JPH1180141A - Diphenyl compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new diphenyl compound showing antitumor activity, useful as an antitumor agent for treating various tumors. SOLUTION: This compound is shown by formula I [X is 0, S or NR<4> (R<4> is H or an alkyl); Y is a ketone group or OH; R<1> is nitro or amino; R<2> and R<3> are each H, OH, a halogen, nitro, amino, an alkoxy or an alkyl; R<5> and R<6> are each H or an alkyl], its salt, its hydrate such as (2-morpholino-5- nitrophenyl)phenylmethanone. The compound of the formula I is obtained, for example, by converting a halogenonitrobenzoic acid into an acid chloride, then subjecting the acid chloride to Friedel-Crafts reaction with any of various substituted benzene derivatives to give a benzophenone compound of formula II, then reacting the compound with any of various alicyclic amino compounds to give a nitrogen-containing heterocyclic group-containing benzophenone compound and further carrying out a reduction or an alkylation so as to give a fixed substituent group.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel compound having an antitumor effect.

[0002]

BACKGROUND OF THE INVENTION Antitumor drugs often acquire resistance and continue to be less effective when administered for treatment. Therefore, there is a need for the development of antitumor agents having a novel structure, skeleton, and novel mechanism of action. The present inventors have conducted intensive studies to find an antitumor agent having a novel structure and mode of action. As a result, they have found that a compound having a structure represented by the following general formula (I) has a strong antitumor effect, and have completed the present invention. Regarding benzophenone compounds, there are reports of immunomodulatory effects (US Pat.
528, 294), and there is no report on the antitumor effect.

[0003]

That is, the present invention provides a compound having a structure represented by the general formula (I), a salt thereof, a hydrate thereof, and a method for producing the same.

[0004]

Embedded image (Wherein X is an oxygen atom, a sulfur atom, or a structure

[0005]

Embedded image means> N-R ^4, Y means a keto group (= O), or a hydroxyl group, bond indicated by the dotted line forms a double bond (between C = O) A bond or forms a bond (—H) with a hydrogen atom (attached to the carbon atom to which Y is attached). R
¹ represents a nitro group or an amino group; R ² and R ³ each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, a nitro group, an amino group, an alkoxyl group having 1 to 6 carbon atoms, or a carbon number It means 1 to 6 alkylamino groups. R ⁴ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the alkyl group has a hydroxyl group, a carboxyl group, an amino group, or an alkoxyl group having 1 to 6 carbon atoms as a substituent. You may. R ⁵ and R ⁶ are each independently a hydrogen atom, or a group having 1 to 6 carbon atoms.
Means an alkyl group. Further, the present invention provides a compound having a structure of the following formula, a salt thereof, and a hydrate thereof:

[0006]

Embedded image (Wherein X is an oxygen atom, a sulfur atom, or a structure

[0007]

Embedded image means> ^{N-R 4, R 1} denotes a nitro group or an amino group,, ^{R 2} and ^{R 3} are each independently a hydrogen atom, a hydroxyl group, a halogen atom, a nitro group, an amino Group, an alkoxyl group having 1 to 6 carbon atoms, or an alkylamino group having 1 to 6 carbon atoms. R ⁴ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the alkyl group has a hydroxyl group, a carboxyl group, an amino group, or an alkoxyl group having 1 to 6 carbon atoms as a substituent. You may. R ⁵ and R ⁶ each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. ); X is
The above-mentioned compound which is an oxygen atom or a sulfur atom, a salt thereof, and a hydrate thereof; the above-mentioned compound, wherein the substituent R ¹ is a nitro group, a salt thereof, and a hydrate thereof; a substituent R ² or The above compound, wherein one of R ³ is a halogen atom, a salt thereof, and a hydrate thereof; the above compound, wherein the halogen atom is a chlorine atom, a salt thereof, and a hydrate thereof; (2-morpholino- 5-nitrophenyl) phenylmethanone [in the formula (I), X is an oxygen atom;
= Keto group; R ¹ = nitro group; R ² , R ³ , R ⁵ and R
⁶ is a hydrogen atom], a salt thereof, and a hydrate thereof; (2-morpholino-5-nitrophenyl) (4-chlorophenyl) methanone [in the formula (I), X is an oxygen atom; Y is a keto group. R ¹ = nitro group; one of R ^{2 and} R ³ is a 4-chloro atom and the other is a hydrogen atom; both R ⁵ and R ⁶ are hydrogen atoms], salts thereof, and hydrates thereof; -Thiomorpholino-5-nitrophenyl) phenylmethanone [in the formula (I), X = sulfur atom; Y
= Keto group; R ¹ = nitro group; R ² , R ³ , R ⁵ and R
⁶ is a hydrogen atom], a salt thereof, and a hydrate thereof; (2-thiomorpholino-5-nitrophenyl) (4
-Chlorophenyl) methanone [in the formula (I), X =
Sulfur atom; Y = keto group; R ¹ = nitro group; R ² or R
³ is a 4-chloro atom and the other is a hydrogen atom; R ⁵ and R ⁶ are both hydrogen atoms], salts thereof, and hydrates thereof.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The substituent and the structure of the compound of the present invention will be described. R ¹ is a nitro group or an amino group, preferably a nitro group. R ² and R ³ are each independently a hydrogen atom, a hydroxyl group, a halogen atom, a nitro group, an amino group, an alkoxyl group having 1 to 6 carbon atoms, or an alkylamino group having 1 to 6 carbon atoms. Among these, the alkyl group of the alkoxyl group or the alkylamino group may be linear or branched.
Preferably, one of R ² and R ³ is a hydrogen atom, and the other is a halogen atom, an alkyl group, or an alkoxyl group. The alkyl group and the alkyl group of the alkoxyl group may have 1 to 6 carbon atoms, and may be any of linear, branched or cyclic (when having 3 or more carbon atoms). R ² and R ³ represent a hydrogen atom, a fluorine atom,
A chlorine atom, a methyl group, or a methoxyl group is preferred.

