JPH02138277A - 5-aminoflavone derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I {R is H, lower alkyl, lower alkanoyl, amino, lower alkanoylamino or group shown by formula V [X is OH, mercapto, halogen or -NR<1>R<2>(R<1> nd R<2> are H, lower alkyl, lower alkanoyl or benzyl); n is 1-6]; Q is OH, lower alkoxyl, lower alkanoyloxy, halogen or group shown by formula VI (X<a>=X; m is 1-6); q is 0-3; Z<1> and Z<2> are H or Q} and a salt thereof. EXAMPLE:5-Amino-8-methoxy-2-phenyl-4H-henzopyran-4-one. USE:A drug having antitumor activity and being expected useful as antitumor agent. PREPARATION:A compound shown by formula II (R<3> is lower alkyl; L or OH- protecting group) is condensed with a compound shown by formula III in an inert solvent in the presence of a base to form a compound shown by formula IV, which is then deprotected in an inert solvent by using an acid to give a compound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to novel 5-aminoflavone derivatives having anti-cellular activity.

Background Art Among the derivatives of flavone (2-phenyl-4H-benzopyran-4-one) having an amino group at the 5-position, compounds in which the 6-position is hydroxyl are known [Chemical Abstracts 41, 12Of (1947)] ), but its anti-cellular activity is unknown.

Problems to be Solved by the Invention An object of the present invention is to provide novel 5-aminoflavone derivatives based on the new knowledge that 5-aminoflavone derivatives have anticellular activity.

Means for solving ma The present invention provides formula (1) (wherein R is hydrogen, lower alkyl, lower alkanoyl, amino, lower alkanoylamino and -(CL)n
In the formula Re,
Q represents a group selected from the group consisting of , x'' has the same meaning as the definition of X above, m is an integer of 1 to 6), q is an integer of 0 to 3, and ZI
and Z2 are the same or different and are hydrogen or have the same meaning as the definition of Q above. The same applies to compounds of other formula numbers] and pharmacologically acceptable salts thereof.

In the definition of each group in formula (1), the alkyl moiety in lower alkyl and lower alkoxyl is a linear or branched C1-C6 group, such as methyl, ethyl, propyl, isopropyl, butyl.

isobutyl, 5ec-butyl, tert-butyl,
Includes pentyl and hexyl. The alkanoyl moiety referred to in lower alkanoyl, lower alkanoylamino and lower alkanoyloxy is a linear or branched carbon atom having 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, isopropionyl, butyryl, imbutyryl,
Includes pivaloyl, valeryl, hexanoyl, and the like. Furthermore, halogen includes fluorine, chlorine, bromine, and iodine atoms.

The pharmacologically acceptable salts of compound (I) include pharmacologically acceptable acid addition salts, such as inorganic acid salts such as hydrochloride, hydrobromide, sulfate, and phosphate; Examples include organic acid salts such as salts, acetates, malonates, succinates, fumarates, maleates, tartrates, and citrates.

Next, a method for producing compound (I) will be explained.

In addition, in the production method shown below, if the defined group changes under the conditions of the method or is inappropriate for carrying out the method, methods commonly used in organic synthetic chemistry, such as protection of functional groups, This can be easily carried out by subjecting it to deprotection or other means.

Compound (I) can be produced according to the following reaction steps.

(In the formula, R3 represents lower alkyl, L means a hydroxyl protecting group, and R1, Zl, Z2 and q have the same meanings as above.) Here, the lower alkyl represented by R3 has the same meaning as above. , as a hydroxyl protecting group denoted as L,
Generally known protecting groups for phenols can be used, and for example, tetrahydropyranyl and methoxymethyl, which can be deprotected with a weak acid, are preferably used.

Step (1) Compound (IV) is an equivalent amount of compound (If).
) in an inert solvent in the presence of 1 to 5 equivalents of a base. Bases include sodium hydride, potassium hydride, sodium methoxide,
Sodium ethoxide, potassium tert-butoxide, etc. are used, and suitable inert solvents include tetrahydrofuran, dioxane, dimethylformamide, dimethoxyethane, methanol, ethanol, tert-butanol, toluene, etc. alone or in combination.

The reaction is usually carried out at a temperature of 40° C. to the boiling point of the solvent used, and is completed in 1 to 12 hours.

What is the starting material compound (n)?
7B Publication).

