KR20080088764A - Chromen-4-one derivatives for the treatment or prevention of ischemia - Google Patents

Abstract

Chromen-4-one derivatives are provided to protect cells in the ischemic area by controlling calcium homeostasis and HSP(heat shock protein) expression, so that the compounds are useful for the treatment or prevention of ischemic diseases including angina pectoris, myocardial infarction, cerebral apoplexy and cerebral vascular dementia. Chromen-4-one derivatives represented by the formula(1) are useful for treatment or prevention of ischemic diseases, wherein X is single bond, O, S, S(O), SCH2, Se, NH, CH2, CH2CH2 or CH=CH; R1 is C1-C6 alkyl group; phenyl group optionally substituted by halogen atom, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylcarbonate or amino C1-C6 alkylcarbonate; pyridine group; or piperidine group optionally substituted by C1-C6 alkyl or C1-C6 alkoxy group; R2 is hydrogen atom or C1-C6 alkyl group; R3 is hydrogen atom, hydroxyl, C1-C6 alkoxy group, or C1-C6 alkylcarbonate group; R4 is hydrogen atom, halogen atom, hydroxyl group, C1-C6 alkyl group or C1-C6 alkoxy group; R5 is halogen atom; C1-C6 alkyl group, C1-C6 alkylcarbonate group, C1-C6 alkylhydroxy C1-C6 alkanoate group; hydroxyl group; C1-C6 alkoxy group; hydroxyl C1-C6 alkoxy group; benzyl C1-C6 alkoxy group optionally substituted by halogen atom, C1-C6 alkyl or C1-C6 alkoxy group; phenyl C1-C6 alkoxy group optionally substituted by C1-C6 alkyl or C1-C6 alkoxy group; pyridinyl C1-C6 alkoxy group; oxypyridinyl C1-C6 alkoxy group; piperidinyl C1-C6 alkoxy group; or morpholinyl C1-C6 alkoxy group; and R6 is hydrogen atom, halogen atom, C1-C6 alkyl group or C2-C6 alkenyl group.

Description

Chromen-4-one derivatives for the treatment or prevention of ischemia

Figure 1 is a photograph confirmed by confocal microscopy (confocal microscopy) for the evaluation of myocardial protective activity through the regulation of intracellular calcium constant according to Experimental Example 3.

Figure 2 is a photograph confirming the change in the thickness of the ventricular wall due to the drug in the left anterior descending artery ligation ischemic animal model according to the practical example 4.

The present invention relates to a chromen-4-one compound effective for the prevention and treatment of ischemic diseases.

Ischemic stroke or ischemic heart disease, represented by ischemic disease, causes damage to cerebral nerve cells and heart cells due to ischemia, in which the cerebral artery or coronary artery is closed by blood clots or atherosclerosis and the blood flow decreases below the threshold. Eventually, cell death causes brain infarction and myocardial infarction.

Thus, drugs that prevent or promote regeneration by ischemia can be used as a fundamental therapeutic agent for ischemic brain disease or heart disease.

Ischemic heart disease and cerebrovascular disease represented by myocardial infarction and stroke are the leading cause of death in Korea and around the world.

Drugs currently used for the prevention and treatment of ischemic diseases include beta blockers, nitrates, and calcium channels in order to lower the oxygen demand at the ischemic area to prevent seizures of the ischemic disease or to maintain the therapeutic effect after the seizure. Calcium channel blockers are used, and Thrombolytic agents, Anti-thrombin agents, and Anti-platelet agents are used for perfusion of the ischemic site after a disease attack.

These drugs are not effective or safe, and there is a constant need for new mechanisms for treating ischemic diseases.

Recent studies on ischemic diseases focus on developing drugs that can inhibit or cure cell and tissue damage after ischemia, compared to thrombolytic and coagulation inhibitors, which are less safe and likely to be of limited use.

Na ⁺ / H ⁺ -exchanger (NHE-1) and K ⁺ -channels, which are thought to be involved in the mechanism of inhibiting damage to ischemic cells and tissues by combining with drugs currently used for ischemic diseases for various purposes. Efforts are underway to develop drugs that can protect cardiomyocytes from death due to ischemia and reperfusion, and focus on developing neuroprotective agents that act on targets such as NMDA and glycine receptors during stroke. It is becoming.

Recently, research has been conducted as heat shock protein (HSP) and adenosine receptor A1 are known to be targets for inhibiting apoptosis.

Attention in the present invention is the regulation of homeostasis of calcium excessively released into the cytoplasm under ischemic conditions leading to cell death, and the relationship between HSP and calcium homeostasis control is very important. Until now, it is known that calcium is over-free under ischemic conditions. HSP is also over-expressed under ischemic conditions, indicating a cytoprotective effect. Recently, calcium over-free causes the expression of HSP27 protein, and over-expression of HSP70 causes It has been reported that it suppresses the excessive glass of calcium. Taken together, the discovery of drugs using the relationship between calcium homeostasis and HSP expression is expected to lead to the development of a new concept for treating ischemic diseases.

However, there are few reports on ischemic disease treatment substances that modulate intracellular expression and action of HSP that can improve cell survival under ischemic conditions and protect cells by regulating calcium homeostasis.

The present invention newly confirmed that the chromatin-4-one compound of Korean Patent Publication No. 2006-73834 published by the present applicant has a distinct effect in preventing and treating ischemic disease through the regulation of HSP expression and calcium homeostasis. It was completed by doing.

It is an object of the present invention to provide a new medicinal use using the chromen-4-one compound disclosed in Korean Patent Laid-Open No. 2006-73834 as an agent for preventing and treating ischemic disease.

The present invention is characterized by a pharmaceutical composition or medicament for the prevention and treatment of ischemic diseases containing a chromium-4-one derivative represented by the following formula (1), a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof as an active ingredient It is done.

In Chemical Formula 1,

X is a single bond; O; S; S (O); SCH ₂ ; Se; NH; CH ₂ ; CH ₂ CH ₂ ; Or CH = CH, R ₁ is a C ₁ -C ₆ alkyl group; A phenyl group unsubstituted or substituted with a substituent selected from a halogen atom, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylcarbonate and aminoC ₁ -C ₆ alkylcarbonate group; Pyridine group; Or a piperidine group unsubstituted or substituted with a substituent selected from a C ₁ -C ₆ alkyl and a C ₁ -C ₆ alkoxy group, R ₂ is a hydrogen atom; Or a C ₁ -C ₆ alkyl group, R ₃ is a hydrogen atom; Hydroxy; C ₁ -C ₆ alkoxy group; Or a C ₁ -C ₆ alkylcarbonate group, R ₄ is a hydrogen atom; Halogen atom; Hydroxyl group; C ₁ -C ₆ alkyl group; Or a C ₁ -C ₆ alkoxy group, R ₅ is a halogen atom; C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkylcarbonate group; C ₁ -C ₆ alkylhydroxy C ₁ -C ₆ alkanoate groups; Hydroxyl group; C ₁ -C ₆ alkoxy group; HydroxyC ₁ -C ₆ alkoxy group; A benzylC ₁ -C ₆ alkoxy group unsubstituted or substituted with a substituent selected from a halogen atom, a C ₁ -C ₆ alkyl and a C ₁ -C ₆ alkoxy group; _A phenylC ₁ -C ₆ alkoxy group unsubstituted or substituted with a substituent selected from a C ₁ -C ₆ alkyl and a C ₁ -C ₆ alkoxy group; PyridinylC ₁ -C ₆ alkoxy group; OxypyridinylC ₁ -C ₆ alkoxy group; PiperidinylC ₁ -C ₆ alkoxy group; Or a morpholinylC ₁ -C ₆ alkoxy group, R ₆ is a hydrogen atom; Halogen atom; C ₁ -C ₆ alkyl group; Or a C ₂ -C ₆ alkenyl group, or R ₅ and R ₆ are bonded to each other to form a 5 to 7 membered hetero ring including an oxygen atom.

In the compound represented by the formula (1) is preferably as follows. X is a single bond; O; S; Se; CH ₂ CH ₂ ; Or CH = CH, R ₁ is a C ₁ -C ₆ alkyl group; A phenyl group unsubstituted or substituted with a substituent selected from a halogen atom, hydroxy, C ₁ -C ₆ alkyl, and C ₁ -C ₆ alkoxy; Pyridine group; Or a piperidine group unsubstituted or substituted with a substituent selected from a C ₁ -C ₆ alkyl and a C ₁ -C ₆ alkoxy group, R ₂ represents a hydrogen atom, R ₃ is hydroxy; Or a C ₁ -C ₆ alkylcarbonate group, R ₄ is a hydrogen atom; C ₁ -C ₆ alkyl group; Or a C ₁ -C ₆ alkoxy group, R ₅ is a C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkylcarbonate group; C ₁ -C ₆ alkylhydroxy C ₁ -C ₆ alkanoate groups; Hydroxyl group; C ₁ -C ₆ alkoxy group; HydroxyC ₁ -C ₆ alkoxy group; _A phenylC ₁ -C ₆ alkoxy group unsubstituted or substituted with a substituent selected from a C ₁ -C ₆ alkyl and a C ₁ -C ₆ alkoxy group; PyridinylC ₁ -C ₆ alkoxy group; OxypyridinylC ₁ -C ₆ alkoxy group; PiperidinylC ₁ -C ₆ alkoxy group; Or a morpholinylC ₁ -C ₆ alkoxy group, R ₆ is a hydrogen atom; Or a C ₂ -C ₆ alkenyl group, or R ₅ and R ₆ are bonded to each other to form a 5 to 7 membered heterocycle containing an oxygen atom.

Particularly preferred in the compound represented by the formula (1) is as follows. X represents a single bond, O, S, Se or CH = CH; R ₁ represents a cyclohexyl group, a phenyl group, a hydroxyphenyl group, a fluorophenyl group, toluene group, methoxyphenyl group, ethoxyphenyl group, pyridine group, piperidine group, or methyl piperidine group; R ₂ represents a hydrogen atom; R ₃ represents a hydroxy group, a methyl carbonate group or an ethyl carbonate group, R ₄ represents a hydrogen atom, a methyl group, an ethyl group, a methoxy group or an ethoxy group, and R ₅ represents a hydroxy group, a methyl group, an ethyl group, a methoxy group or an ethoxy group. Period, n-propoxy group, isopropoxy group, benzyl group, methoxybenzyloxy group, ethoxybenzyloxy group, methyl carbonate group, ethyl carbonate group, hydroxymethoxy group, hydroxyethoxy group, hydroxyprop Aoxy group, hydroxybutoxy group, ethyl acetate group, pyridinylmethoxy, pyridinylethoxy, oxypyridinylmethoxy, oxypyridinylethoxy, piperidinylmethoxy, piperidinylethoxy, piperidinyl Propoxy, morpholinylmethoxy or morpholinylethoxy; R ₆ represents a hydrogen atom, 3-methyl-but-2-enyl, or 1,1-dimethylallyl, or R ₅ and R ₆ are bonded to each other to form a 5- or 6-membered heterocycle including an oxygen atom This is the case for compounds that form.

In addition, the compound represented by Formula 1 according to the present invention may form a pharmaceutically acceptable salt, for example, salts with inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide and nitrate Or salts with organic acids such as maleate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p- toluenesulfonate, palmitate, salicylate and stearate It includes.

Some of the compounds of the present invention may be crystallized or recrystallized from solvents such as aqueous and organic solvents. In such cases, solvates may be formed. In addition to various amounts of water-containing compounds that can be prepared by methods such as lyophilization, stoichiometric solvates, including hydrates, are also within the scope of the present invention.

The compound represented by Formula 1 may be an enantiomer, stereoisomer or tautomer. Different isomers can be separated or resolved by conventional methods, or any given isomer can be obtained by conventional synthesis or by stereospecific or asymmetric synthesis.

In addition, the present invention includes a radioactive derivative of the compound represented by the formula (1), these radioactive compounds are useful in the field of biological research.

Specific examples of the compound represented by Formula 1 are shown in Table 1 below:

Compound number X R ₁ R ₂ R ₃ R ₄ R ₅ R ₆ One O 4- (OH) Ph H OH MeO OH H 2 O 4- (OH) Ph H OH MeO OH H 3 S 4- (OH) Ph H OH MeO OH H 4 Se 4- (OH) Ph H OH MeO OH H 5 O 4- (OH) Ph H i -PrO MeO i -PrO H 6 S 4- (OH) Ph H i -PrO MeO i -PrO H 7 NH 4- (OH) Ph H OH MeO OH H 8 NH 4- (OH) Ph H i -PrO MeO i -PrO H 9 O 4- (OH) Ph H OH H OH H 10 O 4- (OH) Ph H i -PrO H i -PrO H 11 S 4- (OH) Ph H OH H OH H 12 S 4- (OH) Ph H i -PrO H i -PrO H 13 CH ₂ 4- (OH) Ph H OH MeO OH H 14 CH ₂ 4- (OH) Ph H i -PrO MeO i -PrO H 15 O Cy H OH MeO OH H 16 S Cy H OH MeO OH H 17 O Ph H OH MeO OH H 18 O Ph H i -PrO MeO i -PrO H 19 S Ph H OH MeO OH H 20 S Ph H i -PrO MeO i -PrO H 21 O 2-Py H OH MeO OH H 22 S 2-Py H OH MeO OH H 23 O 4-Py H OH MeO OH H 24 O 4-Py H i -PrO MeO i -PrO H 25 O 4-Py H OH MeO OH H 26 S 4-Py H OH MeO OH H 27 CH ₂ -CH ₂ 4- (OH) Ph H OH MeO OH H 28 SCH ₂ 4- (OH) Ph H OH MeO OH H 29 CH = CH 4- (OH) Ph H OH MeO OH H 30 CH = CH 4- ( i -PrO) Ph H i -PrO MeO i -PrO H

31 SO 4- (OH) Ph H OH MeO OH H 32 O 4- (MeO) Ph H MeO MeO MeO H 33 O Ph H OH MeO PMBO H 34 O Ph H OH H OH H 35 O Ph H OH H PMBO H 36 S Ph H OH MeO PMBO H 37 S Ph H OH H OH H 38 S Ph H OH H PMBO H 39 O 4- (OH) Ph H OH MeO PMBO H 40 O 4- (OH) Ph H OH H PMBO H 41 S 4- (OH) Ph H OH MeO PMBO H 42 S 4- (OH) Ph H OH H PMBO H 43 O 4-Py H OH H OH H 44 O 4-Py H OH H PMBO H 45 O 4- (MeCO ₂ ) Ph H MeCO ₂ MeO MeCO ₂ H 46 O 4- (EtCO ₂ ) Ph H EtCO ₂ MeO EtCO ₂ H 47 O 4- ( n -PrCO ₂ ) Ph H n -PrCO ₂ MeO n -PrCO ₂ H 48 O 4- ( i -PrCO ₂ ) Ph H i -PrCO ₂ MeO i -PrCO ₂ H 49 O 4- (EtCO ₂ ) Ph H H MeO EtCO ₂ H 50 O 4- ( i -PrCO ₂ ) Ph H OH MeO i -PrCO ₂ H 51 O 4- (OH) Ph H EtCO ₂ MeO EtCO ₂ H 52 O 4- (OH) Ph H i -PrCO ₂ MeO i -PrCO ₂ H 53 O (a) H OH MeO EtCO ₂ H 54 O (a) H OH MeO i -PrCO ₂ H 55 O 4- (OH) Ph H OH OH OH H 56 none OH H OH MeO PMBO H 57 S 4-Py H OH MeO PMBO H 58 S 2-Py H OH MeO PMBO H 59 S 4-Py H OH H PMBO H 60 S 2-Py H OH H PMBO H 61 S 4-Py H OH H OH H 62 S 2-Py H OH H OH H 63 O Ph H OH H OH H 64 O Ph H OH H Me H 65 O Ph H OH H OH Cl 66 O Ph Me OH H OH H 67 O Ph H OH MeO EtO H 68 O 4-Py H OH MeO EtO H 69 O Ph H OH MeO i -PrO H 70 O 4-Py H OH MeO i -PrO H 71 O Ph H OH MeO BnO H 72 O 4-Py H OH MeO BnO H 73 O Ph H OH MeO 4- (F) BnO H 74 O 4-Py H OH MeO 4- (F) BnO H 75 O Ph H OH MeO (b) H 76 O 4-Py H OH MeO (b) H 77 O Ph H H H OH H 78 O Ph H OH Me OH H 79 O Ph H OH H Cl H 80 O Ph H OH Cl OH H

81 O Ph H OH MeO (c) H 82 O 4-Py H OH MeO (c) H 83 O Ph H OH MeO (d) H 84 O 4-Py H OH MeO (d) H 85 O Ph H OH MeO (e) H 86 O 4-Py H OH MeO (e) H 87 O Ph H OH MeO (f) H 88 O 4-Py H OH MeO (f) H 89 O Ph H OH MeO (g) H 90 O 4-Py H OH MeO (g) H 91 O Ph H OH MeO (h) H 92 O Ph H OH H OH Me 93 O 4- (OMe) Ph H OH MeO EtO H 94 O Cy H OH MeO EtO H 95 O 4- (OMe) Ph H OH MeO i -PrO H 96 O Cy H OH MeO i -PrO H 97 O 4- (OMe) Ph H OH MeO BnO H 98 O Cy H OH MeO BnO H 99 O 4- (OMe) Ph H OH MeO 4- (F) BnO H 100 O Cy H OH MeO 4- (F) BnO H 101 O 4- (OMe) Ph H OH MeO (b) H 102 O Cy H OH MeO (b) H 103 O 4- (OMe) Ph H OH MeO (c) H 104 O Cy H OH MeO (c) H 105 O 4- (OMe) Ph H OH MeO (d) H 106 O Cy H OH MeO (d) H 107 O 4- (OMe) Ph H OH MeO (e) H 108 O Cy H OH MeO (e) H 109 O 4- (OMe) Ph H OH MeO (f) H 110 O Cy H OH MeO (f) H 111 O 4- (OMe) Ph H OH MeO (g) H 112 O Cy H OH MeO (g) H 113 O 4- (F) Ph H OH MeO EtO H 114 O 4- (F) Ph H OH MeO i -PrO H 115 O 4- (F) Ph H OH MeO BnO H 116 O 4- (F) Ph H OH MeO 4- (F) BnO H 117 O 4- (F) Ph H OH MeO (b) H 118 O 4- (F) Ph H OH MeO (c) H 119 O 4- (F) Ph H OH MeO (d) H 120 O 4- (F) Ph H OH MeO (e) H 121 O 4- (F) Ph H OH MeO (f) H

122 O 4- (F) Ph H OH MeO (g) H 123 O Ph H OH H i -PrO Cl 124 O 4-Py H OH H i -PrO Cl 125 O Ph H OH H (f) Cl 126 O Ph H OH H (g) Cl 127 O 4- (Me) piperidine H OH MeO EtO H 128 O 4- (Me) piperidine H OH MeO i -PrO H 129 O 4- (Me) piperidine H OH MeO BnO H 130 O 4- (Me) piperidine H OH MeO 4- (F) BnO H 131 O 4- (Me) piperidine H OH MeO (b) H 132 O 4- (Me) piperidine H OH MeO (c) H 133 none Ph H MeCO ₂ MeO MeCO ₂ (i) 134 none Ph H OH MeO MeCO ₂ (i) 135 none Ph H OH MeO OH (i) 136 5-hydroxy-6-methoxy-8,9,9-trimethyl-2-phenyl-8,9-dihydro-furo [2,3-h] chromen-4-one 137 O Ph H OH MeO OH (j) 138 O Ph H OH MeO OH (j) 139 O Ph H MeCO ₂ MeO MeCO ₂ (j) 140 O Ph H OH MeO OH (i) 141 5-hydroxy-6-methoxy-8,8-dimethyl-2-phenyl-8H-pyrano [2,3-f] chromen-4-one 142 5-hydroxy-6-methoxy-8,8-dimethyl-2-phenoxy-8H-pyrano [2,3-f] chromen-4-one

On the other hand, a representative method for producing the chromen-4-one derivatives represented by the general formula (1) and pharmaceutically acceptable salts thereof according to the present invention are shown in the following schemes 1 to 36. Synthesis method according to the following reaction schemes 1 to 36 is a conventional method, if the organic synthesis majors by applying a known synthesis method can be easily synthesized the compound represented by the formula (1).

In addition, the present invention includes a method for treating or preventing ischemic disease consisting of administering the compound represented by the formula (1) to a patient at a dose that can therapeutically reduce apoptosis under ischemic conditions.

Patients described herein mean warm-blooded animals or mammals, including those suffering from ischemic heart disease and ischemic cerebrovascular disease represented by angina pectoris, myocardial infarction, stroke, cerebrovascular dementia. Treatment of patients with ischemic disease means protection of the cells and inhibition of cell death. Diagnosis of ischemic disease patients is within the skill and knowledge of those skilled in the art. Skilled clinicians skilled in the art can readily determine this using clinical trials, physical examinations, medical examination / family history.

The effective dosage of the compound represented by Formula 1 can be easily determined by using conventional techniques and observing the results obtained under similar circumstances. In determining the effective dosage, it is not limited thereby, but the size, age, and general health of the patient, the severity or severity of the disease, the response of each patient, the specific compound of administration, the dosage form, the bioavailability of the administered agent, the selected A number of factors are considered, including dosing and public dosing. In general, the dosage of the compound represented by Formula 1 may be about 1 mg / kg to about 500 mg / kg. When treating a patient, the compound represented by Formula 1 may be administered in any form or method, including oral and parenteral so that the compound has bioavailability in an effective amount. The compound can be administered, for example, orally, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally and the like, in particular oral administration is preferred. One skilled in the art of formulation formulation can readily select the appropriate formulation and mode of administration depending on the severity of the disease and other relevant circumstances.

The compounds of the present invention may be administered in the form of a pharmaceutical composition or medicament prepared in combination with a pharmaceutically acceptable carrier or excipient and the proportions and types of the carrier or excipient are determined in accordance with the route of administration chosen and general pharmaceutical standard guidelines. . Pharmaceutical compositions or medicaments are prepared by methods known in the pharmaceutical art.

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited by Examples.

Example 1 Synthesis of 5,7-Diisopropoxy-6-methoxy-2-methylsulfanyl-chromen-4-one [see Scheme 1]

75 g of 2,4,6-trihydroxyacetophenone monohydrate (500 g) After vacuum drying at ℃ for 1 day, the dried 2,4,6-trihydroxyacetophenone was dissolved in DMF (4.5L), and then i -PrBr (630 mL) and K ₂ CO ₃ (2.3 kg) were added in sequence. Stirred at rt for 1 h 30 min. After cooling the reaction to room temperature, the solid was filtered off. The filtrate was concentrated and the residue was extracted with H ₂ O (5 L) and EtOAc (2 L × 2). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (7% EtOAc / Hexane) to give 1- (2-hydroxy-4,6-diisopropoxy-phenyl) -ethanone (458 g, 68%).