X represents an oxygen atom, a sulfur atom, or a structure

[0010]

Embedded image> NR ⁴ (This “>” indicates that two single bonds are bonded to the nitrogen atom.) That is, the cyclic substituent moiety containing X is a six-membered heterocyclic substituent having at least one nitrogen atom. The ring is preferably a six-membered ring, but may be a five-membered ring or a seven-membered ring. X is the structure

[0011]

When> NR ⁴ , R ⁴ is a hydrogen atom or an alkyl group.
This alkyl group may be linear or branched. The alkyl group may have a hydroxyl group, a carboxyl group, an amino group, or an alkoxyl group having 1 to 6 carbon atoms as a substituent. The position where these substituents are bonded may be any position of the alkyl group,
Those at the ends are more preferred. R ⁵ and R ⁶ each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. This alkyl group has 1 to 6 carbon atoms,
It may be linear, branched or cyclic (in the case of 3 or more carbon atoms). As R ⁵ and R ⁶ , when both are hydrogen atoms, it is preferable that one is a hydrogen atom and the other is a methyl group. Also, when these are alkyl groups,
The substitution position is not particularly limited, and may be at any position on the ring.

X is preferably an oxygen atom or a sulfur atom. In these cases, the portion has an ether or thioether structure, that is, the X portion preferably has a structure that enhances lipophilicity. On the other hand, a structure having a three-dimensionally smaller bulk is preferable.

Y is a keto group (＝ O) or a hydroxyl group, preferably a keto group. That is, as the compound (I), a compound having a benzophenone structure is preferable. Therefore, as the compound of the present application, a compound having a structure having a nitrogen-containing heterocyclic substituent in one phenyl group of benzophenone is preferable. In this part, when the bond shown by the dotted line becomes a single bond to form a double bond, the Y portion forms a keto group, and when the bond shown by the dotted line becomes a bond with a hydrogen atom, The Y portion becomes a hydroxyl group. The compounds of the present application include those having the following structures.

[0014]

Embedded image

The compound of the present invention can be produced by various methods. A typical production method is shown below.

[0016]

Embedded image

That is, halogenonitrobenzoic acid (I
After I) is converted to an acid chloride, the compound is subjected to a Friedel-Crafts reaction with various substituted benzene derivatives to obtain a benzophenone compound (III), which is reacted with various alicyclic amino compounds to obtain a nitrogen-containing heterocyclic group-containing compound. A benzophenone compound can be obtained. The compound (I) in which R ¹ is a nitro group and Y is a keto group is obtained by reducing one or both of the nitro group and the keto group, if desired.
¹ is an amino group, Y is a keto group (I); R ¹ is a nitro group, Y is a hydroxyl compound (I); and R ¹ is an amino group and Y is a hydroxyl compound (I). Can be obtained. Further, the compound obtained by reacting the ketone compound (III) with piperazine as an alicyclic amino compound is further alkylated at the nitrogen atom of piperazine, so that the nitrogen atom at the 4-position can be substituted with various substituents. An alkyl group which may have a group can be introduced. In addition,
When reacting piperazine, one nitrogen atom may be protected by a commonly used protecting group, or may have an alkyl group having various substituents. In this case, the substituent on the alkyl group may be appropriately protected.

