JPH072826A - Flavone derivative - Google Patents

Abstract

PURPOSE:To provide a new derivative useful as an agent for preventing and treating the crisis of infectionous diseases against various DNA viruses, RNA viruses and retro viruses. CONSTITUTION:A compound of the formula (R1 to R10 are OH, mercapto, halogen, formyl, carboxyl, sulfonic, phosphonic, nitro, cyano, amino, amide, alkyloxycarbonyl, aryloxycarbonyl, alkyl, aryl, acyl, alkyloxy, aryloxy, heterocyclic group, etc.,) and its salt, e.g. 5,7-dimethoxy-4-oxo-2-phenyl-4H-1- benzopyrane-8-sulfonyl chloride. The compound of formula I, e.g. the exampled compound, is obtained by reacting chlorosulfonic acid with 5, 7-dimethoxy-4- oxo-2-phenyl-4H-1-benzopyrane. The new flavone derivative has a wide and strong action spectrum and can reduce the toxicity of cells.

Description

Detailed Description of the Invention

[0001]

The present invention relates to various DNA viruses, R
The present invention relates to a preventive and therapeutic agent for infectious diseases caused by NA virus and retrovirus.

[0002]

2. Description of the Related Art Conventionally, modified or unmodified flavones have been known to have various physiological activities. In particular, as a flavone derivative having antiviral activity, R
o09-0179 is known and has been shown to inhibit its replication against the RNA virus picornavirus (Antimicrobial Agents and Chem).
otherapy, Vol.22 (4), 611-361 (1982)) and other viruses have no effect. Furthermore, it is known that rhamnetin and the like are effective against the herpesvirus that is a DNA virus (Acta Virol., Vol.3.
2, 522-525 (1988)), its action intensity is much weaker than that of acyclovir, and its toxicity is also strong. Recently, it has been reported that the flavone derivatives baicalein, quercetin, myricetin, etc. are effective for retroviruses (Metabolism, Vol. 22, 1027-1034 (1991)), but these compounds are polyphenolic compounds, It is extremely toxic in that cytotoxicity appears below the effective concentration, and it is considered that clinical use is impossible. Compounds that are flavone derivatives that are clinically used against virus-infected persons are:
So far unknown.

[0003]

[Problems to be Solved by the Invention] Regarding flavone derivatives having antiviral activity, compounds having effective activity have been found at the stage of basic experiments, but they have strong cytotoxicity and cell membrane permeability. There is no compound that has been clinically used because of its poor toxicity.

In recent years, remarkable progress has been made in research and development of antiviral agents, and various nucleic acid antiviral agents typified by acyclovir have excellent clinical effects against infections caused by herpes simplex virus and herpes zoster virus. Is recognized. However, infectious diseases caused by resistant herpesviruses such as viruses lacking thymidine kinase have become a problem (Oral Surg Oral Med Oral Pathol, Vol.
67, 427-432, (1989)). In addition, these nucleic acid-based antiviral agents are generally ineffective against RNA viruses such as influenza virus.

Antiviral compounds other than nucleic acid compounds, such as DN
Phosphonoformate (PFA, Japanese clinical, 47 (2), 390-394, (198
9)), Phosphonoacetate (PAA, Japanese Clinical, Volume 47)
(2), 390-394, (1989)), cycloxolone (Journa
l of Antimicrobial Chemotherapy, Vol.18, Suppl.B,
185-200, (1986)) and the like are known. However, for phosphonoformates and phosphonoacetates,
As side effects, kidney dysfunction and anemia have become problems,
The antiviral activity of cycloxolone has not been increased until it can be said to be sufficient for treatment.

Amantadine (pediatric practice, 54 volumes) is effective against RNA viruses other than nucleic acid derivatives.
(4), 988-994, (1991)), rimantadine (pediatric practice, 54 (4), 988-994, (1991)), LY253.
963 (thiadiazole derivative, pediatric practice, 54 (4)
, 988-994, (1991)), Dansylcadaverine (US Pa
t. US275,033), fluorenesulfonyl amino acid (Pharmaceutical Journal, 95, 397, (1975)) and the like are known. Amantadine is effective against influenza A virus but ineffective against influenza B virus, and side effect of central nervous system is a problem. For rimantadine, the drawbacks of amantadine have been largely overcome, but the side effects of the central nervous system remain a problem. Regarding LY253963, dansylcadaverine, and fluorenesulfonylamino acid, anti-influenza virus action has been confirmed in basic experiments, but clinical efficacy has not yet been confirmed.

AZ is an effective antiviral agent against retroviruses such as AIDS virus (HIV).
T and DDI (Pediatrics, 54 (4), 981-987, (199
1)) is known. However, although these antiviral agents delay the onset of AIDS, complete cure cannot be expected, and bone marrow suppression is a problem as a side effect.

In recent years, organ transplantation, cancer chemotherapy or HI
The number of immunodeficient patients associated with V infection is on the rise and has become a major medical problem. The viral infections that develop in such patients are extremely diverse and often cannot be treated with existing antiviral agents, and there is great hope for the development of superior antiviral agents.

Therefore, a first object of the present invention is to provide an antiviral agent which has an excellent effect on DNA virus, RNA virus and retrovirus and is highly safe. A second object is to provide an antiviral agent that is effective against viruses that are resistant to conventional antiviral substances.

[0010]

As described above, there are no flavone derivatives that have reached the clinical practical range for the prevention and treatment of viral infections. On the other hand, when looking at the structure of a non-nucleic acid antiviral compound other than a flavone derivative, it is characterized by having a dissociative substituent such as sulfonic acid, sulfuric acid, phosphonic acid, or phosphoric acid. It is presumed that it is important to have antiviral activity in expression or enhancement.

Therefore, we have introduced such a dissociative substituent into the molecule of flavone, which is not a polyphenol, to improve the virus spectrum and activity intensity of the flavone derivative, which has been conventionally free of clinically practical compounds. For the purpose, we conducted extensive research, designed new compounds and investigated their antiviral effects. As a result, surprisingly, some novel flavone derivatives are not only conventional RNA viruses such as picornavirus but also DNA viruses such as adenovirus and vaccinia virus, and influenza which is a clinically important RNA virus. The inventors have found that they have a strong antiviral activity against viruses and at the same time have reduced cytotoxicity, and have completed the present invention. That is, the present inventors succeeded in expanding the virus spectrum, enhancing the activity, and further reducing the toxicity by introducing a dissociative substituent with flavone as the basic skeleton.

In the present invention, the flavone derivative as the active ingredient includes compounds represented by the general formula I and salts thereof. In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R
₈ , R ₉ and R ₁₀ are, simultaneously or separately, a hydroxyl group, a mercapto group, a halogen, a formyl group, a carboxyl group,
Sulfonic acid group, phosphonic acid group, nitro group, cyano group, optionally substituted amino, optionally substituted amide, optionally substituted alkyloxycarbonyl,
Optionally substituted aryloxycarbonyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted acyl, optionally substituted alkyloxy, optionally substituted arule Oxy, optionally substituted alkylthio, optionally substituted arylthio, optionally substituted alkylsulfinyl, optionally substituted arylsulfinyl, optionally substituted alkylsulfonyl, optionally substituted Good arylsulfonyl, optionally substituted alkylaminosulfonyl, optionally substituted arylaminosulfonyl, optionally substituted heterocycle, optionally substituted is, for example, amino, formyl, Hydroxy, alkoxy, aryloxy, halogen Nitro, cyano, thiol, alkylthio, arylthio, acyl, carbamoyl, alkyl silyl, aryl silyl, alkyloxycarbonyl, aryloxycarbonyl, alkylsulfonyl,
Arylsulfonyl, alkylsulfinyl arylsulfinyl, phosphoric acid, phosphonic acid, phosphinic acid, phosphenic acid, sulfuric acid, sulfonic acid, sulfinic acid,
Sulfenic acid, means that it is substituted with boric acid and esters of these acids, and the hetero ring is, for example, condensed with a benzene ring, or may be condensed with each other pyridine, piperidine, pyrazine, It means piperazine, pyrrole, pyrrolidine, oxazole, imidazole, morpholine, diazole, triazole, tetrazole, thiazole, thiadiazole and the like.

Examples of the flavone derivative represented by the general formula I include 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-
Benzopyran-8-sulfonyl chloride, 5,7-dimethoxy
-4-oxo-2-phenyl-4H-1-benzopyran-8- (N-ethoxycarbonylmethyl) sulfonamide, 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-benzopyran-8- ( N-carboxymethyl) sulfonamide, 5,7-dimethoxy-4-
Oxo-2-phenyl-4H-1-benzopyran-8- {N- [N '-(aminoethyl) amido] methyl} sulfonamide, 5,7-dimethoxy-4-oxo-2-phenyl-4H-1- Benzopyran-8
-(N-aminoethyl) sulfonamide, 5,7-dimethoxy-4
-Oxo-2-phenyl-4H-1-benzopyran-8- {N- [N'-
(N "-benzyloxycarbonyl) glycyl] aminoethyl} sulfonamide, 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-benzopyran-8- {N- [N '-(N" -benzyl Oxycarbonyl) -L-alanyl] aminoethyl} sulfonamide, 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-benzopyran-8- [N- (N'-glycyl) aminoethyl] sulfonamide , 5,7-dimethoxy-4-oxo-2-phenyl-4H-
1-benzopyran-8- [N- (N'-L-alanyl) aminoethyl]
Sulfonamide, 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-benzopyran-8-sulfonamide, 5-hydroxy-7-methoxy-4-oxo-2-phenyl-4H-1-benzopyran- 8-sulfonamide, 5,7-dimethoxy-4-oxo-2
-(3-Chlorosulfonyl-4-methoxy) phenyl-4H-1-
Benzopyran-8-sulfonyl chloride, 5,7-dimethoxy
-4-oxo-2- [3- (N-ethoxycarbonylmethyl) aminosulfonyl) -4-methoxy] phenyl-4H-1-benzopyran-8- (N-ethoxycarbonylmethyl) sulfonamide, 5,7-dimethoxy -4-oxo-2- [3- (N-carboxymethyl) aminosulfonyl-4-methoxy] phenyl-4H-1-
Benzopyran-8- (N-carboxymethyl) sulfonamide, 5,7-dimethoxy-4-oxo-2- {3- {N- [N '-(aminoethyl) amido] methyl] aminosulfonyl-4-methoxy} Phenyl-4H-1-benzopyran-8- {N- [N '-(aminoethyl) amido] methyl} sulfonamide, 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-benzopyran-8- {N- {2
-{2- [2- (2-Methoxyethoxy) ethoxy] ethoxy} ethyl}} sulfonamide, 5-hydroxy-7-methoxy-4-
Oxo-2-phenyl-4H-1-benzopyran-8- {N- {2- {2-
[2- (2-Methoxyethoxy) ethoxy] ethoxy} ethyl}} sulfonamide 2- (4-methoxy-3-sulfophenyl) -3,5,7-trimethoxy-4-oxo-4H-1-benzopyran, 2 -(3-chlorosulfonyl-4-methoxyphenyl) -3,
5,7-Trimethoxy-4-oxo-4H-1-benzopyran, 2- [3
-(N-Ethoxycarbonylmethyl) aminosulfonyl-4-
Methoxyphenyl] -3,5,7-trimethoxy-4-oxo-4H-
1-benzopyran, 2- [3- (N-ethoxycarbonylmethyl)
Aminosulfonyl-4-hydroxyphenyl] -5-hydroxy-3,7-dimethoxy-4-oxo-4H-1-benzopyran, 2
-[3- (N-Carboxymethyl) aminosulfonyl-4-hydroxyphenyl] -5-hydroxy-3,7-dimethoxy-4-oxo-4H-1-benzopyran, 2- [3- (N-benzyl) amino Sulfonyl-4-methoxyphenyl] -3,5,7-trimethoxy-4
-Oxo-4H-1-benzopyran, 2- [3- (N-benzyl) aminosulfonyl-4-hydroxyphenyl] -5-hydroxy-
3,7-dimethoxy-4-oxo-4H-1-benzopyran, 2- (3-
Aminosulfonyl-4-hydroxyphenyl) -5-hydroxy-3,7-dimethoxy-4-oxo-4H-1-benzopyran,
2- {3- {N- [5- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)] pentyl} aminosulfonyl-4-methoxyphenyl} -3,5,7 -Trimethoxy-4-oxo-4H-1-benzopyran, 2- {3- {N- [5- (1,3-dihydro-1,3-dioxo
-2H-isoindol-2-yl) pentyl]} aminosulfonyl-4-methoxyphenyl} -5-hydroxy-3,7-dimethoxy-4-oxo-4H-1-benzopyran, 2- {3- [N- (5-Aminopentyl)] aminosulfonyl-4-methoxyphenyl}-
5-hydroxy-3,7-dimethoxy-4-oxo-4H-1-benzopyran, 5,7-dihydroxy-3-methoxy-2- (4-nitrophenyl) -4-oxo-4H-1-benzopyran, 3 , 5,7-Hydroxy-3,7-dimethoxy-2- (4-nitrophenyl) -4-oxo-4
H-1-benzopyran-8-sulfonamide, 2- (4-aminophenyl) -3,5,7-trimethoxy-4-oxo-4H-1-benzopyran-8-sulfonamide, 2- (4-hydroxyphenyl )-
3,5,7-Trimethoxy-4-oxo-4H-1-benzopyran-8-
Sulfonamide, 5-hydroxy-2- (4-hydroxyphenyl) -3,7-dimethoxy-4-oxo-4H-1-benzopyran-8-
Examples thereof include, but are not limited to, sulfonamides and salts thereof.

The flavone derivative represented by the general formula I has potent antiviral activity, low toxicity and is provided in various dosage forms.

The topical agents include liquids, ointments, creams, gels, rectal suppositories, vaginal suppositories and the like for skin and mucous membranes, and eye drops and eye ointments and the like for eyes. ,
The formulation can be carried out by a conventional method. When administered to humans, the dose depends on the type of compound, symptoms, dosage form, etc., but it is generally appropriate to administer it as a preparation containing 0.01 to 10%. For the purpose of promoting absorption, bile acid, saponin, polyoxyethylene higher alcohol ether, polyethylene glycol, DMS, if desired.
Absorption promoters such as O and laurocapram can be added.

Examples of the orally-administered agent include liquids, tablets, capsules, granules, fine granules, buccal, troches and the like. The formulation can be carried out by a conventional method. If desired, an absorption enhancer such as bile acid, saponin or polyoxyethylene higher alcohol ether may be added. When administered to humans, the dose depends on the type of compound, symptoms, dosage form, etc., but is generally 100-
3000 mg / day is suitable. Injectables can also be formulated by a conventional method. The dose to be administered to humans depends on the type of compound, symptoms, dosage form, etc., but is generally 3
0 to 1000 mg / day is suitable.

[0017]

EXAMPLES Next, the present invention will be described in more detail with reference to production examples of the compound according to the present invention, pharmacological effect test examples and formulation examples.

(1) Production Example 1 5,7-Dimethoxy-4-oxo-2-phenyl-4H-1-benzopyr
While maintaining 23.0 ml of lan-8-sulfonyl chloride chlorosulfonic acid at 0-5 ° C under ice cooling, add 10.0 g of 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-benzopyran and stir for 30 minutes. After that, it was left at 20 to 25 ° C for one day. The reaction solution was poured into ice, and the precipitated crystals were collected by filtration, washed with water and dried to give the title compound as pale green powder crystals in an amount of 13.4 g (
Quantitative) was obtained. Melting point: 300 ° C or higher. IR spectrum (KBr) νcm ^-1 : 1345,1180 (SO ₂ Cl). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 3.93 (6H, s, O
CH ₃ × 2), 6.57 (1H, s, C ₆ -H), 6.77 (1H, s, C ₃ -H),
7.33 ~ 7.60 (3H, m, ArH), 8.27 ~ 8.50 (2H, m, ArH).

(2) Production Example 2 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-benzopi
Lan-8- (N-ethoxycarbonylmethyl) sulfonamide hydrochloric acid glycine ethyl ester 20.0 g, triethylamine
Dissolve 20.0 ml in 200 ml of chloroform and cool on ice 0-5.
While maintaining at 0 ° C, 13.5 g of the compound of Production Example 1 was added. 30
After stirring for 1 minute, the mixture was stirred at 20 to 25 ° C for 2 hours. After filtering the insoluble matter, the mother liquor was saturated with an aqueous sodium hydrogen carbonate solution,
The organic layer was washed with 10% aqueous citric acid solution, dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was crystallized with ether to obtain 7.70 g (52.0%) of the title compound as colorless prism crystals. Melting point: 162 ° C. IR spectrum (KBr) νcm ^-1 : 1745 (C = O), 1375 (SO ₂ NH)
． ¹ H-NMR spectrum (CDCl ₃ ) δ _ppm : 1.13 (3H, t, J =
7.0Hz, CH ₃ ), 3.82 (2H, d, J = 5.0Hz, CH ₂ CO), 4.00 (2
H, q, J = 7.0, 16.0Hz, CH ₂ ), 4.00 (3H, s, OCH ₃ ), 4.
07 (3H, s, OCH ₃ ), 6.00 (1H, t, J = 5.0Hz, NH), 6.38 (1
H, s, C ₆ -H), 6.68 (1H, s, C ₃ -H), 7.33 ~ 7.56 (3H,
m, ArH), 7.92-8.20 (2H, m, ArH). MS spectrum (EI / DI) m / z: 447 (M ⁺ , base).

(3) Production Example 3 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-benzopi
5. Lanthanum 8- (N-carboxymethyl) sulfonamide 5.50 g of the compound of Production Example 2 was suspended in 44.0 ml of methanol, and 13.2 ml of 1N aqueous sodium hydroxide solution was added,
The mixture was stirred at 20-25 ° C for 2 hours. After distilling off the methanol,
20 ml of water was added and the pH was adjusted to 3 with 6N hydrochloric acid. The precipitated crystals were collected by filtration, washed with water and dried to give the title compound as colorless powder crystals (5.02 g, 98.3%). Melting point: 230-232 ° C. IR spectrum (KBr) νcm ⁻¹ : 3200 (OH), 1765 (CO). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 3.60 to 4.00 (2
H, m, CH ₂ CO), 3.98 (3H, s, OCH ₃ ), 4.07 (3H, s, C
H ₃ ), 6.50 ~ 7.20 (2H, m, SO ₂ NH and COOH), 6.67 (1
H, s, C ₆ -H), 6.82 (1H, s, C ₃ -H), 7.34 ~ 7.70 (3H,
m, ArH), 8.07-8.36 (2H, m, ArH). MS spectrum (EI / DI) m / z: 283 (base).

