WO2000051959A1

WO2000051959A1 - Fluorinated chalcone derivatives or salts thereof and drugs containing the same as the active ingredient

Info

Publication number: WO2000051959A1
Application number: PCT/JP2000/001275
Authority: WO
Inventors: Toshio Sato; Takeo Taguchi; Isao Umezawa; Tsutomu Inoue; Nobuhide Kawasaki
Original assignee: Toshio Sato; Takeo Taguchi; Isao Umezawa; Tsutomu Inoue; Nobuhide Kawasaki
Priority date: 1999-03-03
Filing date: 2000-03-03
Publication date: 2000-09-08
Also published as: AU2827500A; JP2000256250A

Abstract

Fluorinated chalcone derivatives represented by formula (1) wherein R?1, R4 and R5¿ are the same or different and each represents hydrogen or lower alkyl; and R?2 and R3¿ are the same or different and each represents hydrogen, hydroxy or lower alkoxy. Because of having an excellent anticancer activity and a low toxicity, these compounds are useful as anticancer agents.

Description

Description Fluorinated chalcone derivatives or salts thereof and pharmaceuticals containing them as active ingredients

The present invention relates to a fluorinated chalcone derivative having anticancer activity and a medicine containing the same as an active ingredient. Background art

Current cancer treatments include supportive care, surgery, radiation therapy, chemotherapy, and gene therapy. In the field of chemotherapy, more than 60 types of compounds are currently available for use, but they are roughly classified into alkylating agents, antimetabolites, natural extracts, hormonal agents, BRM agents, etc. It is used mainly in combination with other therapies, alone or in combination with drugs with different effects, depending on the type and progression of the cancer.

In recent years, more than 100 types of anticancer drugs, such as microangiogenesis inhibitors, cytodynamics, monoclonal antibodies, and compounds with more specific actions such as topoisomerase inhibitors, have been developed. .

Factors that have led to the development and development of such a large number of compounds include the fact that there are still few drugs whose efficacy has been clarified as a single agent, and that cancer has developed resistance to various anticancer drugs. It is considered that most of the anticancer drugs have strong side effects.

Therefore, the creation of a new anticancer agent that exhibits reliable anticancer activity and has few side effects is desired. Disclosure of the invention

Under such circumstances, the present inventor has sought a safer and more effective cancer chemotherapeutic agent. As a result of screening using a panel consisting of 39 human cultured cancer cells (cancer and chemotherapy, 24 (2): 129-135, 1997), an excellent anti-fluorinated chalcone derivative was obtained. The present inventors have found that they have cancer activity and have low toxicity, and have completed the present invention.

That is, the present invention provides the following general formula (1)

[Wherein, R ′, R ⁴ and R ⁵ represent a hydrogen atom or a lower alkyl group which may be the same or different, and R ² and R ³ represent a hydrogen atom which may be the same or different, a hydroxyl group or a lower alkoxy group. A fluorinated chalcone derivative or a salt thereof represented by the formula: The present invention also provides a medicament comprising the fluorinated chalcone derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

Further, the present invention provides a pharmaceutical composition comprising the fluorinated chalcone derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The present invention further provides the use of the fluorinated chalcone derivative or a pharmaceutically acceptable salt thereof as a medicament.

Furthermore, the present invention provides a method for treating cancer, which comprises administering the fluorinated chalcone derivative or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE FIGURES

Figure 1 is a diagram showing the relative sensitivity of each cell based on the mean GI5 ₅ value.

FIG. 2 is a diagram showing the relative sensitivity of each cell as viewed from the mean TGI value. 3, the average LC _5. It is a figure showing relative sensitivity of each cell from the viewpoint of a value. BEST MODE FOR CARRYING OUT THE INVENTION

The fluorinated chalcone derivative of the present invention is represented by the general formula (1). In the formula, the lower alkyl group represented by R ′, R ⁴ and R ⁵ is a straight-chain having 1 to 7 carbon atoms. Examples thereof include a chain or branched alkyl group, specifically, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group, n -Pentyl group, isopentyl group, 2-methylbutyl, neopentyl group, n-hexyl group, n-heptyl group, etc., and preferably the number of carbon atoms of methyl group, ethyl group, n-propyl group, isopropyl group, etc. It is a straight-chain or branched alkyl group of 1 to 4, and particularly preferably a methyl group.

