JP2003313182A - Benzamide derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a benzamide derivative useful as a medicine such as a treating and/or ameliorating agent of diseases associated with a telomerase. <P>SOLUTION: This benzamide derivative is a 3-benzamide flavone derivative expressed by formula (1). By using the 3-benzamide flavone derivative as the medicine, it is possible to treat or prevent various diseases associated with cellular propagation. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to use of a benzamide derivative as a drug based on a telomerase inhibitory action.

[0002]

2. Description of the Related Art Telomeres exist at the ends of eukaryotic chromosomes and play an important role in stabilizing chromosomes. In normal cells, telomeres are generated every time a cell divides.
When shortened by 50-200 bases or shorter than a certain length, cell division is stopped, and it is considered to play a role in determining the life span of cells. Therefore, normal cells do not continue to grow indefinitely. For example, even if mutations occur in tumor suppressor genes such as p53 and cells continue to divide abnormally, the shortening of telomeres with division causes
It does not become cancer due to growth arrest or cell death. However, it is known that when these cells express the enzyme that extends telomeres, telomerase, they become immortalized and become cancer cells.

[0003] Therefore, it is expected that if a telomerase inhibitor can suppress the infinite growth of cancer cells, it will be a new anticancer agent with low toxicity. In fact, catechins (Biochem. Biophys. Res. Commun., 249, p391-396,
1998), porphyrin derivatives (J. Am. Chem. Soc., 12
0, 3261-3262, 1998), nucleic acid derivatives (Biochemistry, 35,
15611, 1996), anthraquinone derivative (J. Med. Che
m., 40, 2113, 1997) have been reported as telomerase inhibitors. Furthermore, 2,4-dioxothiazolidine derivatives (JP 2001-72592A), flavomannans (JP 2001-31564A), Spiro [benzo [1,2-
b: 5,4-c '] dipyran-2 (3H) -naphtofuran] derivative
001-81029), a pyridine derivative (JP-A-1
1-49676, 11-49678, 11
Patents such as JP-A-49769, 11-49777) and triazine derivatives (JP-A-11-60573) are known.

[0004] Telomerase is also known to be involved in various diseases related to cell proliferation other than cancer, and telomerase inhibitors are expected to have broad potential. However, in spite of many studies, effective agents that can inhibit telomerase and treat various diseases have not been found.

[0005]

An object of the present invention is to provide a compound useful as a medicine such as a therapeutic and / or ameliorating agent for diseases associated with telomerase.

[0006]

As a result of intensive studies to solve the above problems, the present inventor found a strong telomerase inhibitory activity in a 3-benzamidoflavone derivative and completed the present invention.

That is, according to the present invention, [1] Formula (1) [Formula 4]

[0008]

[Chemical 4]

[Wherein R1, R2, R3, R4, R5,
R6, R7, R8, and R9 are each independently a hydrogen atom, a hydroxyl group, an amino group, a nitro group, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms,
C1-C6 acyl group, C1-C6 alkylamino group, C1-C6 aminoalkyl group, C1-C7
Represents an acyloxy group, a C1-7 acylamino group, and a C1-6 alkoxycarbonyl group, R10 represents a hydrogen atom or a lower alkyl group, and X represents -CO- or -SO2-. ] The 3-benzamido flavone derivative represented by this, or its pharmacologically acceptable, [2] Formula (2)

[0010]

[Chemical 5]

[Wherein R1, R2, R3, R4, R5,
R6 is independently a hydrogen atom, a hydroxyl group, an amino group, a nitro group, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an acyl group having 1 to 6 carbon atoms, and a carbon number. 1 to 6 alkylamino group, 1 to 6 carbon atoms
Alkylamino group, an acyloxy group having 1 to 7 carbon atoms,
It represents an acylamino group having 1 to 7 carbon atoms and an alkoxycarbonyl group having 1 to 6 carbon atoms. ] The 3-benzamido flavone derivative represented by these or its pharmacologically acceptable salt, [3] Formula (3) [Chemical formula 6]

[0012]

[Chemical 6]

[Wherein R1, R2, R3, R4, R5,
R6's each independently represent a hydrogen atom, a hydroxyl group, an amino group, a nitro group, or a halogen atom. ] 3-represented by
A benzamide flavone derivative or a pharmaceutically acceptable salt thereof, which is a telomerase inhibitor containing [4] at least one of the compounds according to any of [1] to [3] as an active ingredient. , [5] said [1]
~ At least 1 of the compounds described in any of [3]
[6] A drug containing at least one of the compounds according to any one of [1] to [3] above as an active ingredient.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below.
The carbon number of 1 to 4 in the present invention represents the carbon number per unit substituent. That is, for example, in the case of dialkyl substitution, it means having 2 to 8 carbon atoms. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The alkyl group having 1 to 6 carbon atoms in the compound represented by the formula (1) is, for example, methyl group, ethyl group,
Examples thereof include n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group and tert-butyl group.

The alkoxy group having 1 to 6 carbon atoms is, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, allyloxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group. And so on.

Examples of the acyl group having 1 to 6 carbon atoms include acetyl group, propanoyl group and butanoyl group.

The alkylamino group having 1 to 6 carbon atoms is, for example, N-methylamino group, N, N-dimethylamino group,
Examples thereof include N, N-diethylamino group, N-methyl-N-ethylamino group and N, N-diisopropylamino group.

Examples of the aminoalkyl group having 1 to 6 carbon atoms include aminomethyl group, 1-aminoethyl group and 2-aminopropyl group.

Examples of the acyloxy group having 1 to 7 carbon atoms include acetyloxy group, propanoyloxy group, butanoyloxy group, benzoyloxy group and nicotinoyloxy group.

Examples of the acylamino group having 1 to 7 carbon atoms include acetylamino group, propanoylamino group, butanoylamino group, benzoylamino group and nicotinoylamino group.

Examples of the alkoxycarbonyl group having 1 to 6 carbon atoms include methoxycarbonyl group and ethoxycarbonyl group.

The pharmaceutically acceptable salt of a compound is an inorganic acid commonly used in this field such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid,
Organic acids such as fumaric acid, maleic acid, citric acid, benzoic acid, trifluoroacetic acid, p-toluenesulfonic acid and methanesulfonic acid, inorganic bases such as sodium, potassium and lithium, and organic bases such as ammonia and methylamine. Can be mentioned as a salt.

The compound represented by the formula (1) can be used as a prodrug by masking a hydroxyl group or an amino group for use as a drug.

When the compound represented by the formula (1) has an asymmetric carbon, it can exist in the form of a mixture of different stereoisomeric forms or stereoisomeric forms including a racemic form. That is, the present invention includes various forms defined as described above, and these can be similarly used as the active ingredient compound.

The pharmaceutical agent is useful as a therapeutic and / or ameliorating agent for diseases related to telomerase. More specifically, diseases related to cell proliferation and diseases related to homeostasis of the living body, that is, malignant tumor, autoimmune disease, skin disease, infectious disease, vascular disease, hematological disease, allergic disease, digestive tract It is useful as a therapeutic and / or ameliorating agent for injuries, hormonal diseases, metabolic diseases, diabetes and the like.