The solvent used in these reactions is not particularly limited as long as it is inert to the reaction. Examples thereof include halogenated hydrocarbon solvents such as dichloromethane, carbon tetrachloride and chloroform; diethyl ether, tetrahydrofuran, Ether solvents such as dioxane; N, N-
Examples thereof include amide solvents such as dimethylformamide, acetamide, and dimethylacetamide. In reactions other than the Friedel-Crafts reaction, in addition to the above-described solvents, alcohol solvents such as methanol, ethanol, and isopropanol; and aromatic hydrocarbon solvents such as benzene, toluene, and xylene can also be used. In practice, these solvents may be appropriately selected and used depending on the characteristics of the reaction. In the Friedel-Crafts reaction,
Usually, an acid catalyst that can be used in this reaction may be used, and examples thereof include aluminum chloride, zinc chloride, and boron fluoride. The reduction reaction includes reduction using a metal hydride compound such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, etc., as well as tin (II) chloride (S) in alcohol.
nCl ₂ ), acid and zinc,
Then, a method by catalytic hydrogenation in the presence of a metal catalyst such as palladium, Raney nickel, and platinum oxide can be used. The alkylation reaction is preferably performed in the presence of a base, and the base may be either an organic base or an inorganic base. Examples of the base include carbonates such as anhydrous sodium carbonate and anhydrous potassium carbonate, and alkoxides such as sodium methoxide and potassium t-butoxide. The reaction time may be in the range of 1 minute to 72 hours, and is usually completed in 10 to 48 hours.

Representative reaction conditions are described below. The reaction between the halogenonitrobenzoic acid derivative (II) and various benzene derivatives is carried out by first treating the benzoic acid derivative (II) with a chlorinating reagent such as thionyl chloride or phosphorus trichloride in a conventional manner to obtain an acid chloride. . This acid chloride is then
In the presence of aluminum chloride and the like in halogenated hydrocarbon solvents such as dichloromethane, carbon tetrachloride and chloroform,
The ketone compound (III) can be obtained by adding various benzene derivatives. The reaction temperature is -2
Although it may be in the range of 0 to 100 ° C, it is usually carried out in the range of 5 to 50 ° C. The ketone compound (III) is N,
Various cyclic amino compounds (nitrogen-containing) in an amide solvent such as N-dimethylformamide, acetamide, dimethylacetamide, or an ether solvent such as tetrahydrofuran or dioxane, or a mixed solvent thereof in the presence of anhydrous potassium carbonate or the like. The compound (I) having a nitrogen-containing heterocyclic substituent, wherein R ¹ is a nitro group and Y is a keto group, can be obtained by reacting the compound (I) with a heterocyclic compound. In this reaction, the reaction proceeds even without anhydrous potassium carbonate or the like. The reaction temperature is preferably in the range of 0 to 200 ° C, and is usually carried out in the range of 50 to 170 ° C.

Compound (I) in which R ¹ is a nitro group and Y is a keto group can be prepared by using tin (II) chloride (SnC) in an alcoholic solvent such as methanol, ethanol, or isopropanol.
By treating with l ₂ ), compound (I) in which R ¹ is an amino group and Y is a keto group can be obtained. Also, R ¹
Is a compound having R ¹ as an amino group and Y as a hydroxyl group by treating the compound (I) having an amino group and Y as a keto group with sodium borohydride or the like in an alcoholic solvent such as methanol, ethanol, or isopropanol. (I) can be obtained. The temperature of these reduction reactions is 0 to 200 ° C.
Is usually performed in a range of 10 to 100 ° C. Furthermore, compounds of Y is a keto group R ¹ is a nitro group and (I), methanol, ethanol, an alcoholic solvent such as isopropanol by treatment with sodium borohydride or the like, R ¹ is the Y-nitro group A compound (I) having a hydroxyl group is obtained. Further, when this compound is treated with tin chloride (SnCl ₂ ) or the like in an alcoholic solvent such as methanol, ethanol, or isopropanol, R ¹ is converted from a nitro group to an amino group. Can be converted to a group. In addition, when reduction by catalytic reduction is performed, first, a nitro group is converted to an amino group, and if reduction is further continued, a keto group can be converted to a hydroxyl group.

In the substitution reaction with the compound (III), the compound obtained by reacting piperazine is reacted with an aromatic hydrocarbon solvent such as xylene, or
Treatment with various alkyl halides (for example, 2-bromoethanol) in the presence of anhydrous potassium carbonate in an amide solvent such as N, N-dimethylformamide, acetamide, dimethylacetamide, etc. Can be obtained. The reaction temperature of this reaction is preferably in the range of 0 to 200 ° C, and usually may be carried out at a temperature in the range of 20 to 150 ° C.

