-NMR(CDCl₃):7.033(d,1H,J＝8.0Hz),6.850(d,1H,J＝8.0Hz),6.761(dd,1H,J＝8.0,1.2Hz),6.598(d,1H,J＝1.2Hz),6.404(d,1H,J＝8.0Hz),4.898(s,1H),4.436(m,1H,J＝10.4,3.2,2.0Hz),4.054(t,1H,J＝10.4Hz),3.551(m,1H),3.048(dd,1H,J＝15.6,11.2Hz),2.906(m,1H,J＝15.6,5.2,1.6Hz),2.664(m,2H),2.536(t,2H,J＝4.4H),1.790(t,2H,J＝6.8Hz),1.599(m,2H),1.35(m,4H),1.348(s,3H),1.333(s,3H),0.908(t,3H,J＝7.4Hz)。

¹³C-NMR(CDCl₃):153.255,152.794,152.125,142.957,127.457,127.344,124.740,121.145,115.485,115.485,112.842,109.258,73.726,69.913,35.383,32.934,32.483,32.333,32.103,30.935,30.581,26.811,26.399,22.519,17.134,14.010。

Example 8: 3- (2-hydroxy-4- (2-methoxyethyl) phenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydro Pyran [2,3-f ]]Synthesis of benzopyran (Compound 9)

3- (2-hydroxy-4- (2-methoxyethyl) phenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ] benzopyran (Compound 9) was obtained in the same manner as in example 2 above, except that methyl (2-benzyloxy-4- (2-methoxyethyl) phenyl) acetate was used instead of methyl (2-benzyloxy-4-methylphenyl) acetate.

¹H-NMR(CDCl₃):7.043(d,1H,J＝8.0Hz),6.843(d,1H,J＝8.0Hz),6.773(dd,1H,J＝8.0,2.0Hz),6.636(d,1H,J＝2.0Hz),6.398(d,1H,J＝8.0Hz),5.762(s,1H),4.416(m,1H,J＝10.4,2.4Hz),4.035(t,1H,J＝10.4Hz),3.647(t,2H,J＝6.8Hz)3.549(m,1H),3.391(s,3H),3.033(dd,1H,J＝15.6,11.2Hz),2.864(m,1H,J＝15.6,5.2,1.6Hz),2.831(t,2H,J＝6.8Hz)2.654(m,2H),1.783(t,2H,J＝6.8H),1.343(s,3H),1.328(s,3H)。

¹³C-NMR(CDCl₃):153.701,152.748,152.100,138.669,127.490,127.449,125.554,121.052,115.967,112.828,109.283,109.227,73.716,73.396,69.838,58.624,35.501,32.294,32.062,30.413,26.787,26.381,17.111。

Example 9: 3- (2-hydroxy-3, 4-dimethylphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2, 3-f]synthesis of benzopyran (Compound 10)

3- (2-hydroxy-3, 4-dimethylphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ] benzopyran (Compound 10) was obtained in the same manner as in example 2 above, except that methyl (2-benzyloxy-3, 4-dimethylphenyl) acetate was used instead of methyl (2-benzyloxy-4-methylphenyl) acetate.

¹H-NMR(CDCl₃):6.901(d,1H,J＝8.0Hz),6.857(d,1H,J＝8.4Hz),6.790(d,1H,J＝8.0Hz),6.411(d,1H,J＝8.4Hz),4.834(s,1H),4.430(m,1H,J＝10.0,3.2,2.0Hz),4.051(t,1H,J＝10.0Hz),3.543(m,1H),3.036(dd,1H,J＝15.6,11.2Hz),2.896(m,1H,J＝15.6,5.2,2.0Hz),2.672(m,2H),2.297(s,3H),2.199(s,3H),1.798(t,2H,J＝6.8Hz),1.357(s,3H),1.344(s,3H)。

¹³C-NMR(CDCl₃):152.849,152.105,151.536,136.143,127.431,124.846,124.061,122.329,121.519,112.767,109.275,73.652,69.998,32.353,32.311,30.781,26.811,26.404,20.154,17.124,11.743。

Example 10: 3- (2-hydroxy-4, 5-dimethylphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f]Synthesis of benzopyran (Compound 11)

(1)2- (2-benzyloxy-4, 5-dimethylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6- Based) production of methyl acrylate

Methyl2- (2-benzyloxy-4, 5-dimethylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate was obtained in the same manner as in example 2(1) above, except that methyl (2-benzyloxy-4, 5-dimethylphenyl) acetate { methyl2-benzyloxy-4,5-dimethylphenyl acetate } produced in production example 9 was used instead of methyl (2-benzyloxy-4-methylphenyl) acetate.

¹H-NMR(CDCl₃):7.894(s,1H),7.26～7.36(m,5H),6.795(s,1H),6.766(s,1H),6.677(d,1H,J＝8.4Hz),6.591(d,1H,J＝10.0Hz),6.161(d,1H,J＝8.4Hz),5.512(d,1H,J＝10.0Hz),4.994(s,2H),3.680(s,3H),2.223(s,3H),2.072(s,3H),1.375(s,6H)。

¹³C-NMR(CDCl₃):169.257,154,688,154.284,150.592,137.994,137.204,135.640,131.947,130.210,129.084,128.604,128.387,128.339,127.573,126.895,122.056,116.624,115.140,114.154,109.504,108.956,76.039,70.161,52.294,27.830,27.781,20.240,18.763。

(2)2- (2-benzyloxy-4, 5-dimethylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6- Yl) production of propan-1-ol

2- (2-benzyloxy-4, 5-dimethylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propan-1-ol was obtained by the same method as that of example 2(2) except that methyl2- (2-benzyloxy-4, 5-dimethylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate obtained in the above (1) was used instead of methyl2- (2-benzyloxy-4-methylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate.

¹H-NMR(CDCl₃):7.30～7.43(m,5H),6.999(s,1H),6.792(s,1H),6.721(d,1H,J＝10.0Hz),6.699(d,1H,J＝8.0Hz),6.293(d,1H,J＝8.0Hz),5.528(d,1H,J＝10.0Hz),5.054(s,2H),3.800(dd,1H,J＝11.2,3.6Hz),3.691(dd,1H,J＝11.2,2.8Hz),3.249(m,1H),3.090(dd,1H,J＝14.0,10.4Hz),2.668(dd,1H,J＝14.0,4.0Hz),2.232(s,3H),2.188(s,3H),1.406(s,3H),1.385(s,3H)。

¹³C-NMR(CDCl₃):153.764,152.283,150.928,136.498,135.796,130.637,129.835,128.952,128.661,128.528,128.448,128.142,127.587,118.246,117.584,113.911,110.276,108.349,75.432,70.689,63.407,42.833,30.722,27.840,27.480,19.817,18.873。

(3)3- (2-benzyloxy-4, 5-dimethylphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2, 3-f)]Benzo (b) is Production of pyrans

3- (2-benzyloxy-4, 5-dimethylphenyl) -8, 8-dimethyl-2, 3,4 was obtained by the same method as in example 2(3) above, except that 2- (2-benzyloxy-4, 5-dimethylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propan-1-ol obtained in the above (2) was used instead of 2- (2-benzyloxy-4-methylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propan-1-ol, 8-tetrahydropyran [2,3-f ] benzopyran.

¹H-NMR(CDCl₃):7.32～7.45(m,5H),6.935(s,1H),6.857(d,1H,J＝8.0Hz),6.810(s,1H),6.697(d,1H,J＝10.0Hz),6.407(d,1H,J＝8.0Hz),5.591(d,1H,J＝10.0Hz),5.115(s,2H),4.414(m,1H,J＝10.0,3.2,2.0Hz),4.060(t,1H,J＝10.0Hz),3.721(m,1H),3.028(dd,1H,J＝14.0,6.8Hz),2.877(dd,1H,J＝14.0,5.2Hz),2.272(s,3H),2.229(s,3H),1.470(s,3H),1.455(s,3H)。

¹³C-NMR(CDCl₃):154.383,151.764,149.792,137.275,135.831,129.162,128.772,128.742,128.544,128.519,127.727,127.064,126.960,116.982,114.536,113.786,109.823,108.514,75.504,70.246,70.192,31.530,30.793,27.746,27.536,19.883,18.973。

(4)3- (2-hydroxy-4, 5-dimethylphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ]] Production of benzopyran

3- (2-hydroxy-4, 5-dimethylphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f ] benzopyran (Compound 11) was obtained in the same manner as in example 2(4) above, except that 3- (2-benzyloxy-4, 5-dimethylphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f ] benzopyran obtained in the above (3) was used instead of 3- (2-benzyloxy-4-methylphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ] benzopyran (Compound 11).