Malignant tumor includes hematopoietic tumors such as acute leukemia, chronic leukemia, malignant lymphoma, multiple myeloma, and macroglobulinemia, as well as colon cancer, brain tumor, head and neck cancer, breast cancer,
Lung cancer, esophageal cancer, gastric cancer, liver cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, islet cell cancer, renal cell cancer, adrenal cortical cancer, bladder cancer, prostate cancer,
Solid tumors such as testicular tumor, ovarian cancer, uterine cancer, choriocarcinoma, thyroid cancer, malignant carcinoid tumor, skin cancer, malignant melanoma, osteosarcoma, soft tissue sarcoma, neuroblastoma, Wilms tumor, retinoblastoma Can be mentioned.

Examples of autoimmune diseases include rheumatism, nephritis, diabetes, systemic lupus erythematosus, human autoimmune lymphoproliferative lymphadenopathy, immunoblastic lymphadenopathy, Crohn's disease, and ulcerative colitis. . Examples of skin diseases include psoriasis, acne, eczema, atopic dermatitis, parasitic skin diseases, alopecia, purulent skin diseases, and skin sclerosis. The infectious disease means a disease caused by infection with various bacteria, viruses or parasites.
Examples of the vascular disease include arteriosclerosis.

Since the drug having a polyhydroxy group of the present invention also has an antioxidant effect, it can be used as a wider drug. The target diseases of the present invention are not limited to these. Further, it is useful not only as a drug but also as a veterinary drug, a food for maintaining health and a functional food, and its addition to food or itself is used in the same form as a medical preparation.

The preparation is prepared by using a diluent or an excipient such as a filler, a filler, a binder, a moisturizer, a disintegrant, a surfactant and a lubricant which are usually used. Various forms of this pharmaceutical preparation can be selected according to the therapeutic purpose, and typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, and injections (solutions, suspensions). Turbidity agents and the like and suppositories and the like.

When molding into tablets, various carriers well known in the art can be widely used as carriers. Examples include lactose, glucose, starch, calcium carbonate, kaolin,
Excipients such as crystalline cellulose, silicic acid, water, ethanol,
Propyl alcohol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, polyvinylpyrrolidone and other binders, dry starch, sodium alginate, agar powder, carmellose calcium, starch, lactose and other disintegrants, Sucrose, cacao butter, disintegration inhibitor such as hydrogenated oil, quaternary ammonium base, absorption enhancer such as sodium lauryl sulfate, humectant such as glycerin and starch, starch, lactose, kaolin, bentonite, colloidal silicic acid, etc. Adsorbents such as talc, lubricants such as talc, stearate, and polyethylene glycol can be used. Further, the tablets may be tablets coated with a usual coating, if necessary, for example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or bilayer tablets or multilayer tablets.

In the case of molding in the form of pills, various carriers conventionally known in this field can be widely used. Examples thereof include crystalline cellulose, lactose, starch,
Examples include hydrogenated vegetable oils, excipients such as kaolin and talc, gum arabic powder, tragacanth powder, binders such as gelatin, and disintegrators such as carmellose calcium and agar.

Capsules are usually prepared by mixing the active ingredient compounds with the various carriers exemplified above and filling them into hard gelatin capsules, soft capsules and the like.

Further, if necessary, a coloring agent, a preservative, a flavoring agent, a flavoring agent, a sweetening agent and the like and other medicinal products can be contained in the pharmaceutical preparation.

The amount of the active ingredient compound to be contained in these pharmaceutical preparations of the present invention is not particularly limited and may be appropriately selected from a wide range, but is usually about 1 to 70% by weight, preferably in the preparation composition. Is preferably about 5 to 50% by weight.

The typical structures of the compounds represented by the formula (1) of the present invention are specifically shown in Table 1 below. The present invention is not limited to these examples.

[0037]

[Chemical 7]

[0038]

[Table 1]

[0039]

The present invention will be described in detail below with reference to examples.
The present invention is not limited to these. Example 1 Synthesis of N- [4-oxo-2- (3,4-dihydroxyphenyl) -4H-benzo [b] -pyran-3-yl] -3,4,5-trihydroxybenzamide (Compound 1) [Chemical 8]

[0040]

[Chemical 8]

(1) p-Toluenesulfonic acid 2-acetylphenyl 2'-hydroxyacetophenone (27.2 g, 0.2 mol), p-
A solution of toluenesulfonyl chloride (37.0 g, 0.194 mol) and potassium carbonate (30.0 g, 0.217 mol) in acetone (200 mL) was stirred for 4 hours. After cooling, the insoluble material was filtered off and concentrated under reduced pressure to obtain a crude product. 0.5% NaOH aqueous solution (300 m
L) and water (400 mL) were washed by suspension, and the obtained crystals were dried to obtain the desired product (white crystals, 52.1 g) (yield 92%). ¹ H-NMR (DMSO-d ₆ ) δ 7.68 (d, 2H, J = 7.7 Hz), 7.63
(dd, 1H, J = 2.0, 7.4 Hz), 7.43 (ddd, 1H, J = 2.0,
7.4, 8.4 Hz), 7.36-7.29 (m, 3H), 7.09 (dd, 1H, J
= 7.9, 1.0 Hz), 2.51 (s, 3H), 2.46 (s, 3H).

(2) 2- (Bromoacetyl) phenyl p-toluenesulfonate [Chemical Formula 9]

[0043]

[Chemical 9]

A solution of 2-acetylphenyl p-toluenesulfonate (10.5 g, 36.1 mmol) and tetrabutylammonium tribromide (19.1 g, 39.6 mmol) in chloroform-methanol (100 mL-20 mL) was stirred at 50 ° C. for 2 hours. . After cooling, hexane (200 mL) and water (200 mL) were added to the reaction solution. After liquid separation, the obtained organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product. Purification by silica gel column chromatography (eluent: chloroform) gave the title compound (11.2 g) (yield 84%). ¹ H-NMR (DMSO-d ₆ ) δ 7.69-7.31 (m, 7H), 7.12 (dd, 1
H, J = 1.0, 8.2 Hz), 4.42 (s, 2H), 2.47 (s, 3H).

(3) 2- (azidoacetyl) phenyl p-toluenesulfonate [Chemical Formula 10]

[0046]

[Chemical 10]

A solution of 2- (bromoacetyl) phenyl p-toluenesulfonate (11.0 g, 29.8 mmol) in DMF (120 mL) was ice-cooled, and sodium azide (2.4 g, 37 mmol) was added.
The reaction solution was stirred under ice cooling for 3 hours, poured into water (200 mL), and extracted with ether (500 mL). The organic phase was washed successively with aqueous sodium thiosulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure
(9.44 g) was obtained (yield 95%). Used in the next reaction without purification. [Chemical Formula 11] ¹ H-NMR (DMSO-d ₆ ) δ7.74-7.33 (m, 7H), 7.16 (dd, 1
H, J = 3.1, 1.1Hz), 4.37 (s, 2H), 2.48 (s, 3H).