1- (2-hydroxy-4,6-diisopropoxy-phenyl) -ethanone (40 g) was added to a 10% aqueous NaOH solution (710 mL) and stirred. Temperature 10 ~ 15 H ₂ O (1 L) solution in which K ₂ S ₂ O ₈ (52 g) was dissolved while slowly maintaining the temperature was slowly added to the reaction for 2 to 3 hours, and the temperature of the reaction was raised to room temperature and stirred overnight. C-HCl (150 mL) was added to the reaction mixture, and extracted with EtOAc (250 mL × 2). Na ₂ SO ₃ (50 g) was added to the H ₂ O layer, and c-HCl (200 mL) was added and refluxed for 30 minutes. The H ₂ O layer was cooled to room temperature, extracted with EtOAc (200 mL × 2), washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (10% EtOAc / Hexane) to give 1- (3,6-dihydroxy-2,4-diisopropoxy-phenyl) -ethanone (32 g, 38%). .

Dissolve 1- (3,6-dihydroxy-2,4-diisopropoxy-phenyl) -ethanone (72 g) in acetone (1 L), and then K ₂ CO ₃ (122 g), dimethyl sulfate (28 mL) was added sequentially and stirred overnight at room temperature. Dimethyl sulfate (2.6 mL) was further added to the reaction and stirred at reflux for 4 hours. After the reaction was cooled to room temperature, the solid was filtered and the filtrate was concentrated. The residue was extracted with 0.5% aqueous HCl solution (300 mL) and EtOAc (50 mL × 2). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (10% EtOAc / Hexane) to give 6-hydroxy-2,4-diisopropoxy-3-methoxy-phenyl) -ethanone (117 g, 77%).

Toluene (500 mL) solution of potassium t- butoxide (133 g) was After the temperature was lowered to 占 폚, a solution of 1- (6-hydroxy-2,4-diisopropoxy-3-methoxy-phenyl) -ethanone (53 g) toluene (250 mL) was added dropwise using a cannula. It was. 0 reactants After stirring for 1 hour at ° C, toluene (250 mL) solution of CS ₂ (35 mL) was added dropwise using a cannula. 0 reactants After stirring for 1 hour at room temperature, the temperature was raised to room temperature, followed by stirring overnight. An aqueous 10% H ₂ SO ₄ (350 mL) solution was added to the reaction, and stirred at room temperature for 5 hours, followed by further addition of an aqueous 10% H ₂ SO ₄ aqueous solution (350 mL) for 30 minutes at room temperature. The organic layer was extracted, washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated to give a 5,7-diisopropoxy-2-mercapto-6-methoxy-2H-chromen-4-ol residue. It was vacuum dried at room temperature for 1 hour and then dissolved in DMF (500 mL), K ₂ CO ₃ (40 g), MeI (23 mL) were added sequentially, and the reaction was stirred at room temperature for 30 minutes. The reaction was concentrated under reduced pressure, and the residue was diluted with EA (500 mL) and washed three times with an aqueous 50% NaCl solution. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated. The residue was purified by column chromatography (50% EtOAc / Hexane) to give 5,7-diisopropoxy-6-methoxy-2-methylsulfanyl-chromen-4-one (43 g, 67%). Got it.

¹ H NMR (CDCl ₃ , 300 MHz) δ 6.61 (s, 1H), 6.00 (s, 1H), 4.62 (septet, J = 6Hz, 1H), 4.52 (septet, J = 6Hz, 1H), 3.84 (s , 1H), 2.49 (s, 1H), 1.44 (d, J = 6.3Hz, 6H), 1.35 (d, J = 6.3Hz, 6H)

Example 2. Synthesis of 5,7-Diisopropoxy-2-methylsulfanyl-chromen-4-one [see Scheme 1]

Obtained in a similar manner to Example 1 using 1- (2-hydroxy-4,6-diisopropoxy-phenyl) -ethanone (81 g). (72 g, 73%)

¹ H NMR (CDCl ₃ , 300 MHz) δ 6.38 (d, J = 2.1 Hz, 1H), 6.33 (d, J = 2.4 Hz, 1H), 5.97 (s, 1H), 4.57 (septet, J = 6 Hz, 2H), 2.47 (s, 3H), 1.43 (d, J = 6.3 Hz, 6H), 1.38 (d, J-6.3 Hz, 6H)

Example 3. 5,7-Dihydroxy-2- (4-hydroxy-phenoxy) -6-methoxy-chromen-4-one (Compound No. 1) and 2- (4-hydroxy-phenoxy C) -5,7-diisopropoxy-6-methoxy-chromen-4-one (Compound No. 5) [See Scheme 1]

5,7-Diisopropoxy-6-methoxy-2-methylsulfanyl-chromen-4-one (36 g) was dissolved in CH ₂ Cl ₂ (600 mL) and m- CPBA (46 g) was dissolved. Put and stirred overnight at room temperature. The reaction was washed with saturated aqueous NaHCO ₃ (250 mL × 3) and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was dissolved in DMF (350 mL), hydroquinone (35 g) and NaOH (25 g) were added sequentially, followed by stirring at room temperature for 2.5 hours. The reaction was concentrated under reduced pressure to about 100 mL, and the residue was added dropwise to 0.1 N aqueous HCl (1.2 L). The resulting crystals were filtered off and dried under reduced pressure. The dried crystals were washed with 50% EtOAc / hexane solution (1 L) and dried to afford 2- (4-hydroxy-phenoxy) -5,7-diisopropoxy-6-methoxy-chromen-4- Warm (37 g, 88%) was obtained.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.72 (s, 1 H), 7.15 (d, J = 8.7 Hz, 2H), 7.03 (s, 1H), 6.86 (d, J = 8.7 Hz, 2H) , 4.90 (s, 1H), 4.81 (septet, J = 6.0 Hz, 1H), 4.36 (septet, J = 6.0 Hz, 1H), 3.71 (s, 3H), 1.34 (d, J = 6.0 Hz, 6H) , 1.20 (d, J = 6.0 Hz, 6H)

2- (4-hydroxy-phenoxy) -5,7-diisopropoxy-6-methoxy-chromen-4-one (10 g) was dissolved in CH ₂ Cl ₂ (250 mL) and then -78 BCl ₃ (100 mL, 1M in CH ₂ Cl ₂ ) was added at ° C. -78 0 at ℃ It stirred for 1 hour after heating up to 1 degreeC over 1 hour. 1N HCl aqueous solution (140 mL) was added to the reaction to terminate the reaction. The reaction was extracted with 10% MeOH / CHCl ₃ (500 mL × 3), and the organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by MPLC (10% acetone / CHCl ₃ ) to give 5,7-dihydroxy-2- (4-hydroxy-phenoxy) -6-methoxy-chromen-4-one (4 g, 51%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.91 (s, 1H), 10.65 (br s, 1H), 9.84 (br s, 1H), 7.17 (d, J = 8.7 Hz, 2H), 6.87 ( d, J = 8.7 Hz, 2H), 6.46 (s, 1H), 5.04 (s, 1H), 3.73 (s, 3H)

Example 4. Synthesis of 5,7-Dihydroxy-2- (4-hydroxy-phenyl) -6-methoxy-chromen-4-one (Compound No. 2) [See Scheme 3]

1- (6-hydroxy-2,4-diisopropoxy-3-methoxy-phenyl) -ethanone (12.3 g, 43.7 mmol), 4-isopropoxy-benzaldehyde (7.2 g, 43.7 mmol) , EtOH (650 mL) solution of KOH (57 g) Stir overnight at ° C. After cooling to room temperature, it was concentrated under reduced pressure and H ₂ O (400 mL) was added. While stirring, the pH was adjusted to 4 with 1N HCl aqueous solution and extracted with EtOAc (200 mL × 2). The organic layer was washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (10% EtOAc / Hexane) to give 1- (6-hydroxy-2,4-diisopropoxy-3-methoxy-phenyl) -3- (4-isopropoxy-phenyl) -Propenone (10.3 g, 55%) was obtained.

1- (6-Hydroxy-2,4-diisopropoxy-3-methoxy-phenyl) -3- (4-isopropoxy-phenyl) -propenone (10.3 g, 24 mmol) and SeO ₂ ( 14.6 g, 132 mmol) of i- amyl alcohol (250 mL) solution was refluxed overnight with stirring. The filtrate was concentrated under reduced pressure after filtration using hot celite. The residue was extracted with H ₂ O (200 mL) and EtOAc (150 mL × 2), and the organic layer was washed with brine. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure, and the residue was purified by MPLC (30% EtOAC / Hexane) to give 5,7-diisopropoxy-2- (4-isopropoxy-phenyl) -6- Methoxy-chromen-4-one (10.3 g) was obtained quantitatively.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.08 (s, 1H), 10.68 (br s, 1H), 10.33 (br s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 6.92 ( d, J = 8.7 Hz, 2H), 6.78 (s, 1H), 6.59 (s, 1H), 3.75 (s, 3H)

 Example 5. 5,7-Dihydroxy-2- (4-hydroxy-phenylsulfanyl) -6-methoxy-chromen-4-one (Compound No. 3) and 2- (4-hydroxy- Synthesis of Phenylsulfanyl) -5,7-diisopropoxy-6-methoxy-chromen-4-one (Compound No. 6) [See Scheme 2]

It obtained by the method of Example 3 using 4-mercaptophenol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 13.10 (s, 1H), 11.13 (br s, 1H), 10.66 (br s, 1H), 7.91 (d, J = 8.7 Hz, 2H), 7.35 ( d, J = 8.7 Hz, 2H), 6.80 (s, 1H), 5.91 (s, 1H), 4.12 (s, 3H)

¹ H NMR (CDCl ₃ , 300 MHz) δ 10.08 (br s, 1 H), 7.34 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 6.70 (s, 1H), 5.59 (s, 1H), 4.65 (septet, J = 6.0 Hz, 1H), 4.50 (septet, J = 6.0 Hz, 1H), 3.84 (s, 3H), 1.46 (d, J = 6.0 Hz, 6H), 1.32 (d, J = 6.0 Hz, 6H)

Example 6. Synthesis of 5,7-Dihydroxy-2- (4-hydroxy-phenylselanyl) -6-methoxy-chromen-4-one (Compound No. 4) [See Scheme 2]

To a solution of 4,4'-diisopropyldiphenyl diselenide (4.19 g, 9.78 mmol) in THF (50 mL) was added NaBH ₄ (0.82 g, 21.2 mmol) to 0. It was put at ℃. The reaction was stirred at rt for 30 min and refluxed for 30 min. After cooling to room temperature, THF (50 mL) solution of the intermediate obtained in the method of Example 3 was slowly added to the reaction. H ₂ O (50 mL) was added to the reaction and extracted with EtOAc (50 mL × 1), CHCl ₃ (50 mL × 2). The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated. The residue was purified by MPLC (15% EtOAc / Hexane) to give 5,7-diisopropoxy-2- (4-isopropoxy-phenylselanyl) -6-methoxy-chromen-4-one (4.4 g, 54%).

This compound (6.31 g, 14.8 mmol) was prepared by the method of Example 3, 5,7-dihydroxy-2- (4-hydroxy-phenylselanyl) -6-methoxy-chromen-4-one (2.23 g, 47%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.66 (s, 1H), 10.72 (s, 1H), 10.12 (s, 1H), 7.56 (d, J = 8.4Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 6.38 (s, 1H), 5.75 (s, 1H), 3.71 (s, 3H)

Example 7. Synthesis of 5,7-Dihydroxy-2- (4-hydroxy-phenylamino) -6-methoxy-chromen-4-one (Compound No. 7) [See Scheme 4]

Obtained by the method of Example 3 using 4-aminophenol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 13.91 (s, 1H), 10.25 (br s, 1H), 9.88 (br s, 1H), 9.60 (br s, 1H), 7.12 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H), 6.28 (s, 1H), 5.10 (s, 1H), 3.71 (s, 3H)

Example 8. Synthesis of 2- (4-hydroxy-phenylamino) -5,7-diisopropoxy-6-methoxy-chromen-4-one (Compound No. 8) [See Scheme 2]

Obtained by the method of Example 3 using 4-aminophenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 9.43 (br s, 1H), 9.25 (br s, 1H), 7.09 (d, J = 8.7 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H) , 6.72 (s, 1H), 5.05 (s, 1H), 4.76 (septet, J = 6.0Hz, 1H), 4.38 (septet, J = 6.0Hz, 1H), 3.69 (s, 3H), 1.33 (d, J = 6.0 Hz, 6H), 1.20 (d, J = 6.0 Hz, 6H)

Example 9. 5,7-Dihydroxy-2- (4-hydroxy-phenoxy) -chromen-4-one (Compound No. 9) and 2- (4-hydroxy-phenoxy) -5, Synthesis of 7-diisopropoxy-chromen-4-one (Compound No. 10) [See Scheme 5]

Obtained by the method of Example 3 using hydroquinone.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.79 (s, 1H), 10.80 (br s, 1H), 9.77 (br s, 1H), 7.18 (d, J = 8.7 Hz, 2H), 6.86 ( d, J = 6.86 Hz, 2H), 6.35 (d, J = 1.8 Hz, 1H), 6.20 (d, J = 1.8 Hz, 1H), 5.02 (s, 1H)

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.86 (s, 1H), 7.13 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 6.66 (d, J = 2.4 Hz, 1H), 6.46 (d, J = 2.4 Hz, 1H), 4.83 (s, 1H), 4.78 (septet, J = 6.0 Hz, 1H), 4.62 (septet, J = 6.0 Hz, 1H), 1.30 (d, J = 6.0 Hz, 6H), 1.26 (d, J = 6.0 Hz, 6H)

Example 10. 5,7-Dihydroxy-2- (4-hydroxy-phenylsulfanyl) -chromen-4-one (Compound No. 11) and 2- (4-hydroxy-phenylsulfanyl)- Synthesis of 5,7-diisopropoxy-chromen-4-one (Compound No. 12) [See Scheme 5]

It obtained by the method of Example 3 using 4-mercaptophenol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.59 (s, 1H), 10.84 (br s, 1H), 10.26 (br s, 1H), 7.51 (d, J = 8.7 Hz, 2H), 6.95 ( d, J = 8.7 Hz, 2H), 6.28 (d, J = 2.1 Hz, 1H), 6.17 (d, J = 2.1 Hz, 1H), 5.51 (s, 1H)

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 10.19 (s, 1H), 7.48 (d, J = 8.7 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 6.58 (d, J = 2.1 Hz, 1H), 6.42 (d, J = 2.1 Hz, 1H), 4.77 (septet, J = 6.0 Hz, 1H), 4.60 (septet, J = 6.0 Hz, 1H), 1.29 (d, J = 6.0 Hz , 6H), 1.25 (d, J = 6.0 Hz, 6H)

Example 11. 5,7-Dihydroxy-2- (4-hydroxy-benzyl) -6-methoxy-chromen-4-one (Compound No. 13) and 2- (4-hydroxy-benzyl) Synthesis of -5,7-Diisopropoxy-6-methoxy-chromen-4-one (Compound No. 14) [See Scheme 6]

Dissolve 1- (6-hydroxy-2,4-diisopropoxy-3-methoxy-phenyl) -ethanone (5.11 g) in CH ₂ Cl ₂ (70 mL), and then add 0. Stir at ° C. Add NaOH (594 mg) to the reaction and add 0 After 30 minutes of stirring at chloromethyl ethyl ether (1.94 mL) was added to 0 Stir at 30 ° C. for 30 minutes. Saturated NH ₄ Cl aqueous solution (40 mL) and H ₂ O (40 mL) were added thereto, stirred for 10 minutes, and the organic layer was extracted with CH ₂ Cl ₂ (50 mL × 2). The organic layer was washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (5% EtOAc / Hexane) to give 1- (6-ethoxymethoxy-2,4-diisopropoxy-3-methoxy-phenyl) -ethanone (3.96 g, 64%). .

Dissolve 1- (6-ethoxymethoxy-2,4-diisopropoxy-3-methoxy-phenyl) -ethanone (6.5 g) in THF (180 mL) and -78 The temperature was lowered to ℃ and stirred. Add lithium diisopropylamine (11.5 mL) to -78 Stir at 30 ° C. for 30 minutes. (4-triisopropylsilanyloxy-phenyl) -acetaldehyde (11.2 g) in THF (120 mL) Slowly add to the reaction at ℃ -78 Stir at 1 ° C. for 1 h, 0 Stir at 30 ° C. for 30 minutes. H ₂ O (100 mL) was added, followed by extraction with CH ₂ Cl ₂ (50 mL × 3). The organic layer was washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (15% EtOAc / Hexane) to give an alcohol compound (12.05 g).

Oxalyl chloride (3.65 mL) was dissolved in CH ₂ Cl ₂ (150 mL) -78 Lower the temperature to ℃, add methyl sulfoxide (6.49 mL) while stirring, add -78 Stir at 30 ° C. for 30 minutes. The alcohol compound (12.05 g) obtained above was dissolved in CH ₂ Cl ₂ (80 mL). Slowly add to reactant at -50 ° C Stir at 1 ° C. for 1 h. Triethylamine (13.3 mL) was added thereto, stirred at room temperature for 30 minutes, and saturated aqueous NH ₄ Cl solution (100 mL) was added and extracted with EtOAc (100 mL × 3). The organic layer was washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (5% EtOAc / Hexane) to 1- (6-ethoxymethoxy-2,4-diisopropoxy-3-methoxy-phenyl) -5- (4-triisopropylsilanyloxy -Phenyl) -butane-1,3-dione (4.3 g, 36%) was obtained.

1- (6-Ethoxymethoxy-2,4-diisopropoxy-3-methoxy-phenyl) -5- (4-triisopropylsilanyloxy-phenyl) -butane-1,3-dione (4.2 g) dissolved in THF (60 mL) and then 0 The temperature was lowered to ℃ and slowly added 1M tetrabutylammonium fluoride solution (7.32 mL) and stirred for 1 hour at room temperature. H ₂ O (100 mL) was added, followed by extraction with EtOAc (50 mL × 3). The organic layer was washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (25% EtOAc / Hexane) to obtain a dione compound (1.05 g).

The resulting dione (1.0 g) was dissolved in acetic acid (15 mL) and stirred at room temperature for 30 minutes, followed by addition of sulfuric acid (0.5 mL) and stirring at room temperature for 1 hour. An aqueous sodium hydrogen carbonate solution (20 mL) was added, followed by extraction with EtOAc (40 mL × 3). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (40% EtOAc / Hexane) to 2- (4-hydroxy-benzyl) -5,7-diisopropoxy-6-methoxy-chromen-4-one (560 mg, 66%) Got.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.08 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 6.78 (br s, 1H), 4.63 (septet, J = 6.3 Hz, 1H), 4.51 (septet, J = 6.3 Hz, 1H), 3.83 (s, 3H), 3.75 (s, 2H), 1.43 (d, J = 6.3 Hz, 6H), 1.34 (d, J = 6.3 Hz, 6H)

2- (4-hydroxy-benzyl) -5,7-diisopropoxy-6-methoxy-chromen-4-one (511 mg) was dissolved in CH ₂ Cl ₂ (13 mL) and -78 BCl ₃ (5.13 mL, 1M with stirring at ° C) in CH ₂ Cl ₂ ) was added slowly. -20 Stir at 30 ° C. for 30 minutes Stir at 30 ° C. for 30 minutes. H ₂ O (30 mL) was added thereto, concentrated under reduced pressure, a portion of the solvent was removed, and then filtered to obtain a yellow solid. The aqueous layer was extracted with 20% MeOH in chloroform solution, combined with a yellow solid to dissolve, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (10% acetone / CHCl ₃ ) to give 5,7-dihydroxy-2- (4-hydroxy-benzyl) -6-methoxy-chromen-4-one (189 mg, 47%). Got

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.84 (s, 1H), 10.68 (br s, 1H), 9.37 (br s, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.74 ( d, J = 8.4 Hz, 2H), 6.40 (s, 1H), 6.07 (s, 1H), 3.85 (s, 2H), 3.72 (s, 3H)

Example 12. Synthesis of 2-cyclohexyloxy-5,7-dihydroxy-6-methoxy-chromen-4-one (Compound No. 15) [See Scheme 2]

Obtained by the method of Example 3 using cyclohexanol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 13.18 (s, 1H), 10.54 (br s, 1H), 6.41 (s, 1H), 5.68 (s, 1H), 4.75-4.69 (m, 1H) , 3.72 (s, 3H), 2.02-1.90 (m, 2H), 1.75-1.60 (m, 2H), 1.60-1.23 (m, 6H)

Example 13. Synthesis of 2-cyclohexylsulfanyl-5,7-dihydroxy-6-methoxy-chromen-4-one (Compound No. 16) [See Scheme 2]

Obtained by the method of Example 3 using cyclohexyl mercaptan.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.83 (s, 1H), 10.42 (br s, 1H), 6.46 (s, 1H), 6.31 (s, 1H), 3.73 (s, 3H), 3.74-3.66 (m, 1H), 2.10-1.90 (m, 2H), 1.80-1.65 (m, 2H), 1.65-1.25 (m, 6H)

Example 14. 5,7-Dihydroxy-6-methoxy-2-phenoxy-chromen-4-one (Compound No. 17) and 5,7-diisopropoxy-6-methoxy-2- Synthesis of phenoxy-chromen-4-one (Compound No. 18) [See Scheme 2]

It obtained by the method of Example 3 using a phenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.87 (s, 1H), 10.70 (br s, 1H), 7.52 ~ 7.43 (m, 2H), 7.43 ~ 7.35 (m, 3H), 6.46 (s, 1H) , 5.15 (s, 1H), 3.74 (s, 1H)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.44 (t, J = 7.5 Hz, 2H), 7.30 (t, J = 7.2 Hz, 1H), 7.18 (d, J = 7.2 Hz, 2H), 6.66 (s , 1H), 5.27 (s, 1H), 4.60 (septet, J = 6.0 Hz, 1H), 4.51 (septet, J = 6.0 Hz, 1H), 3.84 (s, 1H), 1.44 (d, J = 6.0 Hz , 6H), 1.34 (d, J = 6.3 Hz, 6H)

Example 15. 5,7-Dihydroxy-6-methoxy-2-phenylsulfanyl-chromen-4-one (Compound No. 19) and 5,7-diisopropoxy-6-methoxy-2 Synthesis of Phenylsulfanyl-chromen-4-one (Compound No. 20) [See Scheme 2]

Obtained by the method of Example 3 using benzenethiol.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.64 (s, 1H), 10.79 (br s, 1H), 7.69-7.72 (m 2H), 7.53-7.66 (m, 3H), 6.36 (s, 1H ), 5.74 (s, 1H), 3.72 (s, 3H)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.58-7.61 (m, 2H), 7.42-7.47 (m, 3H), 6.58 (s, 1H), 5.75 (s, 1H), 4.60 (septet, J = 6.0 Hz, 1H), 4.46 (septet, J = 6.0 Hz, 1H), 3.82 (s, 3H), 1.42 (d, J = 6.0 Hz, 6H), 1.32 (d, J = 6.0 Hz, 6H)

Example 16 Synthesis of 5,7-Dihydroxy-6-methoxy-2- (pyridin-2-yloxy) -chromen-4-one (Compound No. 21) [See Scheme 2]

Obtained by the method of Example 3 using 2-hydroxypyridine.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.80 (s, 1H), 10.76 (br s, 1H), 8.34 (dd, J ₁ = 3.0 Hz, J ₂ = 1.2 Hz, 1H), 8.04 (td , J = 9.0 Hz, 1.7 Hz, 1H), 7.38-7.43 (m, 1H), 7.36 (d, J = 8.1 Hz, 1H), 6.44 (s, 1H), 5.87 (s, 1H), 3.75 (s , 3H)

Example 17. Synthesis of 5,7-dihydroxy-6-methoxy-2- (pyridin-2-ylsulfanyl) -chromen-4-one (Compound No. 22) [See Scheme 2]

Obtained by the method of Example 3 using 2-mercaptopyridine.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.60 (s, 1H), 10.85 (br s, 1H), 8.57 (br d, J = 3.9 Hz, 1H), 7.88 (td, J ₁ = 7.5 Hz , J ₂ = 1.8Hz, 1H), 7.64 (d, J = 8.1Hz, 1H), 7.40-7.44 (m, 1H), 6.50 (s, 1H), 6.36 (s, 1H), 3.73 (s, 3H )

Example 18. 5,7-Dihydroxy-6-methoxy-2- (pyridin-4-yloxy) -chromen-4-one (Compound No. 23) and 5-hydroxy-6-methoxy- Synthesis of 7- (4-methoxy-benzyloxy) -2- (pyridin-4-yloxy) -chromen-4-one (Compound No. 25) [See Scheme 4]

5,7-Dihydroxy-6-methoxy-2-methylsulfanyl-chromen-4-one (1.3 g) was dissolved in acetone (50 mL), followed by 4-methoxybenzyl chloride (3.1 g), K ₂ CO ₃ (2.8 g) and NaI (0.38 g) were added sequentially and refluxed overnight. After cooling the reaction to room temperature, the solid was filtered off. The filtrate was concentrated and the residue was diluted with EtOAc (50 mL), washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (5% MeOH / CHCl ₃ ) to give 6-methoxy-5,7-bis- (4-methoxy-benzyloxy) -2-methylsulfanyl-chromen-4-one (1.8). g, 73%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.55 (s, 1H), 8.34 (d, J = 8.1 Hz, 2H), 7.44 (d, J = 8.7 Hz, 2H), 7.14 (s, 1H) , 6.99 (d, J = 8.7 Hz, 2H), 6.76 (s, 1H), 6.34 (d, J = 8.1 Hz, 2H), 5.18 (s, 2H), 3.77 (s, 3H), 3.73 (s, 3H)

6-methoxy-5,7-bis- (4-methoxy-benzyloxy) -2-methylsulfanyl-chromen-4-one (1.7 g) was dissolved in CH ₂ Cl ₂ (35 mL) and m - Place the CPBA (1.5 g) was stirred at room temperature overnight. The reaction was washed with saturated aqueous NaHCO ₃ (25 mL × 3) and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was dissolved in DMF (15 mL), hydroquinone (0.5 g) and NaOH (0.2 g) were added sequentially, followed by stirring at room temperature for 2 hours. The reaction was diluted with EtOAc (50 mL), washed with H ₂ O (50 mL × 3), brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC to give 5-hydroxy-6-methoxy-7- (4-methoxy-benzyloxy) -2- (pyridin-4-yloxy) -chromen-4-one (0.9 g, 68 %) Was obtained.