In the formula, examples of the lower alkoxy group represented by R ² and R ³ include an alkoxy group having 1 to 4 carbon atoms, and specifically, a methoxy group, an ethoxy group, an n-propoxy group, an isopropyloxy group, Examples thereof include an n-butoxy group and a butoxy group, and a methoxy group is particularly preferable.

In addition, the fluorinated chalcone derivative represented by the general formula (1) of the present invention can form a pharmaceutically acceptable salt such as a sodium salt and a potassium salt, if desired. It is within the scope of the present invention. Furthermore, the present invention also includes solvates represented by hydrates.

The fluorinated chalcone derivative represented by the general formula (1) of the present invention can be produced, for example, by the following method.

[Wherein, RR ² , R ³ , R ⁴ and R ⁵ represent the same as above]

That is, it can be obtained by condensing a corresponding 2-fluoro-benzaldehyde derivative with a substituted acetophenone derivative in the presence of a base.

The base used herein is not particularly limited as long as it is used as a base in a usual reaction. Examples thereof include alkali metal carbonates such as sodium carbonate, potassium carbonate, and lithium carbonate; sodium hydroxide, Alkali metal hydroxides such as potassium hydroxide, barium hydroxide and lithium hydroxide; alkali metal alkoxides such as sodium methoxide and sodium methoxide; preferably sodium hydroxide And alkali metal hydroxides such as potassium hydroxide.

The solvent is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent. Aliphatic hydrocarbons, aromatic hydrocarbons, esters, alcohols, etc. can be used. Alcohols such as ethanol, n-propanol, isopropanol and n-butanol are preferred.

The reaction temperature is 0 ° (: to 50 ° C, preferably room temperature. The reaction time varies depending on conditions such as the type of the compound and the reaction temperature, but is usually about 1 hour to 10 hours. After completion of the reaction, water is poured into the reaction product, and the mixture is extracted with a water-immiscible solvent, for example, ethyl acetate, and the solvent is distilled off from the extract to obtain the desired product. . When any one of R ¹ , R ⁴ and R ⁵ is a hydrogen atom, or any one of R ² and R ³ is a hydroxyl group, a known protecting group (for example, a tetrahydrovinylanyl group) After appropriately protecting the hydroxyl group with a methoxyethoxymethyl group or the like, the above condensation reaction is carried out, and the protective group is eliminated after the reaction to obtain the desired product.

The fluorinated chalcone derivative (1) or a salt thereof of the present invention has been shown to be effective at a low concentration in a screening system using a panel of human cultured cancer cells 39, and is useful as an anticancer agent.

When the fluorinated chalcone derivative (1) or a salt thereof of the present invention is used as a medicine, it can be used in the form of various preparations depending on its pharmacological action and administration purpose. That is, in the case of oral administration, it can be administered in the form of tablets, capsules, granules, powders or liquids, and in the case of parenteral administration, injections, eye drops, suppositories, patches It can be administered in the form of an agent or an external preparation.

These preparations contain an effective amount of the compound (1) of the present invention or a salt thereof in a pharmaceutically acceptable carrier such as an excipient, a stabilizer, a preservative, a solubilizer, a wetting agent, an emulsifier, a lubricant, a sweetener. Formulations can be made by adding flavors, coloring agents, flavoring agents, tonicity adjusting agents, buffers, antioxidants, and the like.

The dose of the preparation containing the compound of the present invention is appropriately selected depending on the form of the preparation, usage, age, sex, symptoms, etc. of the preparation, but is usually preferably in the range of 1 to 300 mg / kgZ day. Example

Hereinafter, the present invention will be described with reference to Examples and Reference Examples, but the present invention is not limited thereto.