¹H-NMR(CDCl₃):6.886(s,1H),6.857(d,1H,J＝4.8Hz),6.579(s,1H),6.418(d,1H,J＝4.8Hz),4.965(s,1H),4.433(dd,1H,J＝6.0Hz),4.053(t,1H,J＝6.0Hz),3.534(m,1H),3.067(dd,1H,J＝8.8,6.8Hz),2.873(ddd,1H,J＝8.8,2.4,0.8Hz),2.680(m,2H),2.203(s,6H),1.803(t,2H,J＝4.0Hz),1.364(s,3H),1.348(s,3H)。

¹³C-NMR(CDCl₃):152.711,152.083,151.311,135.979,128.741,128.608,127.462,124.557,116.894,112.952,109.284,109.207,73.761,69.985,32.239,32.018,30.643,26.781,26.368,19.374,18.905,17.122。

Example 11: 3- (2-hydroxy-4-fluorophenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f] Synthesis of benzopyran (Compound 12)

3- (2-hydroxy-4-fluorophenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ] benzopyran (Compound 12) was obtained by the same procedure as in the above example 2, except that methyl (2-benzyloxy-4-fluorophenyl) acetate was used instead of methyl (2-benzyloxy-4-methylphenyl) acetate.

¹H-NMR(CDCl3):7.045(dd,1H,J＝8.8,6.6Hz),6.834(d,1H,J＝8.4Hz),6.620(m,1H,J＝8.4,2.4Hz),6.501(dd,1H,J＝9.6,2.4Hz),6.396(d,1H,J＝8.4Hz),5.400(s,1H),4.379(m,1H,J＝10.0,3.2,2.0Hz),4.039(t,1H,J＝10.0Hz),3.523(m,1H),2.997(dd,1H,J＝15.6,11.2Hz),2.892(m,1H,J＝15.6,5.2,2.0Hz),2.642(m,2H),1.777(t,2H,J＝6.8Hz),1.335(s,3H),1.321(s,3H)。

¹³C-NMR(CDCl3):163.144,160.705,154.402,152.812,152.061,128.471,127.447,123.663,112.574,109.401,107.644,103.157,73.880,69.704,32.297,31.821,30.520,26.784,26.390,17.103。

Example 12: 3- (2-hydroxy-4-chlorophenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ]] Synthesis of benzopyran (Compound 13)

3- (2-hydroxy-4-chlorophenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ] benzopyran (Compound 13) was obtained in the same manner as in example 2 above, except that methyl (2-benzyloxy-4-chlorophenyl) acetate was used instead of methyl (2-benzyloxy-4-methylphenyl) acetate.

¹H-NMR(CDCl3):7.026(d,1H,J＝8.4Hz),6.888(dd,1H,J＝8.4,2.0Hz),6.832(d,1H,J＝8.4Hz),6.759(d,1H,J＝2.0Hz),6.397(d,1H,J＝8.4Hz),5.256(s,1H),4.375(m,1H,J＝10.0,3.2,2.0Hz),4.047(t,1H,J＝10.0Hz),3.532(m,1H),2.988(dd,1H,J＝15.6,11.2Hz),2.848(m,1H,J＝15.6,5.2,2.0Hz),2.637(m,2H),1.775(t,2H,J＝6.8Hz),1.333(s,3H),1.320(s,3H)。

¹³C-NMR(CDCl₃):154.027,152.821,152.035,132.695,128.594,127.445,126.551,121.205,115.699,112.435,109.442,109.408,73.892,69.487,32.274,31.905,30.318,26.776,26.393,17.093。

Example 13: 3- (2-hydroxy-4-methoxyphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2, 3-f]synthesis of benzopyran (Compound 14)

(1)2- (2-benzyloxy-4-methoxyphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) Production of methyl acrylate

Methyl2- (2-benzyloxy-4-methoxyphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate was obtained in the same manner as in example 2(1) except that methyl (2-benzyloxy-4-methoxyphenyl) acetate } produced in production example 10 above was used instead of methyl (2-benzyloxy-4-methylphenyl) acetate.

¹H-NMR(CDCl₃):7.875(s,1H),7.24～7.36(m,5H),6.958(d,1H,J＝8.4Hz),6.697(d,1H,J＝8.4Hz),6.598(d,1H,J＝10.0Hz),6.551(d,1H,J＝2.4Hz),6.426(dd,1H,J＝8.4,2.4Hz),6.195(d,1H,J＝8.4Hz),5.783(s,H),5.536(d,1H,J＝10.0Hz),5.030(s,2H),3.777(s,3H),3.700(s,3H),1.395(s,6H)。

¹³C-NMR(CDCl₃):169.002,160,933,157.315,154.665,150.202,136.701,135.651,131.736,130.213,128.726,128.489,128.440,127.733,126.958,117.352,116.537,114.996,109.468,109.063,105.279,100.143,76.114,70.097,55.259,52.262,27.855。

(2)2- (2-benzyloxy-4-methoxyphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) Production of propane-1-ol

Except that methyl2- (2-benzyloxy-4-methoxyphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate obtained in the above (1) was used in place of methyl2- (2-benzyloxy-4-methylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate, 2- (2-benzyloxy-4-methoxyphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propan-1-ol was obtained by the same method as in example 2(2) above.

¹H-NMR(CDCl₃):7.617(s,1H),7.33～7.42(m,5H),7.150(d,1H,J＝8.0Hz),6.725(d,1H,J＝10.0Hz),6.680(d,1H,J＝8.4Hz),6.582(d,1H,J＝2.4hz),6.488(dd,1H,J＝8.0,2.4Hz),6.294(d,1H,J＝8.4Hz),5.550(d,1H,J＝10.0Hz),5.075(s,2H),3.820(m,1H),3.787(s,3H),3.719(m,1H),3.292(m,1H),3.085(dd,1H,J＝14.0,10.4Hz),2.692(dd,1H,J＝14.0,4.0Hz),2.407(m,1H),1.416(s,3H),1.398(s,3H)。

¹³C-NMR(CDCl₃):159.512,156.744,152.398,150.989,136.245,130.750,128.848,128.768,128.648,128.291,127.616,123.685,118.015,117.588,110.284,108.446,104.573100.232,75.508,70.493,63.479,55.380,42.052,30.536,27.905,27.593。

(3)3- (2-benzyloxy-4-methoxyphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2, 3-f)]Benzopyrazine Production of furans

3- (2-benzyloxy-4-methoxyphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [ 2] was obtained by the same method as that of the above-mentioned example 2(3) except that 2- (2-benzyloxy-4-methoxyphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propan-1-ol obtained in the above-mentioned (2) was used instead of 2- (2-benzyloxy-4-methylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propan-1-ol, 3-f ] benzopyran.

¹H-NMR(CDCl₃):7.30～7.45(m,5H),7.047(d,1H,J＝8.0Hz),6.821(d,1H,J＝8.4Hz),6.642(d,1H,J＝10.0Hz),6.544(d,1H,J＝2.0Hz),6.476(dd,1H,J＝8.4,2.0Hz),6.361(d,1H,J＝8.0Hz),5.550(d,1H,J＝10.0Hz),5.295(s,1H),5.087(s,2H),4.369(m,1H),4.023(t,1H,J＝10.0Hz),3.773(s,3H),3.650(m,1H),2.963(dd,1H,J＝15.6,10.8Hz),2.883(dd,1H,J＝15.6,4.4Hz),1.425(s,3H),1.410(s,3H)。

¹³C-NMR(CDCl₃):159.505,157.258,151.862149.841,136.860,129.178,128.834,128.647,127.913,127.725,127.152,122.328,116.978,114.469,109.857,108.582,104.588,100.013,75.558,70.196,70.088,55.347,31.315,30.733,27.795,27.579。

(4)3- (2-hydroxy-4-methoxyphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ]]Benzene and its derivatives Production of benzopyran

3- (2-hydroxy-4-methoxyphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f ] benzopyran (compound 14) was obtained by the same procedure as in example 2(4) above, except that 3- (2-benzyloxy-4-methoxyphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f ] benzopyran obtained in the above-mentioned (3) was used instead of 3- (2-benzyloxy-4-methylphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ] benzopyran (compound 14).

¹H-NMR(CDCl₃):7.022(d,1H,J＝8.4Hz),6.837(d,1H,J＝8.0Hz),6.488(dd,1H,J＝8.0,2.4Hz),6.388(d,1H,J＝8.4Hz),6.364(d,1H,J＝2.4Hz),5.059(s,1H),4.392(m,1H,J＝10.0,2.0Hz),4.024(t,1H,J＝10.0Hz),3.768(s,3H),3.488(m,1H),3.017(dd,1H,J＝15.6,11.2Hz),2.875(m,1H,J＝15.6,6.8,2.0Hz),2.645(m,2H),1.778(t,2H,J＝6.8Hz),1.335(s,3H),1.321(s,3H)。

¹³C-NMR(CDCl₃):159.257,154.516,152.772,152.160,128.184,127.546,120.182,112.994,109.394,109.340,105.957,102.118,73.917,70.069,55.340,32.391,31.811,30.671,26.833,26.459,17.187。

Example 14: 3- (2-hydroxy-4-ethoxyphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2, 3-f]synthesis of benzopyran (Compound 15)

(1)2- (2-benzyloxy-4-ethoxyphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) Production of methyl acrylate

Methyl2- (2-benzyloxy-4-ethoxyphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate was obtained in the same manner as in example 2(1) except that methyl (2-benzyloxy-4-ethoxyphenyl) acetate { methyl (2-benzyloxy-4-ethoxyphenyl) acetate } produced in production example 11 above was used instead of methyl (2-benzyloxy-4-methylphenyl) acetate.