5-Hydroxy-6-methoxy-7- (4-methoxy-benzyloxy) -2- (pyridin-4-yloxy) -chromen-4-one (0.4 g) was added to CH ₂ Cl ₂ (5 mL) and 0 Trifluoroacetic acid was added at ℃. The temperature of the reaction was raised to room temperature and stirred for 1 hour. The reaction was concentrated and the crystals washed with EtOAc (50 mL) and dried to give 5,7-dihydroxy-6-methoxy-2- (pyridin-4-yloxy) -chromen-4-one (0.3 g). , 99%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.70 (br s, 1H), 10.90 (br s, 1H), 8.34 (d, J = 7.8 Hz, 2H), 6.68 (s, 1H), 6.65 ( s, 1H), 6.31 (d, J = 7.8 Hz, 2H), 3.76 (s, 3H)

Example 19. Synthesis of 5,7-diisopropoxy-6-methoxy-2- (pyridin-4-yloxy) -chromen-4-one (Compound No. 24) [See Scheme 2]

Obtained by the method of Example 3 using 4-hydroxypyridine.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 7.84 (d, J = 7.8 Hz, 2H), 6.72 (s, 1H), 6.51 (d, J = 7.8 Hz, 2H), 6.12 (s, 1H) , 4.67 (septet, J = 6.0 Hz, 1H), 4.57 (septet, J = 6.0 Hz, 1H), 3.86 (s, 3H), 1.47 (d, J = 6.0 Hz, 6H), 1.37 (d, J = 6.0 Hz, 6H)

Example 20. Synthesis of 5,7-dihydroxy-6-methoxy-2- (pyridin-4-ylsulfanyl) -chromen-4-one (Compound No. 26) [See Scheme 2]

Obtained by the method of Example 3 using 4-mercaptopyridine.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.55 (s, 1H), 10.85 (s, 1H), 8.61 (d, J = 6.0 Hz, 2H), 7.58 (d, J = 6.0 Hz, 2H) , 6.52 (s, 1H), 6.38 (s, 1H), 3.74 (s, 3H)

Example 21. Synthesis of 5,7-dihydroxy-2- [2- (4-hydroxy-phenyl) -ethyl] -6-methoxy-chromen-4-one (Compound No. 27) Reference]

1- (6-Ethoxymethoxy-2,4-diisopropoxy-3-methoxy-phenyl) -ethanone (6.0 g) obtained by the method of Example 11 was dissolved in THF (120 mL) and -78 Lithium diisopropylamine (10.6 mL) was added while stirring at Stir at 30 ° C. for 30 minutes. Dissolve 3- (4-isopropoxy-phenyl) -propionaldehyde (6.8 g) in THF (50 mL) and add to the reaction. Stir at 1 ° C. for 1 h. 0 After further stirring at 10 ° C., saturated NH ₄ Cl aqueous solution (50 mL) was added thereto, and extracted with EtOAc (50 mL × 3). The organic layer was washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (20% EtOAc / Hexane) to 1- (6-ethoxymethoxy-2,4-diisopropoxy-3-methoxy-phenyl) -3-hydroxy-5- (4-iso Propoxy-phenyl) -pentan-1-one (7.9 g, 84%) was obtained.

Oxalyl chloride (11.9 mL) was dissolved in CH ₂ Cl ₂ (180 mL) -78 After stirring to lower the temperature to ℃, add methyl sulfoxide (2.8 mL) -78 Stir at 30 ° C. for 30 minutes. 1- (6-Ethoxymethoxy-2,4-diisopropoxy-3-methoxy-phenyl) -3-hydroxy-5- (4-isopropoxy-phenyl) -pentan-1-one ( 8.5 g) was dissolved in CH ₂ Cl ₂ (70 mL) -78 Slowly add to reactant at < RTI ID = 0.0 > Stir at 1 ° C. for 1 h. Triethylamine (11.2 mL) was added thereto, stirred at room temperature for 30 minutes, H ₂ O (100 mL) was added, and extracted with CH ₂ Cl ₂ (100 mL × 3). The organic layer was washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (20% EtOAc / Hexane) to 1- (6-ethoxymethoxy-2,4-diisopropoxy-3-methoxy-phenyl) -5- (4-isopropoxy-phenyl) -Pentane-1,3-dione (6.2 g, 80%) was obtained.

1- (6-Ethoxymethoxy-2,4-diisopropoxy-3-methoxy-phenyl) -5- (4-isopropoxy-phenyl) -pentane-1, 3-dione (6.1 g ) Was dissolved in acetic acid (40 mL) and stirred for 30 minutes at room temperature, followed by adding sulfuric acid (0.5 mL) and stirring at room temperature for 2.5 hours. An aqueous sodium hydrogen carbonate solution (20 mL) was added, followed by extraction with CH ₂ Cl ₂ (50 mL × 3). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (20% EtOAc / Hexane) to give chromenon (3.24 g, 62%).

The resulting chromenone (2.13 g) was dissolved in CH ₂ Cl ₂ (60 mL) and BCl ₃ (18.7 mL) was slowly added while stirring at −78 ° C. -78 30 minutes at ℃, -10 30 min at 0 ° C The mixture was stirred at 10 ° C. for 10 minutes, H ₂ O (30 mL) was added, and extracted with CH ₂ Cl ₂ (50 mL × 2) and 20% MeOH / CHCl ₃ (30 mL × 3). The organic layer was washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (3% MeOH / CHCl ₃ ) to give 5,7-dihydroxy-2- [2- (4-hydroxy-phenyl) -ethyl] -6-methoxy-chromen-4-one ( 237 mg, 15.4%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.88 (s, 1H), 10.68 (br s, 1H), 9.17 (br s, 1H), 7.02 (d, J = 8.4Hz, 2H), 6.66 ( d, J = 8.4 Hz, 2H), 6.44 (s, 1H), 6.10 (s, 1H), 3.73 (s, 3H), 2.87 (s, 4H)

Example 22. Synthesis of 5,7-Dihydroxy-2- (4-hydroxy-benzylsulfanyl) -6-methoxy-chromen-4-one (Compound No. 28) [See Scheme 7]

To a solution of 5,7-diisopropoxy-2-mercapto-6-methoxy-2H-chromen-4-ol (5 g, 15.4 mmol) obtained in Example 1 in DMF (40 mL), K ₂ CO ₃ (3.2 g, 23.1 mmol) was added and stirred at room temperature. To this, a solution of DMF (10 mL) of 4-isopropoxybenzyl chloride (5.7 g, 30.8 mmol) was slowly added at room temperature and stirred for 15 minutes. EtOAc (100 mL) was added to the reaction and extracted with 50% aqueous NaCl solution (100 mL × 3) and the H ₂ O layer was extracted with EA (100 mL × 1). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (20% EtOAc / Hexane) to give 5,7-diisopropoxy-2- (4-isopropoxy-benzylsulfanyl) -6-methoxy-chromen-4-one. 5,7-Dihydroxy-2- (4-hydroxy-benzylsulfanyl) -6-methoxy-chromen-4-one (0.35 g, 46%) was obtained by the method of Example 3.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.81 (s, 1H), 10.71 (s, 1H), 9.47 (s, 1H), 7.24 (d, J = 8.1Hz, 2H), 6.72 (d, J = 8.4 Hz, 2H), 6.50 (s, 1H), 6.27 (s, 1H), 4.35 (s, 2H), 3.73 (s, 3H)

Example 23. 5,7-Dihydroxy-2- [2- (4-hydroxy-phenyl) -vinyl] -6-methoxy-chromen-4-one (Compound No. 29) and 5,7- Synthesis of diisopropoxy-2- [2- (4-isopropoxy-phenyl) -vinyl] -6-methoxy-chromen-4-one (Compound No. 30) [See Scheme 3]

3- (4-isopropoxy-phenyl) -propenealdehyde (1.33 eq), Ba (OH) ₂ (4 eq) and cat. Obtained by the method of Example 4 using I ₂ / DMSO conditions.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 13.05 (s, 1 H), 10.71 (br s, 1 H), 10.00 (br s, 1 H), 7.58 (d, J = 15.3 Hz, 1 H), 7.57 ( d, J = 8.7 Hz, 1H), 6.92 (d, J = 15.9 Hz, 1H), 6.83 (d, J = 8.4 Hz, 2H), 6.54 (s, 1H), 6.30 (s, 1H), 3.74 ( s, 3 H)

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.49 (d, J = 8.7 Hz, 2H), 7.44 (d, J = 16.2 Hz, 1H), 6.91 (d, J = 8.7 Hz, 2H), 6.73 (s , 1H), 6.57 (d, J = 15.9 Hz, 1H), 6.09 (s, 1H), 4.50-4.73 (m, 3H), 3.85 (s, 3H), 1.47 (d, J = 6.0 Hz, 6H) , 1.37 (d, J = 6.0 Hz, 12H)

Example 24. Synthesis of 5,7-dihydroxy-2- (4-hydroxy-benzenesulfinyl) -6-methoxy-chromen-4-one (Compound No. 31) [See Scheme 8]

5,7-Dihydroxy-2- (4-hydroxy-phenylsulfanyl) -6-methoxy-chromen-4-one (0.2 g) was dissolved in methanol (6 mL) and then 0. Oxon (Oxone ™, 0.2 g) methanol solution was added at ℃. The temperature of the reaction was raised to room temperature and stirred overnight. The reaction was diluted with CHCl ₃ (30 mL), washed with water (10 mL × 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (10% acetone / CHCl ₃ ) to give 5,7-dihydroxy-2- (4-hydroxy-benzenesulfinyl) -6-methoxy-chromen-4-one (0.1 g , 52%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.39 (s, 1H), 10.95 (s, 1H), 10.48 (s, 1H), 7.69 (d, J = 8.7Hz, 2H), 6.97 (d, J = 8.7 Hz, 2H), 6.73 (s, 1H), 6.39 (s, 1H), 3.72 (s, 3H)

Example 25 Synthesis of 5,6,7-Trimethoxy-2- (4-methoxy-phenoxy) -chromen-4-one (Compound No. 32) [See Scheme 9]

5,7-Dihydroxy-2- (4-hydroxy-phenoxy) -6-methoxy-chromen-4-one (250 mg) was dissolved in DMF (10 mL) and K ₂ CO ₃ (436 mg ), Then add MeI (0.50 mL) 45-50 Stir at 18 ° C. for 18 h. The reaction was filtered, concentrated under reduced pressure and the residue was purified by MPLC (50% EtOAc / Hexane) to give 5,6,7-trimethoxy-2- (4-methoxy-phenoxy) -chromen-4-one (201 mg). , 71%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 7.30 (d, J = 9.3 Hz, 2H), 7.06 (d, J = 9.3 Hz, 2H), 7.04 (s, 1H), 4.99 (s, 1H) , 3.92 (s, 3H), 3.80 (s, 3H), 3.75 (s, 6H)

Example 26. Synthesis of 5-hydroxy-6-methoxy-7- (4-methoxy-benzyloxy) -2-phenoxy-chromen-4-one (Compound No. 33) [See Scheme 4]

It obtained by the method of Example 18 using phenol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.76 (s, 1H), 7.56 (dd, J ₁ , J ₂ = 8.1 Hz, 2H), 7.43-7.39 (m, 5H), 6.98 (d, J = 8.7 Hz, 2H), 6.90 (s, 1H), 5.23 (s, 1H), 5.17 (s, 2H), 3.77 (s, 3H), 3.71 (s, 3H)

Example 27. Synthesis of 5,7-dihydroxy-2-phenoxy-chromen-4-one (Compound No. 34) [See Scheme 5]

It obtained by the method of Example 3 using a phenol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.76 (s, 1H), 10.85 (br s, 1H), 7.58-7.53 (m, 2H), 7.43-7.38 (m, 3H), 6.36 (d, J = 1.8 Hz, 1H), 6.21 (d, J = 1.8 Hz, 1H), 5.13 (s, 1H)

Example 28. Synthesis of 5-hydroxy-7- (4-methoxy-benzyloxy) -2-phenoxy-chromen-4-one (Compound No. 35) [See Scheme 10]

It obtained by the method of Example 18 using phenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.69 (s, 1H), 7.47 (dd, J ₁ , J ₂ = 8.1 Hz, 2H), 7.36-7.31 (m, 3H), 7.19 (d, J = 7.5 Hz, 2H), 6.93 (d, J = 7.5 Hz, 2H), 6.45 (d, J = 2.4 Hz, 1H), 6.43 (d, J = 2.4 Hz, 1H), 5.26 (s, 1H), 5.03 ( s, 2H), 3.83 (s, 3H)

Example 29. Synthesis of 5-hydroxy-6-methoxy-7- (4-methoxy-benzyloxy) -2-phenylsulfanyl-chromen-4-one (Compound No. 36) [See Scheme 10]

Obtained by the method of Example 18 using benzenethiol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.51 (s, 1H), 7.73-7.70 (m, 2H), 7.62-7.58 (m, 3H), 7.40 (d, J = 8.7 Hz, 2H), 6.97 (d, J = 8.7 Hz, 2H), 6.83 (s, 1H), 5.76 (s, 1H), 5.15 (s, 1H), 3.77 (s, 3H), 3.69 (s, 3H)

Example 30. 5,7-Dihydroxy-2-phenylsulfanyl-chromen-4-one (Compound No. 37) and 5-hydroxy-7- (4-methoxy-benzyloxy) -2-phenyl Synthesis of sulfanyl-chromen-4-one (Compound No. 38) [See Scheme 10]

Obtained by the method of Example 18 using benzenethiol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.54 (s, 1H), 10.88 (br s, 1H), 7.70-7.73 (m, 2H), 7.54-7.63 (m, 3H), 6.25 (d, J = 2.1 Hz, 1H), 6.18 (d, J = 1.8 Hz, 1H), 5.73 (s, 1H)

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.56 (s, 1H), 7.61 (m, 2H), 7.45-7.52 (m, 3H), 7.34 (d, J = 8.7 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 6.38 (dd, J = 4.2 Hz, 2.1 Hz, 2H), 5.71 (s, 1H), 5.02 (s, 2H), 3.83 (s, 3H)

Example 31. of 5-hydroxy-2- (4-hydroxy-phenoxy) -6-methoxy-7- (4-methoxy-benzyloxy) -chromen-4-one (Compound No. 39) Synthesis [See Scheme 4]

Obtained by the method of Example 18 using hydroquinone.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.80 (br s, 1H), 9.75 (br s, 1H), 7.42 (d, J = 9.0 Hz, 2H), 7.19 (d, J = 9.0 Hz, 2H), 6.98 (d, J = 9.0 Hz, 2H), 6.91 (s, 1H), 6.88 (d, J = 9.0 Hz, 2H), 5.18 (s, 2H), 5.12 (s, 1H), 3.77 ( s, 1H), 3.71 (s, 1H)

Example 32. Synthesis of 5-hydroxy-2- (4-hydroxy-phenoxy) -7- (4-methoxy-benzyloxy) -chromen-4-one (Compound No. 40) [See Scheme 10] ]

Obtained by the method of Example 18 using hydroquinone.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.82 (br s, 1H), 9.75 (br s, 1H), 7.40 (d, J = 8.7 Hz, 2H), 7.19 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 6.71 (d, J = 2.1 Hz, 1H), 6.46 (d, J = 2.1 Hz, 1H) , 5.13 (s, 2H), 5.08 (s, 1H), 3.76 (s, 3H)

Example 33. 5-Hydroxy-2- (4-hydroxy-phenylsulfanyl) -6-methoxy-7- (4-methoxy-benzyloxy) -chromen-4-one (Compound No. 41) Synthesis of Compounds [See Scheme 4]

Obtained by the method of Example 18 using 4-mercaptophenol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.56 (s, 1H), 10.29 (s, 1H), 7.52 (d, J = 8.7 Hz, 2H), 7.41 (d, J = 8.7 Hz, 2H) , 6.98 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H), 6.86 (s, 1H), 5.53 (s, 1H), 5.16 (s, 2H), 3.77 (s, 3H), 3.69 (s, 3H)

Example 34. Synthesis of 5-hydroxy-2- (4-hydroxy-phenylsulfanyl) -7- (4-methoxy-benzyloxy) -chromen-4-one (Compound No. 42) Reference]

Obtained by the method of Example 18 using 4-mercaptophenol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.60 (br s, 1H), 10.29 (br s, 1H), 7.52 (d, J = 9.0 Hz, 2H), 7.38 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 9.0 Hz, 4H), 6.65 (d, J = 2.1 Hz, 1H), 6.43 (d, J = 2.1 Hz, 1H), 5.52 (s, 1H), 5.11 (s, 2H), 3.76 (s, 3H)

Example 35. Synthesis of 5,7-dihydroxy-2- (pyridin-4-yloxy) -chromen-4-one (Compound No. 43) [See Scheme 5]

Obtained by the method of Example 9 using 4-hydroxypyridine.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.60 (s, 1H), 11.02 (br s, 1H), 8.33 (d, J = 8.0Hz, 2H), 6.68 (s, 1H), 6.55 (d , J = 1.8 Hz, 1H), 6.31 (d, J = 8.4 Hz, 2H), 6.25 (d, J = 2.1 Hz, 1H)

Example 36. Synthesis of 5-hydroxy-7- (4-methoxy-benzyloxy) -2- (pyridin-4-yloxy) -chromen-4-one (Compound No. 44) [See Scheme 10]

Obtained by the method of Example 18 using 4-hydroxypyridine.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.31 (s, 1H), 7.83 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.7 Hz , 2H), 6.52 (d, J = 1.5Hz, 1H), 6.51 (t, J = 2.1Hz, 2H), 6.14 (s, 1H), 5.07 (s, 2H), 3.83 (s, 3H)

Example 37 Synthesis of Acetic Acid 7-Acetoxy-2- (4-acetoxy-phenoxy) -6-methoxy-4-oxo-4H-chromen-5-yl ester (Compound No. 45) Reference]

Dissolve 5,7-dihydroxy-2- (4-hydroxy-phenoxy) -6-methoxy-chromen-4-one (150 mg) in DMF (5 mL) and triethylamine (0.66 mL) , 4- (dimethylamino) pyridine (58 mg) and acetic anhydride (0.45 mL) were added sequentially, followed by stirring at room temperature for 2 hours. H ₂ O (30 mL) was added and extracted with EtOAc (30 mL × 3). The organic layer was washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was subjected to MPLC to give acetic acid 5-acetoxy-2- (4-acetoxy-phenoxy) -chromen-4-one (176 mg, 84%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 7.56 (s, 1H), 7.46 (d, J = 9,0 Hz, 2H), 7.29 (d, J = 9.0 Hz, 2H), 5.19 (s, 1H ), 3.74 (s, 3H), 2.37 (s, 3H), 2.34 (s, 3H), 2.28 (s, 3H)

Example 38. Synthesis of propionic acid 6-methoxy-4-oxo-7-propionyloxy-2- (4-propionyloxy-phenoxy) -4H-chromen-5-yl ester (Compound No. 46) See Scheme 11]

Obtained by the method of Example 37 using propionic anhydride.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 7.56 (s, 1H), 7.46 (d, J = 9.0 Hz, 2H), 7.29 (d, J = 9.0 Hz, 2H), 5.19 (s, 1H) , 3.74 (s, 3H), 2.73-2.59 (m, 6H), 1.21-1.13 (m, 9H)

Example 39. Synthesis of Butyric Acid 7-butyryloxy-2- (4-butyryloxy-phenoxy) -6-methoxy-4-oxo-4H-chromen-5-yl ester (Compound No. 47) See Scheme 11]

Obtained by the method of Example 37 using butyric anhydride.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 7.57 (s, 1 H), 7.46 (d, J = 8.7 Hz, 2H), 7.28 (d, J = 8.7 Hz, 2H), 5.19 (s, 1H) , 3.73 (s, 3H), 2.68-2.56 (m, 6H), 1.74-1.64 (m, 6H), 1.03-0.96 (m, 9H)

Example 40. Isobutyric acid 7-isobutyryloxy-2- (4-isobutyryloxy-phenoxy) -6-methoxy-4-oxo-4H-chromen-5-yl ester (Compound No. 48) Synthesis of Compounds

Obtained by the method of Example 37 using iso -butyric anhydride.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 7.57 (s, 1H), 7.46 (d, J = 9.0 Hz, 2H), 7.28 (d, J = 9.0 Hz, 2H), 5.21 (s, 1H) , 3.72 (s, 3H), 2.96-2.80 (m, 3H), 1.29-1.23 (m, 18H)

Example 41. Synthesis of propionic acid 5-hydroxy-6-methoxy-4-oxo-2- (4-propionyloxy-phenoxy) -4H-chromen-7-yl ester (Compound No. 49) 12 see]

To a solution of compound No. 1 (0.8 g, 2.53 mmol) and acetone (20 mL) of K ₂ CO ₃ (0.7 g, 5.1 mmol) was added propionic anhydride (0.9 mL, 5.1 mmol) and stirred at room temperature for 1 hour. The reaction was diluted with H ₂ O (50 mL) and the pH was adjusted to 3-4 with 1N HCl aqueous solution. After extracting with EA (50 mL × 2), the organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was MPLCed to give propionic acid 5-hydroxy-6-methoxy-4-oxo-2- (4-propionyloxy-phenoxy) -4H-chromen-7-yl ester (1 g, 91%). Got it.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.90 (s, 1H), 7.20 (s, 4H), 6.64 (s, 1H), 5.39 (s, 1H), 3.91 (s, 3H), 2.70-2.58 ( m, 4H), 1.33-1.26 (m, 6H)

Example 42 Synthesis of 5-isobutyric Acid 5-hydroxy-2- (4-isobutyryloxy-phenoxy) -6-methoxy-4-oxo-4H-chromen-7-yl ester (Compound No. 50) Reaction Scheme 12

Obtained by the method of Example 41 using i- butyric anhydride.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.88 (s, 1H), 7.19 (s, 4H), 5.39 (s, 1H), 3.90 (s, 3H), 2.85 (septet, J = 6.9Hz, 2H) , 1.35 (t, J = 6.3 Hz, 12H)

Example 43. Synthesis of propionic acid 2- (4-hydroxy-phenoxy) -6-methoxy-4-oxo-5-propionyloxy-4H-chromen-7-yl ester (Compound No. 51) 13]

5,7-Dihydroxy-6-methoxy-2-methylsulfanyl-chromen-4-one (1 g, 3.93 mmol), DMAP (0.48 g, 3.93 mmol) obtainable by the method of Example 18 Et ₃ N (1.5 mL, 9.83 mmol) and propionic anhydride (1.7 mL, 9.86 mmol) were added to a solution of DMF (50 mL), followed by stirring at room temperature for 2 hours. 50% aqueous NaCl solution (70 mL) was added to the reaction and extracted with EtOAc (70 mL). The organic layer was washed with 50% aqueous NaCl solution (50 mL × 2), and the H ₂ O layer was extracted with EtOAc (70 mL). The combined organic layers were dried over MgSO ₄ , filtered, concentrated under reduced pressure, and the residue was purified by MPLC to give propionic acid 6-methoxy-2-methylsulfanyl-4-oxo-5-propionyloxy-4H-chromen-7-yl ester. Obtained quantitatively.