Step (2) Next, the compound (rV) obtained in step (1) is subjected to a deprotection reaction. At that time, compound (1) and/or compound (V) are produced depending on the type of compound or reaction conditions.

When the above-mentioned tetrahydropyranyl or methoxymethyl is used as a protecting group, the reaction can be carried out by converting the compound (rV) into lower alcohols such as methanol, ethanol, propatool, isopropanol, or dioxane, tetrahydro-7rane, etc. An inert solvent such as ethers alone or as a mixed solvent with water, using an acid or an acid diluted with water, usually 0.5 to IO at 0 to 50°C.
done in time. Acids include hydrochloric acid, sulfuric acid, acetic acid, and formic acid.

Examples include cichoic acid, and the concentration in the solvent is 0.1 to 2.
Regulation is preferred.

Step (3) The optimization reaction from compound (V) to compound (1) is performed using a method known as a flavone synthesis method [Bull, Chem.

Soc, Jpn, 60.1919 (1987)] acidic resin (Amberlyst 15; Rohm &
(manufactured by Haas).

The reaction is carried out by heating in an inert solvent using Amberlyst 15 in an amount of 0.2 to 5 times the weight of compound (V).

Inert solvents include benzene, toluene, chloroform, acetonitrile, ethanol, impropanol,
Dioxane, tetrahydrofuran, etc. are used alone or as a mixed solvent, and the temperature range from 60°C to the boiling point of the solvent is usually 2 to 2.
The reaction is completed in 20 hours.

Further, the cyclization reaction from compound (V) to compound (1) can be carried out under the same conditions as in step (2) using the same acid or an acid diluted with water.

Among the compounds (1) obtained here, further novel derivatives (1) can also be obtained by using them as synthetic intermediates.

In compound (1), if desired, a compound in which the 5th position is an amino group (R=H) [hereinafter referred to as compound (I a)] can be obtained by hydrolyzing a compound in which R is a lower alkanoyl group. Can be done.

For example, compound (I) in which R is a pivaloyl group and hydrochloric acid in an inert solvent that can be mixed with a lower alcohol or water,
It is usually carried out for 1 to 10 hours at 50° C. to the boiling point of the solvent.

Examples of lower alcohols include those described in step (2), and examples of inert solvents that are miscible with water include tetrahydrofuran, dioxane, dimethoxyethane, and the like. For hydrochloric acid, 4 to 1O normal is 0.1 of the solvent.
~1 times the capacity is used.

In compound (1), at least one of Q, Z' and Z2 is -0(C)1. >mX' (in the formula, m, !; Yohi 1- (CHz)mX' (Vr)(
In the formula, Hal represents a halogen such as chlorine, bromine, or iodine, and xm and m are as defined above) or optionally an acid addition salt thereof (e.g., hydrochloride, hydrobromide, sulfate, acetate, Triple oloacetate, $)-) luenesulfonate, etc. In the following description, similar addition salts are also referred to)) in the presence of an equivalent to excess base in an inert solvent at room temperature to 120°C for 1 to 24 hours. When Hal in compound (VT) is chlorine or bromine, the reaction may be accelerated by using 0.05 to 1 equivalent of sodium iodide or potassium iodide as a catalyst. Examples of the base include sodium hydride, potassium hydride, sodium carbonate, and potassium carbonate, and examples of the inert solvent include dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, and dioxane.

In addition, the compound (1) in which R is -(CL)nX (wherein X and n have the same meanings as above),
Compound (I a) and the compound represented by the following formula (■) Hal (CHi)nX (■) (wherein, X, H
(al and n have the same meanings as above) or optionally an acid addition salt thereof, under substantially the same conditions as in the reaction of compound (VT) described above.

Compound (1) in which R is amino [hereinafter,
Compound (1b>) can be obtained by diazotizing compound (Ia) with 1 to 2 equivalents of IJ nitrite under cooling in an acidic solvent, followed by reduction with a suitable reducing agent. As acidic solvents, acetic acid, hydrochloric acid, sulfuric acid, etc. are used alone or as a mixed solvent with water, and as suitable reducing agents, stannous chloride, zinc powder, iron powder, etc. are used, and it is recommended to use 1 to 5 equivalents. preferable. The diazotization reaction takes 0.1 to 2 hours at -15 to 5°C, and the reduction reaction takes place at 0°C.
~1 to 10 hours at room temperature, respectively.