¹H-NMR(CDCl₃):7.842(s,1H),7.24～7.36(m,5H),6.937(d,1H,J＝8.4Hz),6.699(d,1H,J＝8.4Hz),6.578(d,1H,J＝10.0Hz),6.548(s,1H),6.411(d,1H,J＝8.4Hz),6.193(d,1H,J＝8.4Hz),5.719(s,H),5.532(d,1H,J＝10.0Hz),5.016(s,2H),3.994(q,2H,J＝6.8Hz),3.693(s,3H),1.389(s,6H),1.389(t,3H)。

¹³C-NMR(CDCl₃):168.924,160,391,157.312,154.649,150.070,136.734,135.557,131.731,130.243,128.734,128.692,128.438,127.728,126.969,117.117,116.553,114.983,109.481,109.084,105.879,100.527,76.126,70.096,63.462,52.237,27.863,14.767。

(2)2- (2-benzyloxy-4-ethoxyphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) Production of propane-1-ol

Except that methyl2- (2-benzyloxy-4-ethoxyphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate obtained in the above (1) was used in place of methyl2- (2-benzyloxy-4-methylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate, 2- (2-benzyloxy-4-ethoxyphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propan-1-ol was obtained by the same method as in example 2(2) above.

¹H-NMR(CDCl₃):7.676(s,1H),7.33～7.42(m,5H),7.139(d,1H,J＝8.0Hz),6.734(d,1H,J＝10.0Hz),6.692(d,1H,J＝8.4Hz),6.594(d,1H,J＝2.4hz),6.484(dd,1H,J＝8.0,2.4Hz),6.303(d,1H,J＝8.4Hz),5.559(d,1H,J＝10.0Hz),5.077(s,2H),4.019(q,2H,J＝7.2Hz),3.826(m,1H),3.729(m,1H),3.291(m,1H),3.096(dd,1H,J＝14.0,10.4Hz),2.696(dd,1H,J＝14.0,4.0Hz),2.457(b,1H),1.425(s,3H),1.416(t,3H),1.406(s,3H)。

¹³C-NMR(CDCl₃):158.871,156.742,152.390,150.988,136.262,130.727,128.823,128.744,128.609,128.261,127.598,123.504,118.006,117.584,110.268,108.422,105.250,100.663,75.481,70.479,63.550,63.495,42.148,30.525,27.897,27.584,14.812。

(3)3- (2-benzyloxy-4-ethoxyphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f]Benzopyrazine Production of furans

With the exception of using 2- (2-benzyloxy-4-ethoxyphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propan-1-ol obtained in the above-mentioned (2) in place of 2- (2-benzyloxy-4-methylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propan-1-ol, 3- (2-benzyloxy-4-ethoxyphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f ] benzopyran.

¹H-NMR(CDCl₃):7.30～7.45(m,5H),7.047(d,1H,J＝8.0Hz),6.841(d,1H,J＝8.4Hz),6.665(d,1H,J＝10.0Hz),6.566(d,1H,J＝2.0Hz),6.482(dd,1H,J＝8.4,2.0Hz),6.385(d,1H,J＝8.0Hz),5.571(d,1H,J＝10.0Hz),5.096(s,2H),4.384(m,1H),4.026(q,2H,J＝6.8Hz),4.009(t,1H,J＝10.0Hz),3.661(m,1H),2.980(dd,1H,J＝15.6,10.8Hz),2.878(dd,1H,J＝15.6,4.4Hz),1.446(s,3H),1.430(s,3H),1.411(t,3H,J＝6.8Hz)。

¹³C-NMR(CDCl₃):158.825,157.218,151.784,149.811,136.871,129.153,128.783,128.598,127.850,127.652,127.097,122.093,116.957,114.469,109.814,108.531,105.203,100.385,75.515,70.183,70.013,63.462,31.277,30.706,27.767,27.549,14.809。

(4)3- (2-hydroxy-4-ethoxyphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ]]Benzene and its derivatives Production of benzopyran

3- (2-hydroxy-4-ethoxyphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f ] benzopyran (Compound 15) was obtained in the same manner as in example 2(4) above, except that 3- (2-benzyloxy-4-ethoxyphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f ] benzopyran obtained in the above-mentioned (3) was used in place of 3- (2-benzyloxy-4-methylphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ] benzopyran (Compound 15).

¹H-NMR(CDCl₃):6.989(d,1H,J＝8.4Hz),6.825(d,1H,J＝8.0Hz),6.458(dd,1H,J＝8.0,2.4Hz),6.387(d,1H,J＝8.4Hz),6.324(d,1H,J＝2.4Hz),5.355(s,1H),4.386(m,1H,J＝10.4,3.2,2.0Hz),4.007(t,1H,J＝10.4Hz),3.954(q,2H,J＝7.2Hz),3.484(m,1H),3.006(dd,1H,J＝15.6,11.2Hz),2.852(m,1H,J＝15.6,4.8,1.6Hz),2.641(m,2H),1.770(t,2H,J＝6.8Hz),1.378(t,2H,J＝6.8Hz),1.331(s,3H),1.316(s,3H)。

¹³C-NMR(CDCl₃):158.552,154.340,152.719,152.091,128.075,127.465,119.882,112.909,109.305,109.248,106.572,102.504,73.798,70.018,63.450,32.311,31.749,30.614,26.776,26.390,17.116,14.781。

Example 15: 3- (2-hydroxy-4-propoxyphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2, 3-f]synthesis of benzopyran (Compound 16)

(1)2- (2-benzyloxy-4-propoxyphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) Production of methyl acrylate

Methyl2- (2-benzyloxy-4-propoxyphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate was obtained in the same manner as in example 2(1) above, except that methyl (2-benzyloxy-4-propoxyphenyl) acetate { methyl (2-benzyloxy-4-propoxyphenyl) acetate } produced in production example 12 was used instead of methyl (2-benzyloxy-4-methylphenyl) acetate.

¹H-NMR(CDCl₃):7.816(s,1H),7.24～7.36(m,5H),6.928(d,1H,J＝8.4Hz),6.705(d,1H,J＝8.4Hz),6.562(d,1H,J＝10.0Hz),6.552(d,1H,J＝2.0Hz),6.408(dd,1H,J＝8.4,2.0Hz),6.195(d,1H,J＝8.4Hz),5.599(b,H),5.526(d,1H,J＝10.0Hz),5.012(s,2H),3.880(t,2H,J＝6.4Hz),3.687(s,3H),1.785(m,2H),1.385(s,6H),1.024(t,3H,J＝7.2Hz)。

¹³C-NMR(CDCl₃):169.032,160,423,157.356,154.638,150.111,136.730,135.529,131.711,130.229,128.714,128.632,128.426,127.724,126.989,117.177,116.564,114.994,109.488,109.066,105.932,100.492,76.117,70.086,69.489,52.236,27.857,22.534,10.495。

(2)2- (2-benzyloxy-4-propoxyphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) Production of propane-1-ol

Except that the methyl2- (2-benzyloxy-4-propoxyphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate obtained in the above (1) was used in place of the methyl2- (2-benzyloxy-4-methylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate, 2- (2-benzyloxy-4-propoxyphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propan-1-ol was obtained by the same method as in example 2(2) above.

¹H-NMR(CDCl₃):7.401(b,1H),7.33～7.42(m,5H),7.128(d,1H,J＝8.0Hz),6.722(d,1H,J＝10.0Hz),6.682(d,1H,J＝8.4Hz),6.595(d,1H,J＝2.4hz),6.480(dd,1H,J＝8.0,2.4Hz),6.291(d,1H,J＝8.4Hz),5.548(d,1H,J＝10.0Hz),5.070(s,2H),3.899(t,2H,J＝6.8Hz),3.816(m,1H),3.706(m,1H),3.282(m,1H),3.085(dd,1H,J＝14.0,10.4Hz),2.687(dd,1H,J＝14.0,4.0Hz),2.432(b,1H),1.798(2H,m),1.415(s,3H),1.396(s,3H),1.035(t,3H)。

¹³C-NMR(CDCl₃):159.071,156.734,152.376,150.986,136.252,130.727,128.818,128.740,128.600,128.264,127.621,123.437,118.025,117.586,110.267,108.415,105.290,100.625,75.480,70.480,69.615,63.494,42.178,30.515,27.895,27.571,22.555,10.529。

(3)3- (2-benzyloxy-4-propoxyphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f]Benzopyrazine Production of furans

3- (2-benzyloxy-4-propoxyphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [ 2] was obtained by the same method as that of the above-mentioned example 2(3) except that 2- (2-benzyloxy-4-propoxyphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propan-1-ol obtained in the above-mentioned (2) was used instead of 2- (2-benzyloxy-4-methylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propan-1-ol, 3-f ] benzopyran.