This was used together with 4-triisopropylsilanyloxy-phenol to propionate 6-methoxy-4-oxo-5-propionyloxy-2- (4-triisopropylsilanyloxy-phenoxy by the method of Example 3 C) -4H-chromen-7-yl ester (1.02 g, 60%) was obtained.

It is dissolved in THF (50 mL) solution and the temperature is 0 Lowered to ℃ and TBAF (1.1 eq, 1M in THF) was added. The reaction was heated to room temperature, stirred for 30 minutes, diluted with 50% aqueous NaCl solution (140 mL) and extracted with EtOAc (70 mL × 2). The organic layer was washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. MPLC the residue to give propionic acid 2- (4-hydroxy-phenoxy) -6-methoxy-4-oxo-5-propionyloxy-4H-chromen-7-yl ester (0.6 g, 61%). Got it.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.16 (s, 4H), 6.88 (s, 1H), 6.47 (s, 1H), 3.94 (s, 3H), 2.78 (quartet, J = 7.5 Hz, 2H) , 2.61 (quartet, J = 7.8 Hz, 2H), 1.33-1.25 (m, 6H)

Example 44 Synthesis of Isobutyric Acid 2- (4-Hydroxy-phenoxy) -5-isobutyryloxy-6-methoxy-4-oxo-4H-chromen-7-yl ester (Compound No. 52) See Scheme 13

Obtained by the method of Example 43 using i- butyric anhydride.

¹ H NMR (CDCl ₃ , 300 MHz) δ 6.88 (s, 1H), 6.34 (s, 1H), 5.27 (s, 1H), 3.94 (s, 3H), 3.02 (septet, J = 6.9 Hz, 1H) , 2.81 (septet, J = 6.9 Hz, 1H), 1.39 (d, J = 7.2 Hz, 6H), 1.33 (d, J = 6.9 Hz, 6H)

Example 45. 2-Amino-3-methyl-butyric acid 4- (5-hydroxy-6-methoxy-4-oxo-7-propionyloxy-4H-chromen-2-yloxy) -phenyl ester hydrogen chloride Synthesis of Salt (Compound No. 53) [See Scheme 14]

Propionic acid 2- (4-hydroxy-phenoxy) -6-methoxy-4-oxo-5-propionyloxy-4H-chromen-7-yl ester (0.46 g, 1.01 mmol) obtained in Example 43, EDC (1.5 eq) was added to a CH ₂ Cl ₂ (25 mL) solution of Boc-L-valine (1.3 eq) and DMAP (0.2 eq) and stirred overnight at room temperature. 50% aqueous NaCl solution (100 mL) was added to the reaction, the organic layer was extracted, and the H ₂ O layer was extracted with CH ₂ Cl ₂ (30 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, followed by MPLC to 2 -t -butoxycarbonylamino-3-methyl-butyric acid 4- (6-methoxy-4-oxo-5 , 7-bis-propionyloxy-4H-chromen-2-yloxy) -phenyl ester (0.6 g, 91%) was obtained.

CH this compound (0.3 g)₂Cl₂(15 mL) and then the temperature is 0 Lowered to C and TFA was added slowly. The temperature of the reaction was raised to room temperature and stirred for 1 hour. The reaction was concentrated under reduced pressure, diethyl ether (70 mL) was added to the residue, and 1N HCl (1 eq, in diethyl ether) was added slowly with stirring. The reaction was stirred at rt for 3 h, the resulting solid was filtered off and the solid was vacuum dried for 1 h. H solid₂After dissolving in O (120 mL), membrane filtration and filtrate -78 After freezing at < RTI ID = 0.0 > C) -phenyl ester hydrogen chloride (0.15 g, 65%) was obtained.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 13.25 (br s, 1H), 8.75 (br s, 3H), 7.49 (d, J = 9.0 Hz, 2H), 7.32 (d, J = 9.0 Hz, 2H), 7.09 (s, 1H), 5.41 (s, 1H), 4.28 (br s, 1H), 3.82 (s, 3H), 2.63 (quartet, J = 7.5 Hz, 2H), 1.22-1.12 (m, 9H)

Example 46. 2-Amino-3-methyl-butyric acid 4- (5-hydroxy-7-isobutyryloxy-6-methoxy-4-oxo-4H-chromen-2-yloxy) -phenyl ester Synthesis of Hydrogen Chloride (Compound No. 54) [See Scheme 14]

It was obtained by the method of Example 45 using compound No. 52 obtained in Example 44.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 13.23 (br s, 1H), 8.72 (br s, 2H), 7.49 (d, J = 8.7 Hz, 2H), 7.31 (d, J = 8.7 Hz, 2H), 7.09 (s, 1H), 5.41 (s, 1H), 4.25 (d, J = 4.8 Hz, 1H), 3.82 (s, 3H), 2.85 (septet, J = 7.2 Hz, 1H), 2.38 ( sextet, J = 6 Hz, 1H), 1.25 (d, J = 7.2 Hz, 6H), 1.22-1.12 (m, 9H)

Example 47. Synthesis of 5,6,7-trihydroxy-2- (4-hydroxy-phenoxy) -chromen-4-one (Compound No. 55) [See Scheme 2]

Obtained by the method of Example 3 using compound No. 5 (0.7 g) and BCl ₃ (7 eq).

¹ H NMR (CDCl ₃ , 300 MHz) δ 6.88 (s, 1H), 6.34 (s, 1H), 5.27 (s, 1H), 3.94 (s, 3H), 3.02 (septet, J = 6.9 Hz, 1H) , 2.81 (septet, J = 6.9 Hz, 1H), 1.39 (d, J = 7.2 Hz, 6H), 1.33 (d, J = 6.9 Hz, 6H)

Example 48. Synthesis of 2,5-dihydroxy-6-methoxy-7- (4-methoxy-benzyloxy) -chromen-4-one (Compound No. 56) [See Scheme 15]

Dissolve 5-hydroxy-6-methoxy-7- (4-methoxy-benzyloxy) -2-methylsulfanyl-chromen-4-one (0.5 g) in chloroform (25 mL), followed by m- CPBA. (0.7 g) was added and stirred at room temperature for 3 hours. The reaction was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was washed with diethyl ether (30 mL) and dried under reduced pressure. The dried product was dissolved in THF (15 mL) and LiOH monohydrate (0.2 g) dissolved in water (3 mL) was added. 70 The temperature was raised to ℃ and stirred overnight. The reaction was cooled to room temperature and concentrated. 0.5N HCl aqueous solution (7 mL) was added to the residue, followed by filtration to obtain crystals. The obtained crystals were dried under a reduced pressure to give 2,5-dihydroxy-6-methoxy-7- (4-methoxy-benzyloxy) -chromen-4-one (0.3 g, 67%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 7.42 (d, J = 8.7 Hz, 2H), 6.97 (d, J = 8.7 Hz, 2H), 6.65 (s, 1H), 5.24 (s, 1H) , 5.12 (s, 2H), 3.77 (s, 3H), 3.67 (s, 3H)

Example 49. of 5-hydroxy-6-methoxy-7- (4-methoxy-benzyloxy) -2- (pyridin-4-ylsulfanyl) -chromen-4-one (Compound No. 57) Synthesis [See Scheme 4]

Obtained by the method of Example 18 using 4-mercaptopyridine.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.42 (s, 1 H), 8.61 (d, J = 6.0 Hz, 2H), 7.58 (d, J = 6.0 Hz, 2H), 7.39 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H), 6.86 (s, 1H), 6.60 (s, 1H), 5.14 (s, 2H), 3.77 (s, 3H), 3.71 (s, 3H)

Example 50. of 5-hydroxy-6-methoxy-7- (4-methoxy-benzyloxy) -2- (pyridin-2-ylsulfanyl) -chromen-4-one (Compound No. 58) Synthesis [See Scheme 4]

Obtained by the method of Example 18 using 2-mercaptopyridine.

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.82 (s, 3 H), 3.89 (s, 3 H), 5.09 (s, 2 H), 6.29 (s, 1 H), 6.41 (s, 1 H) , 6.89-6.94 (m, 2H), 7.28-7.36 (m, 3H), 7.48 (d, J = 7.5 Hz, 1 H), 7.73 (td, J ₁ = 7.5 Hz, J ₂ = 1.8 Hz, 1 H), 8.59-8.61 (m, 1 H), 12.42 (s, 1 H)

Example 51. Synthesis of 5-hydroxy-7- (4-methoxy-benzyloxy) -2- (pyridin-4-ylsulfanyl) -chromen-4-one (Compound No. 59) [See Scheme 10] ]

Obtained by the method of Example 18 using 4-mercaptopyridine.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.37 (s, 1 H), 8.65 (d, J = 5.7 Hz, 2H), 7.39 (d, J = 6.0 Hz, 2H), 7.32 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 9.0 Hz, 2H), 6.43 (d, J = 2.1 Hz, 1H), 6.35 (d, J = 2.1 Hz, 1H), 6.23 (s, 1H), 5.01 (s, 2H), 3.82 (s, 3H)

Example 52. 5-hydroxy-7- (4-methoxy-benzyloxy) -2- (pyridin-2-ylsulfanyl) -chromen-4-one (Compound No. 60) and 5,7-di Synthesis of hydroxy-2- (pyridin-2-ylsulfanyl) -chromen-4-one (Compound No. 62) [See Scheme 10]

Obtained by the method of Example 18 using 2-mercaptopyridine.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.48 (s, 1H), 8.61 (d, J = 3.6 Hz, 1H), 7.73 (td, J ₁ = 7.8 Hz, J ₂ = 2.1 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.32 (d, J = 9.0 Hz, 2H), 7.30 (d, J = 8.1 Hz, 1H), 6.92 (d, J = 8.4 Hz, 2H), 6.42 (d , J = 2.1 Hz, 1H), 6.35 (d, J = 2.1 Hz, 1H), 6.29 (s, 1H), 5.00 (s, 2H), 3.82 (s, 3H)

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.21-6.25 (m, 2 H), 6.50 (s, 1 H), 7.40-7.45 (m, 1 H), 7.66 (d, J = 7.5 Hz, 1 H), 7.89 (td, J ₁ = 7.5 Hz, J ₂ = 1.8 Hz, 1 H), 8.57-8.59 (m, 1 H), 10.98 (br s, 1 H), 12.51 (s, 1 H)

Example 53. Synthesis of 5,7-dihydroxy-2- (pyridin-4-ylsulfanyl) -chromen-4-one (Compound No. 61)

5,7-dihydroxy-2-methylsulfanyl-chromen-4-one (630 mg), acetone (50 mL) solution of K ₂ CO ₃ (1.3 eq) After lowering the temperature to ℃ ℃ acetic anhydride (1.2 eq) was added and the reaction stirred at room temperature for 1 hour. H ₂ O (100 mL) and saturated aqueous NaHCO ₃ solution (50 mL) were added to the reaction and stirred for 5 minutes. Extracted with 10% MeOH / CHCl ₃ (50 mL × 2) and the organic layer was washed with brine. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, followed by MPLC (5% EtOAc / CHCl ₃ ) to 5-hydroxy-2-methylsulfanyl-4-oxo-4H-chromen-7-yl ester (675 mg, 91%) was obtained.

This was prepared by the method of Example 3 using 4-mercaptopyridine acetic acid 5-hydroxy-4-oxo-2- (pyridin-4-ylsulfanyl) -4H-chromen-7-yl ester (241 mg, 30%). The compound was dissolved in THF (20 mL) / H ₂ O (3 mL) solution, and then LiOH monohydrate (2.1 eq) was added thereto and refluxed for 2 hours. The reaction was cooled to room temperature and then concentrated under reduced pressure. The residue was diluted with H ₂ O (50 mL), and the pH was adjusted to 5-6 with 1N HCl aqueous solution while stirring. The precipitated solid was filtered, washed with solids in that order, H ₂ O, EA, diethyl ether, and then dried in vacuo (1 hour, 60 ° C) gave 5,7-dihydroxy-2- (pyridin-4-ylsulfanyl) -chromen-4-one (160 mg, 77%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.47 (s, 1H), 10.97 (s, 1H), 8.61 (d, J = 5.1Hz, 2H), 7.58 (d, J = 6.0Hz, 2H) , 6.51 (s, 1H), 6.24 (d, J = 6.6 Hz, 2H)

Example 54. Synthesis of 5-hydroxy-2-phenoxy-chromen-4-one (Compound No. 63) [See Scheme 17]

It obtained by the method of Example 1 and Example 3 using 2, 6- dihydroxy acetophenone.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.58 (s, 1H), 7.46-7.53 (m, 3H), 7.36 (t, J = 7.5Hz, 1H), 7.20 (d, J = 8.1Hz, 2H) , 6.87 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 5.35 (s, 1H)

Example 55. Synthesis of 5-hydroxy-7-methyl-2-phenoxy-chromen-4-one (Compound No. 64) [See Scheme 18]

An acetone (200 mL) solution of orcinol (5.3 g, 42.2 mmol), K ₂ CO ₃ (18 g, 126.6 mmol), MeI (6.6 mL, 105.5 mmol) was refluxed overnight. The reaction was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, 50% NaCl aqueous solution (100 mL) was added to the residue, and the mixture was extracted with EtOAc (50 mL × 2). The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure, and the residue was purified by MPLC (2% EtOAc / Hexane) to give 1,3-dimethoxy-5-methyl-benzene (3.8 g, 62%).

The method described in the literature using 1,3-dimethoxy-5-methyl-benzene ( Tetrahedron , 49 (47 ), 10843-10854, (1993)) to 1- (2,6-dimethoxy-4- Methyl-phenyl) -ethanone (3.9 g, 81%) was obtained.

Dissolve 1- (2,6-dimethoxy-4-methyl-phenyl) -ethanone in CH ₂ Cl ₂ (85 mL) and then adjust the temperature to -78. Lowered to ℃ and BBr ₃ (1M in CH ₂ Cl ₂ , 74 mL, 4 eq) was added slowly, the temperature of the reaction was slowly raised to room temperature and stirred overnight. 0 After the temperature was lowered to ℃, 0.5N HCl aqueous solution (100 mL) solution was slowly added, and the precipitated solid was completely dissolved in MeOH and extracted with 5% MeOH / CHCl ₃ (100 mL × 2) solution. The organic layer was washed with brine, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure, and the residue was purified by MPLC (25% EtOAc / Hexane) to 1- (2,6-dihydroxy-4-methyl-phenyl) -ethanone (2.5 g, 81%).

5-hydroxy-7-methyl-2-phenoxy-chromen- by the method of Example 1 and Example 3 using 1- (2,6-dihydroxy-4-methyl-phenyl) -ethanone 4-one (0.74 g) was obtained.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.45 (s, 1H), 7.48 (t, J = 7.5 Hz, 2H), 7.35 (t, J = 7.5 Hz, 1H), 7.19 (d, J = 7.5 Hz , 2H), 6.68 (s, 1H), 6.64 (s, 1H), 5.32 (s, 1H), 2.40 (s, 3H)

Example 56. Synthesis of 8-chloro-5,7-dihydroxy-2-phenoxy-chromen-4-one (Compound No. 65) [See Scheme 19]

5,7-Dihydroxy-2-methylsulfanyl-chromen-4-one (1.0 g, 4.460 mmol) was suspended in MeOH (100 mL), stirred at room temperature, concentrated with concentrated HCl solution (2 mL) and 30%. A mixture of H ₂ O ₂ aqueous solution (10 mL) was added dropwise, followed by stirring at room temperature under nitrogen stream for 25 hours. Pour the reaction solution into distilled water (500 mL) 15 After stirring at 20 ° C. for 20 minutes, the precipitated solid was filtered and dried under reduced pressure to obtain 8-chloro-5,7-dihydroxy-2-methanesulfinyl-chromen-4-one (675 mg, 55%). .

8-Chloro-5,7-dihydroxy-2-methanesulfinyl-chromen-4-one (600 mg, 2.184 mmol) was dissolved in DMF (30 mL), phenol (617 mg, 6.553 mmol) and K ₂ CO ₃ (453 mg, 3.277 mmol) was added and stirred at room temperature under nitrogen stream for 3 hours. The reaction solution was concentrated under reduced pressure, neutralized with 1N- HCl aqueous solution, and extracted with 10% MeOH / CHCl ₃ (100 mL × 2). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure, and the obtained residue was purified by MPLC (2% MeOH / CHCl ₃ ) to 8-chloro-5,7-dihydroxy-2-phenoxy-chromen- 4-one (597 mg, 90%) was obtained

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 5.33 (s, 1 H), 6.42 (s, 1 H), 7.40-7.45 (m, 3H), 7.53-7.59 (m, 2H), 12.77 (s, 1H)

Example 57. Synthesis of 5,7-dihydroxy-3-methyl-2-phenoxy-chromen-4-one (Compound No. 66) [See Scheme 20]

Phloroglucinol dihydrate (8.13 g, 50.14 mmol) and propionitrile (5.52 g, 100 mmol) were dissolved in diethyl ether and zinc chloride (3.34 g, 24.5 mmol) was added. The reaction solution was treated with hydrochloric acid gas and stirred at room temperature for 3 hours. Water was added thereto and stirred at reflux for 4 hours. The residue obtained by extraction with ethyl acetate, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure was purified by MPLC (50% EtOAc / Hexane) to 1- (2,4,6-trihydroxy-phenyl) -propane-1 -On (8.47 g, 78%) was obtained.

Using this compound, 5,7-dihydroxy-3-methyl-2-phenoxy-chromen-4-one was obtained using the method of Example 1 and Example 3.

¹ HNMR (CDCl ₃ , 300 MHz) δ 12.97 (s, 1 H), 7.44-7.39 (m, 2 H), 7.26-7.25 (m, 1 H), 7.12-7.09 (m, 2H), 6.28 (d, J = 2.1 Hz, 1H), 6.14 (d, J = 2.1 Hz, 1H), 5.56 (s, 1H), 2.03 (s, 3H).

Example 58. Synthesis of 7-ethoxy-5-hydroxy-6-methoxy-2-phenoxy-chromen-4-one (Compound No. 67) [See Scheme 21]

5,7-Dihydroxy-6-methoxy-2-methylsulfanyl-chromen-4-one (3.5 g) was dissolved in acetone / DMF (1: 1, 150 mL) and K ₂ CO ₃ (2.5 g ), EtBr (1.23 mL) was added sequentially and stirred at room temperature for 10 minutes and then refluxed for 4 hours. Concentrated under reduced pressure at room temperature, adjusted to pH = 4 ~ 5 with 1N HCl aqueous solution and extracted with EtOAc (100 mL × 3). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was subjected to MPLC (10% EtOAc / CHCl ₃ ) to give 7-ethoxy-5-hydroxy-6-methoxy-2-methylsulfanyl-chromen-4-one (3.5 g, 90%).

Dissolve 7-ethoxy-5-hydroxy-6-methoxy-2-methylsulfanyl-chromen-4-one (1.0 g) in CH ₂ Cl ₂ (50 mL) After lowering the temperature to ℃ m- CPBA (1.98 g) was added and stirred for 18 hours at room temperature. The reaction was washed with 50% aqueous sodium hydrogen carbonate solution (50 mL × 2), the organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate and hexane to give sulfone (1.2 g).