[0048]

[Chemical 11]

(4) p-toluenesulfonic acid [2-azido-
1-oxo-3- [3,4-bis (benzyloxy) phenyl] -2-propenyl] phenyl p-toluenesulfonate 2- (azidoacetyl) phenyl
(9.42 g, 28.4 mmol), 3,4-bis (benzyloxy) benzaldehyde (10.0 g, 31.4 mmol), piperidine acetate (25 g, 0.172 mol) in ethanol (120 mL) -THF (50
The (mL) solution was stirred at room temperature for 15 hours. Water was added to the reaction solution and extracted with chloroform. The obtained organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product. Purified by silica gel column chromatography (eluent:
Chloroform) to obtain the desired product (16.8 g) (yield 93
%). ¹ H-NMR (DMSO-d ₆ ) δ 7.60-7.29 (m, 18H), 7.11 (d, 1
H, J = 7.9 Hz), 7.06 (dd, 1H, J = 8.6, 2.0 Hz), 6.
86 (d, 1H, J = 8.6 Hz), 5.98 (s, 1H), 5.22 (t, 4H,
J = 10.6 Hz), 2.15 (s, 3H).

(5) 3-Amino-4-oxo-2- [3,4-bis (benzyloxy) phenyl] -4H-benzo [b] pyran [Chemical Formula 12]

[0051]

[Chemical 12]

P-Toluenesulfonic acid [2-azido-1-oxo-3- [3,4-bis (benzyloxy) phenyl] -2-propenyl] phenyl (16.7 g, 26.2 mmol) in ethanol (200 m
Sodium hydroxide (2.4 g, 60 mmol) was added to the
Stir for hours. The reaction solution was concentrated under reduced pressure, water and chloroform were added, and the layers were separated. The obtained organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product. Purify by silica gel column chromatography (chloroform / ethyl acetate = 30/1), and add methanol (50 m
Crystallization from (L) gave the desired product (7.15 g) (yield 61%). ¹ H-NMR (DMSO-d ₆ ) δ8.24 (dd, 1H, J = 1.3, 7.9 Hz),
7.61 (dt, 1H, J _d = 1.3 Hz, J _t = 7.3 Hz), 7.50-7.3
0 (m, 14H), 7.06 (d, 1H, J = 7.9 Hz), 5.26 (s, 4H),
3.82 (br s, 2H).

(6) N- [2- [3,4-bis (benzyloxy)
Phenyl] -4H-benzo [b] -pyran-4-one-3-yl] -3,4,5
-Tris (benzyloxy) benzamide [Chemical Formula 13]

[0054]

[Chemical 13]

3,4,5-Tris (benzyloxy) benzoic acid
Oxalyl chloride (1.4 g) and DMF (10 mg) were added to a toluene (5 mL) solution of (660 mg, 1.5 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction solution is concentrated under reduced pressure, dried, and dried with pyridine.
It was dissolved in (3 mL). 3-amino-4-oxo-2-
[3,4-bis (benzyloxy) phenyl] -4H-benzo [b] pyran (450 mg, 1.0 mmol), 4-dimethylaminopyridine (1
(20 mg, 1.0 mmol) was added, and the mixture was stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (CHCl ₃ / EtOAc = 20/1) to obtain the desired product (6
65 mg) was obtained (yield 76%). ¹ H-NMR (DMSO-d ₆ ) δ 9.83 (s, 1H), 8.12 (dd, 1H, J
= 7.9, 1.3 Hz), 7.93-7.86 (m, 1H), 7.78 (d, 1H, J
= 2.0 Hz), 7.59-7.18 (m, 30H), 5.21 (s, 2H), 5.15
(s, 4H), 5.03 (s, 2H), 4.98 (s, 2H).

[0056]

[Chemical 14]

(7) N- [4-oxo-2- (3,4-dihydroxyphenyl) -4H-benzo [b] -pyran-3-yl] -3,4,5-trihydroxybenzamide N- [ 4-oxo-2- [3,4-bis (benzyloxy) phenyl]
-4H-benzo [b] -pyran-3-yl] -3,4,5-tris (benzyloxy) benzamide (630 mg, 0.72 mmol) in methanol
(10 mL) -Dissolved in chloroform (10 mL), added 10% palladium on activated carbon (0.2 g), and then at room temperature under hydrogen atmosphere.
It was stirred for 0 minutes. The catalyst was filtered off, concentrated under reduced pressure and dried to obtain the desired product (306 mg) (yield 100%). ¹ H-NMR (DMSO-d ₆ ) δ 9.28 (s, 1H), 8.07 (dd, 1H, J
= 7.9, 1.3 Hz), 7.88-7.81 (m, 1H), 7.73 (d, 1H, J
= 8.2 Hz), 7.52 (t, 1H, J = 7.6 Hz), 7.34 (d, 1H,
J = 2.3 Hz), 7.27 (dd, 1H, J = 2.3, 8.2 Hz), 6.93
(s, 2H), 6.83 (d, 1H).

Example 2 N- [4-oxo-2- (3,4-dihydroxyphenyl) -4H-benzo
[b] -Pyran-3-yl] -2,3-bishydroxybenzamide
(Compound 2) (1) N- [2- [3,4-bis (benzyloxy) phenyl] -4H-
Example 1 using benzo [b] -pyran-4-one-3-yl] -2,3-bis (benzyloxy) benzamide 2,3-bis (benzyloxy) benzoic acid
-A reaction was performed in the same manner as in (6) to obtain the above compound. ¹ H-NMR (DMSO-d ₆ ) δ 9.69 (s, 1H), 8.13 (dd, 1H, J
= 1.3, 7.9 Hz), 7.88 (dt, 1H, J = 1.6, 8.6 Hz), 7.
75 (d, 1H, J = 8.2 Hz), 7.65 (d, 1H, J = 2.0 Hz),
7.58-7.15 (m, 25H), 7.05 (d, 1H, J = 8.6 Hz), 5.20
(s, 2H), 5.12 (s, 2H), 5.04 (s, 4H).

(2) N- [4-oxo-2- (3,4-dihydroxyphenyl) -4H-benzo [b] -pyran-3-yl] -2,3-bishydroxybenzamide Example 1- ( Reaction was performed in the same manner as in 7) to obtain the above compound. ¹ H-NMR (DMSO-d ₆ ) δ 12.23 (s, 1H), 10.01 (s, 1H),
9.78 (s, 1H), 9.34 (s, 1H), 9.24 (s, 1H), 8.09 (d
d, 1H, J = 7.9, 1.3 Hz), 7.91-7.84 (m, 1H), 7.76
(d, 1H, J = 7.9 Hz), 7.54 (t, 1H, J = 7.1 Hz), 7.4
5 (dd, 1H, J = 8.2, 1.0 Hz), 7.34 (d, 1H, J = 2.0 H
z), 7.28 (dd, 1H, J = 8.2, 1.0 Hz), 6.84 (d, 1H, J
= 8.2 Hz), 6.76 (t, 1H, J = 7.9 Hz).

Example 3 N- [4-oxo-2- (3,4-dihydroxyphenyl) -4H-benzo
[b] -Pyran-3-yl] -3,4-bishydroxybenzamide
(Compound 3) (1) N- [2- [3,4-bis (benzyloxy) phenyl] -4H-
Example 1 using benzo [b] -pyran-4-one-3-yl] -3,4-bis (benzyloxy) benzamide 3,4-bis (benzyloxy) benzoic acid
-A reaction was performed in the same manner as in (6) to obtain the above compound. ¹ H-NMR (DMSO-d ₆ ) δ 9.70 (s, 1H), 8.10 (dd, 1H, J
= 1.7, 8.0 Hz), 7.88 (dt, 1H, J = 1.7, 7.0 Hz), 7.
78-7.17 (m, 28H), 5.22 (s, 2H), 5.20 (s, 2H), 5.14
(s, 2H), 5.08 (s, 2H).