(4) Production Example 4 5,7-Dimethoxy-4-oxo-2-phenyl-4H-1-benzopi
Lan-8- {N- [N '-(aminoethyl) amido] methyl} sul
5.10 g of the compound of honamide production example 2 was suspended in 150 ml of ethanol,
Ethylenediamine (1.37 g) was added, and the mixture was heated under reflux for 12 hours.
After the reaction solution was concentrated under reduced pressure, 10 ml of ethanol was added for crystallization. Recrystallization from hot ethanol gave the title compound as pale yellow prism crystals (3.63 g, 69.2%). Melting point: 175-190 ° C. IR spectrum (KBr) νcm ^-1 : 3500 〜 3400 (NH ₂ ), 1640
(CO). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 2.63 to 3.13 (4
H, m, CH ₂ × 2), 3.13 to 3.53 (3H, m, NH ₂ and SO ₂ NH),
3.53 ~ 3.86 (2H, m, CH ₂ CO), 3.93 (3H, s, OCH ₃ ), 4.
00 (3H, s, OCH ₃ ), 6.40 (1H, s, C ₆ -H), 6.50 (1H, s, C
₃ -H), 7.13 ~ 7.43 (4H, m, CONH and ArH), 7.83 ~ 8.1
0 (2H, m, ArH). MS spectrum (EI / DI) m / z: 268 (base).

(5) Production Example 5 5,7-Dimethoxy-4-oxo-2-phenyl-4H-1-benzopi
9.30 g of orchid-8- (N-aminoethyl) sulfonamide ethylenediamine was dissolved in 100 ml of chloroform, and the compound 1 of Production Example 1 was prepared while keeping the temperature at 0 to 5 ° C under ice cooling.
4.8 g was added and stirred for 1 hour. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was crystallized from ether to give the title compound as colorless prism crystals (5.20 g, 33.2%). Melting point: 83-84 ° C. IR spectrum (KBr) νcm ^-1 : 3100 (NH ₂ ), 1630 (C = O). ¹ H-NMR spectrum (CDCl ₃ ) δ _ppm : 2.66 to 3.17 (7H,
m, CH ₂ × 2, NH ₂ and NH), 4.02 (3H, s, OCH ₃ ), 4.07 (3
H, s, OCH ₃ ), 6.40 (1H, s, C ₆ -H), 6.68 (1H, s, C _3-
H), 7.33 ~ 7.56 (3H, m, ArH), 7.89 ~ 8.26 (2H, m, Ar
H). MS spectrum (EI / DI) m / z: 282 (base).

(6) Production Example 6 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-benzopi
Orchid-8- {N- [N '-(N " -benzyloxycarbonyl) glycy
[] Aminoethyl} sulfonamide N-benzyloxycarbonylglycine (1.00 g) and triethylamine (0.67 ml) were dissolved in anhydrous tetrahydrofuran (5.0 ml), and ethyl chloroformate (519 mg) was added while cooling to -15 ° C, followed by stirring for 5 minutes. 1.93 g of the compound of Production Example 5 dissolved in 10.0 ml of chloroform was added, and the mixture was stirred at -15 to -20 ° C for 15 minutes, 0 ° C for 30 minutes, and 20 ° C for 2 hours. The procedure of Production Example 2 was repeated to give 2.20 g (82.0%) of the title compound as a colorless amorphous substance. IR spectrum (KBr) νcm ^-1 : 1710 (CO of amide), 1625
(CO of benzopyran). ¹ H-NMR spectrum (CDCl ₃ ) δ _ppm : 2.96 to 3.67 (4H,
m, CH ₂ × 2), 3.83 (2H, d, J = 5.0Hz, CO CH ₂ NH), 3.97
(3H, s, OCH ₃ ), 4.00 (3H, s, OCH ₃ ), 5.06 (2H, s, C
H ₂ Ar), 5.77 (1H, t, J = 5.0Hz, NHCO), 6.07 ~ 6.43 (1H,
m, CONH), 6.35 (1H, s, C ₆ -H), 6.67 (1H, s, C ₃ -H),
6.76 ~ 7.53 (4H, m, SO ₂ NHand ArH), 7.23 (5H, s, Ar
H), 7.92-8.20 (2H, m, ArH). MS spectrum (EI / DI) m / z: 268 (base).

(7) Production Example 7 5,7-Dimethoxy-4-oxo-2-phenyl-4H-1-benzopi
Run-8- {N- [N'- (N "-benzyloxycarbonyl) -L-a
Ranyl] aminoethyl} sulfonamide In the same manner as in Production Example 6, except that N-benzyloxycarbonyl-L was used instead of N-benzyloxycarbonylglycine.
-The reaction was performed with 1.70 g of alanine to obtain 3.17 g (70.1%) of the title compound as a colorless amorphous substance. IR spectrum (KBr) νcm ^-1 : 1720 (CO of amide), 1640
(CO of benzopyran). ¹ H-NMR spectrum (CDCl ₃ ) δ _ppm : 1.68 (3H, d, J =
7.0Hz, CH ₃ ), 2.92 ~ 3.59 (4H, m, CH ₂ × 2), 3.93 (3H,
s, OCH ₃ ), 3.98 (3H, s, OCH3), 4.00 ~ 4.33 (1H, m,
COC H ( CH ₃ ) NH), 5.02 (2H, s, CH ₂ Ar), 5.70 (1H, d, J =
7.0Hz, NHCO), 6.17 ~ 6.43 (1H, m, CONH), 6.32 (1H, s,
C ₆ -H), 6.65 (1H, s, C ₃ -H), 6.92 ~ 7.53 (4H, m, SO
₂ NH and ArH), 7.22 (5H, s, ArH), 7.86 ~ 8.20 (2H, m,
ArH). MS spectrum (EI / DI) m / z: 108 (base).

(8) Production Example 8 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-benzopyr
Lan-8- [N- (N'-glycyl) aminoethyl] sulfonami
Dehydrobromide 25% While maintaining a 25% hydrogen bromide / acetic acid solution at 0 to 5 ° C. under ice cooling, 4.35 g of the compound of Production Example 6 was added, and the mixture was stirred for 30 minutes. 2
After stirring at 0 to 25 ° C for 2 hours, the reaction solution was poured into ether, and the precipitated crystals were collected by filtration and crystallized from methanol / ether to give the title compound as colorless powder crystals (5.05 g, 98.9%). Melting point: 155-160 ° C. IR spectrum (KBr) νcm ^-1 : 3000 (NH ₃ ⁺ ), 1680 (CO)
． ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 2.70 to 3.70 (6
H, m, CH ₂ × 2 and NH CH ₂ CO), 4.00 (3H, s, OCH ₃ ), 4.
10 (3H, s, OCH ₃ ), 6.67 (1H, s, C ₆ -H), 6.80 (1H, s,
C ₃ -H), 7.26 ~ 8.50 (9H, m, SO ₂ NH, CONH, NH ₂ and A
rH). MS spectrum (EI / DI) m / z: 254 (base).

(9) Production Example 9 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-benzopi
Lan-8- [N- (N'-L-alanyl) aminoethyl] sulfone
Hydromidyl hydrobromide In the same manner as in Production Example 8, except that the compound of Production Example 7 was replaced by 5.69 g of the compound of Production Example 6 to obtain 5.14 g (99.2%) of the title compound as colorless powder crystals. It was IR spectrum (KBr) νcm ^-1 : 3000 (NH ₃ ⁺ ), 1680 (CO)
． ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 1.35 (3H, d, J
= 6.0Hz, CH ₃ ), 2.76 ~ 3.50 (4H, m, CH ₂ × 2), 3.76,
~ 4.33 (1H, m, COC H ( CH ₃ ) NH), 4.00 (3H, s, OCH ₃ ),
4.13 (3H, s, OCH ₃ ), 6.70 (1H, s, C ₆ -H), 6.83 (1H,
s, C ₃ -H), 7.30 to 8.65 (10H, m, CONH, NH ₃ ⁺ , SO ₂ N
H ₂ and ArH). MS spectrum (EI / DI) m / z: 268 (base).

(10) Production Example 10 5,7-Dimethoxy-4-oxo-2-phenyl-4H-1-benzopyr
While maintaining 20.0 ml of a 28% aqueous solution of orchi- 8-sulfonamide in ice at 0 to 5 ° C., 7.00 g of the compound of Production Example 1 was added. At 20-25 ° C
After stirring for 14 hours, the precipitated crystals were separated by centrifugation, washed with water, and dried to give 7.10 g (75.3 g of the title compound as pale yellow powder crystals.
%) Obtained. Melting point: 230 ° C. IR spectrum (KBr) νcm ^-1 : 1640 (C = O). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 3.88 (3H, s, O
CH ₃ ), 3.95 (3H, s, OCH ₃ ), 6.58 (1H, s, C ₃ -H), 6.73
(1H, s, C ₆ -H), 6.86 ~ 8.50 (10H, m, ArH). MS spectrum (EI / DI) m / z: 361 (M ⁺ ), 282 (base).

(11) Production Example 11 5-hydroxy-7-methoxy-4-oxo-2-phenyl-4H-
1-Benzopyran-8- sulfonamide 7.10 g of the compound of Production Example 10 and 5.50 g of aluminum chloride were suspended in 100 ml of bromobenzene and heated under reflux for 1 hour. After distilling off bromobenzene, 10 ml of concentrated hydrochloric acid was added and the mixture was heated for 5 minutes. The reaction solution was concentrated and recrystallized from methanol to obtain 5.07 g (74.3%) of the title compound as pale yellow prism crystals. Melting point: 275-276 ° C. IR spectrum (KBr) νcm ^-1 : 1650 (CO). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 4.05 (3H, s, O
CH ₃ ), 6.68 (1H, s, C ₃ -H), 7.15 (1H, s, C ₆ -H), 7.26
~ 7.43 (2H, m, SO ₂ NH ₂ ), 7.43 ~ 7.76 (3H, m, ArH),
8.00 to 8.53 (2H, m, ArH), 13.00 to 14.00 (1H, m, OH). MS spectrum (EI / DI) m / z: 347 (M ⁺ , base).

(12) Production Example 12 5,7-dimethoxy-4-oxo-2- (3-chlorosulfonyl-4-
(Methoxy) phenyl-4H-1-benzopyran-8-sulfonyl
Chloride The same as in Preparation Example 1, except that 5,7-dimethoxy-4-oxo-2- (4-methoxy) was used instead of 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-benzopyran. The reaction was performed using 2.00 g of phenyl-4H-1-benzopyran to obtain 2.20 g (67.5%) of the title compound as pale yellow powder crystals. Melting point: 300 ° C or higher. IR spectrum (KBr) νcm ^-1 : 1345, 1160 (SO ₂ Cl). MS spectrum (EI / DI) m / z: 346 (M ⁺ -135), 72 (base)
．

(13) Production Example 13 5,7-Dimethoxy-4-oxo-2- [3- (N-ethoxycarbonione
Lumethyl) aminosulfonyl-4-methoxy] phenyl-4
H-1-benzopyran-8- (N-ethoxycarbonylmethyl) su
Rufonamide was prepared in the same manner as in Production Example 2, except that 3.00 g of the compound of Production Example 12 was used instead of the compound of Production Example 1, and the reaction was carried out on silica gel column chromatography (developing solvent: chloroform and chloroform / methanol (10: 1)). )
2.50 g (66.0 g) of the title compound as a colorless amorphous substance.
%) Obtained. IR spectrum (KBr) νcm ^-1 : 1740 (C = O), 1330 (SO ₂ NH)
． ¹ H-NMR spectrum (CDCl ₃ ) δ _ppm : 1.17 (3H, t, J =
7.0Hz, CH ₃ ), 3.77 to 4.17 (8H, m, CH ₂ × 4), 4.00, 4.
08 (9H, s × 2, OCH ₃ × 3), 5.80 (1H, t, J = 6.0Hz, SO ₂ N
H), 5.97 (1H, t, J = 6.0Hz, SO ₂ NH), 6.38 (1H, s, C _6-
H), 6.62 (1H, s, C ₃ -H), 7.07 (1H, d, J = 8.0Hz, ArH),
8.26-8.60 (2H, m, ArH). MS spectrum (EI / DI) m / z: 642 (M ⁺ ), 477 (base).

(14) Production Example 14 5,7-Dimethoxy-4-oxo-2- [3- (N-carboxymethyi)
) Aminosulfonyl -4-methoxy] phenyl-4H-1-be
Nzopyran-8- (N-carboxymethyl) sulfonamide In the same manner as in Production Example 3, except that 3.00 g of the compound of Production Example 13 was used instead of the compound of Production Example 2 to react the title compound as colorless powder crystals. 2.40 g (87.5%) was obtained. Melting point: 200-204 ° C. IR spectrum (KBr) νcm ^-1 : 1760 (C = O). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 3.70 (4H, d, J
= 5.0Hz, CH ₂ × 2), 3.93 (6H, s, OCH ₃ × 2), 4.03 (3H,
s, OCH ₃ ), 6.63 (1H, s, C ₆ -H), 6.68 (1H, s, C _3-
H), 7.50 (2H, m, COOH × 2), 7.32 (1H, d, J = 10.0Hz, A
rH), 7.58 (2H, d, J = 5.0Hz, SO ₂ NH x 2), 8.23 to 8.66
(2H, m, ArH). MS spectrum (EI / DI) m / z: 311 (M ⁺ -275), 64 (base).

(15) Production Example 15 5,7-dimethoxy-4-oxo-2- {3- {N- [N '-(aminoethyl
Ru) amido] methyl] aminosulfonyl-4-methoxy}
Phenyl-4H-1-benzopyran-8- {N- [N'- (aminoethyl
A) Amido] methyl} sulfonamide In the same manner as in Production Example 4, except that 3.00 g of the compound of Production Example 14 was used in place of the compound of Production Example 2 to react the title compound as pale yellow prism crystals in an amount of 2.19 g (70.1 %) Obtained. Melting point: 210-225 ° C. IR spectrum (KBr) νcm ⁻¹ : 3500 to 3400 (NH ₂ ), 1640 (CO). ¹ H-NMR spectrum
(DMSO-d ₆ ) δ _ppm : 2.57〜3.13 (8H, m, CH ₂ × 4), 3.17〜3.50 (6H, m, CON
H × 2 and NH ₂ × 2), 3.73 (4H, d, J = 5.0Hz, NH CH ₂ CO ×
2), 3.97, 4.10 (9H, s, OCH ₃ × 3), 6.67 ~ 6.86 (2H, m,
C ₃ -H and C ₆ -H), 7.23 ~ 7.83 (3H, m, SO ₂ NH × 2
and ArH), 8.33 to 8.65 (2H, m, ArH). MS spectrum (EI / DI) m / z: 312 (M ⁺ -358), 94 (base).

(16) Production Example 16 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-benzopyr
Run-8- {N- {2- {2- [2- (2-methoxyethoxy) ethoxy]
Ethoxy} ethyl}} sulfonamide 10.0 g of the compound of Production Example 1 and 2.54 g of anhydrous potassium carbonate were suspended in 100 ml of chloroform, and ice-cooled under an argon stream 0
While maintaining the temperature at -5 ° C, 30 ml of a chloroform solution containing 6.53 g of 2- {2- [2- (2-methoxyethoxy) ethoxy] ethoxy} ethylamine was added, and the mixture was stirred for 1 hour and then stirred at 30 ° C for 21 hours.
The insoluble matter was filtered and washed with chloroform, and the solvent was distilled off.
The residue was purified by silica gel column chromatography (developing solvent was ethyl acetate / methanol (9: 1)) to obtain 14.2 g (98.1%) of the title compound as a yellow oil. Melting point: 36-40 ° C. IR spectrum (KBr) νcm ^-1 : 3200 (SO ₂ NH), 1640 (CO),
1340,1135 (SO ₂ ). ¹ H-NMR spectrum (CDCl ₃ ) δ _ppm : 2.83 to 3.80 (16
H, m, CH ₂ × 8), 3.35 (3H, s, OCH ₃ ), 4.03, 4.10 (6
H, s × 2, OCH ₃ × 2), 5.96 (1H, t, J = 6.0Hz, NH), 6.4
3 (1H, s, C ₆ -H), 6.70 (1H, s, C ₃ -H), 7.30 ~ 7.63 (3
H, m, ArH), 7.90-8.27 (2H, m, ArH). MS spectrum (EI / DI) m / z: 551 (M ⁺ ), 208 (base).

(17) Production Example 17 5-hydroxy-7-methoxy-4-oxo-2-phenyl-4H-
1-benzopyran- 8- {N- {2- {2- [2- (2-methoxyethoxy)
[Ethoxy] ethoxy} Ethyl}} Sulfonamide In the same manner as in Production Example 11, except that 7.22 g of the compound of Production Example 16 was used instead of the compound of Production Example 10 for reaction, and silica gel column chromatography (developing solvent was ethyl acetate). And the title compound as yellow powder crystals in 5.9
0 g (83.4%) was obtained. Melting point: 97-100 ° C. IR spectrum (KBr) νcm ^-1 : 3300 (OH), 2870 (SO ₂ NH),
1640 (CO), 1330, 1150 (SO ₂ ). ¹ H-NMR spectrum (CDCl ₃ ) δ _ppm : 2.95 to 3.78 (16
H, m, CH ₂ × 8), 3.34, 4.03, (6H, s × 2, OCH ₃ × 2),
5.82 (1H, t, J = 6.0Hz, NH), 6.43 (1H, s, C ₆ -H), 6.73
(1H, s, C ₃ -H), 7.32 ~ 7.62 (3H, m, ArH), 7.97 ~ 8.2
6 (2H, m, ArH). MS spectrum (EI / DI) m / z: 537 (M ⁺ ), 268 (base).