The obtained sulfone (600 mg) was dissolved in acetone (30 mL), K ₂ CO ₃ (367 mg) and phenol (202 mg) were added sequentially, followed by stirring at room temperature for 18 hours. Acidified with 1N aqueous HCl solution, water (30 mL) was added, and extracted with 5% MeOH / CH ₂ Cl ₂ . The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was MPLC (30% EtOAc / Hexane) to give 7-ethoxy-5-hydroxy-6-methoxy-2-phenoxy-chromen-4-one (433 mg, 75%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.74 (s, 1H), 7.56 (dd, J ₁ , J ₂ = 7.5 Hz, 2H), 7.43-7.39 (m, 3H), 6.78 (s, 1H ), 5.23 (s, 1H), 4.16 (quartet, J = 6.9 Hz, 2H), 3.73 (s, 3H), 1.38 (t, J = 6.9 Hz, 3H)

Example 59. Synthesis of 7-ethoxy-5-hydroxy-6-methoxy-2- (pyridin-4-yloxy) -chromen-4-one (Compound No. 68) [See Scheme 21]

Obtained by the method of Example 58 using EtBr and 4-hydroxypyridine.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.53 (s, 1H), 8.35 (d, J = 8.1 Hz, 2H), 7.01 (s, 1H), 6.75 (s, 1H), 6.33 (d, J = 8.1 Hz, 2H), 4.19 (quartet, J = 6.9 Hz, 2H), 3.75 (s, 3H), 1.41 (t, J = 6.9 Hz, 3H)

Example 60. Synthesis of 5-hydroxy-7-isopropoxy-6-methoxy-2-phenoxy-chromen-4-one (Compound No. 69) [See Scheme 21]

Obtained by the method of Example 58 using i- PrBr and phenol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.73 (s, 1H), 7.56 (dd, J ₁ , J ₂ = 7.8 Hz, 2H), 7.44-7.39 (m, 3H), 6.83 (s, 1H ), 5.20 (s, 1H), 4.80 (septet. J = 5.7 Hz, 1H), 3.71 (s, 3H), 1.32 (d, J = 5.7 Hz, 6H)

Example 61. Synthesis of 5-hydroxy-7-isopropoxy-6-methoxy-2- (pyridin-4-yloxy) -chromen-4-one (Compound No. 70) [See Scheme 21]

Obtained by the method of Example 58 using i- PrBr and 4-hydroxypyridine.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.52 (s, 1H), 8.36 (d, J = 7.8 Hz, 2H), 7.04 (s, 1H), 6.74 (s, 1H), 6.33 (d, J = 7.8 Hz, 2H), 4.77 (septet, J = 6.0 Hz, 1H), 3.73 (s, 3H), 1.37 (d, J = 6.0 Hz, 6H)

Example 62. Synthesis of 7-benzyloxy-5-hydroxy-6-methoxy-2-phenoxy-chromen-4-one (Compound No. 71) [See Scheme 21]

Obtained by the method of Example 58 using BnBr and phenol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.77 (s, 1H), 7.58-7.36 (m, 10H), 6.91 (s, 1H), 5.27 (s, 2H), 5.24 (s, 1H), 3.74 (s, 3H)

Example 63. Synthesis of 7-benzyloxy-5-hydroxy-6-methoxy-2- (pyridin-4-yloxy) -chromen-4-one (Compound No. 72) [See Scheme 21]

Obtained by the method of Example 58 using BnBr and 4-hydroxypyridine.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.57 (s, 1H), 8.33 (d, J = 8.1 Hz, 2H), 7.52-7.37 (m, 5H), 7.13 (s, 1H), 6.76 ( s, 1H), 6.34 (d, J = 8.1 Hz, 2H), 5.28 (s, 2H), 3.77 (s, 3H)

Example 64. Synthesis of 7- (4-fluoro-benzyloxy) -5-hydroxy-6-methoxy-2-phenoxy-chromen-4-one (Compound No. 73) [See Scheme 21]

 Obtained by the method of Example 58 using 4-fluorobenzyl bromide and phenol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.78 (s, 1H), 7.59-7.52 (m, 4H), 7.44-7.39 (m, 3H), 7.26 (t, J = 8.7 Hz, 2H), 6.91 (s, 1H), 5.24 (s, 3H), 3.72 (s, 3H)

Example 65. Synthesis of 7- (4-fluoro-benzyloxy) -5-hydroxy-6-methoxy-2- (pyridin-4-yloxy) -chromen-4-one (Compound No. 74) See Scheme 21

Obtained by the method of Example 58 using 4-fluorobenzyl bromide and 4-hydroxypyridine

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.57 (s, 1H), 8.33 (d, J = 8.4 Hz, 2H), 7.56 (dd, J ₁ = 8.7 Hz, J ₂ = 5.7 Hz, 2H) , 7.27 (t, J = 8.7 Hz, 2H), 7.14 (s, 1H), 6.76 (s, 1H), 6.34 (d, J = 8.4 Hz, 2H), 5.26 (s, 2H), 3.45 (s, 3H)

Example 66. Synthesis of 5-hydroxy-6-methoxy-7- [2- (4-methoxy-phenyl) -ethoxy] -2-phenoxy-chromen-4-one (Compound No. 75) See Scheme 21

Obtained by the method of Example 58 using 4-methoxyphenethyl bromide and phenol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.73 (s, 1H), 7.55 (dd, J ₁ , J ₂ = 7.8 Hz, 2H), 7.43-7.38 (m, 3H), 7.26 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 6.81 (s, 1H), 5.23 (s, 1H), 4.29 (t, J = 6.6 Hz, 2H), 3.72 (s, 3H ), 3.63 (s, 3H), 3.02 (t, J = 6.6 Hz, 2H)

Example 67. 5-hydroxy-6-methoxy-7- [2- (4-methoxy-phenyl) -ethoxy] -2- (pyridin-4-yloxy) -chromen-4-one ( Synthesis of Compound No. 76) [See Scheme 21]

Obtained by the method of Example 58 using 4-methoxyphenethyl bromide and 4-hydroxypyridine.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.51 (s, 1H), 8.35 (d, J = 8.1Hz, 2H), 7.28 (d, J = 8.4Hz, 2H), 7.06 (s, 1H) , 6.89 (d, J = 8.4 Hz, 2H), 6.74 (s, 1H), 6.32 (d, J = 8.1 Hz, 2H), 4.29 (t, J = 6.6 Hz, 2H), 3.73 (s, 3H) , 3.66 (s, 3H), 3.06 (t, J = 6.6 Hz, 2H)

Example 68. Synthesis of 7-hydroxy-2-phenoxy-chromen-4-one (Compound No. 77) [See Scheme 22]

It obtained by the method of Example 1 and Example 3 using 2, 4- dihydroxy acetophenone.

Example 69. Synthesis of 5,7-dihydroxy-6-methyl-2-phenoxy-chromen-4-one (Compound No. 78) [See Scheme 23]

3,5-dimethoxy-phenol (10.0 g, 64.86 mmol) and TBDMSCl (11.7 g, 77.84 mmol) were dissolved in CH ₂ Cl ₂ (150 mL) and 0 Et ₃ N (18.0 mL, 129.73 mmol) was added dropwise while stirring at room temperature, followed by stirring at room temperature under nitrogen stream for 15 hours. Saturated NaHCO ₃ aqueous solution (100 mL) and distilled water (50 mL) were added to the reaction solution, and the mixture was extracted with CH ₂ Cl ₂ (150 mL × 2). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and then the obtained residue was purified by MPLC (10% EtOAc / Hexanes) to t- butyl- (3,5-dimethoxy-phenoxy) -dimethyl-silane. (16.3 g, 93%) was obtained.

t- Butyl- (3,5-dimethoxy-phenoxy) -dimethyl-silane (3.0 g, 11.18 mmol) was dissolved in THF (60 mL) and dried under nitrogen stream. After stirring and dropwise addition of 2.5 N n- BuLi / hexane solution (4.9 mL, 12.29 mmol) in ℃ was stirred at room temperature for 3 hours. 0 back to reaction MeI (0.77 mL, 12.29 mmol) was added dropwise at 占 폚 and stirred at room temperature for 4 hours. Saturated NaCl aqueous solution (70 mL) and distilled water (30 mL) were added to the reaction solution, and the mixture was extracted with CH ₂ Cl ₂ (150 mL × 2). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, and then the obtained residue was purified by MPLC (2% EtOAc / Hexanes) and t- butyl- (3,5-dimethoxy-4-methyl-phenoxy)- Dimethyl-silane (1.97 g, 62%) was obtained.

t- Butyl- (3,5-dimethoxy-4-methyl-phenoxy) -dimethyl-silane (1.95 g, 6.903 mmol) was dissolved in THF (30 mL) and 0 1N TBAF / THF solution (8.3 mL, 8.284 mmol) was added dropwise while stirring at ° C, followed by stirring at room temperature under nitrogen stream for 30 minutes. The reaction solution was poured into a mixture of 1 N- HCl aqueous solution (30 mL) and saturated NaCl aqueous solution (70 mL), and extracted with CH ₂ Cl ₂ (100 mL × 2). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The obtained residue was purified by MPLC (50% EtOAc / Hexanes) to give 3,5-dimethoxy-4-methyl-phenol (1.10 g, 95%). Obtained.

3,5-dimethoxy-4-methyl-phenol (1.0 g, 5.945 mmol) was suspended in CH ₂ Cl ₂ (30 mL) and 0 Ac ₂ O (0.67 mL, 7.134 mmol) and Et ₃ N (1.66 mL, 11.890 mmol) were added dropwise while stirring at room temperature, followed by stirring at room temperature under nitrogen stream for 2 hours. Saturated NaHCO ₃ aqueous solution (20 mL) and distilled water (20 mL) were added to the reaction solution, and the mixture was extracted with CH ₂ Cl ₂ (50 mL × 2). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure, and the obtained residue was purified by MPLC (10% EtOAc / Hexanes) to give acetic acid 3,5-dimethoxy-4-methyl-phenyl ester (1.23 g, 98%) Obtained.

Acetic acid 3,5-dimethoxy-4-methyl-phenyl ester (1.1 g, 5.232 mmol) was dissolved in benzene (25 mL), AlCl ₃ (837 mg, 6.279 mmol) was added, and heated to reflux for 4 hours under a nitrogen stream. It was. Reaction solution 0 1 N- HCl aqueous solution (30 mL) and saturated NaCl aqueous solution (50 mL) were added thereto, and the mixture was extracted with CH ₂ Cl ₂ (70 mL × 2). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure, and the obtained residue was purified by MPLC (10% EtOAc / Hexanes) to give 1- (6-hydroxy-2,4-dimethoxy-3-methyl-phenyl). Ethanone (836 mg, 76%) was obtained.

5,7-dimethoxy-6 by the method of Example 1 using 1- (6-hydroxy-2,4-dimethoxy-3-methyl-phenyl) -ethanone (820 mg, 3.900 mmol) -Methyl-2-methylsulfanyl-chromen-4-one (485 mg, 47%) was obtained.

5,7-dimethoxy-6-methyl-2-methylsulfanyl-chromen-4-one (370 mg, 1.389 mmol) and oxone (Oxone ™, 1.28 g, 2.084 mmol) were mixed with MeOH (8 mL). It was suspended in a mixture of distilled water (4 mL) and stirred at room temperature for 1 hour. Distilled water (30 mL) was added to the reaction solution, and the mixture was extracted with CH ₂ Cl ₂ (50 mL × 2). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure and dried, and the residue and K ₂ CO ₃ (384 mg, 2.778 mmol) were dissolved in DMF (10 mL), stirred at room temperature, and dissolved in DMF (5 mL). Phenol (157 mg, 1.667 mmol) was added thereto and stirred at room temperature under nitrogen stream for 15 hours. The reaction solution was concentrated under reduced pressure, distilled water (20 mL) was added, and the mixture was extracted with CH ₂ Cl ₂ (50 mL × 3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure, and the obtained residue was purified by MPLC (2% MeOH / CH ₂ Cl ₂ ) to give 5,7-dihydroxy-6-methyl-2-phenoxy-chromen-. 4-one (390 mg, 90%) was obtained.

 5,7-Dihydroxy-6-methyl-2-phenoxy-chromen-4-one (330 mg, 1.057 mmol) was prepared in the manner of Example 55 using 5,7-dihydroxy-6-methyl-2 -Phenoxy-chromen-4-one (249 mg, 83%) was obtained.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.97 (s, 3 H), 5.14 (s, 1 H), 6.42 (s, 1 H), 7.38-7.43 (m, 3 H), 7.53-7.58 (m, 2H), 10.86 (brs, 1H), 12.99 (s, 1H)

Example 70. Synthesis of 7-chloro-5-hydroxy-2-phenoxy-chromen-4-one (Compound No. 79) [See Scheme 24]

1-chloro-3,5-dimethoxy-benzene was obtained through demethylation of BBr ₃ (Example 54) to 1-chloro-3,5-dihydroxy-benzene. This was dissolved in CH ₃ CN (0.2 M), NIS (1.1 eq) was added thereto, and the resultant was stirred at room temperature for 20 minutes. The reaction was diluted with EtOAc, and the organic layer was washed sequentially with saturated aqueous NaHSO ₃ solution and brine. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure, and the residue was purified by MPLC (5% EtOAc / CH ₂ Cl ₂ ) to give 5-chloro-2-iodo-benzene-1,3-diol (62%). .

5-Chloro-2-iodo-benzene-1,3-diol was combined with dimethyl sulfate (2.5 eq), K ₂ CO ₃ (5.0 eq) in the manner of Example 1 to 5-chloro-2-iodo -1,3-dimethoxy-benzene (97%) was obtained.

Dissolve 5-chloro-2-iodo-1,3-dimethoxy-benzene in DMF (0.1M) solution and add CuCN (1.5 eq). The reaction was stirred for 3 h at < RTI ID = 0.0 > The reaction was cooled to room temperature, diluted with EtOAc and washed twice with dilute NH ₄ OH aqueous solution. The organic layer was washed with 50% aqueous NaCl solution, the H ₂ O layer was extracted with EtOAc, the organic layers were collected, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (20% EtOAc / Hexane) to give 4-chloro-2,6-dimethoxy-benzonitrile (92%).

4-Chloro-2,6-dimethoxy-benzonitrile was converted to 1- (4-chloro-2,6-dimethoxy- by the method of J. Am. Chem. Soc . 55 , 3032 (1933). Phenyl) -ethanone (75%) was obtained.

Example 65, Method of literature ( J. Med. Chem. , 43 , 4126-4134 (2000)), using 1- (4-chloro-2,6-dimethoxy-phenyl) -ethanone, Example 5,7-Dihydroxy-6-methyl-2-phenoxy-chromen-4-one was obtained using the method of 1.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.72 (s, 1H), 7.49 (t, J = 7.5Hz, 2H), 7.37 (t, J = 7.5Hz, 1H), 7.19 (d, J = 7.8Hz , 2H), 6.90 (d, J = 2.1 Hz, 1H), 6.83 (d, J = 1.8 Hz, 1H), 5.35 (s, 1H)

Example 71. Synthesis of 6-chloro-5,7-dihydroxy-2-phenoxy-chromen-4-one (Compound No. 80) [See Scheme 25]

CH ₂ Cl ₂ (50 mL) solution of 5-hydroxy-7-isopropoxy-2-methylsulfanyl-chromen-4-one (1.0 g, 3.7 mmol) with AlCl ₃ (500 mg, 3.7 mmol) To NCS (526 mg, 3.7 mmol) was added. After 1 hour 30 minutes, poured into 10% aqueous HCl solution (100 mL) and stirred for 1 hour. After layer separation, the aqueous layer was extracted with 5% MeOH / CHCl ₃ (50 mL × 3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (20% EtOAc / Hexane) to give 6-chloro-5-hydroxy-7-isopropoxy-2-methylsulfanyl-chromen-4-one (580 mg, 51%).

By the method of Example 69 and Example 3 using 6-chloro-5-hydroxy-7-isopropoxy-2-methylsulfanyl-chromen-4-one (450 mg, 1.5 mmol) obtained above Chloro-5,7-dihydroxy-2-phenoxy-chromen-4-one (218 mg, 81%) was obtained.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 5.22 (s, 1H), 6.56 (s, 1H), 7.40-7.44 (m, 3H), 7.53-7.59 (m, 2H), 11.72 (br s, 1H ), 13.53 (s, 1 H)

Example 72. Synthesis of 5-hydroxy-6-methoxy-2-phenoxy-7- (pyridin-4-ylmethoxy) -chromen-4-one (Compound No. 81) [See Scheme 26]

5-hydroxy-6-methoxy-2-methylsulfanyl-7- (pyridin-4-ylmethoxy) -chromen-4-one (600 mg) was added MeOH / H ₂ O (1: 4, 50 mL). ) In 1N HCl aqueous solution (3.47 mL) and add 0. Stir at ° C. Oxone (Oxone ™, 1.07 g) was added to the reaction mixture, stirred at room temperature for 3 hours, adjusted to pH = 10 with aqueous sodium bicarbonate solution, and extracted with 10% MeOH / CHCl ₃ . The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (5% MeOH / CHCl ₃ ) to 5-hydroxy-2-methanesulfinyl-6-methoxy-7- (pyridin-4-ylmethoxy) -chromen-4-one (450 mg, 72%).

220 mg of 5-hydroxy-2-methanesulfinyl-6-methoxy-7- (pyridin-4-ylmethoxy) -chromen-4-one) was dissolved in DMF (20 mL) and K ₂ CO ₃ (126 mg) and phenol (70 mg) were added sequentially and stirred at room temperature for 3 hours. The reaction was concentrated under reduced pressure and then purified by MPLC (5% MeOH / CHCl ₃ ) to 5-hydroxy-6-methoxy-2-phenoxy-7- (pyridin-4-ylmethoxy) -chromen-4-one (166 mg, 70%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.81 (s, 1H), 8.62 (d, J = 5.4 Hz, 2H), 7.55 (dd, J ₁ , J ₂ = 7.5 Hz, 2H), 7.47- 7.39 (m, 3H), 7.46 (d, J = 5.4 Hz, 2H), 6.87 (s, 1H), 5.36 (s, 2H), 5.26 (s, 1H), 3.80 (s, 3H)

Example 73. Synthesis of 5-hydroxy-6-methoxy-7- (pyridin-4-ylmethoxy) -2- (pyridin-4-yloxy) -chromen-4-one (Compound No. 82) [ See Scheme 26]

Obtained by the method of Example 72 using 4- (bromomethyl) -pyridine hydrogen bromide and 4-hydroxypyridine.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.614 (s, 1H), 8.63 (d, J = 6.0Hz, 2H), 8.32 (d, J = 8.1Hz, 2H), 7.47 (d, J = 6.0 Hz, 2H), 7.09 (s, 1H), 6.77 (s, 1H), 6.33 (d, J = 8.1 Hz, 2H), 5.37 (s, 2H), 3.82 (s, 3H)

Example 74. Synthesis of 5-hydroxy-6-methoxy-2-phenoxy-7- (2-piperidin-1-yl-ethoxy) -chromen-4-one (Compound No. 83) [ See Scheme 26]

Obtained by the method of Example 72 using 1- (2-chloroethyl) piperidine hydrogen chloride and phenol

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.74 (s, 1H), 7.56 (dd, J ₁ , J ₂ = 7.8 Hz, 2H), 7.43-7.39 (m, 3H), 6.85 (s, 1H ), 5.25 (s, 1H), 4.21 (t, J = 6.0 Hz, 2H), 3.73 (s, 3H), 2.70 (t, J = 6.0 Hz, 2H), 2.46-2.43 (m, 4H), 1.52 -1.35 (m, 6H)

Example 75 5-Hydroxy-6-methoxy-7- (2-piperidin-1-yl-ethoxy) -2- (pyridin-4-yloxy) -chromen-4-one (compound Synthesis of No. 84) [see Scheme 26]

Obtained by the method of Example 72 using 1- (2-chloroethyl) piperidine hydrogen chloride and 4-hydroxypyridine.

¹ H NMR (MeOH-d ₄ , 300 MHz) δ 8.37 (d, J = 7.8 Hz, 2H), 6.92 (s, 1H), 6.57 (s, 1H), 6.54 (d, J = 7.8 Hz, 2H) , 4.42 (t, J = 5.1 Hz, 2H), 3.87 (s, 3H), 3.32-3.30 (m, 2H), 3.10-2.95 (br s, 4H), 1.83-1.75 (m, 4H), 1.65- 1.59 (m, 2 H)

Example 76. Synthesis of 5-hydroxy-6-methoxy-7- (2-morpholin-4-yl-ethoxy) -2-phenoxy-chromen-4-one (Compound No. 85) 26]

Obtained by the method of Example 72 using 4- (2-chloroethyl) morpholine hydrogen chloride and phenol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.74 (s, 1H), 7.56 (dd, J ₁ , J ₂ = 7.8 Hz, 2H), 7.44-7.39 (m, 3H), 6.84 (s, 1H ), 5.25 (s, 1H), 4.23 (t, J = 5.7 Hz, 2H), 3.73 (s, 3H), 3.57 (t, J = 5.7 Hz, 4H), 2.74 (t, J = 5.7 Hz, 2H )

Example 77. 5-hydroxy-6-methoxy-7- (2-morpholin-4-yl-ethoxy) -2- (pyridin-4-yloxy) -chromen-4-one (Compound No. 86) Synthesis [See Scheme 26]

Obtained by the method of Example 72 using 4- (2-chloroethyl) morpholine hydrogen chloride and 4-hydroxypyridine.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.52 (s, 1H), 8.34 (d, J = 8.1Hz, 2H), 7.06 (s, 1H), 6.75 (s, 1H), 6.34 (d, J = 8.1 Hz, 2H), 4.25 (t, J = 5.7 Hz, 2H), 3.75 (s, 3H), 3.58 (t, J = 5.7 Hz, 4H), 2.78 (t, J = 5.7 Hz, 2H)

 Example 78. Synthesis of 5-hydroxy-7- (3-hydroxy-propoxy) -6-methoxy-2-phenoxy-chromen-4-one (Compound No. 87) [See Scheme 27]

5-Hydroxy-6-methoxy-2-methylsulfanyl-7- (3-triisopropylsilanyloxy-propoxy) -chromen-4-one (0.6 g) was added CH ₂ Cl ₂ (13 mL ) Dissolved in m- CPBA (0.6 g) and stirred at room temperature for 4 hours. The reaction was washed with saturated aqueous NaHCO ₃ (10 mL × 3) and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was dissolved in acetone (30 mL), then phenol (0.2 g) and K ₂ CO ₃ (0.3 g) were added and stirred overnight at room temperature. The reaction was diluted with EtOAc (50 mL), washed with saturated aqueous NaHCO ₃ (10 mL × 3), brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (5% EtOAc / CHCl ₃ ) to give 5-hydroxy-6-methoxy-2-phenoxy-7- (3-triisopropylsilanyloxy-propoxy) -chromen-4 -On (0.6 g, 95%) was obtained. Dissolve 5-hydroxy-6-methoxy-2-phenoxy-7- (3-triisopropylsilanyloxy-propoxy) -chromen-4-one (0.6 g) in THF (12 mL) 0 1.0 N tetrabutylammonium fluoride / THF solution (3 mL) was added. The temperature of the reaction was raised to room temperature and stirred for 1 hour. The reaction was diluted with EtOAc (30 mL), washed with 0.3N aqueous HCl solution (10 mL), brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (5% MeOH / CHCl ₃ ) to give 5-hydroxy-7- (3-hydroxy-propoxy) -6-methoxy-2-phenoxy-chromen-4-one (0.2 g , 42%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.74 (s, 1H), 7.56 (dd, J ₁ , J ₂ = 7.8 Hz, 2H), 7.44-7.39 (m, 3H), 6.80 (s, 1H ), 5.24 (s, 1H), 4.59 (t, J = 5.1 Hz, 1H), 4.18 (t, J = 6.3 Hz, 2H), 3.73 (s, 3H), 3.59 (td, J ₁ = 6.3 Hz, J ₂ = 5.1 Hz, 2H), 1.91 (quintet, J = 6.3 Hz, 2H)

Example 79. Synthesis of 5-hydroxy-7- (3-hydroxy-propoxy) -6-methoxy-2- (pyridin-4-yloxy) -chromen-4-one (Compound No. 88) Reaction Scheme 27

Dissolve 5,7-dihydroxy-6-methoxy-2-methylsulfanyl-chromen-4-one (0.5 g) in acetone (10 mL) and DMF (10 mL), then 3-bromo-propane -1-ol (0.4 g) and K ₂ CO ₃ (0.4 g) were added. 70 reactants The temperature was raised to ℃, and stirred for 3 hours. The reaction was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in EtOAc (30 mL), washed with water (25 mL × 3) and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (7% MeOH / CHCl ₃ ) to give 5-hydroxy-7- (3-hydroxy-propoxy) -6-methoxy-2-methylsulfanyl-chromen-4-one ( 0.6 g, 97%).