A compound in which R is lower alkanoyl or lower alkanoylamino group in compound <1) can be obtained by heating the corresponding compound (Ia) or (Ib) in the corresponding lower aliphatic carboxylic acid. The reaction is carried out at a temperature of 0.5 to 1
It ends in 0 hours.

By appropriately combining the methods described above, a compound having a desired functional group at a desired position (
I) can be obtained.

The intermediates and target compounds in each of the above production methods can be isolated and purified by purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, drying, concentration, recrystallization, and various chromatography.

In addition, intermediates can be used in the next reaction without being particularly purified.

When you want to obtain a salt of compound (I), if compound (1) is obtained in the form of a salt, you can simply purify it as it is (or if it is obtained in a free form, you can form the salt by a conventional method. That's fine.

In addition, compound (I) and its pharmacologically acceptable salts are:
It may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention.

Specific examples of compound (1) obtained by the present invention are shown in Table 1.

Chapter 1 Table 1(Ll 2Q4) 3■ QS G21 7QT 18Q[D (q=0) (q=0) (q=0) (q=0) (rabbit 0) 3'-OCH.

4'-0CR.

3'-ROCH1 3'-0CHt, 4'-0Cfls 3'-QC)Is, 4'-ROC)+3 4'-0)1 4'-01(3'-0H 4'-(CH,) ffNcH,CH,03'-(CH
,), NC)1. cH203'-roH, 5'-Off 3'-roCH3,4'-0CII.

3'-roC)1. ．． 4'-OH, 5'-0C)I.

■ 190 2N21) H2'JCH-, 4'-OCH3H H3'-ROCHs, 5'-0CHa HH2
'-OH,4'-OHH H4'-ocL 8 Next, test examples will be shown regarding the anti-cell activity of the compounds obtained according to the present invention.

Test example Human colon cancer cell (WiKo) growth inhibition test; MEM medium (manufactured by Hinaga Pharmaceutical Co., Ltd.), 2mM in a 96-well microtiter plate
Glutamine, 10% tallow serum and 1% Non es
3 with a medium (hereinafter referred to as medium A) consisting of the Sential Amino Acids Kit (manufactured by Dainippon Pharmaceutical Co., Ltd.).
0.1 ml of WiDr cells prepared to x10 cells/ml
It was distributed to the University of the Arts. After culturing the plate in a carbon dioxide gas incubator at 37°C for 20 hours, 0.05 ml of the specimen (test compound) appropriately diluted with medium A was added.
The cells were cultured at 37° C. for 72 hours in a carbon dioxide gas incubator. After removing the culture supernatant, add 0.1 ml each of medium A and 0.02% neutral red to the residue.
Cultivate in a carbon dioxide incubator at 37°C for 1 hour,
Cells were stained. After removing the culture supernatant, the residue was washed once with physiological saline. Then, o, oot normal hydrochloric acid/30%
After extracting the dye with ethanol, the absorbance at 550 nm was measured using a microplate reader. Analyte concentration that inhibits cell proliferation by 50% (IC1°) by comparing the absorbance of untreated cells and cells treated with a known concentration of specimen.
was calculated.

The results are shown in Table 2.

Table 2 As seen in Table 2, compound (I) exhibits anti-cell activity and is expected to be used as an anti-tumor agent.

Examples and reference examples are shown below, and the obtained compounds (
The physicochemical properties of 1) are shown in Table 3.

Example 1 2-(4-hydroxy)phenyl-5-(N-pivaloyl)amino-4H-benzopyran-4-one (compound 1
1) Suspend 0.46 g of sodium hydride (60% oil) in 10 ml of dioxane, heat under reflux, and add 2.0 g of 2-nitoxyluponyl-N-pivaloyl-3-(2-tetrahydropyranyl)oxyaniline and A solution of 1.26 g of the compound a obtained in Reference Example 1 dissolved in 10 ml of dioxane was added dropwise, and the mixture was further heated under reflux for 3.5 hours. After cooling the reaction solution and adding water, it was extracted with ethyl acetate. The ethyl acetate layer was washed with water, anhydrous sulfuric acid, dried over IJum, and concentrated to obtain 3.3 g of an oil.

This product was dissolved in 30 ml of ethanol without purification, 1.9 ml of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 50 minutes. Brine was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed successively with 5% sodium bicarbonate solution and water, dried with anhydrous sulfuric acid, dried over IJum, and concentrated to obtain 1.80 g of an oily substance.