The compound of the present invention can be treated with an inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid or an organic acid such as formic acid, acetic acid or methanesulfonic acid to convert it into an acid addition salt, if desired. It can be a salt that is chemically acceptable. In addition, the compound of the present invention can exist as a hydrate, either in a free form or as a salt.

Examples of tumors for which the compound of the present invention is effective include solid cancers such as lung cancer, stomach cancer, colon cancer and liver cancer, uterine cancer, gynecological cancer such as breast cancer and ovarian cancer, and blood cancers such as acute leukemia.

The compound of the present invention is characterized in that when Y is a hydroxyl group,
Alternatively, stereoisomers may occur when a substituent is present on the heterocyclic substituent. In such a case, it goes without saying that the present invention includes both isomers.

Next, an experiment shows the antitumor effect of the compound of the present invention obtained as described above.

[0026]

【Example】

[Experimental Example 1] P388 mouse leukemia cells were seeded in a 96-well microplate at 5 × 10 ² cells / well, and PC-6 human-derived lung cancer cells were seeded at 5 × 10 ³ cells / well. The sample was added 2 hours after the former and 24 hours after the latter. Thereafter, the cells were cultured under 5% carbon dioxide at 37 ° C. for 3 days, and MTT [3- (4,5-Dimethylt
hiazol-2-yl) -2,5-diphenyl-2H-tetrazolium bromide]
Was added. Next, the culture solution was removed, 150 μl of dimethyl sulfoxide was added to each well, and the generated formazan was measured for absorbance at 540 nm to determine a 50% cell growth inhibitory concentration (GI ₅₀ ) value (ng / ml). Was. Table 1 shows the results.

[0028]

[Table 1]

[Experimental Example 2] 1 × 10 ⁶ mouse leukemia cells P388 were intraperitoneally transplanted into male CDF-1 mice (body weight 21 to 34 g, 6 mice per group) 7 to 10 weeks old.
The test substance was administered intraperitoneally on the day and on the fifth day, and its life-prolonging effect was observed. The test substance was a BTC solution (0.9%
Benzyl alcohol, 0.4% Tween 80, 0.5%
Sodium carboxymethylcellulose, distilled water containing 0.9% saline). Table 2 shows the results. In Table 2, the antitumor effect is a value obtained by multiplying the median days of survival (T) of the group administered with the test substance and the median days of survival (C) of the group administered with the test substance at the time of maximum effectiveness by 100 times ( T / C).

[0030]

[Table 2]

The compounds synthesized in the present invention exhibit antitumor activity as apparent from Tables 1 and 2, and can be applied as antitumor agents for treating various tumors. The antitumor agent can be administered as various injections such as intravenous injection, intramuscular injection and subcutaneous injection, or by various methods such as oral administration. Among these administration methods, intravenous administration by an aqueous preparation and oral administration are preferred. In the case of a compound having an amino group, the aqueous preparation can form an acid adduct with a pharmacologically acceptable acid. In the case of oral administration, it may be in a free form or in a salt form. As a method for preparing an antitumor preparation comprising the compound of the present invention, an appropriate preparation can be selected according to the administration method, and the preparation can be adjusted by a commonly used preparation method for various preparations. As the dosage form of the antitumor preparation of the compound of the present invention, for example, tablets,
Powders, granules, capsules, solutions, syrups, elixirs, oily or aqueous suspensions and the like can be exemplified as oral preparations. Solid preparations include pharmaceutically acceptable additives together with the active compound, such as fillers, extenders, binders, disintegrants, dissolution enhancers, wetting agents, lubricants and the like. They can be selected and mixed as needed to form a formulation. Liquid preparations include solutions, suspensions,
Emulsions and the like can be mentioned, but they may contain a suspending agent, an emulsifier and the like as additives. Injectables may use stabilizers, preservatives and solubilizers in the formulation,
After storing the solution that may contain these adjuvants in the container,
It may be prepared as a solid preparation by freeze-drying or the like and adjusted for use. One dose may be stored in a container, or multiple doses may be stored in the same container. Liquid preparations include solutions, suspensions, emulsions and the like, and may also contain suspending agents, emulsifiers and the like as additives. The dose of the antitumor agent containing the compound of the present invention is in the range of 10 mg to 3 g, preferably 100 mg to 2 g per adult per day.

Next, examples of formulation of the pharmaceutical preparation are shown.

[0033]

Table 3 Formulation Example 1 (Capsule): Compound of Example 2 100.0 mg Cornstarch 23.0 mg CMC Calcium 22.5 mg Hydroxymethylcellulose 3.0 mg Magnesium stearate 1.5 mg Total 150.0 mg Next, examples are described. The present invention will be described in more detail.