5-hydroxy-7- (3-hydroxypropoxy) -6-methoxy-2-methylsulfanyl-chromen-4-one (0.6 g) was added to methanol (12 mL) and H ₂ O (6 mL), Oxon (Oxone ™, 2.3 g) was added and stirred overnight at room temperature. The reaction was diluted with H ₂ O (20 mL) and extracted with 10% methanol / chloroform (30 mL × 3). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was dissolved in acetone (30 mL), pyridine-4-ol (0.2 g) and K ₂ CO ₃ (0.3 g) were added, and the mixture was stirred at room temperature for 3 hours. The reaction was diluted with H ₂ O (20 mL) and then neutralized to pH 7 with 1N HCl aqueous solution. The neutralized reaction was extracted with 10% MeOH / CHCl ₃ (30 mL × 3). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (10% MeOH / CHCl ₃ ) to 5-hydroxy-7- (3-hydroxy-propoxy) -6-methoxy-2- (pyridin-4-yloxy) -chromen-4 -On (0.3 g, 63%) was obtained.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.52 (s, 1H), 8.36 (d, J = 8.1Hz, 2H), 7.04 (s, 1H), 6.75 (s, 1H), 6.33 (d, J = 8.1 Hz, 2H), 4.61 (t, J = 5.1 Hz, 1H), 4.20 (t, 6.3 Hz, 2H), 3.75 (s, 3H), 3.60 (td, J ₁ = 6.3 Hz, J ₂ = 5.1 Hz, 2H), 1.94 (quintet, J = 6.3 Hz, 2H)

Example 80. Synthesis of (5-hydroxy-6-methoxy-4-oxo-2-phenoxy-4H-chromen-7-yloxy) -acetic acid ethyl ester (Compound No. 89) [See Scheme 21]

Obtained by the method of Example 58 using ethyl bromoacetate and phenol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 7.56 (dd, J ₁ , J ₂ = 7.5 Hz, 2H), 7.43-7.39 (m, 3H), 6.81 (s, 1H), 5.24 (s, 1H ), 5.00 (s, 2H), 4.19 (quartet, J = 7.2 Hz, 2H), 3.77 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H)

Example 81. [5-hydroxy-6-methoxy-4-oxo-2- (pyridin-4-yloxy) -4H-chromen-7-yloxy] -acetic acid ethyl ester (Compound No. 90) Synthesis [See Scheme 21]

Obtained by the method of Example 58 using ethyl bromoacetate and 4-hydroxypyridine.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.58 (s, 1H), 8.33 (d, J = 8.1 Hz, 2H), 7.02 (s, 1H), 6.76 (s, 1H), 6.33 (d, J = 8.1 Hz, 2H), 5.00 (s, 2H), 4.20 (quartet, J = 7.2 Hz, 2H), 3.79 (s, 3H), 1.24 (t, 3H)

Example 82. Synthesis of 5-hydroxy-6-methoxy-7- (1-oxy-pyridin-4-ylmethoxy) -2-phenoxy-chromen-4-one (Compound No. 91) Reference]

5-hydroxy-6-methoxy-2-methylsulfanyl-7- (pyridin-4-ylmethoxy) -chromen-4-one (1.0 g) was dissolved in CH ₂ Cl ₂ (50 mL) and 0 After lowering to ℃ m- CPBA (1.62 g) was added and stirred for 18 hours at room temperature. The reaction was washed with aqueous sodium hydrogen carbonate solution (40 mL × 3) and the organic layers were collected. The aqueous layer was reextracted with CH ₂ Cl ₂ (30 mL × 3). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to 5-hydroxy-2-methanesulfinyl-6-methoxy-7- (1-oxy-pyridin-4-ylmethoxy) -Crommen-4-one (970 mg, 89%) was obtained.

5-hydroxy-2-methanesulfinyl-6-methoxy-7- (1-oxy-pyridin-4-ylmethoxy) -chromen-4-one (480 mg) was dissolved in acetone (30 mL) and K ₂ CO ₃ (264 mg) and phenol (145 mg) were added sequentially, followed by stirring at room temperature for 4 hours. H ₂ O (30 mL) was added and extracted with 5% MeOH / chloroform (30 mL × 3). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (7% MeOH / CHCl ₃ ) to 5-hydroxy-6-methoxy-7- (1-oxy-pyridin-4-ylmethoxy) -2-phenoxy-chromen-4-one ( 310 mg, 62%).

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.81 (s, 1H), 8.25 (d, J = 7.2 Hz, 2H), 7.56 (dd, J ₁ , J ₂ = 7.8 Hz, 2H), 7.48 ( d, J = 7.2 Hz, 2H), 7.43-7.39 (m, 3H), 6.88 (s, 1H), 5.27 (s, 2H), 5.26 (s, 1H), 3.77 (s, 3H)

Example 83. Synthesis of 5,7-dihydroxy-8-methyl-2-phenoxy-chromen-4-one (Compound No. 92) [See Scheme 29]

-10 in a solution of 3,5-dimethoxyphenol (10 g, 64.8 mmol) in BF ₃ .Et ₂ O (80 mL) CH (OEt) ₃ (10 mL, 64.8 mmol) was added at ° C. After stirring for 10 minutes, it was poured into 5% aqueous NaOAc solution (250 mL) and extracted with EtOAc (100 mL × 3)). Washed twice with saturated aqueous NaCl solution (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain 2-hydroxy-4,6-dimethoxy-benzaldehyde (5.5 g, 46%). .

To MeOH (70 mL) solution of 2-hydroxy-4,6-dimethoxy-benzaldehyde (2.0 g, 11.0 mmol) obtained above was added 10% Pd / C (500 mg) and replaced with H ₂ 1 Stir for hours. The reaction was filtered through celite and concentrated under reduced pressure. The residue was dissolved in 50% EtOAc / Hexane and filtered through silica gel. Concentrated under reduced pressure and dried under vacuum to give 3,5-dimethoxy-2-methyl-phenol and used for the next reaction.

0 to a CH ₂ Cl ₂ (60 mL) solution of 3,5-dimethoxy-2-methyl-phenol obtained above Ac ₂ O (1.3 mL, 13.2 mmol) and Et ₃ N (3.1 mL, 22.0 mmol) were added sequentially. After stirring for 2 hours, the mixture was poured into diluted aqueous NaCl solution (50 mL) and extracted. The aqueous layer was extracted once more with CH ₂ Cl ₂ (30 mL), the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (10% EtOAc / Hexane) to give acetic acid 3,5-dimethoxy-2-methyl-phenyl ester (1.9 g, two steps 84%).

Acetic acid 3,5-dimethoxy-2-methyl-phenyl ester (1.9 g, 9.2 mmol) was added to the 5,7-dihydroxy-8-methyl-2-phenoxy-chromen using the method of Example 69. 4-one (136 mg, 89%) was obtained.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 1.98 (s, 3H), 5.20 (s, 1H), 6.30 (s, 1H), 7.38-7.43 (m, 3H), 7.53-7.58 (m, 2H) , 10.78 (br s, 1 H), 12.69 (s, 1 H)

Example 84. Synthesis of 7-ethoxy-5-hydroxy-6-methoxy-2- (4-methoxy-phenoxy) -chromen-4-one (Compound No. 93) [See Scheme 21]

Obtained by the method of Example 58 using EtBr and 4-methoxyphenol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.77 (s, 1 H), 7.34 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H), 6.78 (s, 1H) , 5.15 (s, 1H), 4.17 (quartet, J = 6.9Hz, 2H), 3.80 (s, 3H), 3.73 (s, 3H), 1.38 (6.9Hz, 3H)

Example 85. Synthesis of 2-cyclohexyloxy-7-ethoxy-5-hydroxy-6-methoxy-chromen-4-one (Compound No. 94) [See Scheme 30]

Dissolve 7-ethoxy-5-hydroxy-6-methoxy-2-methylsulfanyl-chromen-4-one (0.3 g) in CH ₂ Cl ₂ (10 mL) and then m- CPBA (0.4 g) Was added and stirred at room temperature for 2 hours. The reaction was washed with saturated aqueous NaHCO ₃ (10 mL × 3) and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was dissolved in THF (20 mL) and 0 Cyclohexanol (1 g) and potassium t- butoxide (0.2 g) were added at < RTI ID = 0.0 > The temperature of the reaction was raised to room temperature and stirred for 1 hour. The reaction was diluted with water (30 mL) and neutralized with 1N HCl aqueous solution. The neutralized reaction was extracted with EtOAc (30 mL × 3). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by MPLC (5% EtOAc / CHCl ₃ ) to give 2-cyclohexyloxy-7-ethoxy-5-hydroxy-6-methoxy-chromen-4-one (0.1 g, 41%). Got it.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.85 (s, 1H), 6.36 (s, 1H), 5.44 (s, 1H), 4.56-4.47 (m, 1H), 4.12 (quartet, J = 6.9 Hz, 2H), 3.89 (s, 3H), 2.04-1.99 (m, 2H), 1.90-1.75 (m, 2H), 1.49 (t, J = 6.9 Hz, 3H), 1.72-1.37 (m, 6H)

Example 86. Synthesis of 5-hydroxy-7-isopropoxy-6-methoxy-2- (4-methoxy-phenoxy) -chromen-4-one (Compound No. 95) [See Scheme 21]

Obtained by the method of Example 58 using i- PrBr and 4-methoxyphenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.64 (s, 1H), 7.10 (d, J = 9.3 Hz, 2H), 6.96 (d, J = 9.3 Hz, 2H), 6.42 (s, 1H), 5.24 (s, 1H), 4.63 (septet, J = 6.0 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 1.43 (d, J = 6.0 Hz, 6H)

Example 87. Synthesis of 2-cyclohexyloxy-5-hydroxy-7-isopropoxy-6-methoxy-chromen-4-one (Compound No. 96) [See Scheme 30]

Obtained by the method of Example 85 using i- PrBr and cyclohexanol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.84 (s, 1H), 6.37 (s, 1H), 5.43 (s, 1H), 4.60 (septet, J = 6.0Hz, 1H), 4.54-4.48 (m, 1H), 3.86 (s, 3H), 2.04-1.95 (m, 2H), 1.90-1.75 (m, 2H), 1.41 (d, J = 6.0 Hz, 6H), 1.75-1.33 (m, 6H)

Example 88. Synthesis of 7-benzyloxy-5-hydroxy-6-methoxy-2- (4-methoxy-phenoxy) -chromen-4-one (Compound No. 97) [See Scheme 21]

Obtained by the method of Example 58 using BnBr and 4-methoxyphenol.

_{^{1 H NMR (CDCl 3, 300}} MHz) δ 12.69 (s, 1H), 7.46-7.34 (m, 5H), 7.09 (d, J = 9.3Hz, 2H), 6.95 (d, J = 9.3, 2H), 6.46 (s, 1H), 5.23 (s, 1H), 5.21 (s, 2H), 3.92 (s, 3H), 3.84 (s, 3H)

Example 89. Synthesis of 7-benzyloxy-2-cyclohexyloxy-5-hydroxy-6-methoxy-chromen-4-one (Compound No. 98) [See Scheme 30]

Obtained by the method of Example 85 using BnBr and cyclohexanol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.88 (s, 1H), 7.44-7.31 (m, 5H), 6.40 (s, 1H), 5.43 (s, 1H), 5.19 (s, 2H), 4.52- 4.46 (m. 1H), 3.92 (2, 3H), 2.10-1.98 (m, 2H), 1.90-1.75 (m, 2H), 1.69-1.32 (m, 6H)

Example 90. of 7- (4-Fluoro-benzyloxy) -5-hydroxy-6-methoxy-2- (4-methoxy-phenoxy) -chromen-4-one (Compound No. 99) Synthesis [See Scheme 21]

Obtained by the method of Example 58 using 4-fluorobenzyl bromide and 4-methoxyphenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.70 (s, 1H), 7.42 (dd, J ₁ = 8.1 Hz, J ₂ = 5.1 Hz, 2H), 7.12-7.06 (m, 4H), 6.95 (d, J = 9.0 Hz, 2H), 6.44 (s, 1H), 5.24 (s, 1H), 5.16 (s, 2H), 3.91 (s, 3H), 3.84 (s, 3H)

Example 91. Synthesis of 2-cyclohexyloxy-7- (4-fluoro-benzyloxy) -5-hydroxy-6-methoxy-chromen-4-one (Compound No. 100) See Scheme 30 ]

Obtained by the method of Example 85 using 4-fluorobenzyl bromide and cyclohexanol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.90 (s, 1 H), 7.41 (dd, J ₁ = 8.4 Hz, J ₂ = 5.4 Hz, 2H), 7.08 (t, J = 8,4 Hz, 2H), 6.38 (s, 1H), 5.43 (s, 1H), 5.14 (s, 2H), 4.54-4.45 (m, 1H), 3.90 (s, 3H), 2.04-1.99 (m, 2H), 1.90-1.75 ( m, 2H), 1.70-1.33 (m, 6H)

Example 92. 5-hydroxy-6-methoxy-2- (4-methoxy-phenoxy) -7- [2- (4-methoxy-phenyl) -ethoxy] -chromen-4-one Synthesis of (Compound No. 101) [See Scheme 21]

Obtained by the method of Example 58 using 4-methoxyphenethyl bromide and 4-methoxyphenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.66 (s, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 9.0 Hz, 2H), 6.95 (d, J = 9.0 Hz , 2H), 6.87 (d, J = 8.4 Hz, 2H), 6.39 (s, 1H), 5.25 (s, 1H), 4.22 (t, J = 6.9 Hz, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H), 3.12 (t, J = 6.9 Hz, 2H)

Example 93. 2-cyclohexyloxy-5-hydroxy-6-methoxy-7- [2- (4-methoxy-phenyl) -ethoxy] -chromen-4-one (Compound No. 102) Synthesis of compounds [see Scheme 30]

Obtained by the method of Example 85 using 4-methoxyphenethyl bromide and cyclohexanol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.86 (s, 1H), 7.21 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 6.34 (s, 1H), 5.43 (s, 1H), 4.54-4.48 (m, 1H), 4.20 (t, J = 7.2 Hz, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.11 (t, J = 7.2 Hz, 2H), 2.02-1.98 (m, 2H), 1.95-1.75 (m, 2H), 1.70-1.39 (m, 6H)

Example 94. Synthesis of 5-hydroxy-6-methoxy-2- (4-methoxy-phenoxy) -7- (pyridin-4-ylmethoxy) -chromen-4-one (Compound No. 103) Reaction Scheme 26

Obtained by the method of Example 72 using 4- (bromomethyl) -pyridine hydrogen bromide and 4-methoxyphenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.75 (s, 1H), 8.65 (d, J = 5.4 Hz, 2H), 7.38 (d, J = 5.4 Hz, 2H), 7.09 (d, J = 9.0 Hz , 2H), 6.95 (d, J = 9.0 Hz, 2H), 6.39 (s, 1H), 5.25 (s, 1H), 5.22 (s, 2H), 3.96 (s, 3H), 3.84 (s, 3H)

Example 95. Synthesis of 2-cyclohexyloxy-5-hydroxy-6-methoxy-7- (pyridin-4-ylmethoxy) -chromen-4-one (Compound No. 104) [See Scheme 31]

Obtained by the method of Example 72 using 4- (bromomethyl) -pyridine hydrogen bromide and cyclohexanol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.95 (s, 1H), 8.64 (d, J = 5.4 Hz, 2H), 7.36 (d, J = 5.4 Hz, 2H), 6.32 (s, 1H), 5.44 (s, 1H), 5.21 (s, 2H), 4.54-4.45 (m, 1H), 3.95 (s, 3H), 2.04-1.98 (m, 2H), 1.90-1.75 (m, 2H), 1.70-1.33 (m, 6H)

Example 96. 5-hydroxy-6-methoxy-2- (4-methoxy-phenoxy) -7- (2-piperidin-1-yl-ethoxy) -chromen-4-one ( Synthesis of Compound No. 105) [See Scheme 26]

Obtained by the method of Example 72 using 1- (2-chloroethyl) piperidine hydrogen chloride and 4-methoxyphenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.67 (s, 1H), 7.10 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 6.44 (s, 1H), 5.26 (s, 1H), 4.21 (t, J = 6.0 Hz, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 2.86 (t, J = 6.0 Hz, 2H), 2.60-2.50 (br s , 4H), 1.7-1.45 (m, 6H)

Example 97. of 2-cyclohexyloxy-5-hydroxy-6-methoxy-7- (2-piperidin-1-yl-ethoxy) -chromen-4-one (Compound No. 106) Synthesis [See Scheme 31]

Obtained by the method of Example 95 using 1- (2-chloroethyl) piperidine hydrogen chloride and cyclohexanol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.87 (s, 1H), 6.39 (s, 1H), 5.44 (s, 1H), 4.56-4.48 (m, 1H), 4.19 (t, J = 6.0 Hz, 2H), 3.88 (s, 3H), 2.85 (t, J = 6.0 Hz, 2H), 2.60-2.50 (br s, 4H), 2.10-1.95 (m, 2H), 1.90-1.75 (m, 2H), 1.75-1.30 (m, 12H)

Example 98. 5-Hydroxy-6-methoxy-2- (4-methoxy-phenoxy) -7- (2-morpholin-4-yl-ethoxy) -chromen-4-one (compound Synthesis of No. 107) [See Scheme 26]

Obtained by the method of Example 72 using 4- (2-chloroethyl) morpholine hydrogen chloride and 4-methoxyphenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.68 (s, 1H), 7.11 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 6.43 (s, 1H), 5.26 (s, 1H), 4.20 (t, J = 5.7 Hz, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 3.73 (t, J = 4.8 Hz, 4H), 2.88 (t, J = 5.7 Hz, 2H), 2.61 (t, J = 4.8 Hz, 4H)

Example 99. Synthesis of 2-cyclohexyloxy-5-hydroxy-6-methoxy-7- (2-morpholin-4-yl-ethoxy) -chromen-4-one (Compound No. 108) Reaction Scheme 31

Obtained by the method of Example 95 using 4- (2-chloroethyl) morpholine hydrogen chloride and cyclohexanol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.88 (s, 1H), 6.38 (s, 1H), 5.44 (s, 1H), 4.55-4.49 (m, 1H), 4.19 (t, J = 5.7 Hz, 2H), 3.88 (s, 3H), 3.73 (t, J = 4.5 Hz, 4H), 2.87 (t, J = 5.7 Hz, 2H), 2.62 (t, J = 4.5 Hz, 4H), 2.10-1.95 ( m, 2H), 1.90-1.75 (m, 2H), 1.75-1.33 (m, 6H)

Example 100. of 5-hydroxy-7- (3-hydroxy-propoxy) -6-methoxy-2- (4-methoxy-phenoxy) -chromen-4-one (Compound No. 109) Synthesis [See Scheme 21]

Obtained by the method of Example 58 using 3-bromo-1-propanol and 4-methoxyphenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.69 (s, 1H), 7.10 (d, J = 9.0 Hz, 2H), 6.95 (d, J = 9.0 Hz, 2H), 6.45 (s, 1H), 5.26 (s, 1H), 4.23 (t, J = 6.0 Hz, 2H), 3.93 (t, J = 5.7 Hz, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 2.13 (quintet, J = 5.7 Hz, 2H), 1.92 (t, J = 2.1 Hz, 1H)

Example 101. Synthesis of 2-cyclohexyloxy-5-hydroxy-7- (3-hydroxy-propoxy) -6-methoxy-chromen-4-one (Compound No. 110) [See Scheme 32] ]

Obtained by the method of Example 7, 58, 67 using 3-bromo-1-propanol and cyclohexanol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.88 (s, 1H), 6.40 (s, 1H), 5.44 (s, 1H), 4.55-4.48 (m, 1H), 4.21 (t, J = 6.0Hz, 2H), 3.88 (s, 3H), 3.88 (t, J = 6.0 Hz, 2H), 2.16-2.08 (m, 2H), 2.08-1.95 (m, 3H), 1.90-1.75 (m, 2H), 1.75 -1.33 (m, 6H)

Example 102. [5-Hydroxy-6-methoxy-2- (4-methoxy-phenoxy) -4-oxo-4H-chromen-7-yloxy] -acetic acid ethyl ester (Compound No. 111) Synthesis of compounds [see Scheme 21]

Obtained by the method of Example 58 using bromo ethyl acetate and 4-methoxyphenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.75 (s, 1H), 7.10 (d, J = 9.0 Hz, 2H), 6.95 (d, J = 9.0 Hz, 2H), 6.33 (s, 1H), 5.25 (s, 1H), 4.76 (s, 2H), 4.28 (quartet, J = 6.9 Hz, 2H), 3.95 (s, 3H), 3.84 (s, 3H), 1.31 (t, J = 6.9 Hz, 3H)

Example 103. Synthesis of (2-cyclohexyloxy-5-hydroxy-6-methoxy-4-oxo-4H-chromen-7-yloxy) -acetic acid ethyl ester (Compound No. 112) Reference]

Obtained by the method of Example 7, 58, 67 using bromo ethyl acetate and cyclohexanol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.95 (s, 1H), 6.28 (s, 1H), 5.45 (s, 1H), 4.74 (s, 2H), 4.55-4.48 (m, 1H), 4.24 ( quartet, J = 6.9 Hz, 2H), 3.94 (s, 3H), 2.10-1.95 (m, 2H), 1.90-1.75 (m, 2H), 1.75-1.33 (m, 6H), 1.30 (t, J = 6.9 Hz, 3H)

Example 104. Synthesis of 7-ethoxy-2- (4-fluoro-phenoxy) -5-hydroxy-6-methoxy-chromen-4-one (Compound No. 113) [See Scheme 21]

Obtained by the method of Example 58 using EtBr and 4-fluorophenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.58 (s, 1H), 7.16 (d, J = 5.7 Hz, 4H), 6.41 (s, 1H), 5.27 (s, 1H), 4.14 (quartet, J = 6.9 Hz, 2H), 3.89 (s, 3H), 1.50 (t, J = 6.9 Hz, 3H)

Example 105. Synthesis of 2- (4-fluoro-phenoxy) -5-hydroxy-7-isopropoxy-6-methoxy-chromen-4-one (Compound No. 114) [See Scheme 21]

Obtained by the method of Example 58 using i- PrBr and 4-fluorophenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.57 (s, 1H), 7.16 (d, J = 6.0 Hz, 4H), 6.41 (s, 1H), 5.26 (s, 1H), 4.63 (septet, J = 6.0 Hz, 1H), 3.87 (s, 3H), 1.42 (d, J = 6.3 Hz, 6H)

Example 106. Synthesis of 7-benzyloxy-2- (4-fluoro-phenoxy) -5-hydroxy-6-methoxy-chromen-4-one (Compound No. 115) [See Scheme 21]

Obtained by the method of Example 58 using BnBr and 4-fluorophenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.61 (s, 1H), 7.33-7.46 (m, 5H), 7.15 (d, J = 6.0Hz, 4H), 6.46 (s, 1H), 5.25 (s, 1H), 5.21 (s, 2H), 3.93 (s, 3H)

Example 107. of 7- (4-Fluoro-benzyloxy) -2- (4-fluoro-phenoxy) -5-hydroxy-6-methoxy-chromen-4-one (Compound No. 116) Synthesis [See Scheme 21]