¹H-NMR(CDCl₃):7.30～7.45(m,5H),7.045(d,1H,J＝8.0Hz),6.834(d,1H,J＝8.4Hz),6.664(d,1H,J＝10.0Hz),6.575(d,1H,J＝2.0Hz),6.498(dd,1H,J＝8.4,2.0Hz),6.380(d,1H,J＝8.0Hz),5.562(d,1H,J＝10.0Hz),5.097(s,2H),4.376(m,1H),4.0346(t,1H,J＝10.0Hz),3.899(t,2H,J＝6.4Hz),3.663(m,1H),2.982(dd,1H,J＝15.6,10.8Hz),2.874(dd,1H,J＝15.6,4.4Hz),1.785(m,2H),1.444(s,3H),1.429(s,3H),1.041(t,3H,J＝7.2Hz)。

¹³C-NMR(CDCl₃):159.044,157.236,151.790,149.823,136.889,128.784,128.598,127.855,127.647,127.124,122.042,116.967,114.482,109.821,108.532,105.286,100.380,75.523,70.199,70.036,69.553,31.287,30.720,27.773,27.560,22.549,10.525。

(4)3- (2-hydroxy-4-propoxyphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f]Benzene and its derivatives Production of benzopyran

3- (2-hydroxy-4-propoxyphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f ] benzopyran (Compound 16) was obtained in the same manner as in example 2(4) above, except that 3- (2-benzyloxy-4-propoxyphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f ] benzopyran obtained in the above-mentioned (3) was used instead of 3- (2-benzyloxy-4-methylphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ] benzopyran (Compound 16).

¹H-NMR(CDCl₃):6.976(d,1H,J＝8.4Hz),6.817(d,1H,J＝8.0Hz),6.452(dd,1H,J＝8.0,2.0Hz),6.392(d,1H,J＝8.4Hz),6.316(d,1H,J＝2.0Hz),5.600(s,1H),4.380(d,1H,J＝10.0Hz),4.000(t,1H,J＝10.0Hz),3.812(t,2H,J＝6.4Hz),3.488(m,1H),2.997(dd,1H,J＝15.6,11.2Hz),2.837(dd,1H,J＝15.6,4.4Hz),2.640(m,2H),1.782(t,2H,J＝6.8Hz),1.765(m,2H),1.329(s,3H),1.314(s,3H),0.994(t,3H,J＝7.2Hz)。

¹³C-NMR(CDCl₃):158.678,154.412,152.596,152.054,128.015,127.483,119.827,113.016,109.299,109.226,106.588,102.460,73.888,70.014,69.537,32.287,31.702,30.552,26.728,26.349,22.453,17.096,10.458。

Example 16: 3- (2-hydroxy-4-isopropoxyphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f]Synthesis of benzopyran (Compound 17)

3- (2-hydroxy-4-isopropoxyphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ] benzopyran (Compound 17) was obtained in the same manner as in example 2 above, except that methyl (2-benzyloxy-4-isopropoxyphenyl) acetate was used instead of methyl (2-benzyloxy-4-methylphenyl) acetate.

¹H-NMR(CDCl₃):7.000(d,1H,J＝8.4Hz),6.845(d,1H,J＝8.0Hz),6.472(dd,1H,J＝8.0,2.4Hz),6.404(d,1H,J＝8.4Hz),6.344(d,1H,J＝2.4Hz),5.333(s,1H),4.450(m,1H,J＝6.0Hz),4.409(m,1H,J＝10.4,3.2,2.0Hz),4.026(t,1H,J＝10.4Hz),3.498(m,1H),3.026(dd,1H,J＝15.2,11.2Hz),2.871(m,1H,J＝15.2,4.8,1.6Hz),2.669(m,2H),1.789(t,2H,J＝6.8Hz),1.378(t,2H,J＝6.8Hz),1.349(s,3H),1.331(s,3H),1.324(d,6H,J＝6.0Hz)。

¹³C-NMR(CDCl₃):157.519,154.443,152.755,152.116,128.071,127.463,119.886,112.931,109.311,109.266,107.931,103.837,73.778,70.102,70.044,32.349,31.818,30.655,26.787,26.401,22.044,17.128。

Example 17: 3- (2-hydroxy-4-butoxyphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2, 3-f]synthesis of benzopyran (Compound 18)

(1)2- (2-benzyloxy-4-butoxyphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) Production of methyl acrylate

Methyl2- (2-benzyloxy-4-butoxyphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate was obtained in the same manner as in example 2(1) above, except that methyl (2-benzyloxy-4-butoxyphenyl) acetate } produced in production example 13 was used instead of methyl (2-benzyloxy-4-methylphenyl) acetate.

¹H-NMR(CDCl₃):7.836(s,1H),7.24～7.36(m,5H),6.928(d,1H,J＝8.4Hz),6.698(d,1H,J＝8.4Hz),6.577(d,1H,J＝10.0Hz),6.546(d,1H,J＝2.0Hz),6.407(dd,1H,J＝8.4,2.0Hz),6.188(d,1H,J＝8.4Hz),5.726(b,H),5.523(d,1H,J＝10.0Hz),5.010(s,2H),3.918(t,2H,J＝6.4Hz),3.683(s,3H),1.752(m,2H),1.468(m,2H),1.383(s,6H),0.986(t,3H,J＝7.2Hz)。

¹³C-NMR(CDCl₃):169.062,160,539,157.338,154.664,150.278,136.737,135.556,131.694,130.196,128.667,128.450,128.405,127.968,126.968,117.138,116.575,115.049,109.499,109.022,105.911,100.487,76.090,70.061,67.676,52.223,31.263,28.050,19.191,13.802。

(2)2- (2-benzyloxy-4-butoxyphenyl) -3- (2,2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) Production of propane-1-ol

Except that methyl2- (2-benzyloxy-4-butoxyphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate obtained in the above (1) was used in place of methyl2- (2-benzyloxy-4-methylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate, 2- (2-benzyloxy-4-butoxyphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propan-1-ol was obtained by the same method as in example 2(2) above.

¹H-NMR(CDCl₃):7.401(b,1H),7.33～7.42(m,5H),7.128(d,1H,J＝8.0Hz),6.723(d,1H,J＝10.0Hz),6.682(d,1H,J＝8.4Hz),6.588(d,1H,J＝2.4hz),6.479(dd,1H,J＝8.0,2.4Hz),6.291(d,1H,J＝8.4Hz),5.547(d,1H,J＝10.0Hz),5.068(s,2H),3.940(t,2H,J＝6.8Hz),3.814(m,1H),3.704(m,1H),3.280(m,1H),3.084(dd,1H,J＝14.0,10.4Hz),2.681(dd,1H,J＝14.0,4.0Hz),2.43(b,1H),1.767(2H,m),1.489(m,2H),1.415(s,3H),1.396(s,3H),0.977(t,3H)。

¹³C-NMR(CDCl₃):159.068,156.721,152.360,150.973,136.220,130.726,128.799,128.729,128.596,128.249,127.611,123.425,118.039,117.579,110.259,108.407,105.271,100.606,75.473,70.464,67.782,63.477,42.119,31.286,30.521,27.884,27.566,19.228,13.838。

(3)3- (2-benzyloxy-4-butoxyphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2, 3-f)]Benzopyrazine Production of furans

3- (2-benzyloxy-4-butoxyphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [ 2] was obtained by the same method as that of the above-mentioned example 2(3) except that 2- (2-benzyloxy-4-butoxyphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propan-1-ol obtained in the above-mentioned (2) was used instead of 2- (2-benzyloxy-4-methylphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propan-1-ol, 3-f ] benzopyran.

¹H-NMR(CDCl₃):7.30～7.45(m,5H),7.022(d,1H,J＝8.0Hz),6.813(d,1H,J＝8.4Hz),6.640(d,1H,J＝10.0Hz),6.548(d,1H,J＝2.0Hz),6.465(dd,1H,J＝8.4,2.0Hz),6.357(d,1H,J＝8.0Hz),5.544(d,1H,J＝10.0Hz),5.075(s,2H),4.359(m,1H),4.012(t,1H,J＝10.0Hz),3.919(t,2H,J＝6.4Hz),3.641(m,1H),2.956(dd,1H,J＝15.6,10.8Hz),2.856(dd,1H,J＝15.6,4.4Hz),1.739(m,2H),1.473(m,2H),1.422(s,3H),1.407(s,3H),0.964(t,3H,J＝7.2Hz)。

¹³C-NMR(CDCl₃):159.063,157.233,151.793,149.826,136.896,128.782,128.600,127.856,127.644,127.126,122.031,116.970,114.483,109.823,108.534,105.279,100.378,75.521,70.201,70.038,67.725,31.291,30.723,27.774,27.561,19.231,13.833。

(4)3- (2-hydroxy-4-butoxyphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f]Benzene and its derivatives Production of benzopyran

3- (2-hydroxy-4-butoxyphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f ] benzopyran (Compound 18) was obtained by the same procedure as in example 2(4) above, except that 3- (2-benzyloxy-4-butoxyphenyl) -8, 8-dimethyl-2, 3,4, 8-tetrahydropyran [2,3-f ] benzopyran obtained in the above-mentioned (3) was used instead of 3- (2-benzyloxy-4-methylphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ] benzopyran.