(2) N- [4-oxo-2- (3,4-dihydroxyphenyl) -4H-benzo [b] -pyran-3-yl] -3,4-bishydroxybenzamide Example 1- ( Reaction was performed in the same manner as in 7) to obtain the above compound. ¹ H-NMR (DMSO-d ₆ ) δ 9.36 (s, 1H), 8.07 (dd, 1H, J
= 1.6, 7.9 Hz), 7.85 (ddd, 1H, J = 1.6, 6.9, 8.6 H
z), 7.73 (d, 1H, J = 7.9 Hz), 7.55-7.48 (m, 1H), 7.
35-7.25 (m, 4H), 6.84-6.79 (m, 2H)

Example 4 N- [4-oxo-2- (3,4-dihydroxyphenyl) -4H-benzo
[b] -Pyran-3-yl] -4-hydroxybenzamide (Compound 4) (1) N- [2- [3,4-bis (benzyloxy) phenyl] -4H-
Benzo [b] -pyran-4-one-3-yl] -4- (benzyloxy)
Example 1 using benzamide 4- (benzyloxy) benzoic acid
The reaction was performed in the same manner as in (6) to obtain the above compound. ¹ H-NMR (DMSO-d ₆ ) δ 9.70 (s, 1H), 8.10 (dd, 1H, J
= 7.9, 1.3 Hz), 7.97 (d, 1H, J = 8.9 Hz), 7.91-7.8
5 (m, 1H), 7.75 (d, 1H, J = 8.6 Hz), 7.67 (d, 1H,
J = 2.0 Hz), 7.58-7.28 (m, 19H), 7.21 (d, 1H, J =
8.6 Hz), 7.14 (d, 1H, J = 8.9 Hz), 5.20 (s, 2H),
5.19 (s, 2H), 5.01 (s, 2H).

(2) N- [4-oxo-2- (3,4-dihydroxyphenyl) -4H-benzo [b] -pyran-3-yl] -4-hydroxybenzamide Example 1- (7) The same reaction was performed to obtain the above compound. ¹ H-NMR (DMSO-d ₆ ) δ 10.07 (s, 1H), 9.71 (s, 1H),
9.44 (s, 1H), 9.27 (s, 1H), 8.07 (dd, 1H, J = 8.9,
1.3 Hz), 7.88-7.72 (m, 4H), 7.52 (t, 1H, J = 7.4 H
z), 7.35 (d, 1H, J = 2.0 Hz), 7.28 (dd, 1H, J = 8.
6, 2.3 Hz), 6.86-6.79 (m, 3H).

Example 5 N- [4-oxo-2- (3,4-dihydroxyphenyl) -4H-benzo
[b] -Pyran-3-yl] -3-amino-4-hydroxybenzamide (Compound 5) (1) N- [2- [3,4-bis (benzyloxy) phenyl] -4H-
Benzo [b] -pyran-4-on-3-yl] -4- (benzyloxy) -3-nitrobenzamido 4- (benzyloxy) -3-nitrobenzoic acid was prepared using Example 1- (6) and The same reaction was performed to obtain the above compound. ¹ H-NMR (DMSO-d ₆ ) δ 10.03 (s, 1H), 8.55 (d, 1H, J
= 2.0 Hz), 8.25 (dd, 1H, J = 7.9, 1.3 Hz), 7.93-7.
85 (m, 1H), 7.77 (d, 1H, J = 8.2 Hz), 7.66-7.27
(m, 19H), 7.22 (d, 1H, J = 8.6 Hz), 5.41 (s, 2H),
5.21 (s, 2H), 5.06 (s, 2H).

(2) N- [4-oxo-2- (3,4-dihydroxyphenyl) -4H-benzo [b] -pyran-3-yl] -3-amino-4
-Hydroxybenzamide Reaction was carried out in the same manner as in Example 1- (7) to obtain the above compound. ¹ H-NMR (DMSO-d ₆ ) δ 9.70 (s, 1H), 9.26 (s, 2H), 8.
07 (dd, 1H, J = 7.9, 1.3 Hz), 7.88-7.81 (m, 1H),
7.73 (d, 1H, J = 7.9), 7.52 (t, 1H, J = 7.4 Hz), 7.
34 (d, 1H, J = 2.3 Hz), 7.28 (dd, 1H, J = 8.2, 2.0
Hz), 7.20 (d, 1H, J = 2.0 Hz), 7.12 (dd, 1H, J =
7.9, 2.0 Hz), 6.81 (d, 1H, J = 8.2 Hz), 6.71 (d, 1
H, J = 7.9 Hz).

Example 6 N- [4-oxo-2- (3,4-dihydroxyphenyl) -4H-benzo
[b] -Pyran-3-yl] benzamide (1) N- [2- [3,4-bis (benzyloxy) phenyl] -4H-
Benzo [b] -pyran-4-one-3-yl] benzamide (Compound 6) Using benzoyl chloride, a reaction was carried out in the same manner as in Example 1- (6) to obtain the above compound. ¹ H-NMR (DMSO-d ₆ ) δ 9.85 (s, 1H), 8.10 (dd, 1H, J
= 7.9, 1.3 Hz), 7.97 (d, 2H, J = 6.9 Hz), 7.93-7.8
6 (m, 1H), 7.77 (d, 1H, J = 2.0 Hz), 7.63-7.29 (m,
15H), 7.23 (d, 1H, J = 8.6 Hz), 5.20 (s, 2H), 5.0
4 (s, 2H).

(2) N- [4-oxo-2- (3,4-dihydroxyphenyl) -4H-benzo [b] -pyran-3-yl] benzamide N- [2- [3,4] Using -bis (benzyloxy) phenyl] -4H-benzo [b] -pyran-4-one-3-yl] benzamide, the reaction was performed in the same manner as in Example 1- (7) to obtain the above compound. ¹ H-NMR (DMSO-d ₆ ) δ 9.74 (s, 2H), 9.31 (s, 1H), 8.
09 (dd, 1H, J = 7.9, 1.3 Hz), 7.94 (d, 1H, J = 6.9
Hz), 7.90-7.83 (m, 1H), 7.75 (d, 1H, J = 7.6 Hz),
7.62-7.49 (m, 4H), 7.37 (d, 1H, J = 2.3 Hz), 7.30
(dd, 1H, J = 8.6, 2.3 Hz), 6.84 (d, 1H, J = 8.2 H
z).