Obtained by the method of Example 58 using 4-fluorobenzyl bromide and 4-fluorophenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.62 (s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.16 (d, J = 5.7 Hz , 4H), 7.09 (t, J = 9.0 Hz, 2H), 6.44 (s, 1H), 5.26 (s, 1H), 5.16 (s, 2H), 3.91 (s, 3H)

Example 108. 2- (4-Fluoro-phenoxy) -5-hydroxy-6-methoxy-7- [2- (4-methoxy-phenyl) -ethoxy] -chromen-4-one Synthesis of (Compound No. 117) [See Scheme 21]

Obtained by the method of Example 58 using 4-methoxyphenethyl bromide and 4-fluorophenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.57 (s, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 6.0 Hz, 4H), 6.86 (d, J = 8.4 Hz , 2H), 6.38 (s, 1H), 5.27 (s, 1H), 4.21 (t, J = 7.2Hz, 2H), 3.82 (s, 3H), 3.79 (s, 3H), 3.12 (t, J = 7.2 Hz, 2H)

Example 109. Synthesis of 2- (4-fluoro-phenoxy) -5-hydroxy-6-methoxy-7- (pyridin-4-ylmethoxy) -chromen-4-one (Compound No. 118) Reaction Scheme 26

Obtained by the method of Example 72 using 4- (bromomethyl) -pyridine hydrogen bromide and 4-fluorophenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.68 (s, 1H), 8.65 (d, J = 5.7 Hz, 2H), 7.37 (d, J = 5.7 Hz, 2H), 7.16 (d, J = 6.3 Hz , 4H), 6.38 (s, 1H), 5.27 (s, 1H), 5.22 (s, 2H), 3.95 (s, 3H)

Example 110. 2- (4-Fluoro-phenoxy) -5-hydroxy-6-methoxy-7- (2-piperidin-1-yl-ethoxy) -chromen-4-one ( Synthesis of Compound No. 119) [See Scheme 26]

Obtained by the method of Example 72 using 1- (2-chloroethyl) piperidine hydrogen chloride and 4-fluorophenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.59 (s, 1H) 7.17 (d, J = 6 Hz, 4H), 6.44 (s, 1H), 5.27 (s, 1H), 4.21 (br t, J = 6 Hz , 2H), 3.88 (s, 3H), 2.86 (br t, J = 5.4 Hz, 2H), 2.55 (br s, 4H), 1.60 (br s, 4H), 1.47 (br d, J = 4.8 Hz, 2H)

Example 111. 2- (4-Fluoro-phenoxy) -5-hydroxy-6-methoxy-7- (2-morpholin-4-yl-ethoxy) -chromen-4-one (compound Synthesis of number 120) [see Scheme 26]

Obtained by the method of Example 72 using 4- (2-chloroethyl) morpholine hydrogen chloride and 4-fluorophenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.60 (s, 1H), 7.17 (d, J = 6Hz, 4H), 6.43 (s, 1H), 5.28 (s, 1H), 4.20 (t, J = 6Hz , 2H), 3.88 (s, 3H), 3.73 (br t, J = 4.5Hz, 4H), 2.88 (t, J = 5.4Hz, 2H), 2.61 (br t, J = 4.5Hz, 4H)

Example 112. of 2- (4-Fluoro-phenoxy) -5-hydroxy-7- (3-hydroxy-propoxy) -6-methoxy-chromen-4-one (Compound No. 121) Synthesis [See Scheme 21]

Obtained by the method of Example 58 using 3-bromo-1-propanol and 4-fluorophenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 2.60 (s, 1H) 7.17 (d, J = 6Hz, 4H), 6.43 (s, 1H), 5.27 (s, 1H), 4.22 (t, J = 6Hz, 2H), 3.88 (s, 5H), 2.13 (quintet, J = 6 Hz, 2H), 2.00 (br s, 1H)

Example 113. [2- (4-Fluoro-phenoxy) -5-hydroxy-6-methoxy-4-oxo-4H-chromen-7-yloxy] -acetic acid ethyl ester (Compound No. 122) Synthesis of compounds [see Scheme 21]

Obtained by the method of Example 58 using bromo ethyl acetate and 4-fluorophenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.67 (s, 1H), 7.16 (d, J = 6Hz, 4H), 6.32 (s, 1H), 5.27 (s, 1H), 4.76 (s, 2H), 4.28 (quartet, J = 7.2 Hz, 2H), 3.94 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H)

Example 114. Synthesis of 8-chloro-5-hydroxy-7-isopropoxy-2-phenoxy-chromen-4-one (Compound No. 123) [See Scheme 33]

Dissolve 5-hydroxy-7-isopropoxy-2-methylsulfanyl-chromen-4-one (0.5 g) in chloroform (20 mL) and then 1.0 N sulfanyl chloride / dichloromethane (5 mL) was added thereto, followed by stirring for 1 hour. Saturated NaHCO ₃ aqueous solution (20 mL) was added to the reaction to terminate the reaction, followed by extraction with chloroform (30 mL × 2). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the residue was purified by MPLC (5% EtOAc / CHCl ₃ ) to 8-chloro-5-hydroxy-7-isopropoxy-2-methylsulpa. Neyl-chromen-4-one (0.4 g, 74%) was obtained.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.77 (s, 1H), 7.47 (dd, J ₁ , J ₂ = 7.5 Hz, 2H), 7.38-7.21 (m, 3H), 6.44 (s, 1H), 5.29 (s, 1H), 4.67 (septet, J = 6.0 Hz, 1H), 1.43 (d, J = 6.0 Hz, 6H)

Example 115. Synthesis of 8-chloro-5-hydroxy-7-isopropoxy-2- (pyridin-4-yloxy) -chromen-4-one (Compound No. 124) [See Scheme 33]

Obtained by the method of Example 114 using i- PrBr and 4-hydroxypyridine.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.33 (s, 1H), 7.94 (d, J = 5.4 Hz, 2H), 6.54 (d, J = 5.4 Hz, 2H), 6.49 (s, 1H), 6.17 (s, 1H), 4.71 (septet, J = 6 Hz, 1H), 1.46 (d, J = 6.3 Hz, 6H)

Example 116. Synthesis of 8-chloro-5-hydroxy-7- (3-hydroxy-propoxy) -2-phenoxy-chromen-4-one (Compound No. 125) [See Scheme 33]

Obtained by the method of Example 114 using 3-bromo-1-propanol and phenol.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.92 (s, 1H), 7.57 (dd, J ₁ , J ₂ = 7.2 Hz, 2H), 7.46-7.40 (m, 3H), 6.71 (s, 1H ), 5.25 (s, 1H), 4.59 (t, J = 4.8 Hz, 1H), 4.25 (t, J = 6.0 Hz, 2H), 3.59 (td, J ₁ = 6.0 Hz, J ₂ = 4.8 Hz, 2H ), 1.91 (tt, J ₁ , J ₂ = 6.0 Hz, 2H)

Example 117. Synthesis of (8-chloro-5-hydroxy-4-oxo-2-phenoxy-4H-chromen-7-yloxy) -acetic acid ethyl ester (Compound No. 126) [See Scheme 33]

Obtained by the method of Example 114 using bromo ethyl acetate and phenol.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.83 (s, 1H), 7.48 (t, J = 7.8 Hz, 2H), 7.36 (t, J = 7.2 Hz, 1H), 7.22 (d, J = 7.8 Hz , 2H), 6.31 (s, 1H), 5.32 (s, 1H), 4.76 (s, 2H), 4.29 (quartet, J = 7.2Hz, 2H), 1.32 (t, J = 7.2Hz, 3H)

Example 118. Synthesis of 7-ethoxy-5-hydroxy-6-methoxy-2- (1-methyl-piperidin-4-yloxy) -chromen-4-one (Compound No. 127) [ See Scheme 30]

Obtained by the method of Example 85 using EtBr and 4-hydroxy-1-methylpiperidine.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.79 (s, 1H), 6.36 (s, 1H), 5.44 (s, 1H), 4.58 (quintet, J = 3.9 Hz, 1H), 4.12 (quartet, J = 7.2 Hz, 2H), 3.88 (s, 3H), 2.68 to 2.70 (m, 2H), 2.35 (s, 5H), 2.04 to 2.12 (m, 2H), 1.89 to 2.00 (m, 2H), 1.49 (t , J = 7.2 Hz, 3H)

Example 119. Synthesis of 5-hydroxy-7-isopropoxy-6-methoxy-2- (1-methyl-piperidin-4-yloxy) -chromen-4-one (Compound No. 128) Reaction Scheme 30

Obtained by the method of Example 85 using i- PrBr and 4-hydroxy-1-methylpiperidine.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.78 (s, 1H), 6.37 (s, 1H), 5.44 (s, 1H), 4.60 (quintet, J = 6Hz, 2H), 3.86 (s, 3H), 2.65 to 2.71 (m, 2H), 2.33 (s, 5H), 2.05 to 2.10 (m, 2H), 1.92 to 2.01 (m, 2H), 1.41 (d, J = 6 Hz, 6H)

Example 120 Synthesis of 7-benzyloxy-5-hydroxy-6-methoxy-2- (1-methyl-piperidin-4-yloxy) -chromen-4-one (Compound No. 129) [ See Scheme 30]

Obtained by the method of Example 85 using BnBr and 4-hydroxy-1-methylpiperidine.

¹ H NMR (CDCl ₃ , 300 MHz) δ 13.05 (s, 1H), 7.90 to 7.87 (m, 2H), 7.64 (d, J = 7.8 Hz, 1H), 7.53 to 7.36 (m, 3H), 6.86 ( s, 1H), 5.23 (s, 2H), 4.80 (quintet, J = 3.6 Hz, 1H), 3.72 (s, 3H), 2.61-2.51 (m, 2H), 2.34 (br t, J = 8.4 Hz, 2H), 2.23 (s, 3H), 2.05-1.95 (m, 2H), 1.82-1.75 (m, 2H)

Example 121. 7- (4-Fluoro-benzyloxy) -5-hydroxy-6-methoxy-2- (1-methyl-piperidin-4-yloxy) -chromen-4-one ( Synthesis of Compound No. 130) [See Scheme 30]

Obtained by the method of Example 85 using 4-fluorobenzyl bromide and 4-hydroxy-1-methylpiperidine.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.84 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.08 (t, J = 8.7 Hz , 2H), 6.39 (s, 1H), 5.44 (s, 1H), 5.14 (s, 2H), 4.55 (quintet, J = 3.6Hz, 1H), 3.90 (s, 3H), 2.65 ~ 2.70 (m, 2H), 2.32 (s, 5H), 2.04-2.11 (m, 2H), 1.89-1.99 (m, 2H)

Example 122 5-hydroxy-6-methoxy-7- [2- (4-methoxy-phenyl) -ethoxy] -2- (1-methyl-piperidin-4-yloxy) -cro Synthesis of Menth-4-one (Compound No. 131) [See Scheme 30]

Obtained by the method of Example 85 using 4-methoxyphenethyl bromide and 4-hydroxy-1-methylpiperidine.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.79 (s, 1H), 7.22 (d, J = 9 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 6.35 (s, 1H), 5.44 ( s, 1H), 4.57 (quintet, J = 3.3 Hz, 1H), 4.20 (t, J = 6.9 Hz, 2H), 3.81 (s, 3H), 3.79 (s, 3H), 3.12 (t, J = 6.9 Hz, 2H), 2.70 (br s, 2H), 2.33 (s, 5H), 2.03-2.17 (m, 2H), 1.90-1.99 (m, 3H)

Example 123. 5-Hydroxy-6-methoxy-2- (1-methyl-piperidin-4-yloxy) -7- (pyridin-4-ylmethoxy) -chromen-4-one (compound Synthesis of No. 132) [See Scheme 31]

Obtained by the method of Example 95 using 4- (bromomethyl) -pyridine hydrogen bromide and 4-hydroxy-1-methylpiperidine.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.89 (s, 1H), 8.64 (d, J = 5.7 Hz, 2H), 7.35 (d, J = 5.7 Hz, 2H), 6.32 (s, 1H), 5.45 (s, 1H), 5.21 (s, 1H), 4.56 (br s, 2H), 3.95 (s, 3H), 2.69 (br s, 2H), 2.33 (s, 5H), 2.01-2.15 (m, 2H ), 1.91-1.99 (m, 2H)

Example 124. Acetic acid 7-acetoxy-8- (1,1-dimethyl-allyl) -6-methoxy-4-oxo-2-phenyl-4H-chromen-5-yl ester (Compound No. 133) Synthesis of [see Scheme 34]

Prenyl bromide (2.5 mL) was added to a suspension of DMF (70 mL) of Oroxylin A (4 g), K ₂ CO ₃ (5.8 g), and TBAI (520 mg), followed by stirring for 1 hour 30 minutes. The reaction suspension was diluted in H ₂ O (30 mL) and acidified with saturated aqueous NH ₄ Cl solution. The solution was extracted with EtOAc (200 mL), the organic layer was washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered and the residue obtained by distillation under reduced pressure was purified by MPLC (20% EtOAc / Hexane) to give 5-hydroxy. -6-methoxy-7- (3-methyl-but-2-enyloxy) -2-phenyl-chromen-4-one (3.6 g, 73%) was obtained.

Ac ₂ to a mixture of 5-hydroxy-6-methoxy-7- (3-methyl-but-2-enyloxy) -2-phenyl-chromen-4-one (800 mg), NaOAc (427 mg) O (32 mL) was added and stirred at reflux for 24 hours. The reaction solution was cooled to room temperature and the reaction was stopped by addition of saturated NaHCO ₃ solution. The resulting solution was extracted with EA (200 mL), washed with H ₂ O and brine, dried over anhydrous Na ₂ SO ₄ , filtered, and distilled under reduced pressure. The residue was purified by MPLC (20% EtOAc / Hexane) to 5-acetoxy-8 acetate. -(1,1-dimethyl-allyl) -6-methoxy-4-oxo-2-phenyl-4H-chromen-7-yl ester (630 mg, 85%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.68 (s, 6H), 2.31 (s, 3H), 2.50 (s, 3H), 3.85 (s, 3H), 4.93-5.00 (m, 2H), 6.33 ( dd, J = 10.7 Hz, 17.6 Hz, 1H), 6.62 (s, 1H), 7.49-7.55 (m, 3H), 7.84-7.87 (m, 2H)

Example 125. Acetic Acid 8- (1,1-Dimethyl-allyl) -5-hydroxy-6-methoxy-4-oxo-2-phenyl-4H-chromen-7-yl ester (Compound No. 134) Synthesis of [see Scheme 34]

Compound No. 133 (300 mg) was dissolved in THF / MeOH 1: 1 solution (15 mL), 8M HCl solution (10 mL) was added, and the mixture was stirred overnight. The reaction solution was extracted with EtOAc, washed with H ₂ O and brine, dried over anhydrous Na ₂ SO ₄ , filtered and distilled under reduced pressure. The obtained residue was purified by MPLC (1% MeOH / CH ₂ Cl ₂ ) to acetic acid 8- (1,1-dimethyl-allyl) -5-hydroxy-6-methoxy-4-oxo-2-phenyl-4H-chrome Men-7-yl ester (225 mg, 83%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.65 (s. 6H), 2.30 (s, 3H), 4.92-4.98 (m, 2H), 6.29 (dd, J ₁ = 10.7 Hz, J ₂ = 17.6 Hz, 1H), 6.71 (s, 1H), 7.50-7.57 (m, 3H), 7.89-7.91 (m, 2H), 13.27 (s, 1H)

Example 126. Synthesis of 8- (1,1-dimethyl-allyl) -5,7-dihydroxy-6-methoxy-2-phenyl-chromen-4-one (Compound No. 135) [Scheme 34 Reference]

To a compound No. 133 (300 mg) was added 1: 1 solution (27 mL) of 1M NaOH aqueous solution and EtOH and stirred overnight. The reaction solution was quenched by the addition of 1M aqueous HCl solution and extracted with EtOAc. The obtained organic layer was washed with H ₂ O and brine, dried over anhydrous Na ₂ SO ₄ , filtered, and distilled under reduced pressure. The obtained residue was subjected to MPLC (1% MeOH / CH ₂ Cl ₂ ) to 8- (1,1-dimethyl-allyl) -5,7-dihydroxy-6-methoxy-2-phenyl-chromen-4- Warm (161 mg, 66%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.70 (s, 6H), 4.06 (s, 3H), 4.92 (s, 2H), 4.97 (d, J = 7.8 Hz, 2H), 6.32 (dd, J ₁ = 10.7 Hz, J ₂ = 17.6 Hz, 1H), 6.64 (s, 1H), 7.04 (s, 1H), 7.48-7.55 (m, 3H), 7.88-7.91 (m, 2H), 13.41 (s, 1H) )

Example 127. 5-Hydroxy-6-methoxy-8,9,9-trimethyl-2-phenyl-8,9-dihydro-puro [2,3-h] chromen-4-one (Compound No. 136) Synthesis [See Scheme 34]

Add MeOH (14 mL) to Compound 133 (300 mg) and NaOH (274 mg) in 60 The reaction was overnight at ° C. After cooling to room temperature, the reaction was stopped by adding 1M aqueous HCl solution, and the organic layer obtained by extraction with EtOAc was washed with H ₂ O and brine, dried over anhydrous Na ₂ SO ₄ , filtered, and distilled under reduced pressure. The obtained residue was purified by MPLC (1% MeOH / CH ₂ Cl ₂ ) to 5-hydroxy-6-methoxy-8,9,9-trimethyl-2-phenyl-8,9-dihydro-puro [2,3- h] chromen-4-one (225 mg, 93%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.34 (s, 3H), 1.47 (d, J = 6.6 Hz, 3H), 1.61 (s, 3H), 3.99 (s, 3H), 4.60 (q, J = 6.6 Hz, 1H), 6.34 (s, 1H), 7.52-7.56 (m, 3H), 7.84-7.87 (m, 2H), 13.08 (s, 1H)

Example 128 Synthesis of 5,7-Dihydroxy-6-methoxy-8- (3-methyl-but-2-enyl) -2-phenyl-chromen-4-one (Compound No. 137) 34]

5-hydroxy-6-methoxy-7- (3-methyl-but-2-enyloxy) -2-phenyl-chromen-4-one (600 mg) and toluene (34 mL) obtained in Example 124 Florisil (6 g) was added to a clear solution of and refluxed and stirred for 22 hours. The reaction solution was cooled to room temperature, diluted with 10% MeOH / CH ₂ Cl ₂ (30 mL), filtered and washed with 10% MeOH / CH ₂ Cl ₂ . The solvent of the obtained solution was distilled under reduced pressure, and the obtained residue was recrystallized from Hexane / EtOAc to give 5,7-dihydroxy-6-methoxy-8- (3-methyl-but-2-enyl) -2-phenyl-chromen. 4-one (130 mg, 22%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.71 (s, 3H), 1.83 (s, 3H), 3.58 (d, J = 6.6 Hz, 2H), 4.05 (s, 3H), 5.27-5.31 (m, 1H), 6.6 (s, 1H), 6.67 (s, 1H), 7.49-7.56 (m. 3H), 7.88-7.91 (m, 2H), 12.93 (s, 1H)

Example 129. Synthesis of 5,7-Dihydroxy-6-methoxy-8- (3-methyl-but-2-enyl) -2-phenoxy-chromen-4-one (Compound No. 138) [ See Scheme 35]

5-hydroxy-6-methoxy-7- (3-methyl obtained by the method of Example 124 using 5,7-dihydroxy-6-methoxy-2-phenoxy-chromen-4-one Toluene (30 mL) was added to a mixture of but-2-enyloxy) -2-phenoxy-chromen-4-one (500 mg) and Florisil (5 g), and the mixture was refluxed and stirred overnight. . The reaction solution was diluted with EtOAc (60 mL) and filtered. The resulting solution was distilled under reduced pressure and MPLC (1.5% MeOH / CH ₂ Cl ₂ ) to give 5,7-dihydroxy-6-methoxy-8- (3-methyl-but-2-enyl) -2-phenoxy- Cromen-4-one (201 mg, 40%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.68 (s, 3H), 1.73 (s, 3H), 3.38 (d, J = 7.2 Hz, 2H), 4.02 (s, 3H), 5.14-5.19 (m, 1H), 5.32 (s, 1H), 6.53 (s, 3H), 7.18-7.21 (m, 2H), 7.31-7.36 (m, 1H), 7.44-7.49 (m, 1H)

Example 130. Acetic acid 5-acetoxy-8- (1,1-dimethyl-allyl) -6-methoxy-4-oxo-2-phenoxy-4H-chromen-7-yl ester (Compound No. 139) ) Synthesis [see Scheme 35]

Ac in a mixture of 5-hydroxy-6-methoxy-7- (3-methyl-but-2-enyloxy) -2-phenoxy-chromen-4-one (400 mg), NaOAc (356 mg) ₂ O (20 mL) was added and refluxed and stirred for 24 hours. The reaction was cooled to room temperature and the reaction was stopped by addition of saturated aqueous NaHCO ₃ solution. The resulting solution was extracted with EtOAc (100 mL), washed with H ₂ O and brine, dried over anhydrous Na ₂ SO ₄ , filtered, and distilled under reduced pressure. The residue was purified by MPLC (20% EtOAc / Hexane) to 5-acetoxy acetate. -8- (1,1-dimethyl-allyl) -6-methoxy-4-oxo-2-phenoxy-4H-chromen-7-yl ester (466 mg, 95%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.54 (s, 6H), 2.28 (s, 3H), 2.43 (s, 3H), 3.82 (s, 3H), 4.88-4.97 (m, 2H), 5.36 ( s, 1H), 6.16 (dd, J ₁ = 10.5 Hz, J ₂ = 17.1 Hz, 1H), 7.15-7.18 (m, 2H), 7.29-7.34 (m, 2H), 7.42-7.47 (m, 2H)

Example 131. Synthesis of 8- (1,1-dimethyl-allyl) -5,7-dihydroxy-6-methoxy-2-phenoxy-chromen-4-one (Compound No. 140) 35]

Dissolve 5-hydroxy-6-methoxy-7- (3-methyl-but-2-enyloxy) -2-phenoxy-chromen-4-one (507 mg) in DMF (20 mL) and NaOMe Divided 70mg slowly two times and stirred for 5 hours. The reaction solution was quenched by adding 1M aqueous HCl solution and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and distilled under reduced pressure. The obtained residue was subjected to MPLC (MeOH / CH ₂ Cl ₂ ) to 8- (1,1-dimethyl-allyl) -5,7-dihydroxy-6-methoxy-2-phenoxy-chromen-4-one (160 mg, 39%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.68 (s, 3H), 1.73 (s, 3H), 3.38 (d, J = 7.2 Hz, 2H), 4.01 (s, 3H), 5.14-5.19 (m, 1H), 5.32 (s, 1H), 6.53 (s, 1H), 7.18-7.20 (m. 2H), 7.31-7.36 (m, 2H), 7.44-7.49 (m, 2H), 12.92 (s, 1H)

Example 132. Synthesis of 5-hydroxy-6-methoxy-8,8-dimethyl-2-phenyl-8H-pyrano [2,3-f] chromen-4-one (Compound No. 141) [ See Scheme 34]

5,7-Dihydroxy-6-methoxy-8- (3-methyl-but-2-enyl) -2-phenyl-chromen-4-one (250 mg, 0.71 mmol) obtained by the method of Example 128 DDQ (214 mg, 0.92 mmol) was added to a benzene (20 mL) solution, and refluxed overnight. After cooling to room temperature the reaction was filtered. The filtrate was concentrated under reduced pressure and purified by MPLC (5% EtOAc / CHCl ₃ ) to give 5-hydroxy-6-methoxy-8,8-dimethyl-2-phenyl-8H-pyrano [2,3-f] chrome. Men-4-one (115 mg, 46%) was obtained.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.88 (s, 1H), 7.89 ~ 7.86 (m, 2H), 7.57 ~ 7.52 (m, 3H), 6.83 (d, J = 9.9Hz, 1H), 6.65 ( s, 1H), 5.65 (d, J = 9.9 Hz, 1H), 3.92 (s, 3H), 1.55 (s, 6H)

Example 133. Synthesis of 5-hydroxy-6-methoxy-8,8-dimethyl-2-phenoxy-8H-pyrano [2,3-f] chromen-4-one (Compound No. 142) Reaction Scheme 35

 Obtained by the method of Example 132 using 5,7-dihydroxy-6-methoxy-8- (3-methyl-but-2-enyl) -2-phenoxy-chromen-4-one.