Reference example 1

2-fluoro-4,5-dimethoxybenzaldehyde

In a 1 L class 3 flask, add 4-chlorofluoroetrol to 51.4 g of dichloromethane. 30 OmL of tan and a stirrer were added, and the mixture was cooled in an ice water bath and stirred to adjust the internal temperature of the reaction solution to 2 to 3 ° C. To this, a solution of 95.07 g of titanium tetrachloride in 15 OmL of dichloromethane was added dropwise at a dropping port over 1.5 hours. The reaction turned brown. Then, at the same temperature, dichloromethyl methyl ether 39.73 g of dichloromethane

The 10 OmL solution was added dropwise using a dropping funnel over 0.5 hour. After stirring at the same temperature for 30 minutes, the ice water bath was removed and the temperature was returned to room temperature, and the mixture was stirred for about 4.5 hours until no hydrochloric acid gas was generated. The reaction solution was poured into 1 L of ice water, the dichloromethane layer was separated with a separatory funnel, and the aqueous layer was extracted with 20 OmL of chloroform. The organic layers were combined, washed successively with water and saturated saline, and then dried using anhydrous magnesium sulfate. After filtration, the residue obtained by concentrating the solvent was crystallized by adding 50 OmL of hexane: ethyl acetate (10: 1). The crystals were suction-filtered, washed with the same solvent, and air-dried to obtain 43.29 g of the desired product as colorless crystals.

Ή-NMR: (Solvent for measurement: CDC1 _3, δ ριη)

10.24 (lH, s), 7.28 (1H, d, J = 6.6Hz), 6.65 (lH, d, J = ll.5Hz),

3.96 (3H, s), 3.91 (3H, s)

Reference example 2

2-fluoro-4,5-dihydroxybenzaldehyde and 2-fluoro-4-hydroxy-5-methoxybenzaldehyde

500 mL of dichloromethane and a stirrer were added to 43.17 g of the product of Reference Example 1 in a 1-L third-class flask, and the mixture was stirred under ice-cooling with water and the internal temperature of the reaction solution was adjusted to 2-3 ° C. 84.10 g of boron tribromide was added dropwise thereto. After stirring at the same temperature for 30 minutes, the mixture was stirred at room temperature for 15 hours. The reaction solution was poured into 1 L of ice water, and extracted with 50 mL of pore form using a separating funnel. The aqueous layer was extracted with 1 L of ethyl acetate. The pore-form layer was washed twice with a saturated saline solution, and then dried using anhydrous magnesium sulfate. After filtration, the solvent was concentrated to obtain crystals, and the crystals were suction-filtered using a mixed solution of chloroform and hexane (1: 1). After washing with the same solvent and air-drying, 2-fluoro-4-hydr 9.45 g of mouth xy-5-methoxybenzaldehyde were obtained as colorless crystals.

The ethyl acetate layer extracted from the above aqueous layer was washed twice with a saturated saline solution, and then dried using magnesium sulfate anhydride. After filtration, the crystalline residue obtained by concentrating the solvent was subjected to short silica gel column chromatography (silica gel BW-820MH, 200 g) using ethyl acetate as a developing solvent to give 2-fluoro-4,5-dihydroxyl. 28.50 g of a 6: 1 mixture of benzaldehyde and 2-fluoro-4-hydroxy-5-methoxybenzaldehyde as colorless crystals were obtained.

2-fluoro-4-hydroxy-1-methoxybenzaldehyde

Melting point: 137-138. C

Ή-NMR: (Solvent for _{measurement: DMS0- d 6, (5 pm} )

10.05 (lH, s), 9.57 (lH, s), 7.11 (lH, d, J = 6.9Hz),

7.02 (lH, d, J = 12.2Hz), 3.88 (3H, s)

2-fluoro-4,5-dihydroxybenzaldehyde

Melting point: 160-162. C

Ή-NMR: (Solvent for measurement: DMS0- d _6, δρριη)