¹H-NMR(CDCl₃):7.009(d,1H,J＝8.4Hz),6.847(1d,1H,J＝8.0Hz),6.482(dd,1H,J＝8.0,2.0Hz),6.408(d,1H,J＝8.4Hz),6.355(d,1H,J＝2.0Hz),5.313(s,1H),4.407(m,1H,J＝10.0Hz),4.027(t,1H,J＝10.0Hz),3.906(t,2H,J＝6.4Hz),3.503(m,1H),3.027(dd,1H,J＝15.6,11.2Hz),2.874(dd,1H,J＝15.6,4.4Hz),2.662(m,2H),1.70～1.90(m,4H),1.482(m,2H),1.351(s,3H),1.337(s,3H),0.977(t,3H,J＝7.2Hz)。

¹³C-NMR(CDCl₃):158.793,154.331,152.721,152.092,128.047,127.461,119.777,112.909,109.299,109.248,106.628,102.511,73.786,70.023,67.738,32.317,31.756,31.227,30.626,26.777,26.390,19.193,17.117,13.807。

Example 18: 3- (2-hydroxy-4-n-pentyloxyphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f]Synthesis of benzopyran (Compound 19)

3- (2-hydroxy-4-n-pentyloxyphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ] benzopyran (Compound 19) was obtained in the same manner as in example 2 above, except that methyl (2-benzyloxy-4-n-pentyloxyphenyl) acetate was used instead of methyl (2-benzyloxy-4-methylphenyl) acetate.

¹H-NMR(CDCl₃):7.008(d,1H,J＝8.0Hz),6.847(d,1H,J＝8.0Hz),6.482(dd,1H,J＝8.0,2.4Hz),6.409(d,1H,J＝8.0Hz),6.355(d,1H,J＝2.4Hz),5.324(s,1H),4.408(m,1H,J＝10.4Hz),4.029(t,1H,J＝10.4Hz),3.897(t,2H,J＝6.4Hz),3.494(m,1H),3.028(dd,1H,J＝15.6,11.2Hz),2.875(m,1H,J＝15.6,4.4Hz),2.663(m,2H),1.71～1.88(m,4H),1.35～1.50(m,4H),1.353(s,3H),1.338(s,3H),0.941(t,3H,J＝7.2Hz)。

¹³C-NMR(CDCl₃):158.726,154.374,152.646,152.062,128.017,127.468,119.767,112.957,109.290,109.222,106.546,102.460,73.833,70.016,68.022,32.287,31.706,30.571,28.862,28.121,26.750,26.362,22.403,17.102,13.997。

Example 19: 3- (2-hydroxy-4- (3-methylbutoxy) phenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydro Pyran [2,3-f ]]Synthesis of benzopyran (Compound 20)

3- (2-hydroxy-4- (3-methylbutyloxy) phenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ] benzopyran (Compound 20) was obtained by the same procedure as in example 2 above, except that methyl (2-benzyloxy-4- (3-methylbutyloxy) phenyl) acetate was used instead of methyl (2-benzyloxy-4-methylphenyl) acetate.

¹H-NMR(CDCl₃):7.001(d,1H,J＝8.4Hz),6.833(d,1H,J＝8.4Hz),6.477(dd,1H,J＝8.4,2.4Hz),6.381(d,1H,J＝8.4Hz),6.352(d,1H,J＝2.4Hz),4.852(s,1H),4.387(m,1H,J＝10.4,2.0,1.2Hz),4.015(t,1H,J＝10.4Hz),3.939(t,2H,J＝6.4Hz),3.470(m,1H),3.014(dd,1H,J＝15.6,11.2Hz),2.866(m,1H,J＝15.6,3.6,1.6Hz),2.659(m,2H),1.802(m,1H),1.774(t,2H,J＝6.4Hz),1.654(q,2H,J＝6.4Hz),1.331(s,3H),1.317(s,3H),0.951(d,6H,J＝6.4Hz)。

¹³C-NMR(CDCl₃):158.881,154.197,152.861,152.137,128.120,127.459,119.736,112.789,109.298,109.284,106.724,102.561,73.700,70.031,66.431,37.940,32.345,31.805,30.710,26.839,26.434,25.031,22.573,17.150。

Example 20: 3- (2-hydroxy-4- (methoxymethoxy) phenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydro Pyran [2,3-f ]]Synthesis of benzopyran (Compound 21)

3- (2-hydroxy-4- (methoxymethoxy) phenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ] benzopyran (Compound 21) was obtained in the same manner as in example 2 above, except that methyl (2-benzyloxy-4- (methoxymethoxy) phenyl) acetate was used instead of methyl (2-benzyloxy-4-methylphenyl) acetate.

¹H-NMR(CDCl₃):7.023(d,1H,J＝8.4Hz),6.839(d,1H,J＝8.4Hz),6.615(dd,1H,J＝8.4,2.4Hz),6.524(d,1H,J＝2.4Hz),6.396(d,1H,J＝8.4Hz),5.443(s,1H),5.142(s,2H),4.400(m,1H,J＝10.4,3.2,2.4Hz),4.028(t,1H,J＝10.4Hz),3.514(m,1H),3.487(s,3H),3.020(dd,1H,J＝15.6,11.2Hz),2.892(m,1H,J＝15.6,5.2,1.6Hz),2.653(m,2H),1.783(t,2H,J＝6.8Hz),1.342(s,3H),1.327(s,3H)。

¹³C-NMR(CDCl₃):156.730,154.424,152.790,152.106,128.178,127.448,121.402,112.808,109.314,109.295,108.608,103.952,94.398,73.752,69.932,55.957,32.337,31.833,30.573,26.783,26.405,17.123。

Example 21: 3- (2-hydroxy-4- (2-methoxyethoxy) phenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexa Hydropyran [2,3-f ]]Synthesis of benzopyran (Compound 22)

3- (2-hydroxy-4- (2-methoxyethoxy) phenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ] benzopyran (Compound 22) was obtained in the same manner as in example 2 above, except that methyl (2-benzyloxy-4- (2-methoxyethoxy) phenyl) acetate was used instead of methyl (2-benzyloxy-4-methylphenyl) acetate.

¹H-NMR(CDCl₃):6.976(d,1H,J＝8.4Hz),6.833(d,1H,J＝8.4Hz),6.489(d,1H,J＝2.4Hz),6.433(dd,1H,J＝8.4,2.4Hz),6.386(d,1H,J＝8.4Hz),6.170(s,1H),4.388(m,1H,J＝10.4,2.4Hz),4.083(t,2H,J＝4.4Hz),3.997(t,1H,J＝10.4Hz),3.784(t,2H,J＝4.4Hz),3.500(m,1H),3.475(s,3H),3.006(dd,1H,J＝15.6,11.2Hz),2.853(m,1H,J＝15.6,3.6Hz),2.650(t,2H),1.777(t,2H,J＝6.8Hz),1.336(s,3H),1.322(s,3H)。

¹³C-NMR(CDCl₃):158.296,154.797,152.783,152.137,127.862,127.448,120.507,112.917,109.274,109.231,105.465,103.206,73.683,71.131,66.834,59.012,32.346,31.791,30.559,26.802,26.410,17.130。

Example 22: 3- (2-hydroxy-4-methoxyphenyl) -8, 8-diethyl-2, 3,4,8,9, 10-hexahydropyran [2, 3-f]synthesis of benzopyran (Compound 23)

(1)2- (2-benzyloxy-4-methoxyphenyl) -3- (2, 2-diethyl-5-hydroxy-2H-1-benzopyran-6-yl) Production of methyl acrylate

Except that methyl (2-benzyloxy-4-methylphenyl) acetate } was replaced with methyl (2-benzyloxy-4-methoxyphenyl) acetate prepared in the above preparation example 10, and the 6-formyl-2, 2-dimethyl-2H-benzopyran-5-benzoic acid prepared from the preparation example 14 was used in place of the 6-formyl-2, 2-diethyl-2H-benzopyran-5-benzoic acid, by carrying out the operation in the same manner as in example 2 above, methyl2- (2-benzyloxy-4-methoxyphenyl) -3- (2, 2-diethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate was obtained.

¹H-NMR(CDCl₃):7.857(s,1H),7.24～7.36(m,5H),6.973(d,1H,J＝8.4Hz),6.677(d,1H,J＝10.0Hz),6.675(d,1H,J＝8.4Hz),6.550(d,1H,J＝2.4Hz),6.441(dd,1H,J＝8.4,2.4Hz),6.172(d,1H,J＝8.4Hz),5.620(s,H),5.412(d,1H,J＝10.0Hz),5.022(s,2H),3.783(s,3H),3.700(s,3H),1.699(m,2H),1.602(m,2H),0.901(t,6H)。

¹³C-NMR(CDCl₃):168.950,160,945,157.335,155.775,150.135,136.737,135.601,131.781,130.240,128.438,128.128,127.719,126.973,126.210,117.719,117.451,114.573,109.176,108.622,105.334,100.176,81.856,70.123,55.273,52.218,32.165,7.907。

(2)2- (2-benzyloxy-4-methoxyphenyl) -3- (2, 2-diethyl-5-hydroxy-2H-1-benzopyran-6-yl) Propane-1-ol

Except that methyl2- (2-benzyloxy-4-methoxyphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate obtained in the above (1) was used in place of methyl2- (2-benzyloxy-4-methoxyphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) acrylate, 2- (2-benzyloxy-4-methoxyphenyl) -3- (2, 2-diethyl-5-hydroxy-2H-1-benzopyran-6-yl) propan-1-ol was obtained by the same method as in example 13(2) above.