¹ H NMR (CDCl ₃ , 300 MHz) δ 12.87 (s, 1H), 7.48 (t, J = 7.5 Hz, 2H), 7.35 (t, J = 7.2 Hz, 1H), 7.19 (d, J = 7.8 Hz , 2H), 6.60 (d, J = 9.9 Hz, 1H), 5.60 (d, J = 10.2 Hz, 1H), 5.27 (s, 1H), 3.89 (s, 3H), 1.52 (s, 6H)

On the other hand, the compound represented by Formula 1 according to the present invention can be formulated in various forms according to the purpose. The following illustrates some formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

Preparation Example 1 Preparation of Tablet

Tablets for oral administration were prepared using the wet granulation method and the dry granulation method with the following composition using the compound of the present invention.

[Furtherance]

200 mg of active compound, 10 mg of hard silicic anhydride, 2 mg of magnesium stearate, 50 mg of microcrystalline cellulose, 25 mg of sodium starch glycolate, 113 mg of corn starch, proper amount of ethanol anhydride.

Preparation Example 2 Preparation of Ointment

Using the compound of the present invention was prepared an ointment with the following composition.

[Furtherance]

Active compound 5 g, cetyl palmitate 20 g, cetanol 40 g, stearyl alcohol 40 g, myristan isopropyl 80 g, monostearic acid sorbitan 20 g, polysorbate 60 g, paraoxybenzoic acid propyl 1 g, para 1 g of methyl oxyanate, phosphoric acid and purified water

Preparation Example 3 Preparation of Injection

Injections were prepared using the compounds of the present invention in the following compositions.

[Furtherance]

Active Compound 100 mg, mannitol 180 mg, sodium dihydrogen phosphate 25 mg, water for injection 2974 mg

Experimental Example 1. Evaluation of protective activity of primary cultured cardiomyocytes

To evaluate cardiomyocyte protective activity, cardiomyocytes were first isolated and cultured in the heart of rats immediately after birth. Experimental method for this is as follows. The ventricle was separated from the extracted heart and red blood cells were removed from Dulbecco's phosphate-buffered saline solution (pBS 7.4, Gibco BRL). Under 10 mL of collagenase I (0.8 mg / mL, 262 units / mg, Gibco BRL) solution, cut with a micro-dissecting scissor to a size of approximately 1 mm ³ and 15 minutes at 37 ° C. To be processed. The supernatant of the collagenase I solution was collected, and the remaining tissues were treated with fresh collagenase I solution and reacted at 37 ° C. for 15 minutes. Separately collected supernatant was diluted in α-MEM (Gibco, BRL) containing 10% FBS (fetal bovine serum). The precipitated cell pellet was centrifuged at 1200 rpm for 4 minutes at room temperature, and the cell pellet was resuspended in α-MEM medium containing 5 mL of 10% FBS (fetal bovine serum).

The above procedure was repeated about 10 to 15 times until the tissue shape was changed, and suspended cells were collected and cultured in a 100 mm tissue culture dish at 37 ° C. for 2 hours to reduce contamination of fibroblasts.

The cells that did not adhere to the tissue culture dish were collected and cultured in 96 well plates at 1 × 10 ⁴ cells / well. After incubation for 4 to 6 hours, the medium was washed twice with 0.1 μM of bromodeoxyuridine (BrdU, bromodeoxyuridine). Cells were incubated in 37 ° C., 5% CO ₂ incubator.

After overnight incubation in 96-well plates, serum-free α-MEM degassed in an airtight humidified chamber (anaerobic system, Technomart INC, Seoul, Korea) containing 5% CO ₂ , 5% H ₂ , 85% N ₂ After washing twice with medium, the test compound was added, and 200 μL of medium was added thereto to maintain hypoxia at 37 ° C. for 12 hours.

 After 12 hours, the cell medium was removed and then 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide solution (Sigma, St. Louis, MO) ) Was added at a final concentration of 0.5 mg / mL per well and incubated at 37 ° C. for 2 hours to allow MTT reaction. Formazan crystals formed in each well were dissolved by adding dimethyl sulfoxide (DMSO), which was measured for absorbance at 570 nm in an optical spectrometer.

compound Cell survival rate (%) compound Cell survival rate (%) Compound number 4 -74.1 Compound number 84 37.6 Compound number 9 -76.8 Compound number 85 25.0 Compound number 16 -124.6 Compound number 86 10.9 Compound number 22 26.3 Compound number 89 18.3 Compound number 25 -79.0 Compound number 97 -33.9 Compound number 26 60.3 Compound number 98 -38.8 Compound number 29 66.2 Compound number 101 -3.0 Compound number 35 -47.3 Compound number 103 1.2 Compound number 37 -177.2 Compound number 104 -5.8 Compound number 39 -62.9 Compound number 105 -0.3 Compound number 42 3.1 Compound number 106 -0.3 Compound number 51 6.7 Compound number 107 3.9 Compound number 59 -14.3 Compound number 108 17.9 Compound number 64 -43.8 Compound number 111 -87.5 Compound number 70 -77.7 Compound number 115 0.0 Compound number 72 -151.3 Compound number 117 15.8 Compound number 75 4.5 Compound 118 28.6 Compound number 79 -42.0 Compound number 120 26.2 Compound number 81 10.9 Compound number 121 -22.8 Compound number 82 35.3 Compound number 122 -23.7 Compound number 83 2.8 Compound number 132 8.2

Experimental Example 2. Measurement of HSP (Heat Shock Protein) Expression Control

Heat shock response element (HSRE) (GAANNTTC) sequenced three times in DNA sequence containing the NheI site on the 5 'side and the BglII site on the 3' side (see sequence below) and its complementary sequence. Prepared and heated at 80 ℃ for 5 minutes and then annealed at room temperature to make a double helix DNA.

5'-GCCTCACGTTCA GCTAGC TA GAA TG TTC TAGATCTA GAA CA TTC TAGCTA GAA TG TTC TA AGATCT GA CATGCCTAGC-3 '

The italics are NheI and BglII sites, respectively, and the underlined parts are repeated three times of HSRE (GAANNTTC).

The ends of the DNA sequences were cut with NheI, BglII restriction enzymes and introduced into pLUC vectors (BD Biosciences, San Jose, CA, USA). This was transformed into Escherichia coli DH5α and cultured in a liquid medium (LB broth) containing ampicillin, and the vector was isolated using a plasmid DNA prep kit (Qiagen, Hilden, Germany) to DNA sequence through DNA sequencing. Finally, the vector was completed and named as pHSR3. To introduce the neomycin resistance gene into the pHSR3 vector, the pcDNA3.1 plasmid (Invitroen, Carlsbad, CA, USA) was templated to include the neomycin resistance gene ORF, the SV40 initial promoter, the origin, and the polyA signal. 1.5kb DNA was obtained by PCR and introduced into pHSR3 by BamHI single cut. This was transformed into E. coli DH5α and cultured to complete a new plasmid vector pHSR3-neo. In order to prepare an established cell line using this, transfected with lipofectamin (Invitrogen) when HeLa cells were 60% to 80% confluent growth in a culture dish. After some time, the cells were diluted with the medium, transferred to a new culture dish, and replaced with a medium containing G418. Colonies showing resistance to G418 were seen by maintaining the cells for three weeks while changing the medium once every two days.The resulting colonies were covered with colony separators, treated with trypsin to remove them with tips, one on a 96 well plate. Moved. The cells were incubated for two months in a medium containing G418, and the cells were gradually expanded to 24-well, 6-well, and petri dishes. Each drug was treated in the prepared cell line, cultured in a CO ₂ incubator, and after 24 hours, the activity of luminase was measured using a luciferase activity assay kit (BD Biosciences).

compound HSP (Fold Increase) compound HSP (Fold Increase) Compound number 4 1.91 Compound number 72 1.57 Compound number 9 1.96 Compound number 79 2.38 Compound number 16 1.86 Compound number 83 1.50 Compound number 22 1.17 Compound number 85 2.97 Compound number 25 1.81 Compound number 89 2.96 Compound number 26 1.65 Compound number 97 2.07 Compound number 29 3.70 Compound number 98 2.02 Compound number 35 1.22 Compound number 101 1.85 Compound number 37 3.38 Compound number 103 1.53 Compound number 39 1.16 Compound number 104 1.94 Compound number 42 3.09 Compound number 107 2.09 Compound number 51 1.72 Compound number 111 2.82 Compound number 59 1.50 Compound number 115 1.07 Compound number 64 2.33 Compound number 121 1.86 Compound number 70 3.16 Compound number 122 1.32

Experimental Example 3. Evaluation of myocardial protective activity through the regulation of intracellular calcium constants

Cytosolic free Ca ²⁺ was measured by confocal microscopy analysis. Neonatal white cardiomyocytes were incubated with 10% FBS α-MEM supplemented with 0.1 μM bromodeoxyuridine (BrdU) for 24 hours in 4 well plates (1 × 10 ⁵ cells / well) coated with 1.5% gelatin.

After 24 hours, the cells were washed twice with serum free media, treated with fluo-4 at a final concentration of 2 μM at room temperature with 500 μL of medium per well, and then in a 37 ° C. incubator for 20 minutes. . After washing with PBS, put the PBS to dry and covered with a cover slide. The fluorescence image was activated at 488 nm of an argon laser to collect the light emitted through a bandpass filter in the 510-560 nm range. The relative change in free intracellular Ca ²⁺ was determined by measuring the fluorescence intensity.

Experimental Example 4. Analysis of action activity in left anterior descending artery ligation ischemic animal model

Myocardial infarction in rats was induced by left anterior descending coronary artery ligation. Positive pressure circulation (180 mL / min) after inserting a tube into the airway into an 8-week-old Spraque Dawley male rat (approximately 250 g) anesthetized with 1 mL / rat ketamine A ventilator was used to maintain room air with oxygen (2 L / min) added. Rat heart was exposed by left thoracotomy at 2 cm. The left anterior descending paper was tied with a 7-0 silk suture and raised in a normal environment in a nursery for 3 days. Treatment of the drug was administered by intraperitoneal injection immediately after ligation of the left anterior descending branch and was performed for 3 days at a frequency of 10 mg / kg once daily. The solution was dissolved and heated to 70 ° C. before use. Evaluation of the efficacy of the drug under ischemic condition was confirmed by the color change of the heart muscle of rats treated after 3 days. For this purpose, TTC (triphenyltetrazolium chloride) staining method was used, and H & E staining method was used to measure the change of ventricular wall thickness by drug. Was used. Based on the above results, it was possible to select that the infarcted site was reduced compared to the control group for the candidate drug having myocardial protective function.

As described above, the chromen-4-one compound represented by Chemical Formula 1 according to the present invention is excellent in cytoprotective and calcium homeostasis and HSP (Heat Shock Protein) expression regulating activity. It is useful for the prevention and treatment of ischemic heart disease and ischemic cerebrovascular disease represented by infarction, stroke and cerebrovascular dementia.

Claims (13)

A pharmaceutical composition for preventing and treating ischemic diseases containing a chromium-4-one derivative represented by the following Chemical Formula 1, a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof as an active ingredient: [Formula 1]

In Chemical Formula 1, X is a single bond; O; S; S (O); SCH ₂ ; Se; NH; CH ₂ ; CH ₂ CH ₂ ; Or CH = CH, R ₁ is a C ₁ -C ₆ alkyl group; A phenyl group unsubstituted or substituted with a substituent selected from a halogen atom, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylcarbonate and aminoC ₁ -C ₆ alkylcarbonate group; Pyridine group; Or a piperidine group unsubstituted or substituted with a substituent selected from a C ₁ -C ₆ alkyl and a C ₁ -C ₆ alkoxy group, R ₂ is a hydrogen atom; Or a C ₁ -C ₆ alkyl group, R ₃ is a hydrogen atom; Hydroxy; C ₁ -C ₆ alkoxy group; Or a C ₁ -C ₆ alkylcarbonate group, R ₄ is a hydrogen atom; Halogen atom; Hydroxyl group; C ₁ -C ₆ alkyl group; Or a C ₁ -C ₆ alkoxy group, R ₅ is a halogen atom; C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkylcarbonate group; C ₁ -C ₆ alkyl hydroxy C ₁ -C ₆ alkanoate groups; Hydroxyl group; C ₁ -C ₆ alkoxy group; HydroxyC ₁ -C ₆ alkoxy group; A benzylC ₁ -C ₆ alkoxy group unsubstituted or substituted with a substituent selected from a halogen atom, a C ₁ -C ₆ alkyl and a C ₁ -C ₆ alkoxy group; _A phenylC ₁ -C ₆ alkoxy group unsubstituted or substituted with a substituent selected from a C ₁ -C ₆ alkyl and a C ₁ -C ₆ alkoxy group; PyridinylC ₁ -C ₆ alkoxy group; OxypyridinylC ₁ -C ₆ alkoxy group; PiperidinylC ₁ -C ₆ alkoxy group; Or a morpholinylC ₁ -C ₆ alkoxy group, R ₆ is a hydrogen atom; Halogen atom; C ₁ -C ₆ alkyl group; Or a C ₂ -C ₆ alkenyl group, or R ₅ and R ₆ are bonded to each other to form a 5 to 7 membered hetero ring including an oxygen atom. The method of claim 1, X is a single bond; O; S; Se; CH ₂ CH ₂ ; Or CH = CH, R ₁ is a C ₁ -C ₆ alkyl group; A phenyl group unsubstituted or substituted with a substituent selected from a halogen atom, hydroxy, C ₁ -C ₆ alkyl, and C ₁ -C ₆ alkoxy; Pyridine group; Or a piperidine group unsubstituted or substituted with a substituent selected from a C ₁ -C ₆ alkyl and a C ₁ -C ₆ alkoxy group, R ₂ represents a hydrogen atom, R ₃ is hydroxy; Or a C ₁ -C ₆ alkylcarbonate group, R ₄ is a hydrogen atom; C ₁ -C ₆ alkyl group; Or a C ₁ -C ₆ alkoxy group, R ₅ is a C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkylcarbonate group; C ₁ -C ₆ alkylhydroxy C ₁ -C ₆ alkanoate groups; Hydroxyl group; C ₁ -C ₆ alkoxy group; HydroxyC ₁ -C ₆ alkoxy group; _A phenylC ₁ -C ₆ alkoxy group unsubstituted or substituted with a substituent selected from a C ₁ -C ₆ alkyl and a C ₁ -C ₆ alkoxy group; PyridinylC ₁ -C ₆ alkoxy group; OxypyridinylC ₁ -C ₆ alkoxy group; PiperidinylC ₁ -C ₆ alkoxy group; Or a morpholinylC ₁ -C ₆ alkoxy group, R ₆ is a hydrogen atom; Or a C ₂ -C ₆ alkenyl group, or R ₅ and R ₆ are bonded to each other to form a 5 to 7 membered heterocyclic ring containing an oxygen atom. The method of claim 1, X represents a single bond, O, S, Se or CH = CH; R ₁ represents a cyclohexyl group, a phenyl group, a hydroxyphenyl group, a fluorophenyl group, toluene group, methoxyphenyl group, ethoxyphenyl group, pyridine group, piperidine group, or methyl piperidine group; R ₂ represents a hydrogen atom; R ₃ represents a hydroxy group, a methyl carbonate group or an ethyl carbonate group, R ₄ represents a hydrogen atom, a methyl group, an ethyl group, a methoxy group or an ethoxy group, and R ₅ represents a hydroxy group, a methyl group, an ethyl group, a methoxy group or an ethoxy group. Period, n-propoxy group, isopropoxy group, benzyl group, methoxybenzyloxy group, ethoxybenzyloxy group, methyl carbonate group, ethyl carbonate group, hydroxymethoxy group, hydroxyethoxy group, hydroxyprop Foxy, hydroxybutoxy, ethyl acetate group, pyridinylmethoxy, pyridinylethoxy, oxypyridinylmethoxy, oxypyridinylethoxy, piperidinylmethoxy, piperidinylethoxy, piperidinyl Propoxy, morpholinylmethoxy or morpholinylethoxy; R ₆ represents a hydrogen atom, 3-methyl-but-2-enyl, or 1,1-dimethylallyl, or R ₅ and R ₆ are bonded to each other to form a 5- or 6-membered heterocycle including an oxygen atom Pharmaceutical composition, characterized in that to form a. A prophylactic and therapeutic agent for an ischemic disease containing a chromium-4-one derivative represented by the following Chemical Formula 1, a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof: [Formula 1]

In Chemical Formula 1, X is a single bond; O; S; S (O); SCH ₂ ; Se; NH; CH ₂ ; CH ₂ CH ₂ ; Or CH = CH, R ₁ is a C ₁ -C ₆ alkyl group; A phenyl group unsubstituted or substituted with a substituent selected from a halogen atom, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylcarbonate and aminoC ₁ -C ₆ alkylcarbonate group; Pyridine group; Or a piperidine group unsubstituted or substituted with a substituent selected from a C ₁ -C ₆ alkyl and a C ₁ -C ₆ alkoxy group, R ₂ is a hydrogen atom; Or a C ₁ -C ₆ alkyl group, R ₃ is a hydrogen atom; Hydroxy; C ₁ -C ₆ alkoxy group; Or a C ₁ -C ₆ alkylcarbonate group, R ₄ is a hydrogen atom; Halogen atom; Hydroxyl group; C ₁ -C ₆ alkyl group; Or a C ₁ -C ₆ alkoxy group, R ₅ is a halogen atom; C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkylcarbonate group; C ₁ -C ₆ alkylhydroxy C ₁ -C ₆ alkanoate groups; Hydroxyl group; C ₁ -C ₆ alkoxy group; HydroxyC ₁ -C ₆ alkoxy group; A benzylC ₁ -C ₆ alkoxy group unsubstituted or substituted with a substituent selected from a halogen atom, a C ₁ -C ₆ alkyl and a C ₁ -C ₆ alkoxy group; _A phenylC ₁ -C ₆ alkoxy group unsubstituted or substituted with a substituent selected from a C ₁ -C ₆ alkyl and a C ₁ -C ₆ alkoxy group; PyridinylC ₁ -C ₆ alkoxy group; OxypyridinylC ₁ -C ₆ alkoxy group; PiperidinylC ₁ -C ₆ alkoxy group; Or a morpholinylC ₁ -C ₆ alkoxy group, R ₆ is a hydrogen atom; Halogen atom; C ₁ -C ₆ alkyl group; Or a C ₂ -C ₆ alkenyl group, or R ₅ and R ₆ are bonded to each other to form a 5 to 7 membered hetero ring including an oxygen atom. The method of claim 4, wherein X is a single bond; O; S; Se; CH ₂ CH ₂ ; Or CH = CH, R ₁ is a C ₁ -C ₆ alkyl group; A phenyl group unsubstituted or substituted with a substituent selected from a halogen atom, hydroxy, C ₁ -C ₆ alkyl, and C ₁ -C ₆ alkoxy; Pyridine group; Or a piperidine group unsubstituted or substituted with a substituent selected from a C ₁ -C ₆ alkyl and a C ₁ -C ₆ alkoxy group, R ₂ represents a hydrogen atom, R ₃ is hydroxy; Or a C ₁ -C ₆ alkylcarbonate group, R ₄ is a hydrogen atom; C ₁ -C ₆ alkyl group; Or a C ₁ -C ₆ alkoxy group, R ₅ is a C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkylcarbonate group; C ₁ -C ₆ alkylhydroxy C ₁ -C ₆ alkanoate groups; Hydroxyl group; C ₁ -C ₆ alkoxy group; HydroxyC ₁ -C ₆ alkoxy group; _A phenylC ₁ -C ₆ alkoxy group unsubstituted or substituted with a substituent selected from a C ₁ -C ₆ alkyl and a C ₁ -C ₆ alkoxy group; PyridinylC ₁ -C ₆ alkoxy group; OxypyridinylC ₁ -C ₆ alkoxy group; PiperidinylC ₁ -C ₆ alkoxy group; Or a morpholinylC ₁ -C ₆ alkoxy group, R ₆ is a hydrogen atom; Or a C ₂ -C ₆ alkenyl group, or R ₅ and R ₆ are bonded to each other to form a 5 to 7 membered heterocyclic ring containing an oxygen atom. The method of claim 4, wherein X represents a single bond, O, S, Se or CH = CH; R ₁ represents a cyclohexyl group, a phenyl group, a hydroxyphenyl group, a fluorophenyl group, toluene group, methoxyphenyl group, ethoxyphenyl group, pyridine group, piperidine group, or methyl piperidine group; R ₂ represents a hydrogen atom; R ₃ represents a hydroxy group, a methyl carbonate group or an ethyl carbonate group, R ₄ represents a hydrogen atom, a methyl group, an ethyl group, a methoxy group or an ethoxy group, and R ₅ represents a hydroxy group, a methyl group, an ethyl group, a methoxy group or an ethoxy group. Period, n-propoxy group, isopropoxy group, benzyl group, methoxybenzyloxy group, ethoxybenzyloxy group, methyl carbonate group, ethyl carbonate group, hydroxymethoxy group, hydroxyethoxy group, hydroxyprop Aoxy group, hydroxybutoxy group, ethyl acetate group, pyridinylmethoxy, pyridinylethoxy, oxypyridinylmethoxy, oxypyridinylethoxy, piperidinylmethoxy, piperidinylethoxy, piperidinyl Propoxy, morpholinylmethoxy or morpholinylethoxy; R ₆ represents a hydrogen atom, 3-methyl-but-2-enyl, or 1,1-dimethylallyl, or R ₅ and R ₆ are bonded to each other to form a 5- or 6-membered heterocycle including an oxygen atom Drugs characterized in that forming. The drug according to any one of claims 4 to 6, wherein the ischemic disease is ischemic heart disease and ischemic cerebrovascular disease. The agent according to any one of claims 4 to 6, wherein the ischemic disease is angina pectoris. The agent according to any one of claims 4 to 6, wherein the ischemic disease is myocardial infarction. The agent according to any one of claims 4 to 6, wherein the ischemic disease is stroke. The agent according to any one of claims 4 to 6, wherein the ischemic disease is cerebrovascular dementia. 8. A medicament according to claim 7, formulated in a form suitable for oral, subcutaneous, intramuscular, intravenous, transdermal, intranasal or rectal administration. 13. A medicament according to claim 12, formulated as a tablet, ointment or injection.

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