(18) Production Example 18 2- (4-methoxy-3-sulfophenyl) -3,5,7-trimethoxy
2- (4-Methoxyphenyl) -3,5,7-trimethoxy-4-oxo-4H-1-while keeping 1.06 ml of cy -4-oxo-4H-1- benzopyransulfate at 0-5 ° C under ice cooling. 200 mg of benzopyran was added, and the mixture was stirred at 80 ° C for 2 hours. Pour the reaction mixture into ether and crystallize to give the title compound 2
Obtained 47 mg (quantitative). IR spectrum (KBr) νcm ^-1 ： 1220 (SO ₂ ). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 3.69, 3.79,
3.83 (12H, s × 3, OCH ₃ × 4), 6.38 (1H, d, J = 2.0Hz, C
₆ -H), 6.63 (1H, d, J = 2.0Hz, C ₈ -H), 7.09 (1H, d, J
= 9.0Hz, ArH), 7.11 (1H, s, SO ₃ H), 7.90 (1H, dd, J =
9.0, 2.0Hz, ArH), 8.31 (1H, d, J = 2.0Hz, ArH).

(19) Production Example 19 2- (3-chlorosulfonyl-4-methoxyphenyl) -3,5,7-
Trimethoxy-4-oxo-4H-1-benzopyran 33.7 g of the compound of Production Example 18 was dissolved in 392 ml of pyridine,
Ether was added and crystallized to obtain 39.7 g. Of these, 13.5
g was suspended in chloroform, 6.70 g of phosphorus pentachloride was added under an argon stream, and the mixture was stirred at 60 ° C. for 3 hours. Water was added under ice cooling, the chloroform layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off to give the title compound as an orange oily substance (7.40 g).
(64.9%) obtained. IR spectrum (KBr) νcm ^-1 ： 1220 (SO ₂ ). ¹ H-NMR spectrum (CDCl ₃ ) δ _ppm : 3.69, 3.79, 3.8
3 (12H, s × 3, OCH ₃ × 4), 6.25 (1H, d, J = 2.0Hz, C _6-
H), 6.43 (1H, d, J = 2.0Hz, C ₈ -H), 7.17 (1H, d, J = 9.
0Hz, ArH), 8.38 (1H, dd, J = 9.0, 2.0Hz, ArH), 8.53 (1
H, d, J = 2.0Hz, ArH).

(20) Production Example 20 2- [3- (N-ethoxycarbonylmethyl) aminosulfonyl
-4-Methoxyphenyl] -3,5,7-trimethoxy-4-oxy
So-4H-1-benzopyran In the same manner as in Production Example 2, except that 5.40 g of the compound of Production Example 19 was used instead of the compound of Production Example 1 for purification, and purified by silica gel column chromatography (developing solvent: ethyl acetate). The title compound as a yellow oil, 3.20 g (5
1.7%) was obtained. IR spectrum (KBr) νcm ^-1 : 1740 (CO). ¹ H-NMR spectrum (CDCl ₃ ) δ _ppm : 1.14 (3H, t, J =
7.0Hz, CH ₃ ), 3.73 ~ 3.97 (2H, m, NH CH ₂ ), 3.86, 3.9
0, 4.03 (12H, s × 3, OCH ₃ × 4), 4.04 (2H, q, J = 7.0Hz,
OCH ₂ ), 5.61 (1H, t, J = 5.5Hz, SO ₂ NH), 6.25 (1H, d,
J = 2.0Hz, C6 -H), 6.45 (1H, d, J = 2.0Hz, C ₈ -H), 7.05
(1H, d, J = 9.0Hz, ArH), 8.24 (1H, dd, J = 9.0, 2.0Hz, Ar
H), 8.43 (1H, d, J = 2.0Hz, ArH). MS spectrum (EI / DI) m / z: 507 (M ⁺ ), 342 (base).

(21) Production Example 21 2- [3- (N-ethoxycarbonylmethyl) aminosulfonyl
-4-Hydroxyphenyl] -5-hydroxy-3,7-dimeth
Xy-4-oxo-4H-1-benzopyran 150 mg of the compound of Production Example 20 was dissolved in methylene chloride, and -2
A solution of boron tribromide (0.11 ml) in methylene chloride was added while maintaining the temperature at 0 to -10 ° C. After stirring for 2 hours, water and chloroform were added for extraction, the organic layer was separated, dried and the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / methylene chloride (1: 1)) to give 82.0 mg (57.7%) of the title compound as yellow prism crystals.
%) Obtained. Melting point: 160-162 ° C. IR spectrum (KBr) νcm ^-1 : 1740 (CO). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 1.10 (3H, t, J
= 7.0Hz, CH ₃ ), 3.76 ~ 3.89 (2H, m, NH CH ₂ ), 3.79, 3.
83 (6H, s × 2, OCH ₃ × 2), 3.97 (2H, q, J = 7.0Hz, OCH
₂ ), 6.30 (1H, d, J = 2.0Hz, C ₆ -H), 6.64 (1H, d, J = 2.
0Hz, C ₈ -H), 7.13 (1H, d, J = 9.0Hz, ArH), 8.06 (1H, d
d, J = 9.0, 2.0Hz, ArH), 8.36 (1H, d, J = 2.0Hz, ArH), 1
1.33 (1H, s, OH). MS spectrum (EI / DI) m / z: 479 (M ⁺ ), 312 (base).

(22) Production Example 22 2- [3- (N-carboxymethyl) aminosulfonyl-4-hydr
Roxyphenyl] -5- hydroxy-3,7-dimethoxy-4-o
Xo-4H-1-benzopyran In the same manner as in Production Example 3, except that the compound of Production Example 21 was replaced with 46.0 mg of the compound of Production Example 21 to give the title compound as yellow prism crystals, 41.0 mg (95.0%) Obtained. Melting point: 231-234 ° C. IR spectrum (KBr) νcm ^-1 : 1700 (CO). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 3.59 to 4.00 (2
H, m, NH CH ₂ ), 3.79, 3.84 (6H, s × 2, OCH ₃ × 2), 6.3
1 (1H, d, J = 2.0Hz, C ₆ -H), 6.64 (1H, d, J = 2.0Hz, C
₈ -H), 7.10 (1H, d, J = 9.0Hz, ArH), 8.05 (1H, dd, J = 9.
0, 2.0Hz, ArH), 8.35 (1H, d, J = 2.0Hz, ArH), 12.59 (1
H, s, OH).

(23) Production Example 23 2- [3- (N-benzyl) aminosulfonyl-4-methoxyphene
Nyl] -3,5,7-trimethoxy-4-oxo-4H-1-benzopyra
The emissions benzylamine 3.12g dissolved in water 4.6 ml, under ice-cooling 0 ~
Chloroform solution of 5.00 g of the compound of Production Example 19 at 5 ° C 4
0.0 ml was added. After stirring for 2 hours, the mixture was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent was ethyl acetate) to give the title compound as brown prism crystals, 3.65 g (62.
9%) obtained. Melting point: 109-114 ° C. IR spectrum (KBr) νcm ^-1 : 1620 (CO). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 3.76, 3.83,
3.89 (12H, s × 3, OCH ₃ × 4), 4.10 (2H, d, J = 6.0Hz, NH C
H ₂ ), 6.43 (1H, d, J = 2.0Hz, C ₆ -H), 6.68 (1H, d, J =
2.0Hz, C ₈ -H), 7.13 (5H, s, ArH), 7.17 (1H, d, J = 9.0H
z, ArH), 8.10 (1H, dd, J = 9.0, 2.0Hz, ArH), 8.31 (1H,
d, J = 2.0Hz, ArH). MS spectrum (EI / DI) m / z: 511 (M ⁺ , base).

(24) Production Example 24 2- [3- (N-benzyl) aminosulfonyl-4-hydroxyphenyl group
[Ethyl] -5-hydroxy-3,7-dimethoxy-4-oxo-4H-
1-Benzopyran The compound of Production Example 23 (1.00 g) was dissolved in methylene chloride (26.0 ml), and the mixture was kept at 0-5 ° C. under ice-cooling while maintaining boron tribromide (0.60 m).
2.0 ml of methylene chloride solution of 1 was added and stirred for 40 minutes. Water was added for extraction, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: ether / hexane (2: 1)),
335 mg (35.4%) of the title compound was obtained as yellow prism crystals. Melting point: 174-177 ° C. IR spectrum (KBr) νcm ^-1 : 1660 (CO). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 3.80, 3.84, (6
H, s × 2, OCH ₃ × 2), 3.97 to 4.26 (2H, m, NH CH ₂ ), 6.
30 (1H, d, J = 2.0Hz, C ₆ -H), 6.61 (1H, d, J = 2.0Hz,
C ₈ -H), 7.06 (1H, d, J = 9.0Hz, ArH), 7.06 ~ 7.36 (5H,
m, ArH), 8.01 (1H, dd, J = 9.0, 2.0Hz, ArH), 8.31 (1H,
d, J = 2.0Hz, ArH), 10.33 (1H, s, OH), 12.63 (1H, s, O
H). MS spectrum (EI / DI) m / z: 483 (M ⁺ , base).

(25) Production Example 25 2- (3-aminosulfonyl-4-hydroxyphenyl) -5-hi
Droxy-3,7-dimethoxy-4-oxo-4H-1-benzopyra
Methanesulfonic acid compound 1.60g of emissions Preparation 24 6.70Ml
And was stirred with heating at 95 ° C for 10 minutes. The reaction solution was poured into ice water, and the precipitated crystals were collected by filtration and dried. Recrystallization from tetrahydrofuran / chloroform gave the title compound (810 mg). The mother liquor was purified by silica gel column chromatography (developing solvent: methanol / chloroform (2: 1)) to obtain 170 mg of the title compound. Together as a yellow prism crystal
Obtained 980 mg (75.3%). Melting point: 226-229 ° C. IR spectrum (KBr) νcm ^-1 : 1660 (CO). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 3.79, 3.83 (6
H, s × 2, OCH ₃ × 2), 6.33 (1H, d, J = 2.0Hz, C ₆ -H),
6.64 (1H, d, J = 2.0Hz, C ₈ -H), 6.83 ~ 7.23 (2H, br,
SO ₂ NH ₂ ), 7.12 (1H, d, J = 9.0Hz, ArH), 8.07 (1H, dd,
J = 9.0, 2.0Hz, ArH), 8.36 (1H, d, J = 2.0Hz, ArH), 12.
66 (1H, s, OH). MS spectrum (EI / DI) m / z: 393 (M ⁺ , base).

(26) Production Example 26 2- {3- {N- [5- (1,3-dihydro-1,3-dioxo-2H-isoin
Dol-2-yl)] pentyl} aminosulfonyl-4-meth
Xyphenyl} -3,5,7-trimethoxy-4- oxo-4H-1-be
Nzopyran In the same manner as in Preparation Example 23, except that 2- (5-aminopentyl) -1H-isoindole-1,3 (2
The reaction was carried out using 2.99 g of (H) -dione hydrochloride and purified by silica gel column chromatography (developing solvent: ethyl acetate) to obtain 4.07 g (62.6%) of the title compound as a yellow oil. IR spectrum (KBr) νcm ^-1 : 1710 (CO). ¹ H-NMR spectrum (CDCl ₃ ) δ _ppm : 1.33 ~ 2.00 (6H, m, CH ₂ × 3), 2.94 (2H, q, J = 6.0Hz, S
O ₂ NH CH ₂ ), 3.59 (2H, t, J = 6.0Hz, (CO) ₂ NH CH ₂ ), 3.
87, 3.91, 4.05 (12H, s × 3, OCH ₃ × 4), 5.12 (1H, t, J =
6.0Hz, SO ₂ NH), 6.25 (1H, d, J = 2.0Hz, C ₆ -H), 6.46
(1H, d, J = 2.0Hz, C ₈ -H), 7.07 (1H, d, J = 9.0Hz, Ar
H), 7.46 ~ 7.86 (4H, m, ArH), 8.25 (1H, dd, J = 9.0, 2.0
Hz, ArH), 8.45 (1H, d, J = 2.0Hz, ArH). MS spectrum (EI / DI) m / z: 636 (M ⁺ ), 231 (base).

(27) Production Example 27 2- {3- {N- [5- (1,3-dihydro-1,3-dioxo-2H-isoin
Dol-2-yl) pentyl]} aminosulfonyl-4-meth
Xyphenyl} -5-hydroxy-3,7-dimethoxy-4-oxy
So-4H-1-benzopyran In the same manner as in Production Example 24, except that 1.00 g of the compound of Production Example 26 was used instead of the compound of Production Example 23 for reaction, and silica gel column chromatography (developing solvent was ethyl acetate / chloroform ( 1: 5)) to give the title compound as a yellow oil (810 mg, 82.6%). IR spectrum (KBr) νcm ^-1 : 1710 (CO). ¹ H-NMR spectrum (CDCl ₃ ) δ _ppm : 1.17 to 2.00 (6H,
m, CH ₂ × 3), 2.90 (2H, q, J = 6.0Hz, SO ₂ NH CH ₂ ), 3.5
6 (2H, t, J = 6.0Hz, (CO) ₂ NH CH ₂ ), 3.83, 3.86, 4.06 (9
H, s × 3, OCH ₃ × 3), 4.97 (1H, t, J = 6.0Hz, SO ₂ N
H), 6.23 (1H, d, J = 2.0Hz, C ₆ -H), 6.38 (1H, d, J = 2.0
Hz, C ₈ -H), 7.07 (1H, d, J = 9.0Hz, ArH), 7.53 to 7.83
(4H, m, ArH), 8.24 (1H, dd, J = 9.0, 2.0Hz, ArH), 8.48
(1H, d, J = 2.0Hz, ArH), 12.43 (1H, s, OH). MS spectrum (EI / DI) m / z: 622 (M ⁺ ), 325 (base).

(28) Production Example 28 2- {3- [N- (5-aminopentyl)] aminosulfonyl-4-me
Toxyphenyl} -5- hydroxy-3,7-dimethoxy-4-o
Xo-4H-1-benzopyran hydrochloride 2.00 g of the compound of Production Example 27 was added to 2.0 ml of sulfuric acid, dioxane 2
Suspend in 0.0 ml and water (3.2 ml) and seal in a sealed tube at 150-160 ° C for 9
Stir for 0 hours. The reaction mixture was concentrated, water was added, the mixture was washed with chloroform, and the precipitated crystals were collected by filtration, extracted with saturated aqueous sodium hydrogen carbonate solution and methanol / chloroform (1: 4), dried over anhydrous sodium sulfate and the solvent was distilled off. Crystallize with methanol / hydrochloric acid and recrystallize with methanol / methyl ethyl ketone to give the title compound as pale brown prism crystals.
1.03 g (60.7%) was obtained. Melting point: 141-146 ° C. IR spectrum (KBr) νcm ^-1 : 1660 (CO). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 1.17 to 1.86 (6
H, m, CH ₂ × 3), 2.53 to 3.07 (4H, m, SO ₂ NH CH _{2 and} CO
NH CH ₂ ), 3.83, 3.86, 4.00 (9H, s × 3, OCH ₃ × 3), 6.
33 (1H, d, J = 2.0Hz, C ₆ -H), 6.66 (1H, d, J = 2.0Hz, C
₈ -H), 7.07 (1H, d, J = 9.0Hz, ArH), 8.20 (1H, dd, J = 9.
0, 2.0Hz, ArH), 8.41 (1H, d, J = 2.0Hz, ArH). MS spectrum (EI / DI) m / z: 492 (M ⁺ ), 129 (base).

(29) Production Example 29 5,7-dihydroxy-3-methoxy-2- (4-nitrophenyl)-
4-oxo-4H-1-benzopyran 1- (2,4,6-trihydroxyphenyl) -2-methoxy-1-ethanone (198 g), 4-nitrobenzoic anhydride (950 g), potassium 4-nitrobenzoate (308 g) were added to Dausam A2. Suspended in .00l,
The mixture was stirred at 185 to 195 ° C for 2 hours. N-hexane 1.
50 l was added, and the precipitated crystals were collected by filtration, washed with 3.50 l of n-hexane and then dissolved in 6.00 l of tetrahydrofuran. The insoluble matter was filtered off and the filtrate was concentrated to give the title compound as brown powder crystals.
92.9 g (28.2%) was obtained. Melting point: 250-255 ° C. IR spectrum (KBr) νcm ^-1 : 3500 〜 3300 (OH), 1650 (C
O). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 3.85 (3H, s, O
CH ₃ ), 6.12 (1H, d, J = 2.0Hz, C ₆ -H), 6.35 (1H, d, J =
_{2.0Hz, C 8 -H), 7.90} ~8.40 (4H, m, ArH), MS spectrum (EI / DI) m / z : 329 (M +, base).

(30) Production Example 30 3,5,7-trimethoxy-2- (4-nitrophenyl) -4-oxo-4
H-1-Benzopyran 80.0 g of the compound of Production Example 29 was suspended in 2.43 l of acetone, 205 g of dimethylsulfate and 516 g of anhydrous potassium carbonate were added, and the mixture was heated under reflux with stirring for 1.5 hours. The reaction solution was filtered, the residue was washed with hot chloroform, the filtrate was concentrated, and the precipitated crystals were filtered. This crystal was recrystallized from chloroform / methanol to give the title compound as yellow needle crystals, 71.4 g (82.3%)
Obtained. Melting point: 200-202 ° C. IR spectrum (KBr) νcm ^-1 : 1650 ~ 1630 (CO), 1515,13
45 (NO ₂ ). ¹ H-NMR spectrum (CDCl ₃ ) δ _ppm : 3.75 to 3.95 (9H,
s × 2, OCH ₃ × 3), 6.20 (1H, d, J = 2.0Hz, C ₆ -H), 6.37
(1H, d, J = 2.0Hz, C ₈ -H), 8.20 (4H, s, ArH). MS spectrum (EI / DI) m / z: 375 (M ⁺ , base).