¹H-NMR(CDCl₃):7.547(s,1H),7.33～7.42(m,5H),7.181(d,1H,J＝8.0Hz),6.829(d,1H,J＝10.0Hz),6.680(d,1H,J＝8.0Hz),6.599(d,1H,J＝2.4hz),6.508(dd,1H,J＝8.0,2.4Hz),6.295(d,1H,J＝8.0Hz),5.452(d,1H,J＝10.0Hz),5.086(s,2H),3.817(m,1H),3.800(s,3H),3.741(m,1H),3.311(m,1H),3.083(dd,1H,J＝14.0,10.4Hz),2.696(dd,1H,J＝14.0,4.0Hz),2.427(b,1H),1.721(m,2H),1.666(m,2H),0.953(t,3H),0.938(t,3H)。

¹³C-NMR(CDCl₃):159.490,156.750,153.281,150.879,136.250,130.632,128.794,128.736,128.381,128.248,127.598,123.780,118.861,117.559,109.991,107.937,104.604,100.237,81.040,70.494,63.501,55.350,42.006,31.828,31.773,30.589,8.051,7.920。

(3)3- (2-benzyloxy-4-methoxyphenyl) -8, 8-diethyl-2, 3,4, 8-tetrahydropyran [2,3-f]Benzopyrazine Production of furans

With the exception of using 2- (2-benzyloxy-4-methoxyphenyl) -3- (2, 2-diethyl-5-hydroxy-2H-1-benzopyran-6-yl) propan-1-ol obtained in the above-mentioned (2) in place of 2- (2-benzyloxy-4-methoxyphenyl) -3- (2, 2-dimethyl-5-hydroxy-2H-1-benzopyran-6-yl) propan-1-ol, 3- (2-benzyloxy-4-methoxyphenyl) -8, 8-diethyl-2, 3,4, 8-tetrahydropyran [2,3-f ] benzopyran.

¹H-NMR(CDCl₃):7.28～7.45(m,5H),7.095(d,1H,J＝8.0Hz),6.846(d,1H,J＝8.0Hz),6.789(d,1H,J＝10.0Hz),6.598(d,1H,J＝2.0Hz),6.531(dd,1H,J＝8.0,2.0Hz),6.400(d,1H,J＝8.0Hz),5.482(d,1H,J＝10.0Hz),5.134(s,1H),5.087(s,2H),4.412(m,1H),4.061(t,1H,J＝10.0Hz),3.817(s,3H),3.702(m,1H),3.002(dd,1H,J＝15.6,10.8Hz),2.899(dd,1H,J＝15.6,4.4Hz),1.65～1.83(m,4H),0.96～1.02(m,6H)。

¹³C-NMR(CDCl₃):159.490,157.254,152.699,149.752,136.848,129.098,128.615,127.877,127.684,127.134,126.304,122.359,118.237,113.980,109.504,108.073,104.606,100.012,81.135,70.175,70.077,55.300,31.834,31.825,31.334,30.742,8.029,7.965。

(4)3- (2-hydroxy-4-methoxyphenyl) -8, 8-diethyl-2, 3,4,8,9, 10-hexahydropyran [2, 3-f)]Benzene and its derivatives Production of benzopyran

3- (2-hydroxy-4-methoxyphenyl) -8, 8-diethyl-2, 3,4, 8-tetrahydropyran [2,3-f ] benzopyran (Compound 23) was obtained by the same procedure as in example 13(4) above, except that 3- (2-benzyloxy-4-methoxyphenyl) -8, 8-diethyl-2, 3,4, 8-tetrahydropyran [2,3-f ] benzopyran obtained in the above-mentioned (3) was used instead of 3- (2-benzyloxy-4-methoxyphenyl) -8, 8-dimethyl-2, 3,4,8,9, 10-hexahydropyran [2,3-f ] benzopyran (Compound 23).

¹H-NMR(CDCl₃):7.027(d,1H,J＝8.4Hz),6.843(d,1H,J＝8.4Hz),6.493(dd,1H,J＝8.4,2.4Hz),6.422(d,1H,J＝8.4Hz),6.357(d,1H,J＝2.4Hz),5.184(s,1H),4.398(m,1H,J＝10.4,2.0,1.2Hz),4.026(t,1H,J＝10.4Hz),3.766(s,3H),3.498(m,1H),3.022(dd,1H,J＝15.6,11.2Hz),2.896(m,1H,J＝15.6,6.8,2.0Hz),2.619(m,2H),1.787(t,2H,J＝6.8Hz),1.55～1.75(m,4H),0.88～0.95(m,6H)。

¹³C-NMR(CDCl₃):159.248,154.383,152.918,152.031,128.137,127.390,120.145,112.642,109.810,109.416,105.987,102.114,77.969,70.004,55.290,31.826,30.665,28.123,27.794,27.458,16.489,7.592。

Experimental example 1: PTP1B inhibition assay

The degree of Inhibition (IC) of glabridin, the compounds of production example 2 (compound 1), example 2 (compound 3), example 3 (compound 4), example 4 (compound 5), example 13 (compound 14), example 14 (compound 15), example 15 (compound 16), example 17 (compound 18), example 18 (compound 19) and example 20 (compound 21) was compared with PTP1B for the compound of glabridin₅₀). For this purpose, the degree of decarbonylation was measured using 2mM p-NPP (p-nitrophenylphosphate) as a substrate, and the degree of inhibitory activity against PTP1B was examined. First, PTP1B diluted with distilled water was reacted with 2mM p-NPP { p-nitrophenyl phosphate,0.1M NaCl,1mM EDTA,50mM citrate pH6.0,1mM Dithiolite (DTT) }, and various concentrations of Compound 1 at 30 ℃ for 30 minutes, and then the reaction was terminated with a 1N-sodium hydroxide (NaOH) solution. The degree of Inhibition (IC) of the activity of PTP1B according to the concentration of Compound 1 was confirmed by measuring the absorbance (405nm) of the sample prepared by the above method₅₀). The same method was carried out for glabridin, compound 3, compound 4, compound 5, compound 14, compound 15, compound 16, compound 18, compound 19 and compound 21. The results are shown in table 1 and fig. 1.

[ Table 1]

Experimental group	IC50＝μM
		Glabridin	48
Compound 1	46
		Compound 3	7.0
Compound 4	2.9
		Compound 5	2.8
Compound 14	6.5
		Compound 15	8.6
Compound 16	1.9
		Compound 18	3.4
Compound 19	1.2
		Compound 21	2.3

As shown in table 1 and fig. 1, the compounds according to the present invention are thought to inhibit PTP1B 5 to 10 times as compared to glabridin.

Experimental example 2: experiment on anti-obesity Effect of DIO mice (DIO-mice)

Female C57BL/6 mice (NARA biotech) 5 weeks old were purchased and fed only with high fat diet for a minimum period of more than ten weeks to induce DIO (diet induced obesity). The compounds of production example 1 (glabridin) and examples of the present invention (compounds 1 to 5, 7, 9, 11, 14 to 16, 21 and 23) were accurately sampled according to the dose, put into a centrifuge tube (Falcon tube), and then 3ml of a 0.5% methylcellulose solution was added, and after lightly mixed once with a vortex mixer (vortex), the mixture was homogenized with a homogenizer (30,000rpm,t10Basic, IKA) for 3 minutes. The specimens prepared by the above method were orally administered once daily (oral gavage) for 28 days (4 weeks) with a disposable plastic syringe. DIO mice were raised by the above method and body weight was weighed 2 times per week. The anti-obesity effect (%) was calculated according to the following defined mathematical formula based on the data obtained by the above method.

Anti-obesity effect { (control group weight) - (experimental group weight) }/(control group weight) × 100

The results obtained by the above method are shown in table 2.

[ Table 2]

Compound numbering	Anti-obesity Effect (%)	Administration time and dosage
			Glabridin	2	150mg/kg for 4 weeks
Compound 1	8	150mg/kg for 4 weeks
			Compound 2	8	200mg/kg for 4 weeks
Compound 3	19	200mg/kg for 4 weeks
			Compound 4	18	150mg/kg for 4 weeks
Compound 5	19	150mg/kg for 4 weeks
			Compound 7	14	150mg/kg for 4 weeks
Compound 9	10	150mg/kg for 4 weeks
			Compound 11	8	150mg/kg for 4 weeks
Compound 14	12	150mg/kg for 4 weeks
			Compound 15	14	150mg/kg for 4 weeks
Compound 16	7	150mg/kg for 4 weeks
			Compound 21	16	150mg/kg for 4 weeks
Compound 23	11	200mg/kg for 4 weeks

As shown in the above Table 2, the anti-obesity activity of the pyranookra fiber isocresol derivative according to the present invention is significantly superior to that of glabridin.

As described above, 28 days (4 weeks) after the experiment, the experimental animals were finally discarded and blood was taken, and different organs (liver, heart, kidney, pancreas, adipose tissue) were extracted and weighed, and special matters were observed.

[ Table 3]

And (4) Dose: dosage form

BMI: body Mass indexes (Body weight index)

Liver: weight of liver

Fat: weight of fat extracted from accessory testis and periphery of kidney

AST: aspartame aminotransferase; aspartate aminotransferase

ALT: an Alanine aminotransferase; alanine aminotransferase

LDL: a Low dense lipoprotein; low density lipoprotein

FFA: free failure acid; free fatty acids

In the above table 3, { }, (-), etc. are used for distinguishing experiments performed at different periods. The experiments without brackets were all performed simultaneously under the same conditions.