Example 7 N- [4-oxo-2- (3,4-dihydroxyphenyl) -4H-benzo
[b] -Pyran-3-yl] -4-hydroxy-3-nitrobenzamide (Compound 7) [Chemical Formula 15]

[0069]

[Chemical 15]

N- [4-oxo synthesized in Example 5- (1)
-2- [3,4-bis (benzyloxy) phenyl] -4H-benzo
A solution of [b] -pyran-3-yl] -3-nitro-4-benzyloxybenzamide (290 mg, 0.41 mmol) in chloroform (20 mL) was cooled to -60 ° C, and boron tribromide-dichloromethane solution was added.
(1.0 M, 3.5 mL) was added. The mixture was stirred for 2 hours while gradually raising the temperature from -60 ° C to -10 ° C. 2N-hydrochloric acid was added to the reaction solution to stop the reaction, and the precipitated product was collected by filtration. The crystals were washed with methanol (5 mL) -water (1 mL) and then dissolved in 2N-sodium hydroxide aqueous solution. The insoluble material was filtered off, concentrated hydrochloric acid was added to the resulting filtrate to acidify it, and the precipitated crystals were collected by filtration. The obtained crystals were washed successively with water and ethanol and dried under reduced pressure to obtain the desired product (145 mg) (yield 82
%). ¹ H-NMR (DMSO-d ₆ ) δ 11.74 (s, 1H), 9.86 (s, 1H),
9.72 (s, 1H), 9.33 (s, 1H), 8.53 (d, 1H, J = 2.3 H
z), 8.13-8.06 (m, 2H), 7.90-7.83 (m, 1H), 7.75 (d,
1H, J = 8.2 Hz), 7.53 (t, 1H, J = 7.5 Hz), 7.34
(d, 1H, J = 2.0 Hz), 7.30-7.23 (m, 2H), 6.84 (d, 1
H, J = 8.2 Hz).

Example 8 N- [4-oxo-2- (3,4-dihydroxyphenyl) -4H-benzo
[b] -Pyran-3-yl] -3,4-dichlorobenzamide (Compound
8) (1) N- [2- [3,4-bis (benzyloxy) phenyl] -4H-
Benzo [b] -pyran-4-one-3-yl] -3,4-dichlorobenzamide 3,4-dichlorobenzoic acid chloride was used in Example 1-
The reaction was performed in the same manner as in (6) to obtain the above compound. ¹ H-NMR (DMSO-d ₆ ) δ 10.08 (s, 1H), 8.21 (d, 1H, J
= 2.0 Hz), 7.95-7.86 (m, 2H), 7.83 (d, 1H, J = 8.2
Hz), 7.64 (d, 1H, J = 2.0 Hz), 7.59-7.51 (m, 2H),
7.47-7.29 (m, 10H), 7.23 (d, 1H, J = 8.9 Hz), 5.2
1 (s, 2H), 5.06 (s, 2H).

(2) N- [4-oxo-2- (3,4-dihydroxyphenyl) -4H-benzo [b] -pyran-3-yl] benzamide N- [2- [3,4] in the above synthesis Using -bis (benzyloxy) phenyl] -4H-benzo [b] -pyran-4-one-3-yl] benzamide, the reaction was performed in the same manner as in Example 1- (7) to obtain the above compound. ¹ H-NMR (DMSO-d ₆ ) δ 9.88 (s, 1H), 9.75 (s, 1H), 9.
37 (s, 1H), 8.17 (d, 1H, J = 2.0 Hz), 8.09 (dd, 1H,
J = 7.9, 1.3 Hz), 7.94-7.81 (m, 3H), 7.75 (d, 1H,
J = 7.9 Hz), 7.34 (d, 1H, J = 2.3 Hz), 7.27 (dd, 1
H, J = 8.2, 2.0 Hz), 6.85 (d, 1H, J = 8.2 Hz).

Example 9 N- [4-oxo-2- (3,4-dihydroxyphenyl) -4H-benzo
[b] -Pyran-3-yl] -4-amino-3-hydroxybenzamide (Compound 9) (1) N- [2- [3,4-bis (benzyloxy) phenyl] -4H-
Benzo [b] -pyran-4-one-3-yl] -3- (benzyloxy)
4-Nitrobenzamide 3- (benzyloxy) -4-nitrobenzoic acid was used to carry out a reaction in the same manner as in Example 1- (6) to obtain the above compound. ¹ H-NMR (DMSO-d ₆ ) δ 10.15 (s, 1H), 8.12 (dd, 1H, J
= 7.9, 1.3 Hz), 8.06 (d, 1H, J = 8.2 Hz), 7.94 (s,
1H), 7.89 (dd, 1H, J = 7.9, 1.3 Hz), 7.78 (d, 1H,
J = 8.2 Hz), 7.70 (dd, 1H, J = 8.6, 1.3 Hz), 7.66
(d, 1H, J = 2.3 hz), 7.59-7.52 (m, 2H), 7.45-7.27
(m, 15H), 7.21 (d, 1H, J = 8.6 Hz), 5.35 (s, 2H),
5.21 (s, 2H), 5.07 (s, 2H).

(2) N- [4-oxo-2- (3,4-dihydroxyphenyl) -4H-benzo [b] -pyran-3-yl] -4-amino-3-
Hydroxybenzamide Reaction was carried out in the same manner as in Example 1- (7) to obtain the above compound. ¹ H-NMR (DMSO-d ₆ ) δ 9.71 (brs, 1H), 9.30 (brs, 1
H), 9.24 (brs, 1H), 9..18 (s, 1H), 8.07 (dd, 1H, J
= 7.9, 1.6 Hz), 7.85 (ddd, 1H, J = 8.6, 6.9, 1.6 H
z), 7.73 (d, 1H, J = 7.9 Hz), 7.55-7.48 (m, 1H),
7.34 (d, 1H, J = 2.0 Hz), 7.30-7.23 (m, 3H), 6.80
(d, 1H, J = 8.2 Hz), 6.62 (d, 1H, J = 8.2 Hz).

Example 10 N- [4-oxo-2- (3,4-dihydroxyphenyl) -4H-benzo
[b] -Pyran-3-yl] -3,4-dimethoxybenzamide (Compound 10) (1) N- [2- [3,4-bis (benzyloxy) phenyl] -4H-
Benzo [b] -pyran-4-one-3-yl] -3,4-dimethoxybenzamide 3,4-dimethoxybenzoic acid was used and a reaction was performed in the same manner as in Example 1- (6) to obtain the above compound. . ¹ H-NMR (DMSO-d ₆ ) δ 9.69 (s, 1H), 8.10 (dd, 1H, J
= 7.9, 1.7 Hz), 7.92-7.85 (m, 1H), 7.76 (d, 1H, J
= 7.9 Hz), 7.69 (d, 1H, J = 2.0 Hz), 7.63 (d, 1H,
J = 8.2 Hz), 7.58-7.52 (m, 2H), 7.45-7.28 (m, 11
H), 7.22 (d, 1H, J = 8.6 Hz), 7.07 (d, 1H, J = 8.6
Hz), 5.20 (s, 2H), 5.02 (s, 2H), 3.82 (s, 3H), 3.7
8 (s, 3H).

(2) N- [4-oxo-2- (3,4-dihydroxyphenyl) -4H-benzo [b] -pyran-3-yl] -3,4-dimethoxybenzamide Example 1- (7 ) And the above compound was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 9.74 (brs, 1H), 9.58 (s, 1H),
9.28 (brs, 1H), 8.09 (dd, 1H, J = 7.9, 1.3 Hz), 7.
89-7.83 (m, 1H), 7.75 (d, 1H, J = 8.2 Hz), 7.58-7.
53 (m, 2H), 7.51 (d, 1H, J = 1.6 Hz), 7.35 (d, 1H,
J = 2.3 Hz), 7.29 (dd, 1H, J = 2.3, 8.2 Hz), 7.07
(d, 1H, J = 8.6 Hz), 6.82 (d, 1H, J = 8.2 Hz), 3.
84 (s, 3H), 3.82 (s, 3H).