Example 1 (2-morpholino-5-d)
In addition nitrophenyl) phenylmethanone (2-chloro-5-nitrophenyl) phenylmethanone (1.31 g), anhydrous potassium carbonate (0.69 g), morpholine (0.65 g) in DMF (13 ml),
The mixture was heated and stirred at 120 ° C. for 4 hours. The reaction solution was concentrated under reduced pressure,
Chloroform was added to the residue, washed with water, dried over anhydrous sodium sulfate, and the organic layer was concentrated. The residue was recrystallized from ethanol to give the title compound (1.37 g, yield 88%). Melting point: 122-123 ° C. ¹ H-NMR (CDCl ₃ ) δ (ppm): 3.0-
_{3.2 (m, 4H, CH 2} × 2), 3.3-3.5
(M, 4H, CH ₂ × 2), 7.03 (d, 1H, J =
10 Hz, Ar-H), 7.48 (t, 2H, J = 8H)
z, Ar-H), 7.6-7.7 (m, 1H, Ar-
H), 7.7-7.9 (m, 2H, Ar-H), 8.2.
-8.4 (m, 2H, Ar-H)

Example 2 (2-morpholino-5-d)
Trophenyl) (4-chlorophenyl) methanone (1) (2-chloro-5-nitrophenyl) (4-chloro
Thionyl chloride (6.3 g) was added to ( lophenyl) methanone 2-chloro-5-nitrobenzoic acid (10 g), and the mixture was heated under reflux for 3 hours and concentrated under reduced pressure. Dichloromethane (120
ml), chlorobenzene (15.6 g) and aluminum chloride (7 g) were added, and the mixture was stirred at room temperature overnight. The reaction solution was poured into ice water containing dilute hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with 1N-NaOH and water. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure to give the title compound 6.5.
g was obtained in a yield of 44%. (2) (2-morpholino-5-nitrophenyl) (4
-Chlorophenyl) methanone (1), the compound obtained (1.50 g), anhydrous potassium carbonate (0.69 g) and morpholine (0.65 g) in DM
F (13 ml), and the mixture was heated and stirred at 120 ° C. for 4 hours. The reaction solution was concentrated under reduced pressure, chloroform was added to the residue, washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound 1.
33 g were obtained with a yield of 77%. Melting point: 171-172 ° C. ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.9-
_{3.2 (m, 4H, CH 2} × 2), 3.3-3.5
(M, 4H, CH ₂ × 2), 7.05 (d, 1H, J =
9 Hz, Ar-H), 7.47 (d, 2H, J = 9H)
z, Ar-H), 7.73 (t, 2H, J = 9 Hz, A
r-H), 8.2-8.4 (m, 2H, Ar-H)

Example 3 (2-thiomorpholino-5)
Example 1 using thiomorpholine instead of -nitrophenyl ) phenylmethanone morpholine
The reaction was carried out in the same manner as described above, followed by recrystallization after post-treatment to obtain the title compound in a yield of 73%. Melting point: 114-115 ° C. ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.3-
_{2.5 (m, 4H, CH 2} × 2), 3.3-3.5
(M, 4H, CH ₂ × 2), 7.06 (d, 1H, J =
8 Hz, Ar-H), 7.49 (t, 2H, J = 8H)
z, Ar-H), 7.64 (d, 1H, J = 8 Hz, A
r-H), 7.78 (d, 2H, J = 8 Hz, Ar-
H), 8.2-8.4 (m, 2H, Ar-H)

Example 4 (2-thiomorpholino-5)
-Nitrophenyl) (4-chlorophenyl) methanone The compound obtained in Example 2 (1) was reacted with thiomorpholine in the same manner as in Example 2 (2). After work-up, the title compound was obtained in a yield of 81. %. Melting point: 141-143 ° C. ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.3-
_{2.5 (m, 4H, CH 2} × 2), 3.3-3.5
(M, 4H, CH ₂ × 2), 7.07 (d, 1H, J =
9 Hz, Ar-H), 7.46 (d, 2H, J = 8H)
z, Ar-H), 7.72 (d, 2H, J = 8 Hz, A
rH), 8.25 (d, 1H, J = 2 Hz, Ar-
H), 8.30 (dd, 1H, J = 9, 2 Hz, Ar−
H)

Example 5 [2- (4-methyl-1-)
Piperazinyl) -5-nitrophenyl] (4-chlorofu
Enyl) methanone The compound obtained in Example 2 (1) was reacted with N-methylpiperazine in the same manner as in Example 2 (2). After work-up, the title compound was obtained in a yield of 56%. Melting point: 159-161 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.16
(T, 4H, J = 6 Hz, CH ₂ × 2), 2.20
_{(S, 3H, CH 3)} , 3.17 (t, 4H, J = 6H
z, CH ₂ × 2), 7.09 (d, 1H, J = 12H)
z, Ar-H), 7.50 (d, 2H, J = 10 Hz,
Ar-H), 7.78 (d, 2H, J = 10 Hz, Ar
-H), 8.31 (s, 1H, Ar-H), 8.30-
8.40 (m, 1H, Ar-H)