As shown in table 3, since the weight loss of DIO mice and the weight loss of adipose tissues are closely related to each other during the administration of the pyrano-okra cello-cresol derivative of the present invention, it was confirmed that the biochemical index was improved in a better direction as the BMI of DIO mice was decreased.

Experimental example 3: c ₂C₁₂ Glucose uptake (uptake) assay in cells

The compound of example 14 (compound 15) of the present invention was targetedTo mix C₂C₁₂The glucose uptake capacity in cells was compared with that of rosiglitazone (rosiglitazone) and Metformin (Metformin) which have been used or are in use as a diabetes therapeutic agent. At 5% CO₂Next, C was cultured in a medium (Dulbecco's modified eagle medium; DMEM) containing 10% Fetal Bovine Serum (FBS), penicillin (120unit/mL) and streptomycin (75. mu.g/mL)₂C₁₂Cells, the medium for differentiation was DMEM medium containing 1% horse serum (horse serum), and C was cultured₂C₁₂The cells were incubated for four days. Culturing the cells in a medium containing 2- [ N- (7-nitrophenyl-2-oxo-1, 3-oxadiazol-4-yl) amino group]Low-sugar serum-free (low-glucose, serum-free) medium of-2-deoxy-d-glucose (2-NBDG), treated with compound 15 for 24 hours, and glucose absorbance was measured at an excitation wavelength of 485nm and an emission wavelength of 535nm using a fluorescence detector. The same process was also performed for rosiglitazone and metformin. The results of the experiment are shown in table 4 below.

[ Table 4]

As shown in table 4 above, compound 15 is superior in glucose absorption-promoting ability to the existing therapeutic agents for diabetes.

Experimental example 4: db/db rat (db/db-mie) antidiabetic effect experiment

C57BLKS/J-db/db, male, 5 week old (central laboratory animals) were purchased and acclimated for 2 weeks before use in the experiment. The compounds (compounds 5 and 16) prepared in example 4 and example 15 in the examples of the present invention were accurately sampled according to the dose, and then placed in a centrifuge tube, and a 0.5% methylcellulose aqueous solution in refrigerated storage was left at room temperature, and then the excipient was brought to room temperature, and after that, 16ml of each 50ml centrifuge tube was added, followed by gently mixing once with a vortex mixer, and then treated with a homogenizer (30,000rpm, CPT-1600E, Kinemtica, Sweitzerland) for 3 minutes to suspend and homogenize the mixture, and then further subjected to ultrasonic treatment for 30 minutes. The sample prepared by the above method was orally administered once a day for 42 days (6 weeks) using a disposable syringe attached to an oral administration probe (oralgavage).

Db/db mice were bred by the above method, and glycated hemoglobin (HbA1c) was measured. Glycated hemoglobin measurements were performed 2 days before, 4 weeks after, and 6 weeks after group separation, wherein blood was drawn from the tail vein and measured with a glycated hemoglobin meter (SD A1cCare, SDBiosensor, inc., Korea) 4 hours after the day of measurement and before administration of each substance, 4 hours after the day of measurement. The measurement results are shown in table 5 below.

[ Table 5]

As shown in Table 5 above, the pyrano-okra fiber isocresol derivatives according to the present invention can adjust blood glucose to almost normal levels (normal blood glucose: HbA1c 6.0.0 or less).

In this example, after 6 weeks after administration of compound 16, a dissection was performed after final elimination, and after the extracted rat liver was incised, the tissue was observed with a microscope after being stained with H & E (hematoxin and eosin; hematoxylin and eosin) and lipid droplet-coated protein antibody (perilipin antibody), respectively, and the results are shown in fig. 2 and fig. 5. For comparison of photomicrographs of the case where compound 16 was administered (fig. 2a, 3a, 4a, 5a), photographs of a control group to which no drug was administered (fig. 2b, 3b, 4b, 5b) are shown.

FIG. 2a is a photomicrograph (at 100X magnification) of H & E (hematoxin and eosin; hematoxylin and eosin) stained liver tissues of mice extracted by a dissection examination after the final elimination of compound 16 of the present invention after 6 weeks of administration. Figure 2b is a photomicrograph of a control group not administered compound 16. FIG. 3a is a photomicrograph (200X magnification) of H & E (hematoxin and eosin; hematoxylin and eosin) stained liver tissues of mice extracted by a dissection after 6 weeks of administration of Compound 16 of the present invention after final elimination. Figure 3b is a photomicrograph of a control group not administered compound 16. Fig. 4a is a photomicrograph (at 100-fold magnification) of liver tissue of mice, which was extracted by dissection after final elimination after 6 weeks of administration of compound 16 of the present invention, stained with lipid droplet-coated protein antibody (perilipin antibody). Figure 4b is a photomicrograph of a control group not administered compound 16. Fig. 5a is a photomicrograph (200-fold magnification) of a lipid droplet-coated protein antibody (perilipin antibody) stained rat liver tissue extracted by a dissection after final elimination after 6 weeks of administration of compound 16 of the present invention.

As shown in fig. 2 to 5, in contrast to the control group in which giant adipocytes occupy more space and can find more necrotic cells, the liver tissues of mice to which compound 16 was administered were smaller and dense, and thus were healthy on an overall level.

Experimental example 5: BV2 cell NO assay (anti-inflammatory efficacy confirmation assay)

In 96-well plates, at 1 × 10⁴Concentration of cells/well after culturing BV2 microroglia cells (microglia) for 24 hours, the compounds were pretreated for 3 hours at 3 concentrations that did not inhibit cell proliferation (5. mu.M, 10. mu.M and 20. mu.M for glabridin; 2.5. mu.M, 5. mu.M and 10. mu.M for compound 4,5, 15, 16 and 18). After pretreatment, 0.5mg/ml of MTT (Sigma, M2128) reagent was additionally added. At 5% CO₂After culturing for 4 hours, the supernatant was removed, 150. mu.l of DMSO was added, the mixture was shaken for 30 minutes, and then the absorbance was measured at a wavelength of 540nm using an ELISA microplate reader (ELISA micro plate reader; Bio Rad Laboratories Inc., California, USA, Model 680). Calculating cell protection rate of control group by using 3 times of repeated experiment values, averaging to obtain all experiment values, and generating no cytotoxicityThe NO production inhibition experiment was performed for each compound at the concentration of (2).

At 5 × 10⁵After 24 hours of incubation of BV2 microroglia cells (microglia) in 24-well plates at cell/well level, compounds were pretreated for 3 hours at 3 concentrations that did not inhibit cell proliferation (5 μ M, 10 μ M and 20 μ M for glabridin; 2.5 μ M, 5 μ M and 10 μ M for compounds 4,5, 15, 16 and 18) followed by LPS (1 μ g/ml) treatment and 24 hours later the amount of NO dispensed from the medium was reflected with Griess reagent (0.1% (w/v) N- (1-napthyl) -ethylene diamine and 1% (w/v) sulfonilamide in 5% (v/v) phosphoric acid). After the reaction, measurement was performed at 540nm using an ELISA plate reader (ELISAmicro plate reader; Bio Rad Laboratories Inc., California, USA, Model 680). The inhibition rate was calculated from the difference in NO production amount between the experimental group and the control group, and as shown in table 6 and fig. 6 below, the compounds 4,5, 15, 16, 18, etc. of the present invention exhibited superior NO production inhibition effects, even 5 to 9 times as much as glabridin.

[ Table 6]

Compound (I)	BV2(IC50)(μM)
		Glabridin	19.6
Compound 4	3.7
		Compound 5	3.8
Compound 15	2.7
		Compound 16	2.3
Compound 18	2.8

Example 6: NO assay of RAW264.7 macrophage (anti-inflammatory efficacy test)

In 96-well plates, at 1 × 10⁴Cell/well concentration RAW264.7 macrophages were cultured for 24 hours and compounds were pretreated for 3 hours at 3 concentrations that did not inhibit cell proliferation (10. mu.M, 20. mu.M and 40. mu.M for glabridin; 5. mu.M, 10. mu.M and 20. mu.M for compound 4, compound 5, compound 15, compound 16 and compound 18). After pretreatment, MTT (Sigma, M2128) reagent was added at a concentration of 0.5 mg/ml. At 5% CO₂After culturing for 4 hours, the supernatant was removed, 150. mu.l of DMSO was added, the mixture was shaken for 30 minutes, and then the absorbance was measured at a wavelength of 540nm using an ELISA microplate reader (ELISA microplate reader; Bio Rad Laboratories Inc., California, USA, Model 680). All the test values were obtained by calculating the cell protection ratio with respect to the control group using the repeated test values of 3 times, respectively, and averaging, and NO production inhibition tests were performed on each compound at a concentration that did not cause cytotoxicity.

At 5 × 10⁵RAW264.7 macrophages were cultured in 24-well plates at a cell/well level for 24 hours at 3 concentrations that did not inhibit cell proliferation (10. mu.M, 20. mu.M, and 40. mu.M for glabridin; 5. mu.M, 10. mu.M, and 20. mu.M for Compound 4, Compound 5, Compound 15, Compound 16, and Compound 18)M concentration), the compound was pretreated for 3 hours, then treated with LPS (1 μ g/ml), and the amount of NO dispensed from the medium was reacted with Griess reagent (0.1% (w/v) N- (1-napthyl) -ethylene diamine and 1% (w/v) sulfonilamide in 5% (v/v) phosphoricid) after 24 hours. After the reaction, measurement was performed at 540nm using an ELISA microplate reader (ELISA microplate reader; Bio Rad Laboratories Inc., California, USA, Model 680). The inhibition rate was calculated from the difference in NO production amount between the test group and the control group, and as shown in table 7 below, the compounds 4,5, 15, 16, 18 and the like of the present invention exhibited superior NO production inhibition effects.