(31) Production Example 31 3,5,7-trimethoxy-2- (4-nitrophenyl) -4-oxo-4
H-1-Benzopyran-8-sulfonyl chloride In the same manner as in Production Example 1, except that 5,0.0-dimethoxy-4-oxo-2-phenyl-4H-1-benzopyran was replaced by the compound of Production Example 30 (40.0 g). To give 48.0 g (94.1%) of the title compound as yellow powder crystals. Melting point: 130-133 ° C. IR spectrum (KBr) νcm ^-1 : 1650 (CO), 1410 (SO ₂ ), 13
45 (NO ₂ ). ¹ H-NMR spectrum (CF ₃ COOD) δ _ppm : 3.87, 4.17,
4.27 (9H, s × 3, OCH ₃ × 3), 6.85 (1H, s, C ₆ -H), 8.1
7 (2H, d, J = 8.0Hz, ArH), 8.47 (2H, d, J = 8.0Hz, ArH)
． MS spectrum (EI / DI) m / z: 357 [(M-SO2 Cl + 1) ⁺ , bas
e].

(32) Production Example 32 3,5,7-trimethoxy-2- (4-nitrophenyl) -4-oxo-4
H-1-Benzopyran- 8-sulfonamide In the same manner as in Production Example 10, except that 45.0 g of the compound of Preparative Example 31 was used instead of the compound of Preparative Example 1, and the title compound was obtained as yellow powder crystals in an amount of 33.0 g ( 78.9%) obtained. Melting point: 238-240 ° C. IR spectrum (KBr) νcm ^-1 : 3600 ~ 3300 (NH ₂ ), 1640
〜1630 (CO), 1350〜1330 (SO ₂ , NO ₂ ). ¹ H-NMR spectrum (CF ₃ COOD) δ _ppm : 4.02, 4.33,
4.40 (9H, s × 3, OCH ₃ ), 7.02 (1H, s, C ₆ -H), 8.35 (2
H, d, J = 8.0Hz, ArH), 8.67 (2H, d, J = 8.0Hz, ArH). MS spectrum (EI / DI) m / z: 357 [(M-SO ₂ NH) ⁺ , base]
．

(33) Production Example 33 5-hydroxy-3,7-dimethoxy-2- (4-nitrophenyl)-
4-Oxo-4H-1-benzopyran-8-sulfonamide In the same manner as in Preparation Example 11, except that the compound of Preparation Example 32 was replaced by 800 mg of the compound of Preparation Example 10, and acetonitrile was replaced by bromobenzene. React using
Silica gel column chromatography (Developing solvent is dimethylformamide / methanol / chloroform (2: 1: 2
0)) to give 320 mg of the title compound as yellow needles.
(41.3%) was obtained. Melting point: 294-297 ° C. IR spectrum (KBr) νcm ^-1 : 1640 (CO). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 3.92, 4.03 (6
H, s × 2, OCH ₃ × 2), 6.66 (1H, s, C ₆ -H), 7.16 ~
7.40 (2H, m, SO ₂ NH ₂ ), 8.29 (2H, d, J = 9.0Hz, ArH),
8.53 (2H, d, J = 9.0Hz, ArH), 13.40 (1H, br, OH). MS spectrum (EI / DI) m / z: 422 (M ⁺ , base).

(34) Production Example 34 2- (4-aminophenyl) -3,5,7-trimethoxy-4-oxy
So-4H-1-benzopyran-8-sulfonamide 36.0 g of the compound of Production Example 32 was added to dimethylformamide 2.1.
Suspend in 0 l and stir for 1 hour at 80 ° C under argon flow, 50-
7.20 g of 10% palladium carbon was added at 55 ° C and under hydrogen flow 2
Stir for hours. The reaction solution was filtered, the mother liquor was concentrated, and the precipitated crystals were suspended in methanol, collected by filtration and dried to give the title compound as red powder crystals (30.3 g, 90.3%). Melting point: 238-242 ° C. IR spectrum (KBr) νcm ^-1 : 3500-3200 (NH ₂ ), 1630
~ 1600 (CO), 1340 (SO ₂ ). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 3.68, 3.92,
4.00 (9H, s × 3, OCH ₃ × 3), 6.53 (2H, d, J = 8.0Hz, Ar
H), 6.55 (1H, s, C ₆ -H), 7.00 ~ 7.23 (2H, br, SO ₂ N
H ₂ ), 7.97 (2H, d, J = 8.0Hz, ArH). MS spectrum (EI / DI) m / z: 327 [(M-SO ₂ NH) ⁺ , base]
．

(35) Production Example 35 2- (4-hydroxyphenyl) -3,5,7-trimethoxy-4-
Oxo-4H-1-benzopyran-8-sulfonamide 6.10 g of the compound of Production Example 34 was dissolved in 65% sulfuric acid to give -10 to
Aqueous solution of sodium nitrite 1.05g while keeping at -11 ℃ 1
5.0 ml was added. After stirring for 40 minutes, the reaction solution was poured into 675 ml of cold water and stirred at 70 to 75 ° C for 20 minutes. After cooling, the precipitated crystals were collected by filtration, washed with water and dried to give the title compound as red powder crystals.
Obtained 3.70 g (60.5%). Melting point: 248-251 ° C. IR spectrum (KBr) νcm ^-1 : 3500-3300 (NH ₂ ), 1630
~ 1600 (CO), 1345 (SO ₂ ). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 3.73, 3.97,
4.03 (9H, s × 3, OCH ₃ × 3), 6.63 (1H, s, C ₆ -H), 6.8
3 (2H, d, J = 9.0Hz, ArH), 6.97 ~ 7.40 (2H, br, SO ₂ NH
₂ ), 8.15 (2H, d, J = 9.0Hz, ArH). MS spectrum (EI / DI) m / z: 407 (M ⁺ ), 327 [(M-SO ₂ NH
₂ ) ⁺ , base].

(36) Production Example 36 5-hydroxy-2- (4-hydroxyphenyl) -3,7-dimeth
Xy-4-oxo-4H- 1-benzopyran-8-sulfonamide In the same manner as in Production Example 33, except that, instead of the compound in Production Example 32, 5.09 g of the compound in Production Example 35 was used to react.
Purification by silica gel column chromatography (developing solvent: chloroform / methanol (20: 1 → 10: 1)) gave 3.08 g (62.7%) of the title compound as yellow powder crystals. Melting point: 244-245 ° C. IR spectrum (KBr) νcm ^-1 : 3450 ~ 3300 (OH), 1640 (C
O). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 3.73, 3.90 (6
H, s × 2, OCH ₃ × 2), 6.50 (1H, s, C ₆ -H), 6.77 (2H,
d, J = 9.0Hz, ArH), 6.97 ~ 7.23 (2H, br, SO ₂ NH ₂ ),
8.10 (2H, d, J = 9.0Hz, ArH), 9.97 ~ 10.20 (1H, br, C
_{4 -OH), 13.60 ~13.80 (1H} , br, C 5 -OH). MS spectrum (EI / DI) m / z: 314 [(M-SO ₂ NH) ⁺ , base]
．

[0054]

【Example】

(Example of drug efficacy test) In vitro anti-vaccinia virus action and cytotoxic action Vero cells (derived from African green monkey kidney) were cultured in a monolayer in a 96-well plate, and vaccinia virus (DIE
Strain) and the test compound were added and cultured for 3 days, and then the cytopathic effect (CPE) by the virus, the CPE inhibitory effect by the test compound and the cytotoxic effect by the test compound were observed under a microscope. T using virus-based CPE as an index
CID ₅₀ was calculated, and T of the test compound treated group and the untreated group was calculated.
ΔTCID ₅₀ (log ₁₀ ) was calculated from CID _50, and the antiviral effect of the test compound was evaluated.

Table 1 In Vitro Anti-Vaccinia Virus Action Test Compound Anti-viral Activity (ΔTCID ₅₀ (log ₁₀ )) Drug Concentration (μg / ml) 1 10 50 Production Example-11 1.80 (-)> 3.72 (-)> 3.72 ( +) Production example-22 0.10 (-) 2.82 (-)> 3.30 (+) Production example -25 0.00 (-) 1.30 (-) 2.30 (+) Production example-36 0.00 (-) 0.33 (-) 0.78 (+ ) In Table 1, the value in () indicates the degree of cytotoxicity, and (-)
Is no cytotoxicity, (±) is very mild cytotoxicity,
(+) Indicates that there is cytotoxicity, but antiviral activity can be observed.

It was revealed that the compound according to the present invention had a remarkable anti-vaccinia virus action and that the compound of Production Example 11 had weak cytotoxicity and strong selective toxicity.

2. In vitro anti-human adenovirus action and cytotoxic action Hela cells (derived from human uterine cancer) were cultured in a monolayer in a 96-well plate, human adenovirus type 3 and a test compound were added, and the cells were cultured for 4 days, followed by cytopathic change by virus. Effect (CP
E), CPE inhibitory effect of the test compound and cytotoxic effect of the test compound were observed under a microscope. Calculating the TCID ₅₀ of the CPE by the virus as an indicator, DerutaTCI from TCID ₅₀ treatment group and the untreated group of test compounds
D ₅₀ (log ₁₀ ) was determined and the antiviral action of the test compound was evaluated.

Table 2 In vitro anti-adenovirus action test compound Antiviral activity (ΔTCID ₅₀ (log ₁₀ )) Drug concentration (μg / ml) 1 10 50 Production Example-11 0.20 (-) 1.33 (-)> 3.30 (+) ) Production Example-22 0.00 (-) 1.57 (-) 1.57 (+) Production Example -25 0.00 (-) 0.80 (±) 1.25 (+) In Table 2, () indicates the cytotoxicity, (-)
Is no cytotoxicity, (±) is very mild cytotoxicity,
(+) Indicates that there is cytotoxicity, but antiviral activity can be observed.

The compound according to the present invention showed a remarkable inhibitory effect not only on vaccinia virus but also on human adenovirus lacking an envelope.

3. In vitro anti-influenza virus action and cytotoxic action MDCK cells (derived from dog kidney) were cultured in a monolayer in a 96-well plate, the influenza virus (A / PR / 8 strain) and a test compound were added, and the cells were cultured for 2 days, then the virus was added. The cytopathic effect (CPE) by the test compound, the CPE inhibitory effect by the test compound, and the cytotoxic effect by the test compound were observed under a microscope. TCID using CPE by virus as an index
₅₀ was calculated, and TCID of the test compound-treated group and the untreated group
DerutaTCID ₅₀ seek (log ₁₀₎ from _50, to evaluate the antiviral effect of the test compound.

Table 3 In vitro anti-influenza virus action test compound Antiviral activity (ΔTCID ₅₀ (log ₁₀ )) Drug concentration (μg / ml) 1 10 100 Preparation example -11 0.00 (-) 1.05 (-)> 3.30 (+ ) Production Example -22 0.00 (-) 0.55 (-) 1.57 (+) Production Example -25 0.00 (-) 0.80 (±) 1.25 (±) In Table 3, () indicates the cytotoxic strength, (-)
Is no cytotoxicity, (±) is very mild cytotoxicity,
(+) Indicates that there is cytotoxicity, but antiviral activity can be observed.

The compounds according to the present invention are not limited to vaccinia virus and adenovirus, which are DNA viruses, and RN.
It also showed a remarkable inhibitory effect against influenza virus which is A virus.

Formulation Example Formulation Example 1 (Ointment ) An ointment was prepared by the usual method according to the following formulation and filled in an aluminum tube. Compound of Production Example 11 3 g White petrolatum Appropriate amount 100 g

Formulation Example 2 (oral ointment) An oral ointment was prepared by the usual method according to the following formulation and filled in an aluminum tube. Compound of Preparation Example-22 0.3 g Carboxymethylcellulose (Na) 3.1 g Liquid paraffin 3.1 g White petrolatum 1.2 g Plastibase Suitable total 10 g

Formulation Example 3 (Capsules) Capsules having the following formulation were prepared by a conventional method. Production Example-25 compound 100 mg Magnesium stearate 5 mg Lactose Suitable amount Total 150 mg

Formulation Example 4 (tablet) A tablet was obtained by compounding with an excipient in the following formulation and tableting by a conventional method. Compound of Preparation Example-36 100 mg Sodium lauryl sulfate 10 mg Magnesium stearate 5 mg Polyvinylpyrrolidone K30 11 mg Carboxymethylcellulose (Ca) 7 mg Lactose 60 mg Corn starch Suitable total amount 210 mg

[0067]

INDUSTRIAL APPLICABILITY The novel flavone derivative of the present invention has an excellent antiviral action and is useful as an excellent preventive and therapeutic agent for infectious diseases caused by various DNA, RNA viruses and retroviruses. The flavone derivative of the present invention has a broader spectrum of action and is more potent than conventional flavone derivatives. Further, these compounds, unlike existing flavone derivatives, are also effective against infectious diseases caused by viruses that are resistant to existing antiviral substances. In addition, the spectrum was expanded to viruses not present in the original compound or the cytotoxicity could be reduced with further enhancement of antiviral activity.

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] January 12, 1993

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] Full text

[Correction method] Change

[Correction content]

[Document name] Statement

Title of the invention Flavone derivative

[Claims]

[Chemical 1] (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ ,
R ₈ , R ₉ and R ₁₀ are simultaneously or separately a hydroxyl group,
Mercapto group, halogen, formyl group, carboxyl group, sulfonic acid group, phosphonic acid group, nitro group, cyano group, optionally substituted amino, optionally substituted amide, optionally substituted alkyloxycarbonyl , Optionally substituted aryloxycarbonyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted acyl, optionally substituted alkyloxy, optionally substituted Aryloxy, optionally substituted alkylthio, optionally substituted arylthio, optionally substituted alkylsulfinyl, optionally substituted arylsulfinyl, optionally substituted alkylsulfonyl, optionally substituted Optionally arylsulfonyl, optionally substituted aryl Le aminosulfonyl, optionally substituted aryl aminosulfonyl means a heterocycle which may be substituted, amino example and may be substituted, formyl, hydroxy, alkoxy,
Aryloxy, halogen, nitro, cyano, thiol, alkylthio, arylthio, acyl, carbamoyl, alkylsilyl, arylsilyl, alkyloxycarbonyl, aryloxycarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfinyl,
Arylsulfinyl, which means substituted with phosphoric acid, phosphonic acid, phosphinic acid, phosphenic acid, sulfuric acid, sulfonic acid, sulfinic acid, sulfenic acid, boric acid and esters of these acids, etc. And, for example, condensed with a benzene ring, or pyridine which may be condensed with each other, piperidine, pyrazine, piperazine,
Pyrrole, pyrrolidine, oxazole, imidazole,
It means morpholine, diazole, triazole, tetrazole, thiazole, thiadiazole and the like. ) And a flavone derivative containing a salt thereof as a main component

Detailed Description of the Invention

[0001]

The present invention relates to various DNA viruses, R
The present invention relates to a preventive and therapeutic agent for infectious diseases caused by NA virus and retrovirus.

[0002]

2. Description of the Related Art Conventionally, modified or unmodified flavones have been known to have various physiological activities. In particular, as a flavone derivative having antiviral activity, R
o09-0179 is known and has been shown to inhibit its replication against the RNA virus picornavirus (Antimicrobial Agents and Chem).
otherapy, Vol.22 (4), 611-361 (1982)) and other viruses have no effect. Furthermore, it is known that rhamnetin and the like are effective against the herpesvirus that is a DNA virus (Acta Virol., Vol.3.
2, 522-525 (1988)), its action intensity is much weaker than that of acyclovir, and its toxicity is also strong. Recently, it has been reported that the flavone derivatives baicalein, quercetin, myricetin, etc. are effective for retroviruses (Metabolism, Vol. 22, 1027-1034 (1991)), but these compounds are polyphenolic compounds, It is extremely toxic in that cytotoxicity appears below the effective concentration, and it is considered that clinical use is impossible. Compounds that are flavone derivatives that are clinically used against virus-infected persons are:
So far unknown.

[0003]

[Problems to be Solved by the Invention] Regarding flavone derivatives having antiviral activity, compounds having effective activity have been found at the stage of basic experiments, but they have strong cytotoxicity and cell membrane permeability. There is no compound that has been clinically used because of its poor toxicity.

In recent years, remarkable progress has been made in research and development of antiviral agents, and various nucleic acid antiviral agents typified by acyclovir have excellent clinical effects against infections caused by herpes simplex virus and herpes zoster virus. Is recognized. However, infectious diseases caused by resistant herpesviruses such as viruses lacking thymidine kinase have become a problem (Oral Surg Oral Med Oral Pathol, Vol.
67, 427-432, (1989)). In addition, these nucleic acid-based antiviral agents are generally ineffective against RNA viruses such as influenza virus.

Antiviral compounds other than nucleic acid compounds, such as DN
Phosphonoformate (PFA, Japanese clinical, 47 (2), 390-394, (198
9)), Phosphonoacetate (PAA, Japanese Clinical, Volume 47)
(2), 390-394, (1989)), cycloxolone (Journa
l of Antimicrobial Chemotherapy, Vol.18, Suppl.B,
185-200, (1986)) and the like are known. However, for phosphonoformates and phosphonoacetates,
As side effects, kidney dysfunction and anemia have become problems,
The antiviral activity of cycloxolone has not been increased until it can be said to be sufficient for treatment.

Amantadine (pediatric practice, 54 volumes) is effective against RNA viruses other than nucleic acid derivatives.
(4), 988-994, (1991)), rimantadine (pediatric practice, 54 (4), 988-994, (1991)), LY253.
963 (thiadiazole derivative, pediatric practice, 54 (4)
, 988-994, (1991)), Dansylcadaverine (US Pa
t. US275,033), fluorenesulfonyl amino acid (Pharmaceutical Journal, 95, 397, (1975)) and the like are known. Amantadine is effective against influenza A virus but ineffective against influenza B virus, and side effect of central nervous system is a problem. For rimantadine, the drawbacks of amantadine have been largely overcome, but the side effects of the central nervous system remain a problem. Regarding LY253963, dansylcadaverine, and fluorenesulfonylamino acid, anti-influenza virus action has been confirmed in basic experiments, but clinical efficacy has not yet been confirmed.