Example 6 [2- (4-methyl-1-)
Piperazinyl) -5-nitrophenyl] (4-methoxy
Phenyl) methanone (1) (2-chloro-5-nitrophenyl) (4-meth
Example 2 using anisole instead of ( xyphenyl) methanone chlorobenzene
The reaction was carried out in the same manner as in (1) to give the title compound in a yield of 83%. (2) [2- (4-methyl-1-piperazinyl) -5-
Nitrophenyl] (4-methoxyphenyl) methanone (1) was reacted with N-methylpiperazine in the same manner as in Example 2 (2). After post-treatment, the title compound was obtained in a yield of 67%. I got it. Melting point: 145-147 ° C. ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.1-
_{2.3 (m, 7H, CH 3} , CH 2 × 2), 3.21
(T, 4H, J = 6 Hz, CH ₂ × 2), 3.93
(S, 3H, OCH ₃ ), 6.99 (d, 2H, J = 1
2Hz, Ar-H), 7.04 (m, 1H, Ar-
H), 7.83 (d, 2H, J = 12 Hz, Ar-
H), 8.27 (s, 1H, Ar-H), 8.29-
8.31 (m, 1H, Ar-H)

Example 7 [2- (4-methyl-1-)
Piperazinyl) -5-nitrophenyl] (4-fluoro
Phenyl) methanone (1) (2-chloro-5-nitrophenyl) (4-fur
The reaction was carried out in the same manner as in Example 2 (1) using fluorobenzene instead of ( olophenyl) methanonechlorobenzene , followed by treatment to obtain the title compound in a yield of 74%. (2) [2- (4-methyl-1-piperazinyl) -5-
[Nitrophenyl] (4-fluorophenyl) methanone (1) was reacted with N-methylpiperazine in the same manner as in Example 2 (2). After work-up, the title compound was obtained in a yield of 67%. I got it. Melting point: 147-149 ° C. ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.1-
_{2.3 (m, 7H, CH 3} , CH 2 × 2), 3.1-
_{3.2 (m, 4H, CH 2} × 2), 6.9-7.3
(M, 3H, Ar-H), 7.78 (dd, 2H, J =
6,3 Hz, Ar-H), 7.90 (s, 1H, Ar-
H), 8.33 (dd, 1H, J = 6.3 Hz, Ar-
H)

Example 8 [2- (4-methyl-1-)
Piperazinyl) -5-nitrophenyl) (3,4-dim
( Toxiphenyl) methanone (1) (2-chloro-5-nitrophenyl) (3,4-
Using 3,4-dimethoxybenzene instead of dimethoxyphenyl) methanone chlorobenzene, and reacted as in Example 2 (1), to give the title compound was worked up with 12% yield. (2) [2- (4-methyl-1-piperazinyl) -5-
Nitrophenyl] (3,4-dimethoxyphenyl) meta
Using the compound obtained in the non (1) and N-methylpiperazine, the reaction was carried out in the same manner as in Example 2 (2). After post-treatment, the title compound was obtained in a yield of 73%. Melting point: 140-142 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.1-
_{2.3 (m, 7H, CH 3} , CH 2 × 2), 3.25
(Br-t, 4H, J = 6Hz, CH 2 × 2), 3.9
_{4 (s, 3H, OCH 3} ), 3.97 (s, 3H, OC
_{H 3), 6.8-7.5 (m,} 4H, Ar-H), 8.
2-8.3 (m, 2H, Ar-H)

Example 9 [2- (1-Piperazini)
L) -5-Nitrophenyl] phenylmethanone The reaction was carried out in the same manner as in Example 1 using piperazine instead of morpholine, followed by post-treatment and recrystallization to obtain the title compound in a yield of 91%. Melting point: 139-140 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.46
(S, 1H, NH), 2.5-2.7 (m, 4H, CH
₂ × 2), 3.1-3.3 (m, 4H, CH ₂ × 2),
6.9-7.1 (m, 1H, Ar-H), 7.48
(T, 2H, J = 8 Hz, Ar-H), 7.62 (t,
1H, J = 8 Hz, Ar-H), 7.79 (d, 2H,
J = 8 Hz, Ar-H), 8.30 (s, 1H, Ar-
H), 8.2-8.4 (m, 1H, Ar-H)