This also has 30ml of isopropanol without refining.
151.8 g of Amberlyst was added thereto, and the mixture was heated under reflux for 1 hour. The reaction solution from which Amberlyst 15 was removed by filtration was concentrated. The residue was dissolved in chloroform/acetone (
20/I V/V) as an eluent by silica gel column chromatography to obtain 0.56 g of the title compound (
A total yield of 29%) was obtained.

Example 2 5-amino-2-(4-hydroxy)phenyl-4H-
0.33 g of benzopyran-4-one (Compound 12> Compound 11 obtained in Example 1) was heated under reflux in 10 ml of ethanol and 5 ml of concentrated hydrochloric acid for 6 hours. 0.23 g of hydrochloride of the title compound (yield 77%)
I got it.

Example 3 5-amino-2-C3-hydroxy)phenyl-48-
Benzopyran-4-one (Compound 13) The title compound was obtained according to the method of Examples 1 and 2.

Example 4 5-amino-2-(3,5-dihydroxy)phenyl-
4H-benzopyran-4-one (compound 16) Example 1
The title compound was obtained according to method 2.

Example 5゜5-amino-2-(4-(2-dimethylaminoethyl)
oxy]phenyl-4H-benzopyran-4-one (compound 14) 100 mg of compound 12 obtained in Example 2 and N,
N-dimethylaminoethyl chloride hydrochloride 114mg
was suspended in 3 ml of dimethylformamide, 55K of sodium hydride (60% oil) was added, and the mixture was stirred at 50°C.

After 3 hours, 10 mg of sodium chloride and 15 kg of sodium iodide were added, and the mixture was further stirred at 50°C for 2.5 hours. Brine was added to the reaction solution and extracted with chloroform, and the chloroform layer was washed with water, dried over anhydrous sodium sulfate, and concentrated.

The residue was purified by silica gel thin layer chromatography using chloroform/methanol (4/IV/V) as a developing solvent to obtain 49 mg (yield 37.8%) of the title compound.

This product was made into a hydrochloride salt according to a conventional method.

Example 6゜5-amino-2-(3-(2-dimethylaminoethyl)
Oxy]phenyl-4H-benzopyran-4-one (Compound 15) Compound 13 obtained in Example 3 Example 5 from 150■
The title compound 78■ (yield 40.7%) was obtained according to the method described in .

Example 7 8-methoxy-2-(3,4-dimethoxy) phenyl-5-(N-pivaloyl)amino-4H-benzopyran-4-one (compound 9) Sodium hydride (60% oil) 0. Suspend 42 g in 5 ml of dioxane and heat under reflux to obtain 2 g of 2-ethoxycarbonyl-4-methoxy-N-pivaloyl-3-(2-tetrahydropyranyl)oxyaniline and 3.4-
A solution of 0.96 g of dimethoxyacetophenone in 6 ml of dioxane was added dropwise, and the mixture was further heated under reflux for 4 hours. After adding water to the reaction solution and extracting the oil with petroleum ether, the aqueous layer was neutralized with diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and concentrated to 1.93
g of oil was obtained.

This product was dissolved in 20 ml of ethanol without purification, 1.2+nl of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 40 minutes. The reaction solution was cooled and the precipitated crystals were filtered and washed with cold ethanol to obtain 0.66 g of the title compound (yield 42.8%).
) was obtained.

Example 8 5-amino-8-methoxy-2-(3,4-dimethoxy)phenyl-4H-benzopyran-4-one (compound 1
0) Dioxane 2 was added to 90.66 g of the compound obtained in Example 7.
0 ml and 10 ml of concentrated hydrochloric acid were added, and the mixture was heated under reflux for 7 hours. The reaction solution was cooled and the precipitated crystals were treated with P and washed with cold ethanol to obtain 0.49 g of the hydrochloride of the title compound (
A yield of 82.5%) was obtained.

Example 9 5-Amino-8-methoxy-2-phenyl-4H-benzopyran-4-one (Compound 5) According to the method of Examples 7 and 8, the title compound was obtained.

Example 10 5-Amino-8-methoxy-2-(3-methoxy)phenyl-4H-benzopyran-4-one (Compound 6) According to the method of Examples 7 and 8, the title compound was obtained.