AZ is an effective antiviral agent against retroviruses such as AIDS virus (HIV).
T and DDI (Pediatrics, 54 (4), 981-987, (199
1)) is known. However, although these antiviral agents delay the onset of AIDS, complete cure cannot be expected, and bone marrow suppression is a problem as a side effect.

In recent years, organ transplantation, cancer chemotherapy or HI
The number of immunodeficient patients associated with V infection is on the rise and has become a major medical problem. The viral infections that develop in such patients are extremely diverse and often cannot be treated with existing antiviral agents, and there is great hope for the development of superior antiviral agents.

Therefore, a first object of the present invention is to provide an antiviral agent which has an excellent effect on DNA virus, RNA virus and retrovirus and is highly safe. A second object is to provide an antiviral agent that is effective against viruses that are resistant to conventional antiviral substances.

[0010]

As described above, there are no flavone derivatives that have reached the clinical practical range for the prevention and treatment of viral infections. On the other hand, when looking at the structure of a non-nucleic acid antiviral compound other than a flavone derivative, it is characterized by having a dissociative substituent such as sulfonic acid, sulfuric acid, phosphonic acid, or phosphoric acid. It is presumed that it is important to have antiviral activity in expression or enhancement.

Therefore, we have introduced such a dissociative substituent into the molecule of flavone, which is not a polyphenol, to improve the virus spectrum and activity intensity of the flavone derivative, which has been conventionally free of clinically practical compounds. For the purpose, we conducted extensive research, designed new compounds and investigated their antiviral effects. As a result, surprisingly, some novel flavone derivatives are not only conventional RNA viruses such as picornavirus but also DNA viruses such as adenovirus and vaccinia virus, and influenza which is a clinically important RNA virus. The inventors have found that they have a strong antiviral activity against viruses and at the same time have reduced cytotoxicity, and have completed the present invention. That is, the present inventors succeeded in expanding the virus spectrum, enhancing the activity, and further reducing the toxicity by introducing a dissociative substituent with flavone as the basic skeleton.

[0012]

[Chemical 2] General Formula I In the present invention, the flavone derivative as the active ingredient includes compounds represented by General Formula I and salts thereof. In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ ,
R ₇ , R ₈ , R ₉ and R ₁₀ are simultaneously or separately substituted with a hydroxyl group, a mercapto group, a halogen, a formyl group, a carboxyl group, a sulfonic acid group, a phosphonic acid group, a nitro group, a cyano group or a substituent. Optionally amino, optionally substituted amide, optionally substituted alkyloxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted alkyl, optionally substituted aryl, substituted Optionally substituted acyl, optionally substituted alkyloxy, optionally substituted aryloxy, optionally substituted alkylthio, optionally substituted arylthio, optionally substituted alkylsulfinyl, substituted Optionally substituted arylsulfinyl, optionally substituted alkylsulfonyl, substituted Optionally arylsulfonyl, optionally substituted alkylaminosulfonyl, optionally substituted arylaminosulfonyl, optionally substituted heterocycle, optionally substituted is, for example, amino, Formyl, hydroxy, alkoxy,
Aryloxy, halogen, nitro, cyano, thiol, alkylthio, arylthio, acyl, carbamoyl, alkylsilyl, arylsilyl, alkyloxycarbonyl, aryloxycarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfinyl arylsulfinyl, phosphoric acid, phosphon Acid, phosphinic acid, phosphenic acid, sulfuric acid, sulfonic acid, sulfinic acid, sulfenic acid, means that is substituted with boric acid and esters of these acids, etc., and the heterocycle is, for example, condensed with a benzene ring, Alternatively, pyridine which may be condensed with each other, piperidine, pyrazine, piperazine, pyrrole, pyrrolidine, oxazole, imidazole, morpholine, diazole, triazole, tetrazole,
Means thiazole, thiadiazole and the like.

Examples of the flavone derivative represented by the general formula I include 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-
Benzopyran-8-sulfonyl chloride, 5,7-dimethoxy
-4-oxo-2-phenyl-4H-1-benzopyran-8- (N-ethoxycarbonylmethyl) sulfonamide, 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-benzopyran-8- ( N-carboxymethyl) sulfonamide, 5,7-dimethoxy-4-
Oxo-2-phenyl-4H-1-benzopyran-8- {N- [N '-(aminoethyl) amido] methyl} sulfonamide, 5,7-dimethoxy-4-oxo-2-phenyl-4H-1- Benzopyran-8
-(N-aminoethyl) sulfonamide, 5,7-dimethoxy-4
-Oxo-2-phenyl-4H-1-benzopyran-8- {N- [N'-
(N "-benzyloxycarbonyl) glycyl] aminoethyl} sulfonamide, 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-benzopyran-8- {N- [N '-(N" -benzyl Oxycarbonyl) -L-alanyl] aminoethyl} sulfonamide, 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-benzopyran-8- [N- (N'-glycyl) aminoethyl] sulfonamide , 5,7-dimethoxy-4-oxo-2-phenyl-4H-
1-benzopyran-8- [N- (N'-L-alanyl) aminoethyl]
Sulfonamide, 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-benzopyran-8-sulfonamide, 5-hydroxy-7-methoxy-4-oxo-2-phenyl-4H-1-benzopyran- 8-sulfonamide, 5,7-dimethoxy-4-oxo-2
-(3-Chlorosulfonyl-4-methoxy) phenyl-4H-1-
Benzopyran-8-sulfonyl chloride, 5,7-dimethoxy
-4-oxo-2- [3- (N-ethoxycarbonylmethyl) aminosulfonyl) -4-methoxy] phenyl-4H-1-benzopyran-8- (N-ethoxycarbonylmethyl) sulfonamide, 5,7-dimethoxy -4-oxo-2- [3- (N-carboxymethyl) aminosulfonyl-4-methoxy] phenyl-4H-1-
Benzopyran-8- (N-carboxymethyl) sulfonamide, 5,7-dimethoxy-4-oxo-2- {3- {N- [N '-(aminoethyl) amido] methyl] aminosulfonyl-4-methoxy} Phenyl-4H-1-benzopyran-8- {N- [N '-(aminoethyl) amido] methyl} sulfonamide, 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-benzopyran-8- {N- {2
-{2- [2- (2-Methoxyethoxy) ethoxy] ethoxy} ethyl}} sulfonamide, 5-hydroxy-7-methoxy-4-
Oxo-2-phenyl-4H-1-benzopyran-8- {N- {2- {2-
[2- (2-Methoxyethoxy) ethoxy] ethoxy} ethyl}} sulfonamide 2- (4-methoxy-3-sulfophenyl) -3,5,7-trimethoxy-4-oxo-4H-1-benzopyran, 2 -(3-chlorosulfonyl-4-methoxyphenyl) -3,
5,7-Trimethoxy-4-oxo-4H-1-benzopyran, 2- [3
-(N-Ethoxycarbonylmethyl) aminosulfonyl-4-
Methoxyphenyl] -3,5,7-trimethoxy-4-oxo-4H-
1-benzopyran, 2- [3- (N-ethoxycarbonylmethyl)
Aminosulfonyl-4-hydroxyphenyl] -5-hydroxy-3,7-dimethoxy-4-oxo-4H-1-benzopyran, 2
-[3- (N-Carboxymethyl) aminosulfonyl-4-hydroxyphenyl] -5-hydroxy-3,7-dimethoxy-4-oxo-4H-1-benzopyran, 2- [3- (N-benzyl) amino Sulfonyl-4-methoxyphenyl] -3,5,7-trimethoxy-4
-Oxo-4H-1-benzopyran, 2- [3- (N-benzyl) aminosulfonyl-4-hydroxyphenyl] -5-hydroxy-
3,7-dimethoxy-4-oxo-4H-1-benzopyran, 2- (3-
Aminosulfonyl-4-hydroxyphenyl) -5-hydroxy-3,7-dimethoxy-4-oxo-4H-1-benzopyran,
2- {3- {N- [5- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)] pentyl} aminosulfonyl-4-methoxyphenyl} -3,5,7 -Trimethoxy-4-oxo-4H-1-benzopyran, 2- {3- {N- [5- (1,3-dihydro-1,3-dioxo
-2H-isoindol-2-yl) pentyl]} aminosulfonyl-4-methoxyphenyl} -5-hydroxy-3,7-dimethoxy-4-oxo-4H-1-benzopyran, 2- {3- [N- (5-Aminopentyl)] aminosulfonyl-4-methoxyphenyl}-
5-hydroxy-3,7-dimethoxy-4-oxo-4H-1-benzopyran, 5,7-dihydroxy-3-methoxy-2- (4-nitrophenyl) -4-oxo-4H-1-benzopyran, 3 , 5,7-Trimethoxy-2- (4-nitrophenyl) -4-oxo-4H-1-benzopyran, 3,5,7-trimethoxy-2- (4-nitrophenyl) -4-oxo-4H-1 -Benzopyran-8-sulfonyl chloride, 3,5,7-
Trimethoxy-2- (4-nitrophenyl) -4-oxo-4H-1-
Benzopyran-8-sulfonamide, 5-hydroxy-3,7-
Dimethoxy-2- (4-nitrophenyl) -4-oxo-4H-1-benzopyran-8-sulfonamide, 2- (4-aminophenyl)-
3,5,7-Trimethoxy-4-oxo-4H-1-benzopyran-8-
Sulfonamide, 2- (4-hydroxyphenyl) -3,5,7-trimethoxy-4-oxo-4H-1-benzopyran-8-sulfonamide, 5-hydroxy-2- (4-hydroxyphenyl) -3, 7-
There are, but not limited to, dimethoxy-4-oxo-4H-1-benzopyran-8-sulfonamide, and salts thereof, which are prepared by commonly known chemical reactions.

The flavone derivative represented by the general formula I has potent antiviral activity, low toxicity and is provided in various dosage forms.

The topical agents include liquids, ointments, creams, gels, rectal suppositories, vaginal suppositories and the like for skin and mucous membranes, and eye drops and eye ointments and the like for eyes. ,
The formulation can be carried out by a conventional method. When administered to humans, the dose depends on the type of compound, symptoms, dosage form, etc., but it is generally appropriate to administer it as a preparation containing 0.01 to 10%. For the purpose of promoting absorption, bile acid, saponin, polyoxyethylene higher alcohol ether, polyethylene glycol, DMS, if desired.
Absorption promoters such as O and laurocapram can be added.

Examples of the orally-administered agent include liquids, tablets, capsules, granules, fine granules, buccal, troches and the like. The formulation can be carried out by a conventional method. If desired, an absorption enhancer such as bile acid, saponin or polyoxyethylene higher alcohol ether may be added. When administered to humans, the dose depends on the type of compound, symptoms, dosage form, etc., but is generally 100-
3000 mg / day is suitable. Injectables can also be formulated by a conventional method. The dose to be administered to humans depends on the type of compound, symptoms, dosage form, etc., but is generally 3
0 to 1000 mg / day is suitable.

[0017]

EXAMPLES Next, the present invention will be described in more detail with reference to production examples of the compound according to the present invention, pharmacological effect test examples and formulation examples.

(1) Production Example 1 5,7-Dimethoxy-4-oxo-2-phenyl-4H-1-benzopyr
While maintaining 23.0 ml of lan-8-sulfonyl chloride chlorosulfonic acid at 0-5 ° C under ice cooling, add 10.0 g of 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-benzopyran and stir for 30 minutes. After that, it was left at 20 to 25 ° C for one day. The reaction solution was poured into ice, and the precipitated crystals were collected by filtration, washed with water and dried to give the title compound as pale green powder crystals in an amount of 13.4 g (
Quantitative) was obtained. Melting point: 300 ° C or higher. IR spectrum (KBr) νcm ^-1 : 1345,1180 (SO ₂ Cl). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 3.93 (6H, s, O
CH ₃ × 2), 6.57 (1H, s, C ₆ -H), 6.77 (1H, s, C ₃ -H),
7.33 ~ 7.60 (3H, m, ArH), 8.27 ~ 8.50 (2H, m, ArH).

(2) Production Example 2 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-benzopi
Lan-8- (N-ethoxycarbonylmethyl) sulfonamide hydrochloric acid glycine ethyl ester 20.0 g, triethylamine
Dissolve 20.0 ml in 200 ml of chloroform and cool on ice 0-5.
While maintaining at 0 ° C, 13.5 g of the compound of Production Example 1 was added. 30
After stirring for 1 minute, the mixture was stirred at 20 to 25 ° C for 2 hours. After filtering the insoluble matter, the mother liquor was saturated with an aqueous sodium hydrogen carbonate solution,
The organic layer was washed with 10% aqueous citric acid solution, dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was crystallized with ether to obtain 7.70 g (52.0%) of the title compound as colorless prism crystals. Melting point: 162 ° C. IR spectrum (KBr) νcm ^-1 : 1745 (C = O), 1375 (SO ₂ NH)
． ¹ H-NMR spectrum (CDCl ₃ ) δ _ppm : 1.13 (3H, t, J =
7.0Hz, CH ₃ ), 3.82 (2H, d, J = 5.0Hz, CH ₂ CO), 4.00 (2
H, q, J = 7.0, 16.0Hz, CH ₂ ), 4.00 (3H, s, OCH ₃ ), 4.
07 (3H, s, OCH ₃ ), 6.00 (1H, t, J = 5.0Hz, NH), 6.38 (1
H, s, C ₆ -H), 6.68 (1H, s, C ₃ -H), 7.33 ~ 7.56 (3H,
m, ArH), 7.92-8.20 (2H, m, ArH). MS spectrum (EI / DI) m / z: 447 (M ⁺ , base).

(3) Production Example 3 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-benzopi
5. Lanthanum 8- (N-carboxymethyl) sulfonamide 5.50 g of the compound of Production Example 2 was suspended in 44.0 ml of methanol, and 13.2 ml of 1N aqueous sodium hydroxide solution was added,
The mixture was stirred at 20-25 ° C for 2 hours. After distilling off the methanol,
20 ml of water was added and the pH was adjusted to 3 with 6N hydrochloric acid. The precipitated crystals were collected by filtration, washed with water and dried to give the title compound as colorless powder crystals (5.02 g, 98.3%). Melting point: 230-232 ° C. IR spectrum (KBr) νcm ^-1 : 3200
(OH), 1765 (CO). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 3.60 to 4.00 (2
H, m, CH ₂ CO), 3.98 (3H, s, OCH ₃ ), 4.07 (3H, s, C
H ₃ ), 6.50 ~ 7.20 (2H, m, SO ₂ NH and COOH), 6.67 (1
H, s, C ₆ -H), 6.82 (1H, s, C ₃ -H), 7.34 ~ 7.70 (3H,
m, ArH), 8.07-8.36 (2H, m, ArH). MS spectrum (EI / DI) m / z: 283 (base).

(4) Production Example 4 5,7-Dimethoxy-4-oxo-2-phenyl-4H-1-benzopi
Lan-8- {N- [N '-(aminoethyl) amido] methyl} sul
5.10 g of the compound of honamide production example 2 was suspended in 150 ml of ethanol,
Ethylenediamine (1.37 g) was added, and the mixture was heated under reflux for 12 hours.
After the reaction solution was concentrated under reduced pressure, 10 ml of ethanol was added for crystallization. Recrystallization from hot ethanol gave the title compound as pale yellow prism crystals (3.63 g, 69.2%). Melting point: 175-190 ° C. IR spectrum (KBr) νcm ^-1 : 3500 〜 3400 (NH ₂ ), 1640
(CO). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 2.63 to 3.13 (4
H, m, CH ₂ × 2), 3.13 to 3.53 (3H, m, NH ₂ and SO ₂ NH),
3.53 ~ 3.86 (2H, m, CH ₂ CO), 3.93 (3H, s, OCH ₃ ), 4.
00 (3H, s, OCH ₃ ), 6.40 (1H, s, C ₆ -H), 6.50 (1H, s, C
₃ -H), 7.13 ~ 7.43 (4H, m, CONH and ArH), 7.83 ~ 8.1
0 (2H, m, ArH). MS spectrum (EI / DI) m / z: 268 (base).

(5) Production Example 5 5,7-Dimethoxy-4-oxo-2-phenyl-4H-1-benzopi
9.30 g of orchid-8- (N-aminoethyl) sulfonamide ethylenediamine was dissolved in 100 ml of chloroform, and the compound 1 of Production Example 1 was prepared while keeping the temperature at 0 to 5 ° C under ice cooling.
4.8 g was added and stirred for 1 hour. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was crystallized from ether to give the title compound as colorless prism crystals (5.20 g, 33.2%). Melting point: 83-84 ° C. IR spectrum (KBr) νcm ^-1 : 3100 (NH ₂ ), 1630 (C = O). ¹ H-NMR spectrum (CDCl ₃ ) δ _ppm : 2.66 to 3.17 (7H,
m, CH ₂ × 2, NH ₂ and NH), 4.02 (3H, s, OCH ₃ ), 4.07 (3
H, s, OCH ₃ ), 6.40 (1H, s, C ₆ -H), 6.68 (1H, s, C _3-
H), 7.33 ~ 7.56 (3H, m, ArH), 7.89 ~ 8.26 (2H, m, Ar
H). MS spectrum (EI / DI) m / z: 282 (base).

(6) Production Example 6 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-benzopi
Orchid-8- {N- [N '-(N "-benzyloxycarbonyl) glycy
[] Aminoethyl} sulfonamide N-benzyloxycarbonylglycine (1.00 g) and triethylamine (0.67 ml) were dissolved in anhydrous tetrahydrofuran (5.0 ml), and ethyl chloroformate (519 mg) was added while cooling to -15 ° C, followed by stirring for 5 minutes. 1.93 g of the compound of Production Example 5 dissolved in 10.0 ml of chloroform was added, and the mixture was stirred at -15 to -20 ° C for 15 minutes, 0 ° C for 30 minutes, and 20 ° C for 2 hours. The procedure of Production Example 2 was repeated to give 2.20 g (82.0%) of the title compound as a colorless amorphous substance. IR spectrum (KBr) νcm ^-1 : 1710 (CO of amide), 1625
(CO of benzopyran). ¹ H-NMR spectrum (CDCl ₃ ) δ _ppm : 2.96 to 3.67 (4H,
m, CH ₂ × 2), 3.83 (2H, d, J = 5.0Hz, CO CH ₂ NH), 3.97
(3H, s, OCH ₃ ), 4.00 (3H, s, OCH ₃ ), 5.06 (2H, s, C
H ₂ Ar), 5.77 (1H, t, J = 5.0Hz, NHCO), 6.07 ~ 6.43 (1H,
m, CONH), 6.35 (1H, s, C ₆ -H), 6.67 (1H, s, C ₃ -H),
6.76 ~ 7.53 (4H, m, SO ₂ NHand ArH), 7.23 (5H, s, Ar
H), 7.92-8.20 (2H, m, ArH). MS spectrum (EI / DI) m / z: 268 (base).