Example 10 1- (4-Fluorophene)
Nil) -1- [2- (4-methyl-1-piperazinyl)
[5-Nitrophenyl] methanol isopropanol (45 ml), the compound obtained in Example 7 (2) (3.43 g) was added, and sodium borohydride was gradually added over 1 hour. After stirring, it was confirmed by TLC that the raw materials had disappeared. The reaction solution was cooled, poured into ice water, and the precipitate was collected by filtration and washed with water. The precipitate was applied to a silica gel column, isolated by elution with a mixed solvent of chloroform-methanol (95: 5), and recrystallized from ethanol to obtain 2.05 g of the title compound in a yield of 59%. Melting point: 170-173 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.70
(Br-s, 1H, OH), 2.34 (s, 3H, CH
₃ ), 2.4-2.6 (m, 4H, CH ₂ × 2), 2.
8-3.0 (m, 4H, CH ₂ × 2), 6.09 (s,
1H, Ar-CH), 6.9-7.6 (m, 5H, Ar
-H), 8.0-8.3 (m, 2H, Ar-H)

Example 11 [2- [4- (2-Hydrogen)
Roxyethyl) -1-piperazinyl] -5-nitrophen
Nyl] phenylmethanone The compound obtained in Example 9 (2.2 g), 2-bromoethanol (1.75 g), anhydrous sodium carbonate (2.2 g)
2 g) was added to xylene (4 ml), and the mixture was heated with stirring at 100 ° C. for 1 hour. Chloroform was added to the reaction solution, and after washing with water,
The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column and eluted with a mixed solvent of chloroform-ethanol (98: 2) to give the title compound 1.
72 g were obtained with a yield of 69%. Melting point: 111-113 ° C. ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.24
(Br-t, 4H, J = 6 Hz, CH ₂ × 2), 2.4
1 (t, 2H, J = 5 Hz, CH ₂ ), 3.17 (br
−t, 4H, J = 6 Hz, CH ₂ × 2), 3.55
(T, 2H, J = 5 Hz, CH2), 6.9-7.1.
(M, 1H, Ar-H), 7.50 (t, 2H, J = 8)
Hz, Ar-H), 7.6-7.9 (m, 3H, Ar-
H), 8.28 (s, 1H, Ar-H), 8.2-8.
4 (m, 1H, Ar-H)

Example 12 (2-morpholino-5)
-Aminophenyl) (4-chlorophenyl) methanone The compound (2.7 g) obtained in Example 2 (2) and tin (II) chloride (SnCl ₂ ; 26 g) were added to ethanol (2
00 ml) and heated under reflux for 20 minutes. The reaction solution was poured into ice water and extracted with ethyl acetate. Organic layer 10N-
After washing with NaOH and water, it was dried over sodium sulfate and concentrated under reduced pressure. The residue was applied to a silica gel column and eluted with ethyl acetate to give the title compound (1.93 g) in a yield of 79%
I got it. Melting point: 174-176 ° C. ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.74
(T, 4H, J = 4 Hz, CH ₂ × 2), 3.28
(T, 4H, J = 4 Hz, CH ₂ × 2), 3.6-3.
_{9 (br-s, 2H,} NH 2), 6.73 (d, 1H,
J = 3 Hz, Ar-H), 6.81 (dd, 1H, J =
8,3 Hz, Ar-H), 6.98 (d, 1H, J = 8)
Hz, Ar-H), 7.38 (d, 2H, J = 8 Hz,
Ar-H), 7.69 (d, 2H, J = 8 Hz, Ar-
H)

Example 13 [2- (4-methyl-1)
-Piperazinyl) -5-aminophenyl] (4-methoxy
(Ciphenyl) methanone The compound obtained in Example 6 (2) was reacted and worked up in the same manner as in Example 12 to give the title compound in a yield of 48%.
I got it. Melting point: 137-141 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.0-
2.2 (m, 4H, CH ₂ × 2), 2.13 (s, 3
_{H, CH 3), 2.84 (} br-t, 4H, J = 6H
z, CH ₂ × 2), 3.62 (br-s, 2H, N
_{H 2), 3.90 (s,} OCH 3), 6.72 (d, 1
H, J = 3 Hz, Ar-H), 6.80 (dd, 1H,
J = 10,3 Hz, Ar-H), 6.91 (d, 2H,
J = 12 Hz, Ar-H), 7.00 (d, 1H, J =
10 Hz, Ar-H), 7.78 (d, 2H, J = 12)
Hz, Ar-H)