Example 11 N- [4-oxo-2- (3,4-dihydroxyphenyl) -4H-benzo
[b] -Pyran-3-yl] -3-hydroxy-4-nitrobenzamide (Compound 11) N- [4-oxo-2- [3,4-bis (benzyloxy) phenyl]
Using -4H-benzo [b] -pyran-3-yl] -4-nitro-3-benzyloxybenzamide, a reaction was performed in the same manner as in Example 7 to obtain the above compound. ¹ H-NMR (DMSO-d ₆ ) δ 9.76 (s, 1H), 9.69 (s, 1H), 9.
31 (s, 1H), 8.09 (dd, 1H, J = 7.9, 1.3 Hz), 7.90-7.
83 (m, 1H), 7.75 (d, 1H, J = 8.2 Hz), 7.56-7.50 (m,
1H), 7.35 (d, 1H, J = 2.0 Hz), 7.28 (dd, 1H, J =
8.9, 2.3Hz), 7.09 (d, 2H, J = 2.3 Hz), 6.84 (d, 1
H, J = 8.2 Hz), 6.71 (d, 1H, J = 2.3 Hz).

Example 12 N- [4-oxo-2- (3,4-dihydroxyphenyl) -4H-benzo
[b] -Pyran-3-yl] -3,5-dimethoxybenzamide (Compound 12) (1) N- [2- [3,4-bis (benzyloxy) phenyl] -4H-
Benzo [b] -pyran-4-one-3-yl] -3,5-dimethoxybenzamide 3,5-dimethoxybenzoic acid was used and a reaction was carried out in the same manner as in Example 1- (6) to obtain the above compound. . ¹ H-NMR (DMSO-d ₆ ) δ 9.80 (s, 1H), 8.11 (dd, 1H, J
= 7.9, 1.6 Hz), 7.92-7.85 (m, 1H), 7.76 (d, 1H, J
= 7.6 Hz), 7.69 (d, 1H, J = 2.3 Hz), 7.58-7.52 (m,
2H), 7.46-7.28 (m, 11H), 7.24 (d, 1H, J = 8.6 H
z), 7.14 (d, 1H, J = 2.3 Hz), 6.73-6.71 (m, 1H), 5.
21 (s, 2H), 5.05 (s, 2H), 3.78 (s, 6H).

(2) N- [4-oxo-2- (3,4-dihydroxyphenyl) -4H-benzo [b] -pyran-3-yl] -3,5-dihydroxybenzamide As in Example 7. A reaction was performed to obtain the above compound. ¹ H-NMR (DMSO-d ₆ ) δ 11.45-11.24 (broad peak, 1H),
9.98 (s, 1H), 9.77 (s, 1H), 9.36 (s, 1H), 8.09 (d
d, 1H, J = 8.1, 1.5 Hz), 8.01 (d, 1H, J = 8.6 Hz),
7.91-7.84 (m, 1H), 7.76 (d, 1H, J = 7.9 Hz), 7.61
(d, 1H, J = 1.6 Hz), 7.54 (dt, 1H, J _d = 1.0, J _t =
7.4 Hz), 7.48 (dd, 1H, J = 8.2, 1.6 Hz), 7.33 (d,
1H, J = 2.0 Hz), 7.28 (dd, 1H, J = 8.2, 2.3 Hz),
6.85 (d, 1H, J = 8.6 Hz).

Example 13 N- [4-oxo-2- (3,4-dihydroxyphenyl) -4H-benzo
[b] -Pyran-3-yl] -3-chloro-4-hydroxybenzamide (Compound 13) (1) N- [2- [3,4-bis (benzyloxy) phenyl] -4H-
Benzo [b] -pyran-4-one-3-yl] -3-chloro-4- (benzyloxy) benzamido 3-chloro-4- (benzyloxy) benzoic acid was used, Example 1- (6) Reaction was performed in the same manner as above to obtain the above compound. ¹ H-NMR (DMSO-d ₆ ) δ 9.81 (s, 1H), 8.12-8.08 (m, 2
H), 7.95-7.86 (m, 2H), 7.76 (d, 1H, J = 7.6 Hz), 7.
58-7.28 (m, 19H), 7.22 (d, 1H, J = 8.6Hz), 5.31
(s, 2H), 5.21 (s, 2H), 5.03 (s, 2H).

(2) N- [4-oxo-2- (3,4-dihydroxyphenyl) -4H-benzo [b] -pyran-3-yl] -3-chloro-4-
Hydroxybenzamide Reaction was carried out in the same manner as in Example 1- (7) to obtain the above compound. ¹ H-NMR (DMSO-d ₆ ) δ 10.93 (s, 1H), 9.73 (s, 1H),
9.60 (s, 1H), 9.32 (s, 1H), 8.07 (dd, 1H, J = 7.9,
1.6 Hz), 7.97 (d, 1H, J = 2.0 Hz), 7.89-7.83 (m, 1
H), 7.78-7.72 (m, 2H), 7.53 (dt, J _d = 7.9, J _t = 1.
0 Hz), 7.33 (d, 1H, J = 2.3 Hz), 7.26 (dd, 1H, J =
8.2, 2.6 Hz), 7.06 (d, 1H, J = 8.2 Hz), 6.83 (d, 1
H, J = 8.6 Hz).

Example 14 N- [4-oxo-2- (3,4-dihydroxyphenyl) -4H-benzo
[b] -Pyran-3-yl] -2,4-bishydroxybenzamide
(Compound 14) (1) N- [2- [3,4-bis (benzyloxy) phenyl] -4H-
Example 1 using benzo [b] -pyran-4-one-3-yl] -2,4-bis (benzyloxy) benzamide 2,4-bis (benzyloxy) benzoic acid
-A reaction was performed in the same manner as in (6) to obtain the above compound. ¹ H-NMR (DMSO-d ₆ ) δ 9.38 (s, 1H), 8.22 (dd, 1H, J
= 1.6, 7.9 Hz), 8.16 (dd, 1H, J = 8.6, 15.5 Hz),
7.64-7.60 (m, 1H), 7.51 (d, 1H, J = 2.0Hz), 7.45-
7.20 (m, 23H), 6.93 (d, 1H, J = 8.6 Hz), 6.68-6.57
(m, 3H), 5.19-5.02 (m, 6H), 4.97 (s, 2H).

(2) N- [4-oxo-2- (3,4-dihydroxyphenyl) -4H-benzo [b] -pyran-3-yl] -2,4-bishydroxybenzamide Example 1- ( Reaction was performed in the same manner as in 7) to obtain the above compound. ¹ H-NMR (DMSO-d ₆ ) δ 12.46 (s, 1H), 10.22 (s, 1H),
9.77 (s, 1H), 9.75 (s, 1H), 9.33 (s, 1H), 8.08 (d
d, 1H, J = 7.9, 1.6 Hz), 7.90-7.82 (m, 2H), 7.75
(d, 1H, J = 2.3 Hz), 7.56-7.50 (m, 1H), 7.34 (d, 1
H, J = 2.3 Hz), 7.27 (dd, 1H, J = 8.2, 2.3 Hz), 6.
83 (d, 1H, J = 8.2 Hz), 6.36 (dd, 1H, J = 8.6, 2.3
Hz), 6.28 (d, 1H, J = 2.3 Hz).