10.69 (lH, br), 10.00 (lH, s), 7.11 (1H, d, J-6.9Hz),

6.68 (1H, d, J = 12.2Hz)

Reference example 3

2-fluoro-4,5-bis (2-tetrahydrobilanyloxy) benzaldehyde

A stirring bar was added to 28.5 Og of the mixture obtained in Reference Example 2, and 100 mL of dichloromethane was added to suspend the mixture. Subsequently, 70 OmL of ethyl acetate was added to dissolve the mixture. The mixture was cooled and stirred in an ice water bath to adjust the internal temperature of the reaction solution to 2 to 3 ° C. Among them, 3,5.0-dihydro-1H-pyran 75.0 g and D-10-camphorsulfonic acid 0.1 g

(Amount of catalyst) was added, and the mixture was stirred at the same temperature for 6 hours, and then stirred at 5 ° C for 4 hours and further at room temperature for 2 hours. Drain the reaction solution into a separatory funnel and add saturated aqueous sodium hydrogen carbonate The solution was washed successively with 100 mL of water, 30 OmL of water and 20 OmL of saturated saline, and dried using anhydrous magnesium sulfate. After filtration, the solvent was concentrated to give a crystalline residue, which was subjected to silica gel column chromatography (silica gel BW—820 MH, 200 g) using hexane: ethyl acetate (4: 1) as a developing solvent. The desired product, 2-fluoro-4,5-bis (2-tetrahydrobilanyloxy) benzaldehyde, was obtained as colorless crystals (2.976 g). At the same time, 2-fluoro-5-hydroxy-4- (2- 12.83 g of tetrahydropyranyloxy) benzaldehyde and 5.70 g of 2-fluoro-5-methoxy-1- (2-tetrahydrovilanyloxy) benzaldehyde were obtained as colorless crystals.

2-fluoro-4,5-bis (2-tetrahydrobilanyloxy) benzaldehyde

Melting point: 150-152 ° C

Ή-NMR: (Solvent for measurement: CDC1 _3, d pm)

10.20 (lH, s), 7.56 (1H, dd, J = 6.9, 1.3Hz),

6.95 (lH, dd, J = 12, 1.3Hz), 5.53 (lH, m), 5.40 (1H, m),

3.92 to 4.04 (1H, m), 3.78 to 3.88 (1H, m), 3.60 to 3.70 (2H, m),

1.55-2.05 (12H, m)

2-Fluoro-5-hydroxy-1- (2-tetrahydroviranyloxy) benzaldehyde

Melting point: 107-145. C

Ή-NMR: (Solvent for measurement: CDC1 _3, δ ppm)

10.17 (lH, s), 7.57 (1H, d, J = l.6Hz), 7.55 (1H, dd, J = 7, 1Hz),

6.71 (lH, d, J = 11.2Hz), 5.12 (1H, m), 3.96 to 4.04 (lH, m),

3.6 G 3.70 (lH, m) ₍ 1.90 to 2.04 (2H, m), 1.75 to 1.90 (lH, m),

1.57 to 1.75 (3H, m)

2-fluoro-5-methoxy-4- (2-tetrahydropyranyloxy) ben Zaldehyde

Melting point: 102-103 ° C

Ή-NMR: (Solvent for measurement: CDC1 _3, δ ριη)

10.24 (lH, s), 7.55 (1H, d, J = 6.9Hz), 6.65 (1H, d, J = l 1.7Hz),

5.38 (1H, t, J = 3.2Hz), 3.96 (1H, m), 3.92 (3H, s), 3.62 (lH, m),

1.86 to 2.09 (3H, m), 1.59 to 1.76 (3H, m)