Example 14 [2- (4-methyl-1)
-Piperazinyl) -5-aminophenyl] (4-fluoro
(Rophenyl) methanone The compound obtained in Example 7 (2) was reacted and worked up in the same manner as in Example 12 to give the title compound in a yield of 75%.
I got it. Melting point: 161-163 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.9-
_{2.7 (m, 7H, CH 3} , CH 2 × 2), 2.66
(Br-t, 4H, J = 6 Hz, CH ₂ × 2), 3.5
_{5 (br-s, 2H,} NH 2), 6.6-7.2 (m,
5H, Ar-H), 7.5-7.7 (m, 2H, Ar-
H)

Example 15 [2- (4-methyl-1)
-Piperazinyl) -5-aminophenyl) (3,4-di
(Methoxyphenyl) methanone The compound obtained in Example 8 (2) was reacted and worked up in the same manner as in Example 12 to give the title compound in a yield of 31%.
I got it. Melting point: 180-183 ° C (decomp.) ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.9-
_{2.7 (m, 7H, CH 3} , CH 2 × 2), 2.66
(Br-t, 4H, J = 6 Hz, CH ₂ × 2), 3.5
_{5 (br-s, 2H,} NH 2), 6.6-7.2 (m,
5H, Ar-H), 7.5-7.7 (m, 2H, Ar-
H)

Example 16 1- (4-Fluorophene)
Nil) -1- [2- (4-methyl-1-piperazinyl)
[-5-Aminophenyl] methanol The compound obtained in Example 14 was reacted and worked up in the same manner as in Example 10 to give the title compound in 61% yield. Melting point: 198-200 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.75
(Br-s, 1H, OH), 2.31 (s, 3H, CH
_{3), 2.4-2.8 (m, 8H} , CH 2 × 4), 3.
_{60 (br-s, 2H,} NH 2), 5.75 (br-
s, 1H, Ar-CH), 6.37 (d, 1H, J = 3
Hz, Ar-H), 6.57 (dd, 1H, J = 9,3)
Hz, Ar-H), 6.8-7.5 (m, 5H, Ar-
H)

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07D 241/04 C07D 241/04 265/30 265/30 295/08 295/08 ZA (72) Inventor: Tamotsu Miwa Edogawa, Tokyo 1-16-13 Kita-Kasai-ku, Tokyo The Daiichi Pharmaceutical Co., Ltd. Tokyo Research and Development Center

Claims (10)

[Claims] 1. Compounds of the structure of formula (I), their salts and their hydrates (Wherein, X represents an oxygen atom, a sulfur atom, or a structure:> N—R ⁴ , Y represents a keto group or a hydroxyl group, and the bond shown by a dotted line is a double bond. R ¹ represents a nitro group or an amino group, and R ² and R ³ each independently represent a hydrogen atom, a hydroxyl group, a halogen atom or a hydrogen atom. atom, means a nitro group, an amino group, an alkylamino group alkoxyl group having 1 to 6 carbon atoms, or from 1 to 6 carbon atoms .R ⁴
Represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. This alkyl group may have a hydroxyl group, a carboxyl group, an amino group, or an alkoxyl group having 1 to 6 carbon atoms as a substituent. Good. R ⁵ and R ⁶ are
Each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. ) 2. A compound having the following structure, a salt thereof, and a hydrate thereof: (Wherein X represents an oxygen atom, a sulfur atom, or NR> R ⁴ , R ¹ represents a nitro group or an amino group, and R ² and R ³ are each independently to, .R ⁴ meaning a hydrogen atom, a hydroxyl group, a halogen atom, a nitro group, an amino group, an alkylamino group alkoxyl group having 1 to 6 carbon atoms, or from 1 to 6 carbon atoms is a hydrogen atom or a carbon atoms, To 6, which may have a hydroxyl group, a carboxyl group, an amino group, or an alkoxyl group having 1 to 6 carbon atoms as a substituent, wherein R ⁵ and R ⁶ are Each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.) 3. The compound according to claim 1, wherein X is an oxygen atom or a sulfur atom, a salt thereof, and a hydrate thereof. 4. The compound according to claim 1, 2, or 3, wherein the substituent R ¹ is a nitro group, a salt thereof, and a hydrate thereof. 5. The compound according to claim 1, 2, 3, or 4, wherein one of the substituents R ² or R ³ is a halogen atom, a salt thereof, and a hydrate thereof. 6. The compound according to claim 5, wherein the halogen atom is a chlorine atom, a salt thereof, and a hydrate thereof. 7. (2-morpholino-5-nitrophenyl) phenylmethanone, a salt thereof, and a hydrate thereof 8. (2-morpholino-5-nitrophenyl) (4-chlorophenyl) methanone, a salt thereof, and a hydrate thereof 9. (2-thiomorpholino-5-nitrophenyl) phenylmethanone, salts thereof, and hydrates thereof 10. (2-thiomorpholino-5-nitrophenyl) (4-chlorophenyl) methanone, a salt thereof, and a hydrate thereof