Example 15 N- [4-oxo-2- (2,3-dihydroxyphenyl) -4H-benzo
[b] -Pyran-3-yl] -3,4-bishydroxybenzamide (Compound 15) N- [2- [2,3-bis (benzyloxy) phenyl] was synthesized in the same manner as in Example 1. -4H-benzo [b] -pyran-4-one-3
-Yl] -3,4-bis (benzyloxy) benzamide was reacted in the same manner as in Example 1- (7) to obtain the above compound. ¹ H-NMR (DMSO-d ₆ ) δ 9.60-9.00 (broad peak, 4H), 8.
11 (dd, 1H, J = 8.3, 1.2 Hz), 7.86-7.81 (m, 1H),
7.66 (d, 1H, J = 8.3 Hz), 7.55-7.50 (m, 1H), 7.26
(d, 1H, J = 1.8 Hz), 7.18 (dd, 1H, J = 2.0, 8.3 H
z), 6.91-6.88 (m, 2H), 6.74-6.64 (m, 2H).

Example 16 N- (4-oxo-2-phenyl-4H-benzo [b] -pyran-3-yl) -3,4-bishydroxybenzamide (1) N- (4-oxo- 2-phenyl-4H-benzo [b] -pyran-3
-Yl) -3,4-bis (benzyloxy) benzamide (Compound 16) 3-Amino-4-oxo-2- [3,4-bis (Synthesis 16) was synthesized in the same manner as in Example 1- (5). Using benzyloxy) phenyl] -4H-benzo [b] pyran and 3,4-bis (benzyloxy) benzoic acid, a reaction was performed in the same manner as in Example 1- (6) to obtain the above compound. ¹ H-NMR (CDCl ₃ ) δ 8.23 (dd, 1H, J = 7.9, 1.5 Hz),
7.64-7.31 (m, 20H), 7.05 (d, 1H, J = 7.9 Hz), 5.26
(s, 4H).

(2) N- (4-oxo-2-phenyl-4H-benzo [b] -pyran-3-yl) -3,4-bishydroxybenzamide Reaction was carried out in the same manner as in Example 1- (7). The above compound was obtained. ¹ H-NMR (DMSO-d ₆ ) δ 8.19 (dd, 1H, J = 7.9, 1.3 H
z), 7.77-7.43 (m, 9H), 7.39 (dd, 1H, J = 8.3, 2.3
Hz), 7.06 (d, 1H, J = 8.6 Hz).

Example 17 N- [4-oxo-2- (3,4-dihydroxyphenyl) -4H-benzo
[b] -Pyran-3-yl] -3,4-dinitrobenzamide (Compound 17) (1) N- [2- [3,4-bis (benzyloxy) phenyl] -4H-
Benzo [b] -pyran-4-one-3-yl] -3,4-dinitrobenzamide Using 3,4-dinitrobenzoic acid, the reaction was carried out in the same manner as in Example 1- (6) to obtain the above compound. . ¹ H-NMR (DMSO-d ₆ ) δ 10.46 (s, 1H), 8.72 (d, 1H, J
= 1.3 Hz), 8.49-8.38 (m, 2H), 8.11 (dd, 1H, J = 8.
2, 1.6 Hz), 7.92-7.88 (m, 1H), 7.78 (d, 1H, J = 7.9
Hz), 7.64 (d, 1H, J = 2.0 Hz), 7.60-7.27 (m, 12
H), 7.23 (d, 1H, J = 8.9 Hz), 5.22 (s, 2H), 5.11
(s, 2H).

(2) N- [4-oxo-2- (3,4-dihydroxyphenyl) -4H-benzo [b] -pyran-3-yl] -3,4-dimethoxybenzamide As in Example 7. A reaction was performed to obtain the above compound. ¹ H-NMR (DMSO-d ₆ ) δ 10.40 (s, 1H), 9.74 (s, 1H),
9.40 (s, 1H), 8.69 (d, 1H, J = 1.5 Hz), 8.10 (dd, 1
H, J = 8.1-1.5 Hz), 7.88-7.75 (m, 2H), 7.54 (t, 1
H, J = 7.3 Hz), 7.35 (d, 1H, J = 2.2 Hz), 7.29 (d
d, 1H, J = 2.2, 8.3 Hz), 6.85 (d, 1H, J = 8.3 Hz).

Example 18 N- [4-oxo-2- (3,4-dihydroxyphenyl) -4H-benzo
[b] -Pyran-3-yl] -6-bromo-3,4-dihydroxybenzamide (Compound 18) N- [4-oxo-2- [3,4-bis (benzyloxy) phenyl]
Using -4H-benzo [b] -pyran-3-yl] -6-bromo-3,4-bis (benzyloxy) benzamide, the same reaction was carried out as in Example 7 to obtain the above compound. ¹ H-NMR (DMSO-d ₆ ) δ 9.85-9.20 (m, 5H), 8.10 (dd, 1
H, J = 1.5, 8.1 Hz), 7.87-7.83 (m, 1H), 7.36-7.33
(m, 2H), 7.08 (s, 1H), 6.97 (s, 1H), 6.87 (d, 1H,
J = 9.0 Hz).

Example 19 N- [4-oxo-2- (3,4-dihydroxyphenyl) -4H-benzo
[b] -Pyran-3-yl] -3,4-diaminobenzamide (Compound 19) N- [4-oxo-2- [3,4-bis (benzyloxy) phenyl]
Using -4H-benzo [b] -pyran-3-yl] -3,4-bis (benzyloxy) benzamide, a reaction was performed in the same manner as in Example 7 to obtain the above compound. ¹ H-NMR (DMSO-d ₆ ) δ 9.69 (s, 1H), 9.23 (s, 1H), 9.
08 (s, 1H), 8.08 (d, 1H, J = 1.7 Hz), 7.86-7.81 (m,
1H), 7.72 (d, 1H, J = 8.1 Hz), 7.53-7.49 (m, 1H),
7.34 (d, 1H, J = 2.2 Hz), 7.27 (dd, 1H, J = 8.3,
2.2 Hz), 7.12-7.10 (m, 2H), 6.79 (d, 1H, J = 8.3 H
z), 5.05 (s, 2H), 4.58 (s, 2H).