[ Table 7]

Experimental example 7: comparative experiment of chemical stability

The relative chemical stability of glabridin of production example 1, and example 3 (compound 4), example 4 (compound 5) and example 14 (compound 15) were compared. That is, glabridin, compound 4, compound 5, and compound 15 were accurately weighed at 50mg, melted in 50ml of a 1% HCl MeOH solution and 10ml of a 1% NaOH MeOH solution, and then the concentrations thereof were obtained by HPLC at 0 hour, 8 hour, 12 hour, 24 hour, 48 hour, and 72 hour. At this time, the concentration of the reagent remaining in a 1% HCl and 1% NaOH solution in MeOH was determined using an internal standard (compound 14 of example 13). Specifically, after 10mg of compound 14 was accurately check-weighed and melted in 100ml of acetonitrile, 9ml of this solution was mixed with 1ml of each reagent obtained at different times, and the mixture was analyzed by HPLC, whereby the concentration of the internal standard and the concentration remaining in each obtained reagent were determined by comparison with the initial values.

The residual concentrations of reagents in the time-phased 1% HCl in MeOH solutions for these samples are shown in table 8 below and fig. 7, and the residual concentrations in the 1% NaOH in MeOH solutions are shown in table 9 below and fig. 8.

In tables 8 and 9 below, the values exceeding 100% refer to the measured concentration slightly higher than the initial measured value because it is simply represented by the average value of the measured values without considering the statistical error generated at the time of measurement. The measurement value of about 95% or more is considered to have no substantial concentration change, and therefore the chemical stability of the compound of the present invention is excellent.

[ Table 8]

1% HCl in MeOH	0	8h	24h	48h	72h
						Glabridin	100％	99％	94％	82％	74％
Compound 4	100％	99％	101％	101％	100％
						Compound 5	100％	102％	102％	101％	101％
Compound 15	100％	98％	100％	98％	100％

[ Table 9]

1% NaOH in MeOH	0	8h	24h	48h	72h
						Glabridin	100％	71％	38％	23％	13％
Compound 4	100％	101％	101％	99％	100％
						Compound 5	100％	101％	102％	100％	102％
Compound 15	100％	100％	100％	98％	100％

As shown in said tables 8 and 9, unlike glabridin, compound 4, compound 5 and compound 15 according to the present invention were quite stable within three days (72 hours) under the conditions of 1% HCl in MeOH and 1% NaOH in MeOH.

Claims (17)

1. A compound of the formula (I), a pharmacologically acceptable salt thereof, or a solvate thereof,

[ chemical formula 1]

In the above-mentioned chemical formula, the metal oxide,

R¹is a hydrogen atom, a methyl group, a methoxy group or a halogen atom,

R²is a hydrogen atom, substituted orUnsubstituted straight or branched chain C₁-C₆Alkyl, halogen, substituted or unsubstituted, straight or branched C₁-C₆Alkoxy, or substituted or unsubstituted, straight or branched C₁-C₄A thioalkyl group,

R³and R⁴Each independently is a hydrogen atom or C₁-C₂An alkyl group, a carboxyl group,

wherein, for substituted alkyl, substituted alkoxy and substituted thioalkyl, the substituent is straight or branched chain C₁-C₅Alkyl, halogen, straight or branched C₁-C₅Alkoxy, or straight or branched C₁-C₃A thioalkyl group.

2. The compound of formula (I), a pharmacologically acceptable salt thereof, or a solvate thereof according to claim 1, wherein,

the R is¹Is a hydrogen atom;

the R is²Is a hydrogen atom, straight or branched C₁-C₆Alkyl, straight or branched C₁-C₅Alkoxy, or straight or branched C₁-C₃A thioalkyl group.

3. The compound of formula (I), a pharmacologically acceptable salt thereof, or a solvate thereof according to claim 2, wherein,

the R is¹Is a hydrogen atom;

the R is²Is methyl, ethyl, n-propyl, n-butyl, ethoxy, n-propoxy, n-butoxy, or methoxymethoxy.

4. The compound of formula (I), a pharmacologically acceptable salt thereof, or a solvate thereof according to claim 1, wherein the compound of formula (I) is any one of the following compounds:

5. a pharmaceutical composition for the prevention or treatment of metabolic syndrome, comprising a compound of the following formula (I'), a pharmacologically acceptable salt thereof, or a solvate thereof,

in the above-mentioned chemical formula, the metal oxide,

R¹is a hydrogen atom, a methyl group, a methoxy group or a halogen atom,

R²is a hydrogen atom, a hydroxyl group, a substituted or unsubstituted straight or branched C₁-C₆Alkyl, halogen, substituted or unsubstituted, straight or branched C₁-C₆Alkoxy, or substituted or unsubstituted, straight or branched C₁-C₄A thioalkyl group,

R³and R⁴Each independently is a hydrogen atom or C₁-C₂An alkyl group, a carboxyl group,

wherein, for substituted alkyl, substituted alkoxy and substituted thioalkyl, the substituent is straight or branched chain C₁-C₅Alkyl, halogen, straight or branched C₁-C₅Alkoxy, or straight or branched C₁-C₃A thioalkyl group.

6. The pharmaceutical composition for the prevention or treatment of metabolic syndrome according to claim 5, wherein, in the formula (I'),

R¹is a hydrogen atom;

R²is a hydrogen atom, a hydroxyl group, a straight chain or branched C₁-C₆Alkyl, straight or branched C₁-C₅Alkoxy, or straight or branched C₁-C₃A thioalkyl group.

7. The pharmaceutical composition for the prevention or treatment of metabolic syndrome according to claim 6, wherein, in the formula (I'),

R¹is a hydrogen atom;

R²is methyl, ethyl, n-propyl, n-butyl, ethoxy, n-propoxy, n-butoxy, or methoxymethoxy.

8. The pharmaceutical composition for the prophylaxis or treatment of metabolic syndrome according to claim 5, wherein the compound of formula (I') is one or more compounds selected from the group consisting of:

9. the pharmaceutical composition for the prevention or treatment of metabolic syndrome according to claim 5, wherein said metabolic syndrome is one or more of obesity, diabetes, hyperlipidemia and fatty liver.

10. The pharmaceutical composition for the prevention or treatment of metabolic syndrome according to claim 9, wherein said diabetes is type ii diabetes.

11. The pharmaceutical composition for the prevention or treatment of metabolic syndrome as claimed in claim 5, wherein said metabolic syndrome is a complex disease of type II diabetes and obesity.

12. A pharmaceutical composition for the prevention or treatment of inflammatory diseases, comprising a compound of the following formula (I'), a pharmacologically acceptable salt thereof, or a solvate thereof,

in the chemical formula, the compound represented by the formula,

R¹is a hydrogen atom, a methyl group, a methoxy group or a halogen atom,

R²is a hydrogen atom, a hydroxyl group, a substituted or unsubstituted straight or branched C₁-C₆Alkyl, halogen, substituted or unsubstituted, straight or branched C₁-C₆Alkoxy, or substituted or unsubstituted, straight or branched C₁-C₄A thioalkyl group,

R³and R⁴Each independently is a hydrogen atom or C₁-C₂An alkyl group, a carboxyl group,

wherein, for substituted alkyl, substituted alkoxy and substituted thioalkyl, the substituent is straight or branched chain C₁-C₅Alkyl, halogen, straight or branched C₁-C₅Alkoxy, or straight or branched C₁-C₃A thioalkyl group.

13. The pharmaceutical composition for the prophylaxis or treatment of inflammatory diseases according to claim 12, wherein, in the formula (I'),

R¹is a hydrogen atom;

R²is a hydrogen atom, a hydroxyl group, a straight chain or branched C₁-C₆Alkyl, straight or branched C₁-C₅Alkoxy, or straight or branched C₁-C₃A thioalkyl group.

14. The pharmaceutical composition for the prophylaxis or treatment of inflammatory diseases according to claim 12, wherein, in the formula (I'),

R¹is a hydrogen atom;

is methyl, ethyl, n-propyl, n-butyl, ethoxy, n-propoxy, n-butoxy, or methoxymethoxy.

15. The pharmaceutical composition for the prophylaxis or treatment of an inflammatory disease according to claim 12, wherein the compound represented by the formula (I') is 1 or more compounds among the following compounds:

16. the pharmaceutical composition for the prophylaxis or treatment of inflammatory diseases according to claim 12, wherein, in the formula (I'),

R¹is a hydrogen atom;

R²is methyl, ethyl, n-propyl, n-butyl, ethoxy, n-propoxy, n-butoxy, or methoxymethoxy.

17. The pharmaceutical composition for preventing or treating an inflammatory disease according to claim 12, wherein the inflammatory disease is one or more of the following diseases:

rheumatoid arthritis;

degenerative arthritis; and

inflammatory diseases caused by asthma, allergy, diabetes or myocardial infarction.