(7) Production Example 7 5,7-Dimethoxy-4-oxo-2-phenyl-4H-1-benzopi
Run-8- {N- [N'- (N "-benzyloxycarbonyl) -L-a
Ranyl] aminoethyl} sulfonamide In the same manner as in Production Example 6, except that N-benzyloxycarbonyl-L was used instead of N-benzyloxycarbonylglycine.
-The reaction was performed with 1.70 g of alanine to obtain 3.17 g (70.1%) of the title compound as a colorless amorphous substance. IR spectrum (KBr) νcm ^-1 : 1720 (CO of amide), 1640
(CO of benzopyran). ¹ H-NMR spectrum (CDCl ₃ ) δ _ppm : 1.68 (3H, d, J =
7.0Hz, CH ₃ ), 2.92 ~ 3.59 (4H, m, CH ₂ × 2), 3.93 (3H,
s, OCH ₃ ), 3.98 (3H, s, OCH3), 4.00 ~ 4.33 (1H, m,
COC H ( CH ₃ ) NH), 5.02 (2H, s, CH ₂ Ar), 5.70 (1H, d, J =
7.0Hz, NHCO), 6.17 ~ 6.43 (1H, m, CONH), 6.32 (1H, s,
C ₆ -H), 6.65 (1H, s, C ₃ -H), 6.92 ~ 7.53 (4H, m, SO
₂ NH and ArH), 7.22 (5H, s, ArH), 7.86 ~ 8.20 (2H, m,
ArH). MS spectrum (EI / DI) m / z: 108 (base).

(8) Production Example 8 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-benzopyr
Lan-8- [N- (N'-glycyl) aminoethyl] sulfonami
Dehydrobromide 25% While maintaining a 25% hydrogen bromide / acetic acid solution at 0 to 5 ° C. under ice cooling, 4.35 g of the compound of Production Example 6 was added, and the mixture was stirred for 30 minutes. 2
After stirring at 0 to 25 ° C for 2 hours, the reaction solution was poured into ether, and the precipitated crystals were collected by filtration and crystallized from methanol / ether to give the title compound as colorless powder crystals (5.05 g, 98.9%). Melting point: 155-160 ° C. IR spectrum (KBr) νcm ^-1 : 3000 (NH ₃ ⁺ ), 1680 (CO)
． ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 2.70 to 3.70 (6
H, m, CH ₂ × 2 and NH CH ₂ CO), 4.00 (3H, s, OCH ₃ ), 4.
10 (3H, s, OCH ₃ ), 6.67 (1H, s, C ₆ -H), 6.80 (1H, s,
C ₃ -H), 7.26 ~ 8.50 (9H, m, SO ₂ NH, CONH, NH ₂ and A
rH). MS spectrum (EI / DI) m / z: 254 (base).

(9) Production Example 9 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-benzopi
Lan-8- [N- (N'-L-alanyl) aminoethyl] sulfone
Hydromidyl hydrobromide In the same manner as in Production Example 8, except that the compound of Production Example 7 was replaced by 5.69 g of the compound of Production Example 6 to obtain 5.14 g (99.2%) of the title compound as colorless powder crystals. It was IR spectrum (KBr) νcm ^-1 : 3000 (NH ₃ ⁺ ), 1680 (CO)
． ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 1.35 (3H, d, J
= 6.0Hz, CH ₃ ), 2.76 ~ 3.50 (4H, m, CH ₂ × 2), 3.76,
~ 4.33 (1H, m, COC H ( CH ₃ ) NH), 4.00 (3H, s, OCH ₃ ),
4.13 (3H, s, OCH ₃ ), 6.70 (1H, s, C ₆ -H), 6.83 (1H,
s, C ₃ -H), 7.30 to 8.65 (10H, m, CONH, NH ₃ ⁺ , SO ₂ N
H ₂ and ArH). MS spectrum (EI / DI) m / z: 268 (base).

(10) Production Example 10 5,7-Dimethoxy-4-oxo-2-phenyl-4H-1-benzopyr
While maintaining 20.0 ml of a 28% aqueous solution of orchi- 8-sulfonamide in ice at 0 to 5 ° C., 7.00 g of the compound of Production Example 1 was added. At 20-25 ° C
After stirring for 14 hours, the precipitated crystals were separated by centrifugation, washed with water, and dried to give 7.10 g (75.3 g of the title compound as pale yellow powder crystals.
%) Obtained. Melting point: 230 ° C. IR spectrum (KBr) νcm ^-1 : 1640 (C = O). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 3.88 (3H, s, O
CH ₃ ), 3.95 (3H, s, OCH ₃ ), 6.58 (1H, s, C ₃ -H), 6.73
(1H, s, C ₆ -H), 6.86 ~ 8.50 (10H, m, ArH). MS spectrum (EI / DI) m / z: 361 (M ⁺ ), 282 (base).

(11) Production Example 11 5-hydroxy-7-methoxy-4-oxo-2-phenyl-4H-
1-Benzopyran-8-sulfonamide 7.10 g of the compound of Production Example 10 and 5.50 g of aluminum chloride were suspended in 100 ml of bromobenzene and heated under reflux for 1 hour. After distilling off bromobenzene, 10 ml of concentrated hydrochloric acid was added and the mixture was heated for 5 minutes. The reaction solution was concentrated and recrystallized from methanol to obtain 5.07 g (74.3%) of the title compound as pale yellow prism crystals. Melting point: 275-276 ° C. IR spectrum (KBr) νcm ^-1 : 1650 (CO). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 4.05 (3H, s, O
CH ₃ ), 6.68 (1H, s, C ₃ -H), 7.15 (1H, s, C ₆ -H), 7.26
~ 7.43 (2H, m, SO ₂ NH ₂ ), 7.43 ~ 7.76 (3H, m, ArH),
8.00 to 8.53 (2H, m, ArH), 13.00 to 14.00 (1H, m, OH). MS spectrum (EI / DI) m / z: 347 (M ⁺ , base).

(12) Production Example 12 5,7-dimethoxy-4-oxo-2- (3-chlorosulfonyl-4-
(Methoxy) phenyl-4H-1-benzopyran-8-sulfonyl
Chloride The same as in Preparation Example 1, except that 5,7-dimethoxy-4-oxo-2- (4-methoxy) was used instead of 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-benzopyran. The reaction was performed using 2.00 g of phenyl-4H-1-benzopyran to obtain 2.20 g (67.5%) of the title compound as pale yellow powder crystals. Melting point: 300 ° C or higher. IR spectrum (KBr) νcm ^-1 : 1345, 1160 (SO ₂ Cl). MS spectrum (EI / DI) m / z: 346 (M ⁺ -135), 72 (base)
．

(13) Production Example 13 5,7-Dimethoxy-4-oxo-2- [3- (N-ethoxycarbonione
Lumethyl) aminosulfonyl-4-methoxy] phenyl-4
H-1-benzopyran-8- (N-ethoxycarbonylmethyl) su
Rufonamide was prepared in the same manner as in Production Example 2, except that 3.00 g of the compound of Production Example 12 was used instead of the compound of Production Example 1, and the reaction was carried out on silica gel column chromatography (developing solvent: chloroform and chloroform / methanol (10: 1)). )
2.50 g (66.0 g) of the title compound as a colorless amorphous substance.
%) Obtained. IR spectrum (KBr) νcm ^-1 : 1740 (C = O), 1330 (SO ₂ NH)
． ¹ H-NMR spectrum (CDCl ₃ ) δ _ppm : 1.17 (3H, t, J =
7.0Hz, CH ₃ ), 3.77 to 4.17 (8H, m, CH ₂ × 4), 4.00, 4.
08 (9H, s × 2, OCH ₃ × 3), 5.80 (1H, t, J = 6.0Hz, SO ₂ N
H), 5.97 (1H, t, J = 6.0Hz, SO ₂ NH), 6.38 (1H, s, C _6-
H), 6.62 (1H, s, C ₃ -H), 7.07 (1H, d, J = 8.0Hz, ArH),
8.26-8.60 (2H, m, ArH). MS spectrum (EI / DI) m / z: 642 (M ⁺ ), 477 (base).

(14) Production Example 14 5,7-Dimethoxy-4-oxo-2- [3- (N-carboxymethyi)
) Aminosulfonyl -4-methoxy] phenyl-4H-1-be
Nzopyran-8- (N-carboxymethyl) sulfonamide In the same manner as in Production Example 3, except that 3.00 g of the compound of Production Example 13 was used instead of the compound of Production Example 2 to react the title compound as colorless powder crystals. 2.40 g (87.5%) was obtained. Melting point: 200-204 ° C. IR spectrum (KBr) νcm ^-1 : 1760 (C = O). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 3.70 (4H, d, J
= 5.0Hz, CH ₂ × 2), 3.93 (6H, s, OCH ₃ × 2), 4.03 (3H,
s, OCH ₃ ), 6.63 (1H, s, C ₆ -H), 6.68 (1H, s, C _3-
H), 7.50 (2H, m, COOH × 2), 7.32 (1H, d, J = 10.0Hz, A
rH), 7.58 (2H, d, J = 5.0Hz, SO ₂ NH x 2), 8.23 to 8.66
(2H, m, ArH). MS spectrum (EI / DI) m / z: 311 (M ⁺ -275), 64 (base).

(15) Production Example 15 5,7-dimethoxy-4-oxo-2- {3- {N- [N '-(aminoethyl
Ru) amido] methyl] aminosulfonyl-4-methoxy}
Phenyl-4H-1-benzopyran-8- {N- [N'- (aminoethyl
A) Amido] methyl} sulfonamide In the same manner as in Production Example 4, except that 3.00 g of the compound of Production Example 14 was used in place of the compound of Production Example 2 to react the title compound as pale yellow prism crystals in an amount of 2.19 g (70.1 %) Obtained. Melting point: 210-225 ° C. IR spectrum (KBr) νcm ^-1 : 3500 ~ 3400 (NH ₂ ), 1640
(CO). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 2.57 to 3.13 (8
H, m, CH ₂ × 4), 3.17 ~ 3.50 (6H, m, CONH × 2 and NH ₂
× 2), 3.73 (4H, d, J = 5.0Hz, NH CH ₂ CO × 2), 3.97, 4.
10 (9H, s, OCH ₃ × 3), 6.67 ~ 6.86 (2H, m, C ₃ -H and
C ₆ -H), 7.23 ~ 7.83 (3H, m, SO ₂ NH × 2 and ArH), 8.
33-8.65 (2H, m, ArH). MS spectrum (EI / DI) m / z: 312 (M ⁺ -358), 94 (base).

(16) Production Example 16 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-benzopyr
Run-8- {N- {2- {2- [2- (2-methoxyethoxy) ethoxy]
Ethoxy} ethyl}} sulfonamide 10.0 g of the compound of Production Example 1 and 2.54 g of anhydrous potassium carbonate were suspended in 100 ml of chloroform, and ice-cooled under an argon stream 0
While maintaining the temperature at -5 ° C, 30 ml of a chloroform solution containing 6.53 g of 2- {2- [2- (2-methoxyethoxy) ethoxy] ethoxy} ethylamine was added, and the mixture was stirred for 1 hour and then stirred at 30 ° C for 21 hours.
The insoluble matter was filtered and washed with chloroform, and the solvent was distilled off.
The residue was purified by silica gel column chromatography (developing solvent was ethyl acetate / methanol (9: 1)) to obtain 14.2 g (98.1%) of the title compound as a yellow oil. Melting point: 36-40 ° C. IR spectrum (KBr) νcm ^-1 : 3200 (SO ₂ NH), 1640 (CO),
1340,1135 (SO ₂ ). ¹ H-NMR spectrum (CDCl ₃ ) δ _ppm : 2.83 to 3.80 (16
H, m, CH ₂ × 8), 3.35 (3H, s, OCH ₃ ), 4.03, 4.10 (6
H, s × 2, OCH ₃ × 2), 5.96 (1H, t, J = 6.0Hz, NH), 6.4
3 (1H, s, C ₆ -H), 6.70 (1H, s, C ₃ -H), 7.30 ~ 7.63 (3
H, m, ArH), 7.90-8.27 (2H, m, ArH). MS spectrum (EI / DI) m / z: 551 (M ⁺ ), 208 (base).

(17) Production Example 17 5-hydroxy-7-methoxy-4-oxo-2-phenyl-4H-
1-benzopyran- 8- {N- {2- {2- [2- (2-methoxyethoxy)
[Ethoxy] ethoxy} Ethyl}} Sulfonamide In the same manner as in Production Example 11, except that 7.22 g of the compound of Production Example 16 was used instead of the compound of Production Example 10 for reaction, and silica gel column chromatography (developing solvent was ethyl acetate). And the title compound as yellow powder crystals in 5.9
0 g (83.4%) was obtained. Melting point: 97-100 ° C. IR spectrum (KBr) νcm ^-1 : 3300 (OH), 2870 (SO ₂ NH),
1640 (CO), 1330, 1150 (SO ₂ ). ¹ H-NMR spectrum (CDCl ₃ ) δ _ppm : 2.95 to 3.78 (16
H, m, CH ₂ × 8), 3.34, 4.03, (6H, s × 2, OCH ₃ × 2),
5.82 (1H, t, J = 6.0Hz, NH), 6.43 (1H, s, C ₆ -H), 6.73
(1H, s, C ₃ -H), 7.32 ~ 7.62 (3H, m, ArH), 7.97 ~ 8.2
6 (2H, m, ArH). MS spectrum (EI / DI) m / z: 537 (M ⁺ ), 268 (base).

(18) Production Example 18 2- (4-methoxy-3-sulfophenyl) -3,5,7-trimethoxy
2- (4-Methoxyphenyl) -3,5,7-trimethoxy-4-oxo-4H-1-while keeping 1.06 ml of cy -4-oxo-4H-1-benzopyransulfate at 0-5 ° C under ice cooling. 200 mg of benzopyran was added, and the mixture was stirred at 80 ° C for 2 hours. Pour the reaction mixture into ether and crystallize to give the title compound 2
Obtained 47 mg (quantitative). IR spectrum (KBr) νcm ^-1 ： 1220 (SO ₂ ). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 3.69, 3.79,
3.83 (12H, s × 3, OCH ₃ × 4), 6.38 (1H, d, J = 2.0Hz, C
₆ -H), 6.63 (1H, d, J = 2.0Hz, C ₈ -H), 7.09 (1H, d, J
= 9.0Hz, ArH), 7.11 (1H, s, SO ₃ H), 7.90 (1H, dd, J =
9.0, 2.0Hz, ArH), 8.31 (1H, d, J = 2.0Hz, ArH).

(19) Production Example 19 2- (3-chlorosulfonyl-4-methoxyphenyl) -3,5,7-
Trimethoxy-4-oxo-4H-1-benzopyran 33.7 g of the compound of Production Example 18 was dissolved in 392 ml of pyridine,
Ether was added and crystallized to obtain 39.7 g. Of these, 13.5
g was suspended in chloroform, 6.70 g of phosphorus pentachloride was added under an argon stream, and the mixture was stirred at 60 ° C. for 3 hours. Water was added under ice cooling, the chloroform layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off to give the title compound as an orange oily substance (7.40 g).
(64.9%) obtained. IR spectrum (KBr) νcm ^-1 ： 1220 (SO ₂ ). ¹ H-NMR spectrum (CDCl ₃ ) δ _ppm : 3.69, 3.79, 3.8
3 (12H, s × 3, OCH ₃ × 4), 6.25 (1H, d, J = 2.0Hz, C _6-
H), 6.43 (1H, d, J = 2.0Hz, C ₈ -H), 7.17 (1H, d, J = 9.
0Hz, ArH), 8.38 (1H, dd, J = 9.0, 2.0Hz, ArH), 8.53 (1
H, d, J = 2.0Hz, ArH).

(20) Production Example 20 2- [3- (N-ethoxycarbonylmethyl) aminosulfonyl
-4-Methoxyphenyl] -3,5,7-trimethoxy-4-oxy
So-4H-1-benzopyran In the same manner as in Production Example 2, except that 5.40 g of the compound of Production Example 19 was used instead of the compound of Production Example 1 for purification, and purified by silica gel column chromatography (developing solvent: ethyl acetate). The title compound as a yellow oil, 3.20 g (5
1.7%) was obtained. IR spectrum (KBr) νcm ^-1 : 1740 (CO). ¹ H-NMR spectrum (CDCl ₃ ) δ _ppm : 1.14 (3H, t, J =
7.0Hz, CH ₃ ), 3.73 ~ 3.97 (2H, m, NH CH ₂ ), 3.86, 3.9
0, 4.03 (12H, s × 3, OCH ₃ × 4), 4.04 (2H, q, J = 7.0Hz,
OCH ₂ ), 5.61 (1H, t, J = 5.5Hz, SO ₂ NH), 6.25 (1H, d,
J = 2.0Hz, C6 -H), 6.45 (1H, d, J = 2.0Hz, C ₈ -H), 7.05
(1H, d, J = 9.0Hz, ArH), 8.24 (1H, dd, J = 9.0, 2.0Hz, Ar
H), 8.43 (1H, d, J = 2.0Hz, ArH). MS spectrum (EI / DI) m / z: 507 (M ⁺ ), 342 (base).