Example 11 5-Amino-8-methoxy-2-(4-methoxy)phenyl-4H-benzopyran-4-one (Compound 7) According to the method of Examples 7 and 8, the title compound was obtained.

Example L 2゜5-amino-2-(3-methoxy)phenyl-4H-benzopyran-4-one (compound 8) 2.51 g of compound b obtained in Reference Example 2 was dissolved in 30 ml of isopropanol and Amberlyst 152. 5 g was added and heated under reflux for 1.5 hours. After removing Amberlyst 15 by filtration, the mixture was concentrated to obtain 2.47 g of an amorphous solid.

To 0.93 g of this, 20 ml of ethanol and 10+ nl of concentrated hydrochloric acid were added and heated under reflux for 7 hours. The reaction solution was cooled, and the precipitated solid was filtered out and washed with cold ethanol. This was recrystallized from ethanol-chloroform to obtain 0.41 g (yield 56.4%) of the hydrochloride salt of the title compound.

Example 13 5-amino-2-phenyl-4H-benzopyran-4-
(Compound 1) According to the method of Example 12, the title compound was obtained.

Example 14 5-hydrazino-2-phenyl-48-benzopyran-
4-one (compound 2) 1.00g of compound 1 obtained in Example 13 was dissolved in 20g of acetic acid.
A 3 ml aqueous solution of 0.35 g of sodium nitrite was added dropwise while cooling to about 10°C.

After stirring for 15 minutes at the same temperature, 1m2 chloride hydrate 2.
A solution of 37 g dissolved in 5 ml of concentrated hydrochloric acid was added dropwise, followed by stirring at room temperature for 1.5 hours. Pour the reaction solution into ice water 150a+1
The solids obtained were counted. Add this to 1 part saturated sodium bicarbonate solution
00ml and extracted with 200ml of ethyl acetate.

The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in chloroform/acetone (40/1 v/
v) as an eluent by silica gel column chromatography to obtain 0.44 g of the title compound (yield 41.6%).
) was obtained.

This product was made into a hydrochloride salt according to a conventional method.

Example 15 5-(2-dimethylaminoethyl)amino-2-7enyl-4H-benzopyran-4-one (Compound 3) Compound 1326 and N obtained in Example 13.

792 µ of N-dimethylaminoethyl chloride hydrochloride was suspended in 151 µ of tetrahydrofuran, 330 µ of sodium hydride (60% oil) was added at 0°C, and 30 mg of sodium iodide was added, followed by heating and stirring at 60°C for 7 hours. . The reaction solution was poured into an aqueous ammonium chloride solution and extracted with chloroform. Wash the chloroform layer with water and sulfuric anhydride)
After drying with U ram, it was concentrated. The residue was purified by silica gel column chromatography using chloroform/methanol (9/lV/V) as an eluent to obtain the title compound 63m.
g (yield 14.8%) was obtained.

This product was made into a hydrochloride salt according to a conventional method.

Example 16゜5-(N'-acetyl)hydrazino-2-7enyl-4
H-benzopyran-4-one (compound 4) Compound 256 obtained in Example 14 was dissolved in 1.5 ml of acetic acid.
The mixture was heated and stirred at 5°C for 2 hours.

The reaction solution was poured into water and extracted with chloroform. After washing the chloroform layer with water and saturated sodium bicarbonate solution, it was washed with anhydrous sulfuric acid)
It was dried with IJum and concentrated. The obtained solid was purified by silica gel thin layer chromatography using chloroform/methanol (9/1 v/v) as a developing solvent to obtain 45 mg (yield 68.9%) of the title compound.

Example 17゜5-amino-2-(3,4-dimethoxy)phenyl-4
H-benzopyran-4-one (compound IT) 0.46 g of sodium hydride (60% oil), 2.0 g of 2-ethoxycarbonyl-N-pivaloyl-3-(2-tetrahydropyranyl)oxyaniline and 3. 1-(3゜4-dimethoxy)phenyl-3-[2-
(2-tetrahydropyranyl)oxy-6-(N-pivaloyl)aminocophenylpropane-1,3-dione 2
．． 0! ig (yield 74.1%) was obtained.

This is ethanol 207! Dissolved in concentrated hydrochloric acid 1.2Wdl
was added and stirred at room temperature for 30 minutes. The crystals formed are separated, washed with ethanol, and 2-(3,4-dimethoxy)
Phenyl-5-(N-pivaloyl)amino-4H-benzopyran-4-one 499■ (yield 30.9%)
I got it.