Example 20 N-Methyl-N- [4-oxo-2- (3,4-dihydroxyphenyl)
-4H-benzo [b] -pyran-3-yl] -3,4-dihydroxybenzamide (Compound 203) [Chemical Formula 16]

[0092]

[Chemical 16]

(1) 3-Amino-N-methyl-2- [3,4-bis (benzyloxy) phenyl] -4H-benzo [b] pyran-4-one 3-amino-2- [3,4 -Bis (benzyloxy) phenyl] -4H-
A solution of benzo [b] pyran-4-one (3.43 g, 7.6 mmol) in chloroform (50 mL) was ice-cooled, and triethylamine (2.2 mL,
11.4 mmol) and trifluoroacetic anhydride (2.2 mL) were added.
After stirring under ice cooling for 1 hour, an aqueous sodium hydrogensulfate solution was added. The organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the corresponding trifluoroacetamide (4.35 g, quant.). The amide (2.0 g, 3.6 mmol) obtained in the previous section was added to 2-butanone (50 m
L), methyl iodide (0.4 mL, 6.4 mmol), potassium carbonate (1.0 g, 7.2 mmol), molecular sieves 3A
(2.0 g) was added. After heating under reflux for 2 hours, the insoluble matter was filtered off,
The solvent was distilled off under reduced pressure to obtain an N-methylamide compound. This was dissolved in methanol (10 mL) -THF (10 mL), and 15% aqueous sodium hydroxide solution (5 mL) was added. After stirring at room temperature for 3 hours, the solvent was evaporated under reduced pressure. The obtained residue was dissolved in chloroform-ethyl acetate and washed with diluted hydrochloric acid. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification by silica gel column chromatography gave the desired product (1.03 g) (yield 62%). ¹ H-NMR (DMSO-d ₆ ) δ 8.09 (dd, 1H, J = 1.3, 7.9 H
z), 7.80-7.73 (m, 1H), 7.64-7.61 (m, 2H), 7.51-7.3
1 (m, 12H), 7.26 (d, 1H, J = 8.6 Hz), 5.25 (s, 2
H), 5.22 (s, 2H), 4.71-4.68 (m, 1H), 2.30 (d, 3H,
J = 5.9 Hz).

(2) N- [2- [3,4-bis (benzyloxy)
Phenyl] -4H-benzo [b] -pyran-4-one-3-yl] -3,4
Example 1 using -dinitrobenzamide 3,4-bis (benzyloxy) benzoic acid
-A reaction was performed in the same manner as in (6) to obtain the above compound. ¹ H-NMR (DMSO-d ₆ ) δ 8.26 (dd, 1H, J = 8.2, 1.6 H
z), 7.72-7.65 (m, 1H), 7.46-7.22 (m, 22H), 7.07 (d
d, 1H, J = 8.6, 2.3 Hz), 7.02 (d, 1H, J = 2.3 Hz),
6.96 (d, 1H, J = 8.2 Hz), 6.60 (s, 1H), 6.49 (d, 2
H, J = 1.0 Hz), 5.26 (d, 1H, J = 12.2 Hz), 5.20
(d, 1H, J = 12.2 Hz), 5.17 (d, 1H, J = 12.2 Hz), 5.
11 (d, 1H, J = 12.2 Hz), 4.98 (s, 2H), 4.66 (d, 1
H, J = 11.7 Hz), 4.57 (d, 1H, J = 11.7 Hz), 3.35
(s, 3H).

(3) N- [2- [3,4-bis (benzyloxy)
Phenyl] -4H-benzo [b] -pyran-4-one-3-yl] -3,4
-Dinitrobenzamide Reaction was carried out in the same manner as in Example 7 to obtain the above compound. ¹ H-NMR (DMSO-d ₆ ) δ 9.87 (brs, 1H), 9.53 (brs, 1
H), 9.13 (brs, 1H), 8.93 (brs, 1H), 7.99 (dd, 1H, J
= 7.9, 1.3 Hz), 7.84-7.77 (m, 1H), 7.67 (d, 1H, J
= 7.9 Hz), 7.49-7.43 (m, 1H), 7.36 (d, 1H, J = 2.0
Hz), 7.22 (dd, 1H, J = 8.6, 2.3 Hz), 6.92 (d, 1H,
J = 8.6 Hz), 6.63 (d, 1H, J = 2.0Hz), 6.42 (dd, 1
H, J = 8.2, 1.6 Hz), 6.45-6.40 (m, 2H), 3.09 (s, 3
H).

Evaluation of Compounds To evaluate the activity of compounds, U937 cells were used and the known TRAP method (Kim et al., Science, 266: 2011 (1994), and Nu was used.
cleic Acid Res. 25: 2595-2597, 1997)), IC50 values were calculated and summarized in Table 2.

[0097]

[Table 2]

[0098]

INDUSTRIAL APPLICABILITY The 3-benzamide flavone derivative of the present invention has a high effect as a telomerase inhibitor and is useful as various drugs, especially as a therapeutic drug for diseases associated with cell proliferation. Above all, it is very useful as a cancer therapeutic agent or a cancer preventive agent.

Continuation of front page (51) Int.Cl. ⁷ identification code FI theme code (reference) A61P 3/10 A61P 3/10 5/00 5/00 7/00 7/00 9/00 9/00 9/10 101 9/10 101 13/12 13/12 17/00 17/00 17/06 17/06 17/10 17/10 17/14 17/14 29/00 101 29/00 101 31/04 31/04 31 / 12 31/12 33/00 33/00 35/00 35/00 35/02 35/02 37/02 37/02 37/08 37/08 43/00 111 43/00 111 (72) Inventor Takashi Tsuruo 1-1 1-1 Yayoi, Bunkyo-ku, Tokyo Tokyo University Campus F-term (reference) 4C062 EE50 EE54 4C086 AA01 AA02 AA03 BA08 MA01 MA04 NA14 ZA36 ZA45 ZA66 ZA81 ZA89 ZA92 ZB05 ZB13 ZB15 ZB26 ZB27 ZB33 ZB35 ZC33 ZB35

Claims (6)

[Claims] 1. Formula (1) [Chemical Formula 1] [Wherein R1, R2, R3, R4, R5, R6, R7,
R8 and R9 are each independently a hydrogen atom, a hydroxyl group, an amino group, a nitro group, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an acyl group having 1 to 6 carbon atoms, Alkylamino group having 1 to 6 carbon atoms, 1 carbon atom
~ 6 aminoalkyl group, C1-7 acyloxy group, C1-7 acylamino group, C1-6 alkoxycarbonyl group, R10 represents a hydrogen atom or a lower alkyl group, and X represents , -CO- or -SO2
Represents-. ] The 3-benzamido flavone derivative represented by these, or its pharmacologically acceptable salt. 2. Formula (2) [Formula 2] [Wherein R 1, R 2, R 3, R 4, R 5 and R 6 are each independently a hydrogen atom, a hydroxyl group, an amino group, a nitro group,
Halogen atom, C1-C6 alkyl group, C1-C1
6 alkoxy group, 1 to 6 carbon acyl group, 1 carbon atom
Represents an alkylamino group having 1 to 6 carbon atoms, an alkylamino group having 1 to 6 carbon atoms, an acyloxy group having 1 to 7 carbon atoms, an acylamino group having 1 to 7 carbon atoms, and an alkoxycarbonyl group having 1 to 6 carbon atoms. ] The 3-benzamido flavone derivative represented by these, or its pharmacologically acceptable salt. 3. Formula (3) [Chemical Formula 3] [Wherein R 1, R 2, R 3, R 4, R 5 and R 6 are each independently a hydrogen atom, a hydroxyl group, an amino group, a nitro group,
Represents a halogen atom. ] The 3-benzamido flavone derivative represented by these, or its pharmacologically acceptable salt. 4. A telomerase inhibitor containing at least one of the compounds according to claim 1 as an active ingredient. 5. An anticancer agent containing at least one of the compounds according to claim 1 as an active ingredient. 6. A drug containing at least one of the compounds according to any one of claims 1 to 3 as an active ingredient.