(21) Production Example 21 2- [3- (N-ethoxycarbonylmethyl) aminosulfonyl
-4-Hydroxyphenyl] -5-hydroxy-3,7-dimeth
Xy-4-oxo-4H-1-benzopyran 150 mg of the compound of Production Example 20 was dissolved in methylene chloride, and -2
A solution of boron tribromide (0.11 ml) in methylene chloride was added while maintaining the temperature at 0 to -10 ° C. After stirring for 2 hours, water and chloroform were added for extraction, the organic layer was separated, dried and the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / methylene chloride (1: 1)) to give 82.0 mg (57.7%) of the title compound as yellow prism crystals.
%) Obtained. Melting point: 160-162 ° C. IR spectrum (KBr) νcm ^-1 : 1740 (CO). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 1.10 (3H, t, J
= 7.0Hz, CH ₃ ), 3.76 ~ 3.89 (2H, m, NH CH ₂ ), 3.79, 3.
83 (6H, s × 2, OCH ₃ × 2), 3.97 (2H, q, J = 7.0Hz, OCH
₂ ), 6.30 (1H, d, J = 2.0Hz, C ₆ -H), 6.64 (1H, d, J = 2.
0Hz, C ₈ -H), 7.13 (1H, d, J = 9.0Hz, ArH), 8.06 (1H, d
d, J = 9.0, 2.0Hz, ArH), 8.36 (1H, d, J = 2.0Hz, ArH), 1
1.33 (1H, s, OH). MS spectrum (EI / DI) m / z: 479 (M ⁺ ), 312 (base).

(22) Production Example 22 2- [3- (N-carboxymethyl) aminosulfonyl-4-hydr
Roxyphenyl] -5-hydroxy-3,7-dimethoxy-4-o
Xo-4H-1-benzopyran In the same manner as in Production Example 3, except that the compound of Production Example 21 was replaced with 46.0 mg of the compound of Production Example 21 to give the title compound as yellow prism crystals, 41.0 mg (95.0%) Obtained. Melting point: 231-234 ° C. IR spectrum (KBr) νcm ^-1 : 1700 (CO). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 3.59 to 4.00 (2
H, m, NH CH ₂ ), 3.79, 3.84 (6H, s × 2, OCH ₃ × 2), 6.3
1 (1H, d, J = 2.0Hz, C ₆ -H), 6.64 (1H, d, J = 2.0Hz, C
₈ -H), 7.10 (1H, d, J = 9.0Hz, ArH), 8.05 (1H, dd, J = 9.
0, 2.0Hz, ArH), 8.35 (1H, d, J = 2.0Hz, ArH), 12.59 (1
H, s, OH).

(23) Production Example 23 2- [3- (N-benzyl) aminosulfonyl-4-methoxyphene
Nyl] -3,5,7-trimethoxy-4-oxo-4H-1-benzopyra
The emissions benzylamine 3.12g dissolved in water 4.6 ml, under ice-cooling 0 ~
Chloroform solution of 5.00 g of the compound of Production Example 19 at 5 ° C 4
0.0 ml was added. After stirring for 2 hours, the mixture was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent was ethyl acetate) to give the title compound as brown prism crystals, 3.65 g (62.
9%) obtained. Melting point: 109-114 ° C. IR spectrum (KBr) νcm ^-1 : 1620 (CO). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 3.76, 3.83,
3.89 (12H, s × 3, OCH ₃ × 4), 4.10 (2H, d, J = 6.0Hz, NH C
H ₂ ), 6.43 (1H, d, J = 2.0Hz, C ₆ -H), 6.68 (1H, d, J =
2.0Hz, C ₈ -H), 7.13 (5H, s, ArH), 7.17 (1H, d, J = 9.0H
z, ArH), 8.10 (1H, dd, J = 9.0, 2.0Hz, ArH), 8.31 (1H,
d, J = 2.0Hz, ArH). MS spectrum (EI / DI) m / z: 511 (M ⁺ , base).

(24) Production Example 24 2- [3- (N-benzyl) aminosulfonyl-4-hydroxyphenyl group
[Ethyl] -5-hydroxy-3,7-dimethoxy-4-oxo-4H-
1-Benzopyran The compound of Production Example 23 (1.00 g) was dissolved in methylene chloride (26.0 ml), and the mixture was kept at 0-5 ° C. under ice-cooling while maintaining boron tribromide (0.60 m).
2.0 ml of methylene chloride solution of 1 was added and stirred for 40 minutes. Water was added for extraction, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (developing solvent: ether / hexane (2: 1)),
335 mg (35.4%) of the title compound was obtained as yellow prism crystals. Melting point: 174-177 ° C. IR spectrum (KBr) νcm ^-1 : 1660 (CO). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 3.80, 3.84, (6
H, s × 2, OCH ₃ × 2), 3.97 to 4.26 (2H, m, NH CH ₂ ), 6.
30 (1H, d, J = 2.0Hz, C ₆ -H), 6.61 (1H, d, J = 2.0Hz,
C ₈ -H), 7.06 (1H, d, J = 9.0Hz, ArH), 7.06 ~ 7.36 (5H,
m, ArH), 8.01 (1H, dd, J = 9.0, 2.0Hz, ArH), 8.31 (1H,
d, J = 2.0Hz, ArH), 10.33 (1H, s, OH), 12.63 (1H, s, O
H). MS spectrum (EI / DI) m / z: 483 (M ⁺ , base).

(25) Production Example 25 2- (3-aminosulfonyl-4-hydroxyphenyl) -5-hi
Droxy-3,7-dimethoxy-4-oxo-4H-1-benzopyra
Methanesulfonic acid compound 1.60g of emissions Preparation 24 6.70Ml
And was stirred with heating at 95 ° C for 10 minutes. The reaction solution was poured into ice water, and the precipitated crystals were collected by filtration and dried. Recrystallization from tetrahydrofuran / chloroform gave the title compound (810 mg). The mother liquor was purified by silica gel column chromatography (developing solvent: methanol / chloroform (2: 1)) to obtain 170 mg of the title compound. Together as a yellow prism crystal
Obtained 980 mg (75.3%). Melting point: 226-229 ° C. IR spectrum (KBr) νcm ^-1 : 1660 (CO). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 3.79, 3.83 (6
H, s × 2, OCH ₃ × 2), 6.33 (1H, d, J = 2.0Hz, C ₆ -H),
6.64 (1H, d, J = 2.0Hz, C ₈ -H), 6.83 ~ 7.23 (2H, br,
SO ₂ NH ₂ ), 7.12 (1H, d, J = 9.0Hz, ArH), 8.07 (1H, dd,
J = 9.0, 2.0Hz, ArH), 8.36 (1H, d, J = 2.0Hz, ArH), 12.
66 (1H, s, OH). MS spectrum (EI / DI) m / z: 393 (M ⁺ , base).

(26) Production Example 26 2- {3- {N- [5- (1,3-dihydro-1,3-dioxo-2H-isoin
Dol-2-yl)] pentyl} aminosulfonyl-4-meth
Xyphenyl} -3,5,7-trimethoxy-4-oxo-4H-1-be
Nzopyran In the same manner as in Preparation Example 23, except that 2- (5-aminopentyl) -1H-isoindole-1,3 (2
The reaction was carried out using 2.99 g of (H) -dione hydrochloride and purified by silica gel column chromatography (developing solvent: ethyl acetate) to obtain 4.07 g (62.6%) of the title compound as a yellow oil. IR spectrum (KBr) νcm ^-1 : 1710 (CO). ¹ H-NMR spectrum (CDCl ₃ ) δ _ppm : 1.33 to 2.00 (6H,
m, CH ₂ × 3), 2.94 (2H, q, J = 6.0Hz, SO ₂ NH CH ₂ ), 3.5
9 (2H, t, J = 6.0Hz, (CO) ₂ NH CH ₂ ), 3.87, 3.91, 4.05 (1
2H, s × 3, OCH ₃ × 4), 5.12 (1H, t, J = 6.0Hz, SO ₂ N
H), 6.25 (1H, d, J = 2.0Hz, C ₆ -H), 6.46 (1H, d, J = 2.0
Hz, C ₈ -H), 7.07 (1H, d, J = 9.0Hz, ArH), 7.46 ~ 7.86
(4H, m, ArH), 8.25 (1H, dd, J = 9.0, 2.0Hz, ArH), 8.45
(1H, d, J = 2.0Hz, ArH). MS spectrum (EI / DI) m / z: 636 (M ⁺ ), 231 (base).

(27) Production Example 27 2- {3- {N- [5- (1,3-dihydro-1,3-dioxo-2H-isoin
Dol-2-yl) pentyl]} aminosulfonyl-4-meth
Xyphenyl} -5-hydroxy-3,7-dimethoxy-4-oxy
So-4H-1-benzopyran In the same manner as in Production Example 24, except that 1.00 g of the compound of Production Example 26 was used instead of the compound of Production Example 23 for reaction, and silica gel column chromatography (developing solvent was ethyl acetate / chloroform ( 1: 5)) to give the title compound as a yellow oil (810 mg, 82.6%). IR spectrum (KBr) νcm ^-1 : 1710 (CO). ¹ H-NMR spectrum (CDCl ₃ ) δ _ppm : 1.17 to 2.00 (6H,
m, CH ₂ × 3), 2.90 (2H, q, J = 6.0Hz, SO ₂ NH CH ₂ ), 3.5
6 (2H, t, J = 6.0Hz, (CO) ₂ NH CH ₂ ), 3.83, 3.86, 4.06 (9
H, s × 3, OCH ₃ × 3), 4.97 (1H, t, J = 6.0Hz, SO ₂ N
H), 6.23 (1H, d, J = 2.0Hz, C ₆ -H), 6.38 (1H, d, J = 2.0
Hz, C ₈ -H), 7.07 (1H, d, J = 9.0Hz, ArH), 7.53 to 7.83
(4H, m, ArH), 8.24 (1H, dd, J = 9.0, 2.0Hz, ArH), 8.48
(1H, d, J = 2.0Hz, ArH), 12.43 (1H, s, OH). MS spectrum (EI / DI) m / z: 622 (M ⁺ ), 325 (base).

(28) Production Example 28 2- {3- [N- (5-aminopentyl)] aminosulfonyl-4-me
Toxyphenyl} -5-hydroxy-3,7-dimethoxy-4-o
Xo-4H-1-benzopyran hydrochloride 2.00 g of the compound of Production Example 27 was added to 2.0 ml of sulfuric acid, dioxane 2
Suspend in 0.0 ml and water (3.2 ml) and seal in a sealed tube at 150-160 ° C for 9
Stir for 0 hours. The reaction mixture was concentrated, water was added, the mixture was washed with chloroform, and the precipitated crystals were collected by filtration, extracted with saturated aqueous sodium hydrogen carbonate solution and methanol / chloroform (1: 4), dried over anhydrous sodium sulfate and the solvent was distilled off. Crystallize with methanol / hydrochloric acid and recrystallize with methanol / methyl ethyl ketone to give the title compound as pale brown prism crystals.
1.03 g (60.7%) was obtained. Melting point: 141-146 ° C. IR spectrum (KBr) νcm ^-1 : 1660 (CO). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 1.17 to 1.86 (6
H, m, CH ₂ × 3), 2.53 to 3.07 (4H, m, SO ₂ NH CH _{2 and} CO
NH CH ₂ ), 3.83, 3.86, 4.00 (9H, s × 3, OCH ₃ × 3), 6.
33 (1H, d, J = 2.0Hz, C ₆ -H), 6.66 (1H, d, J = 2.0Hz, C
₈ -H), 7.07 (1H, d, J = 9.0Hz, ArH), 8.20 (1H, dd, J = 9.
0, 2.0Hz, ArH), 8.41 (1H, d, J = 2.0Hz, ArH). MS spectrum (EI / DI) m / z: 492 (M ⁺ ), 129 (base).

(29) Production Example 29 5,7-dihydroxy-3-methoxy-2- (4-nitrophenyl)-
4-oxo-4H-1-benzopyran 1- (2,4,6-trihydroxyphenyl) -2-methoxy-1-ethanone (198 g), 4-nitrobenzoic anhydride (950 g), potassium 4-nitrobenzoate (308 g) were added to Dausam A2. Suspended in 0.001
The mixture was stirred at 185 to 195 ° C for 2 hours. N-hexane 1.
50 l was added, and the precipitated crystals were collected by filtration, washed with 3.50 l of n-hexane and then dissolved in 6.00 l of tetrahydrofuran. The insoluble matter was filtered off and the filtrate was concentrated to give the title compound as brown powder crystals.
92.9 g (28.2%) was obtained. Melting point: 250-255 ° C. IR spectrum (KBr) νcm ^-1 : 3500 〜 3300 (OH), 1650 (C
O). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 3.85 (3H, s, O
CH ₃ ), 6.12 (1H, d, J = 2.0Hz, C ₆ -H), 6.35 (1H, d, J =
_{2.0Hz, C 8 -H), 7.90} ~8.40 (4H, m, ArH), MS spectrum (EI / DI) m / z : 329 (M +, base).

(30) Production Example 30 3,5,7-trimethoxy-2- (4-nitrophenyl) -4-oxo-4
H-1-Benzopyran 80.0 g of the compound of Production Example 29 was suspended in 2.43 l of acetone, 205 g of dimethylsulfate and 516 g of anhydrous potassium carbonate were added, and the mixture was heated under reflux with stirring for 1.5 hours. The reaction solution was filtered, the residue was washed with hot chloroform, the filtrate was concentrated, and the precipitated crystals were filtered. This crystal was recrystallized from chloroform / methanol to give the title compound as yellow needle crystals, 71.4 g (82.3%)
Obtained. Melting point: 200-202 ° C. IR spectrum (KBr) νcm ^-1 : 1650 ~ 1630 (CO), 1515,13
45 (NO ₂ ). ¹ H-NMR spectrum (CDCl ₃ ) δ _ppm : 3.75 to 3.95 (9H,
s × 2, OCH ₃ × 3), 6.20 (1H, d, J = 2.0Hz, C ₆ -H), 6.37
(1H, d, J = 2.0Hz, C ₈ -H), 8.20 (4H, s, ArH). MS spectrum (EI / DI) m / z: 375 (M ⁺ , base).

(31) Production Example 31 3,5,7-trimethoxy-2- (4-nitrophenyl) -4-oxo-4
H-1-Benzopyran- 8-sulfonyl chloride In the same manner as in Production Example 1, except that 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-benzopyran was replaced by the compound of Production Example 30 (40.0 g). To give 48.0 g (94.1%) of the title compound as yellow powder crystals. Melting point: 130-133 ° C. IR spectrum (KBr) νcm ^-1 : 1650 (CO), 1410 (SO ₂ ), 13
45 (NO ₂ ). ¹ H-NMR spectrum (CF ₃ COOD) δ _ppm : 3.
87, 4.17, 4.27 (9H, s × 3, OCH ₃ × 3), 6.85 (1H, s,
C ₆ -H), 8.17 (2H, d, J = 8.0Hz, ArH), 8.47 (2H, d, J = 8.
0Hz, ArH). MS spectrum (EI / DI) m / z: 357 [(M-SO2 Cl + 1) ⁺ , bas
e].

(32) Production Example 32 3,5,7-trimethoxy-2- (4-nitrophenyl) -4-oxo-4
H-1-Benzopyran- 8-sulfonamide In the same manner as in Production Example 10, except that 45.0 g of the compound of Preparative Example 31 was used instead of the compound of Preparative Example 1, and the title compound was obtained as yellow powder crystals in an amount of 33.0 g ( 78.9%) obtained. Melting point: 238-240 ° C. IR spectrum (KBr) νcm ^-1 : 3600 ~ 3300 (NH ₂ ), 1640
〜1630 (CO), 1350〜1330 (SO ₂ , NO ₂ ). ¹ H-NMR spectrum (CF ₃ COOD) δ _ppm : 4.02, 4.33,
4.40 (9H, s × 3, OCH ₃ ), 7.02 (1H, s, C ₆ -H), 8.35 (2
H, d, J = 8.0Hz, ArH), 8.67 (2H, d, J = 8.0Hz, ArH). MS spectrum (EI / DI) m / z: 357 [(M-SO ₂ NH) ⁺ , base]
．

(33) Production Example 33 5-hydroxy-3,7-dimethoxy-2- (4-nitrophenyl)-
4-Oxo-4H-1-benzopyran-8-sulfonamide In the same manner as in Preparation Example 11, except that the compound of Preparation Example 32 was replaced by 800 mg of the compound of Preparation Example 10, and acetonitrile was replaced by bromobenzene. React using
Silica gel column chromatography (Developing solvent is dimethylformamide / methanol / chloroform (2: 1: 2
0)) to give 320 mg of the title compound as yellow needles.
(41.3%) was obtained. Melting point: 294-297 ° C. IR spectrum (KBr) νcm ^-1 : 1640 (CO). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 3.92, 4.03 (6
H, s × 2, OCH ₃ × 2), 6.66 (1H, s, C ₆ -H), 7.16 ~
7.40 (2H, m, SO ₂ NH ₂ ), 8.29 (2H, d, J = 9.0Hz, ArH),
8.53 (2H, d, J = 9.0Hz, ArH), 13.40 (1H, br, OH). MS spectrum (EI / DI) m / z: 422 (M ⁺ , base).