Add this to 60ml of ethanol! 201 g of concentrated hydrochloric acid was added thereto, and the mixture was stirred under heating under reflux for 6 hours. The reaction solution was cooled and the resulting crystals were recrystallized from ethanol to obtain 174 ml of the hydrochloride salt of the title compound (yield: 39.7%).

Example 18 5-Amino-2-(3,5-dimethoxy-4-hydroxy)phenyl-4H-benzopyran-4-one (Compound 18) Sodium hydride (60% oil) 0.50 g, 2-ethoxy 1-(3,5 -dimethoxy-4-(2-
tetrahydropyranyl)oxy]phenyl-3-(2-
(2-tetrahydropyranyl)oxy-6-(N-pivaloyl)aminocophenylpropane-1,3-dione
2.38 g (yield 65.3%) was obtained.

2-(3,5-Simethoxy4-hydroxy)phenyl-5-(N-pivaloyl)amino-4H-benzopyran-4-one 1.1
1 g (67.8%) was obtained.

Furthermore, using this, 371,111 g (yield: 38.0%) of the hydrochloride of the title compound was obtained in the same manner as in Example 17.

Example 19゜5-amino-2-(2,4-dimethoxy)phenyl-4
H-benzopyran-4-one (compound 19) hydrogenation)
Reference example using 0.92 g of Qram (60% oil), 4.0 g of 2-nitoxycarbonyl-N-pivaloyl-3-(2-tetrahydropyranyl)oxyaniline and 2.06 g of 2.4-dimethoxyacetophenone. 1-(2,4-dimethoxy)phenyl-3-(2-
(2-tetrahydropyranyl)oxy-6-(N-pivaloyl)aminocophenylpropane-1,3-dione 4
．． 04g (yield 73.0%) was obtained.

Using this, 2-(2,4-dimethoxy)phenyl-5-(N-pivaloyl)amino-4 was prepared in the same manner as in Example 17.
H-benzopyran-4-one 664■ (yield 20.8
%) was obtained.

Using this, 482 mg (yield: 82.9%) of the hydrochloride of the title compound was obtained in the same manner as in Example 17.

Example 20゜5-amino-2-(3,5-dimethoxy)phenyl-4
H-benzopyran-4-one (compound 20) 0.46 g of sodium hydride (60% oil), 2.0 g of 2-ethoxycarbonyl-N-pivaloyl-3-(2-tetrahydropyranyl)oxyaniline and 3. 1-(3゜5-dimethoxy)phenyl-3-(2
2.01 g (yield 72.7%) of -(2-tetrahydropyranyl)oxy-6-(N-pivaloyl)aminocophenylpropane-1,3-dione was obtained.

Add this to 15al of ethanol! Concentrated hydrochloric acid was added thereto, and the mixture was stirred at room temperature for 1 hour. The resulting residue was purified by silica gel column chromatography using n-hexane/ethyl acetate (4/IV/V) as an eluent.
al., 2-(3,5-dimethoxy)phenyl-5-(
0.47 g (yield 29.6%) of N-pivaloyl)amino-4H-benzopyran-4-one was obtained.

Using this, 333 mg (yield: 81.2%) of the hydrochloride of the title compound was obtained in the same manner as in Example 17.

Example 21゜5-7 minnow 2-(2,4-dihydroxy)phenyl-
4H-Benzopyran-4-one (Compound 21) Sodium hydride (60% oil) 0.46 g, 2-ethoxycarbonyl-N-pivaloyl-3-(2-tetrahydropyranyl)oxyaniline 2.0 g and Reference Example 1-(2,4-dimethoxymethyloxy)phenyl-
3-[2-(2-tetrahydropyranyl)oxy-6-
(N-hi/<royl)aminocophenylpropane-1
, 3-dione (2.32 g (yield 74.7%)) was obtained.

Using 0.92 g of this, it was dissolved in 10-tetrahydrofuran, and concentrated hydrochloric acid 2rId! After stirring at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using chloroform/methanol (15/1 v/v) as an eluent to obtain 2-(2,4-
dihydroxy)phenyl-5-(N-pivaloyl)amino-4H-benzopyran-4-one 0.22 g (yield 3
6.4%).

Dissolve this in ethanol 45mN and make salt w120m!
was added and stirred for 4 hours under heating under reflux. The crystals obtained by cooling the reaction solution were mixed with chloroform/methanol/water (80/
The title compound 145ag (yield: 86.9%) was obtained by purification by silica gel column chromatography using 30/3 v/v/v) as an elution solvent.

Example 22 5-Amino-2-(4-methoxy)phenyl-4H-benzopyran-4-one (Compound 22) Sodium hydride (60% oil) 0.27 g, 2-ethoxycarbonyl-N-pivaloyl- 3-(2-tetrahydropyranyl)
1-(4-
methoxy)phenyl-3-[2-(2-tetrahydropyranyl)oxy-6-(N-pivaloyl)aminocophenylpropane-1,3-dione 0.50 g (yield 32
．． 1%).

Using 0.4g of this, 2-(4
0.39 g of -methoxy)phenyl-5-(N-pivaloyl)amino-4H-benzopyran-4-one was obtained.

Dissolve this in 10InIl of dioxane, add 5al of concentrated hydrochloric acid
! was added and stirred for 5.5 hours under heating and reflux. After concentrating the reaction solution under reduced pressure, chloroform/methanol (40/1 v/v)
The product was purified by silica gel column chromatography using as an elution solvent, and then recrystallized from ethyl acetate-n-hexane to obtain the title compound 142a+g (yield 47.9%).

Example 23゜5-amino-2-(4-bromo)phenyl-4H-benzopyran-4-one (compound 23) Sodium hydride (
60% oil) was suspended in 1 ml of toluene, and a toluene solution of 500 mg of 2-ethoxycarbonyl-N-pivaloyl-3-(2-tetrahydropyranyl)oxyaniline and 285 μl of 4-bromoacetophenone was added.
The mixture was stirred at ℃ for 45 minutes. Ethyl acetate was added to the reaction mixture, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using n-hexane/ethyl acetate (4/IV/V) as an eluent to obtain 1-(4-bromo)phenyl-3-C2-(2-tetrahydropyranyl)oxy6.
-(N-pivaloyl)aminocophenylpropane-1,
491 ml of 3-dione (yield 69.5%) was obtained.

This was dissolved in a mixed solvent of 10 ml of isopropanol and 10 tt' of ethanol using 233 ml, and 25 hg of Amberlyst 15 was added thereto, followed by stirring under heating under reflux for 7 hours.

After filtering the reaction solution, it was concentrated under reduced pressure, and the residue was recrystallized from chloroform-ether-n-hexane and 2-(4-bromo)phenyl-5-(N-pivaloyl)amino-4H.
-benzopyran-4-one 181.5■ (yield 96.1
%) was obtained.

Using 100 mg of this product, 52.4 mg (yield 57.2%) of the hydrochloride of the title compound was obtained in the same manner as in Example 17.

Reference Example 1 1-acetyl-4-(2-tetrahydropyranyl)oxybenzene (compound a) 10.0 g of 4-acetylphenol, 1 ml of 2,3-dihydropyran L O and pyridium-p-)luenesulfonic acid 1.5 g in 150 ml of methylene chloride 4.
The mixture was heated and stirred for 5 hours. Cool the reaction solution and add water, 5% sodium bicarbonate solution,
After washing once each with water, the methylene chloride layer was decolorized with activated carbon and then dried with anhydrous sulfuric acid. After filtration, the solvent was concentrated, and the residue was crystallized from hexane to obtain 13.6 g (yield: 84.2%) of the title compound.

NMR (CDCJ3) δ (ppm): 1.65-1
．． 94 (6H, +n), 2.55 (3H, s), 3
．． 61-3.90 (3H, m), 5.51 (IH, b
rs), 7.07 (2H, d, J=9.0Hz).

7, 91 (21(,d, J=9.0f(z) Reference example 2゜1-(3-methoxy)phenyl-3-(2-(2-tetrahydropyranyl)oxy-6-(N-hibaloyl) ) Aminocophenylpropane-1,3-dione (compound b) Hydrogenation) 0.34 g of IJium (60% oil) was suspended in 31 nIl of dioxane and heated under reflux to form 2-ethoxycarbonyl-N-pivaloyl-3. - 1.50 g of (2-tetrahydropyranyl)oxyaniline and 0.64 g of 3-methoxyacetophenone in dioxane solution 4d
was titrated and further heated under reflux for 30 minutes. Water was added to the reaction solution and washed with petroleum ether, and ethyl acetate was added to the aqueous layer for extraction. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using n-hexane/ethyl acetate (3/1 v/v) as an eluent to obtain 0.95 g (yield: 48.8%) of the title compound.