(34) Production Example 34 2- (4-aminophenyl) -3,5,7-trimethoxy-4-oxy
So-4H-1-benzopyran-8-sulfonamide 36.0 g of the compound of Production Example 32 was added to dimethylformamide 2.1.
Suspend in 0 l and stir for 1 hour at 80 ° C under argon flow, 50-
7.20 g of 10% palladium carbon was added at 55 ° C and under hydrogen flow 2
Stir for hours. The reaction solution was filtered, the mother liquor was concentrated, and the precipitated crystals were suspended in methanol, collected by filtration and dried to give the title compound as red powder crystals (30.3 g, 90.3%). Melting point: 238-242 ° C. IR spectrum (KBr) νcm ^-1 : 3500-3200 (NH ₂ ), 1630
~ 1600 (CO), 1340 (SO ₂ ). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 3.68, 3.92,
4.00 (9H, s × 3, OCH ₃ × 3), 6.53 (2H, d, J = 8.0Hz, Ar
H), 6.55 (1H, s, C ₆ -H), 7.00 ~ 7.23 (2H, br, SO ₂ N
H ₂ ), 7.97 (2H, d, J = 8.0Hz, ArH). MS spectrum (EI / DI) m / z: 327 [(M-SO ₂ NH) ⁺ , base]
．

(35) Production Example 35 2- (4-hydroxyphenyl) -3,5,7-trimethoxy-4-
Oxo-4H-1-benzopyran-8-sulfonamide 6.10 g of the compound of Production Example 34 was dissolved in 65% sulfuric acid to give -10 to
Aqueous solution of sodium nitrite 1.05g while keeping at -11 ℃ 1
5.0 ml was added. After stirring for 40 minutes, the reaction solution was poured into 675 ml of cold water and stirred at 70 to 75 ° C for 20 minutes. After cooling, the precipitated crystals were collected by filtration, washed with water and dried to give the title compound as red powder crystals.
Obtained 3.70 g (60.5%). Melting point: 248-251 ° C. IR spectrum (KBr) νcm ^-1 : 3500-3300 (NH ₂ ), 1630
~ 1600 (CO), 1345 (SO ₂ ). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 3.73, 3.97,
4.03 (9H, s × 3, OCH ₃ × 3), 6.63 (1H, s, C ₆ -H), 6.8
3 (2H, d, J = 9.0Hz, ArH), 6.97 ~ 7.40 (2H, br, SO ₂ NH
₂ ), 8.15 (2H, d, J = 9.0Hz, ArH). MS spectrum (EI / DI) m / z: 407 (M ⁺ ), 327 [(M-SO ₂ NH
₂ ) ⁺ , base].

(36) Production Example 36 5-hydroxy-2- (4-hydroxyphenyl) -3,7-dimeth
Xy-4-oxo-4H- 1-benzopyran-8-sulfonamide In the same manner as in Production Example 33, except that, instead of the compound in Production Example 32, 5.09 g of the compound in Production Example 35 was used to react.
Purification by silica gel column chromatography (developing solvent: chloroform / methanol (20: 1 → 10: 1)) gave 3.08 g (62.7%) of the title compound as yellow powder crystals. Melting point: 244-245 ° C. IR spectrum (KBr) νcm ^-1 : 3450 ~ 3300 (OH), 1640 (C
O). ¹ H-NMR spectrum (DMSO-d ₆ ) δ _ppm : 3.73, 3.90 (6
H, s × 2, OCH ₃ × 2), 6.50 (1H, s, C ₆ -H), 6.77 (2H,
d, J = 9.0Hz, ArH), 6.97 ~ 7.23 (2H, br, SO ₂ NH ₂ ),
8.10 (2H, d, J = 9.0Hz, ArH), 9.97 ~ 10.20 (1H, br, C
_{4 -OH), 13.60 ~13.80 (1H} , br, C 5 -OH). MS spectrum (EI / DI) m / z: 314 [(M-SO ₂ NH) ⁺ , base]
．

[0054]

[Example] (Example of drug efficacy test) In vitro anti-vaccinia virus action and cytotoxic action Vero cells (derived from African green monkey kidney) were cultured in a monolayer in a 96-well plate, and vaccinia virus (DIE
Strain) and the test compound were added and cultured for 3 days, and then the cytopathic effect (CPE) by the virus, the CPE inhibitory effect by the test compound and the cytotoxic effect by the test compound were observed under a microscope. T using virus-based CPE as an index
CID ₅₀ was calculated, and T of the test compound treated group and the untreated group was calculated.
ΔTCID ₅₀ (log ₁₀ ) was calculated from CID _50, and the antiviral effect of the test compound was evaluated.

Table 1 In Vitro Anti-Vaccinia Virus Action Test Compound Anti-viral Activity (ΔTCID ₅₀ (log ₁₀ )) Drug Concentration (μg / ml) 1 10 50 Production Example-11 1.80 (-)> 3.72 (-)> 3.72 ( +) Production example-22 0.10 (-) 2.82 (-)> 3.30 (+) Production example -25 0.00 (-) 1.30 (-) 2.30 (+) Production example-36 0.00 (-) 0.33 (-) 0.78 (+ ) In Table 1, the value in () indicates the degree of cytotoxicity, and (-)
Is no cytotoxicity, (±) is very mild cytotoxicity,
(+) Indicates that there is cytotoxicity, but antiviral activity can be observed.

It was revealed that the compound according to the present invention had a remarkable anti-vaccinia virus action and that the compound of Production Example 11 had weak cytotoxicity and strong selective toxicity.

2. In vitro anti-human adenovirus action and cytotoxic action Hela cells (derived from human uterine cancer) were cultured in a monolayer in a 96-well plate, human adenovirus type 3 and a test compound were added, and the cells were cultured for 4 days, followed by cytopathic change by virus. Effect (CP
E), CPE inhibitory effect of the test compound and cytotoxic effect of the test compound were observed under a microscope. Calculating the TCID ₅₀ of the CPE by the virus as an indicator, DerutaTCI from TCID ₅₀ treatment group and the untreated group of test compounds
D ₅₀ (log ₁₀ ) was determined and the antiviral action of the test compound was evaluated.

Table 2 In vitro anti-adenovirus action test compound Antiviral activity (ΔTCID ₅₀ (log ₁₀ )) Drug concentration (μg / ml) 1 10 50 Production Example-11 0.20 (-) 1.33 (-)> 3.30 (+) ) Production Example-22 0.00 (-) 1.57 (-) 1.57 (+) Production Example -25 0.00 (-) 0.80 (±) 1.25 (+) In Table 2, () indicates the cytotoxicity, (-)
Is no cytotoxicity, (±) is very mild cytotoxicity,
(+) Indicates that there is cytotoxicity, but antiviral activity can be observed.

The compound according to the present invention showed a remarkable inhibitory effect not only on vaccinia virus but also on human adenovirus lacking an envelope.

3. In vitro anti-influenza virus action and cytotoxic action MDCK cells (derived from dog kidney) were cultured in a monolayer in a 96-well plate, the influenza virus (A / PR / 8 strain) and a test compound were added, and the cells were cultured for 2 days, then the virus was added. The cytopathic effect (CPE) by the test compound, the CPE inhibitory effect by the test compound, and the cytotoxic effect by the test compound were observed under a microscope. TCID using CPE by virus as an index
₅₀ was calculated, and TCID of the test compound-treated group and the untreated group
DerutaTCID ₅₀ seek (log ₁₀₎ from _50, to evaluate the antiviral effect of the test compound.

Table 3 In vitro anti-influenza virus action test compound Antiviral activity (ΔTCID ₅₀ (log ₁₀ )) Drug concentration (μg / ml) 1 10 100 Preparation example -11 0.00 (-) 1.05 (-)> 3.30 (+ ) Production Example -22 0.00 (-) 0.55 (-) 1.57 (+) Production Example -25 0.00 (-) 0.80 (±) 1.25 (±) In Table 3, () indicates the cytotoxic strength, (-)
Is no cytotoxicity, (±) is very mild cytotoxicity,
(+) Indicates that there is cytotoxicity, but antiviral activity can be observed.

The compounds according to the present invention are not limited to vaccinia virus and adenovirus, which are DNA viruses, and RN.
It also showed a remarkable inhibitory effect against influenza virus which is A virus.

Formulation Example Formulation Example 1 (Ointment ) An ointment was prepared by the usual method according to the following formulation and filled in an aluminum tube. Compound of Production Example 11 3 g White petrolatum Appropriate amount 100 g

Formulation Example 2 (oral ointment) An oral ointment was prepared by the usual method according to the following formulation and filled in an aluminum tube. Compound of Preparation Example-22 0.3 g Carboxymethylcellulose (Na) 3.1 g Liquid paraffin 3.1 g White petrolatum 1.2 g Plastibase Suitable total 10 g

Formulation Example 3 (Capsules) Capsules having the following formulation were prepared by a conventional method. Production Example-25 compound 100 mg Magnesium stearate 5 mg Lactose Suitable amount Total 150 mg

Formulation Example 4 (tablet) A tablet was obtained by compounding with an excipient in the following formulation and tableting by a conventional method. Compound of Preparation Example-36 100 mg Sodium lauryl sulfate 10 mg Magnesium stearate 5 mg Polyvinylpyrrolidone K30 11 mg Carboxymethylcellulose (Ca) 7 mg Lactose 60 mg Corn starch Suitable total amount 210 mg

[0067]

INDUSTRIAL APPLICABILITY The novel flavone derivative of the present invention has an excellent antiviral activity and is effective as a preventive and therapeutic agent for infectious diseases caused by various DNA, RNA viruses and retroviruses. The flavone derivative of the present invention is
It has a broader spectrum of action and is more potent than conventional flavone derivatives. Further, these compounds, unlike existing flavone derivatives, are also effective against infectious diseases caused by viruses that are resistant to existing antiviral substances.
With the enhancement of antiviral activity, it became possible to extend the spectrum to viruses not present in the original compound or reduce cytotoxicity.

Front page continuation (72) Inventor Shuo Onishi, 35, Higashi Sotobori-cho, Higashi-ku, Nagoya City, Sanwa Chemical Research Institute Co., Ltd. (72) Inventor Kogaku Igaragawa, 35, Higashi Sotobori-cho, Higashi-ku, Nagoya (72) Inventor, Takahiko Mitani 35, Higashi-Tobori-cho, Higashi, Nagoya, Nagoya (72) Inventor Yoshiro Ishiwatari 35, Higashi Sotobori-cho, Higashi-ku, Nagoya City, Sanwa Chemical Research Institute Co., Ltd. (72) Inventor Hiroyuki Owaki 35, Higashi-Tohori-cho, Higashi-ku, Nagoya City Sanwa Chemical Research Co., Ltd. (72) Inventor, Kiichi Sawai Higashi-ku, Higashi-ku, Nagoya 35 Sotoboricho Sanwa Chemical Research Institute Co., Ltd.

Claims (7)

[Claims] 1. (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ ,
R ₈ , R ₉ and R ₁₀ are simultaneously or separately a hydroxyl group,
Mercapto group, halogen, formyl group, carboxyl group, sulfonic acid group, phosphonic acid group, nitro group, cyano group, optionally substituted amino, optionally substituted amide, optionally substituted alkyloxycarbonyl , Optionally substituted aryloxycarbonyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted acyl, optionally substituted alkyloxy, optionally substituted Arooloxy, optionally substituted alkylthio, optionally substituted arylthio, optionally substituted alkylsulfinyl, optionally substituted arylsulfinyl, optionally substituted alkylsulfonyl, optionally substituted Optionally arylsulfonyl, optionally substituted aryl Le aminosulfonyl, optionally substituted aryl aminosulfonyl means a heterocycle which may be substituted, amino example and may be substituted, formyl, hydroxy, alkoxy,
Aryloxy, halogen, nitro, cyano, thiol, alkylthio, arylthio, acyl, carbamoyl, alkylsilyl, arylsilyl, alkyloxycarbonyl, aryloxycarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfinyl,
Arylsulfinyl, which means substituted with phosphoric acid, phosphonic acid, phosphinic acid, phosphenic acid, sulfuric acid, sulfonic acid, sulfinic acid, sulfenic acid, boric acid and esters of these acids, etc. And, for example, condensed with a benzene ring, or pyridine which may be condensed with each other, piperidine, pyrazine, piperazine,
Pyrrole, pyrrolidine, oxazole, imidazole,
It means morpholine, diazole, triazole, tetrazole, thiazole, thiadiazole and the like. ) And a flavone derivative containing a salt thereof as a main component 2. The compound according to claim 1 is 5,7-dimethoxy
-4-oxo-2-phenyl-4H-1-benzopyran-8-sulfonyl chloride, 5,7-dimethoxy-4-oxo-2-phenyl
-4H-1-benzopyran-8- (N-ethoxycarbonylmethyl)
Sulfonamide, 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-benzopyran-8- (N-carboxymethyl) sulfonamide, 5,7-dimethoxy-4-oxo-2-phenyl-4H-
1-benzopyran-8- {N- [N '-(aminoethyl) amido] methyl} sulfonamide, 5,7-dimethoxy-4-oxo-2-
Phenyl-4H-1-benzopyran-8- (N-aminoethyl) sulfonamide, 5,7-dimethoxy-4-oxo-2-phenyl-4
H-1-benzopyran-8- {N- [N '-(N "-benzyloxycarbonyl) glycyl] aminoethyl} sulfonamide, 5,
7-Dimethoxy-4-oxo-2-phenyl-4H-1-benzopyran-8- {N- [N '-(N "-benzyloxycarbonyl) -L-alanyl] aminoethyl} sulfonamide, 5,7- Dimethoxy-4
-Oxo-2-phenyl-4H-1-benzopyran-8- [N- (N'-glycyl) aminoethyl] sulfonamide, 5,7-dimethoxy-4-oxo-2-phenyl-4H-1-benzopyran- 8- [N-
(N'-L-alanyl) aminoethyl] sulfonamide, 5,7-
Dimethoxy-4-oxo-2-phenyl-4H-1-benzopyran
-8-Sulfonamide, 5-hydroxy-7-methoxy-4-oxo-2-phenyl-4H-1-benzopyran-8-sulfonamide, 5,7-dimethoxy-4-oxo-2- (3-chlorosulfonyl)
-4-Methoxy) phenyl-4H-1-benzopyran-8-sulfonyl chloride, 5,7-dimethoxy-4-oxo-2- [3- (N-ethoxycarbonylmethyl) aminosulfonyl) -4-methoxy] phenyl- 4H-1-benzopyran-8- (N-ethoxycarbonylmethyl) sulfonamide, 5,7-dimethoxy-4-oxo-2- [3- (N-carboxymethyl) aminosulfonyl-4-
Methoxy] phenyl-4H-1-benzopyran-8- (N-carboxymethyl) sulfonamide, 5,7-dimethoxy-4-oxo
-2- {3- {N- [N '-(aminoethyl) amido] methyl] aminosulfonyl-4-methoxy} phenyl-4H-1-benzopyran
-8- {N- [N '-(aminoethyl) amido] methyl} sulfonamide, 5,7-dimethoxy-4-oxo-2-phenyl-4H-1
-Benzopyran-8- {N- {2- {2- [2- (2-methoxyethoxy)
Ethoxy] ethoxy} ethyl}} sulfonamide, 5-hydroxy-7-methoxy-4-oxo-2-phenyl-4H-1-benzopyran-8- {N- {2- {2- [2- (2-methoxy Ethoxy) ethoxy] ethoxy} ethyl}} sulfonamide, 2- (4-methoxy-3-sulfophenyl) -3,5,7-trimethoxy-4-oxo-4H-1-benzopyran, 2- (3-chlorosulfonyl) -Four-
Methoxyphenyl) -3,5,7-trimethoxy-4-oxo-4H-
1-benzopyran, 2- [3- (N-ethoxycarbonylmethyl)
Aminosulfonyl-4-methoxyphenyl] -3,5,7-trimethoxy-4-oxo-4H-1-benzopyran, 2- [3- (N-ethoxycarbonylmethyl) aminosulfonyl-4-hydroxyphenyl] -5- Hydroxy-3,7-dimethoxy-4-oxo
-4H-1-benzopyran, 2- [3- (N-carboxymethyl) aminosulfonyl-4-hydroxyphenyl] -5-hydroxy-
3,7-dimethoxy-4-oxo-4H-1-benzopyran, 2- [3-
(N-Benzyl) aminosulfonyl-4-methoxyphenyl]
-3,5,7-trimethoxy-4-oxo-4H-1-benzopyran, 2
-[3- (N-Benzyl) aminosulfonyl-4-hydroxyphenyl] -5-hydroxy-3,7-dimethoxy-4-oxo-4H-
1-benzopyran, 2- (3-aminosulfonyl-4-hydroxyphenyl) -5-hydroxy-3,7-dimethoxy-4-oxo
-4H-1-benzopyran, 2- {3- {N- [5- (1,3-dihydro-1,3-
Dioxo-2H-isoindol-2-yl)] pentyl} aminosulfonyl-4-methoxyphenyl} -3,5,7-trimethoxy-4-oxo-4H-1-benzopyran, 2- {3- {N- [ 5- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) pentyl]} aminosulfonyl-4-methoxyphenyl} -5-hydroxy-3,7-dimethoxy-4-oxo- 4H-1-benzopyran, 2- {3- [N- (5-aminopentyl)] aminosulfonyl
-4-Methoxyphenyl} -5-hydroxy-3,7-dimethoxy
-4-oxo-4H-1-benzopyran, 5,7-dihydroxy-3-
Methoxy-2- (4-nitrophenyl) -4-oxo-4H-1-benzopyran, 3,5,7-trimethoxy-2- (4-nitrophenyl) -4-
Oxo-4H-1-benzopyran, 3,5,7-trimethoxy-2- (4-
Nitrophenyl) -4-oxo-4H-1-benzopyran-8-sulfonyl chloride, 3,5,7-trimethoxy-2- (4-nitrophenyl) -4-oxo-4H-1-benzopyran-8-sulfonamide 5-hydroxy-3,7-dimethoxy-2- (4-nitrophenyl) -4-oxo-4H-1-benzopyran-8-sulfonamide,
2- (4-aminophenyl) -3,5,7-trimethoxy-4-oxo
-4H-1-benzopyran-8-sulfonamide, 2- (4-hydroxyphenyl) -3,5,7-trimethoxy-4-oxo-4H-1-benzopyran-8-sulfonamide, 5-hydroxy-2- An antiviral agent, which is a compound selected from (4-hydroxyphenyl) -3,7-dimethoxy-4-oxo-4H-1-benzopyran-8-sulfonamide and salts thereof. 3. The antiviral agent according to claim 1, which is used as a preventive agent and therapeutic agent for the onset of infectious diseases caused by various DNA viruses, RNA viruses and retroviruses. 4. The antiviral agent according to claim 1, which is used as a therapeutic agent for viral infections of the adenoviridae family. 5. The antiviral agent according to claim 1, which is used as a therapeutic agent for vaccinia virus infection. 6. The antiviral agent according to claim 1, which is used as a therapeutic agent for influenza virus infection. 7. An easily absorbable pharmaceutical composition comprising the antiviral compound according to claim 1 and a polyoxyethylene higher alcohol ether or a surface-active substance.