NMR (C-cps'> δ (ppm)
: 1.29 (9H, s), 1.5 to 1.
83(6)1. a+), 3.57-3.86 (21
(,m), 3.86(31(.

s), 5.5H1)1. b), 6.86 (1N,
s), 6.94 (IH, dd).

7.03 (IH, dd>, 7.26~7.53 (4H
, m), 8.09(1)1゜dd), 10.09(
18, s), 16.10 (1) 1. b) Reference Example 3 3.5-Dimethoxy-4-(2-tetrahydroxypyranyl)oxyacetophenone (Compound C) 5.0 g of 3.5-dimethoxy-4-hydroxyacetophenone was dissolved in 50 ml of methylene chloride. 3=dihydropyran4.
65- and pyridinium-p-toluenesulfonic acid 0
．． 52 g was added and stirred for 16.5 hours under heating and reflux. The reaction solution was washed with 5% aqueous sodium bicarbonate and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was diluted with n-hexane/
The title compound 1. was purified by silica gel column chromatography using ethyl acetate (2/1 v/v) as an eluent.
75 g (yield 24.5%) was obtained.

NMR (CDCfs) δ (ppm): 1
．． 64-2.04 (6H, m).

2.57(3)1. s), 3.90 (6H, s),
3.48-3.79 (2H.

m), 5.58 (IH, b), 7.22 (2H, s
) Reference Example 4 2.4-dimethoxymethyloxyacetophenone (compound d) Purification was performed by silica gel column chromatography using san/ethyl acetate (4/l to 3/1 v/v) as an eluent to obtain 3.80 g of the title compound ( A yield of 80.2%) was obtained.

NMR (CDIJ 3) δ (ppm): 2
．． 6G (3H, s), 3.48 (3H, s), 3.
52 (3H, s), 5.19 (2H, s), 5.2
6 (2H, s), 6.65-6.83 (2H, m),
7.77 (18, d) Effects of the Invention According to the present invention, compound (I) and its pharmacologically acceptable salts have anti-cell activity and are expected to be used as anti-tumor agents.

3.0 g of 2.4-dihydroxyacetophenone was dissolved in 50% of tetrahydrofuran, 3.3 d# of chloromethyl methyl ether and 1.73 g of sodium hydride (60% oil) were added under water cooling, and the mixture was stirred for 1 hour under water cooling. The reaction solution was poured into ice water and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
Written amendment to n-hex procedure (voluntary) October 6, 1999 1, Description of the case 1999 Patent Application No. 212811 2, Title of the invention 5-aminoflavone derivative 3, Person making the amendment Relationship Patent applicant postal code 100 Address 6-1 Otemachi-chome, Chiyoda-ku, Tokyo Name (10
2) Add "dichloromethane" after Kyowa Hakko Kogyo Co., Ltd. (03-282-0036).

(2) In the same book, "Compound C" on page 27, line 13 is corrected to "Compound C."

(3) In the same book, add "rl 15 mg" after "sodium hydride (60% oil)" in the first line from the bottom of page 32.

(4) In the same book, on page 42, lines 9 to 10, "2-tetrahydroxypyranyl" is corrected to "2-tetrahydropyranyl."

(5) In the same book, page 43, lines 6-7, r3.90 (6
8゜s), 3.48~3.79 (2H, m) J
r3.48~3.79 (2H, m), 3.9
0 (6H, S) Correct to J.

Detailed description of the invention in the specification 5. Contents of correction

Claims (1)

[Claims] Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R is hydrogen, lower alkyl, lower alkanoyl, amino, lower alkanoylamino and -(CH_2
) nX [wherein X is hydroxyl, mercapto, halogen and -NR^1R^2 (wherein, R^1 and R^
2 are the same or different and represent hydrogen, lower alkyl, lower alkanoyl, or benzyl, and n is an integer of 1 to 6, and Q is the same or Differently, from hydroxyl, lower alkoxyl, lower alkanoyloxy, halogen and -O(CH_2)mX^a (wherein X^a has the same meaning as the definition of X above, and m is an integer from 1 to 6) 5-aminoflavone (represents a group selected from the group consisting of Derivatives and pharmacologically acceptable salts thereof.