Reference example 4

2-fluoro-4,5-bis (2-tetrahydropyranyloxy) _ 2 ', 5' -dimethoxychalcone

In a 30 OmL eggplant-shaped flask, add 10 OmL of ethanol to 16.0 g of 2-fluoro-1,4,5-bis (2-tetrahydrobilanyloxy) benzaldehyde, dissolve it, and add 2 ', 5' dimethoxyacetophenone. 9.78 g, 1 OmL of sodium hydroxide 5% ethanol solution and a stirrer were added, and the mixture was stirred at room temperature for 15 hours. The stirring bar was removed, and the solvent was directly concentrated to about half by evaporator. The mixture was transferred to a separating funnel, diluted with 50 OmL of ethyl acetate, washed successively with 30 OmL of water and 20 OmL of saturated saline, and dried using anhydrous magnesium sulfate. After filtration, the solvent was concentrated to give a yellow residue. Column form: silica gel column chromatography using methanol (100: 3) as the eluent (silica gel BW—820 MH, 300 g) Then, 2.285 g of 2-fluoro-4,5_bis (2-tetrahydroviranyloxy) -1-2 ′, 5 ′ dimethoxychalcone as a yellow crystal was obtained as the target substance.

Melting point: 162-163 ° C

Ή-NMR: (Solvent for measurement: CDC1 _3, (5 pm)

7.67 (1H, d, J = 16Hz), 7.32 to 7.37 (lH, m), 7.35 (1H, d, J = 16Hz),

7.16 (1H, d, J = 3.3Hz), 7.02 (1H, dd, 1 = 8.9, 3.3Hz),

6.9 G 6.95 (2H, m), 5.47 (lH, m), 5.34 (lH, m), 4.04 (lH, m), 3.86 (lH, m), 3.85 (3H, s), 3.81 (3H, s), 3.61 to 3.66 (2H, m), 1.85 to 2.05 (6H, m), 1.60 to 1.75 (6H, m)

Reference example 5

2-Fluoro-4,5-bis (2-tetrahydrobiranyloxy) 1 2 ', 4'-Dimethoxychalcone

In a 30 OmL eggplant-shaped flask, add 10 OmL of ethanol to 10.80 g of 2-fluoro-4,5-bis (2-tetrahydrobilanyloxy) benzaldehyde and dissolve it. 2 ', 4' Dimethoxyacetophenone 6.6 0 g, 1 OmL of sodium hydroxide 5% ethanol solution and a stirrer were added, and the mixture was stirred at room temperature for 15 hours. The stirrer was removed, and the solvent was directly concentrated by evaporation overnight to precipitate crystals. After transferring to a separatory funnel and adding 50 OmL of ethyl acetate to dissolve the crystals, the crystals were washed successively with 300 mL of water and 200 mL of saturated saline, and dried using anhydrous magnesium sulfate. After filtration, the solvent was concentrated to give a crystalline yellow residue. Hexane: ethyl acetate (5: 1) 10 OmL was added to precipitate crystals, followed by suction filtration. The crystals were washed with the same solvent and air-dried. The filtrate is concentrated and then subjected to silica gel column chromatography (silica gel BW-820MH, 300 g) using hexane: ethyl acetate (3: 1) as a developing solvent to obtain the desired product, 2-fluoro-4,4. 13.85 g of 5-bis (2-tetrahydroviranyloxy) 1 2 ', 4' dimethoxychalcone was obtained as yellow crystals.

Melting point: 170-171 ° C

Ή-NMR: (Solvent for measurement: CDC1 _3, δ ριιι)

7.74 (lH, d, J = 8.5Ηζ), 7.69 (1H, d, J = l 5.8Hz),

7.35 (lH, dd, J = 7.5, 1.7Hz), 6.93 (1H, dd, J = 12, 2Hz),

6.56 (1H, dd, J = 8.5, 2Hz), 6.49 (1H, d, J = 2Hz), 5.47 (1H, m),

5.34 (1H, m), 4.00 (1H, m), 3.89 (3H, s), 3.88 (lH, m),

3.87 (3H, s), 3.6 g 3.65 (2H, m), 1.85 to 2.05 (6H, m), 1-60-1.74 (6H, m)

Example 1

2-fluoro-4,5-dihydroxy-2 ', 5'-dimethoxychalcone

In a 30 OmL eggplant-shaped flask, methanol (10 OmL) was added to and dissolved in 22.85 g of the product of Reference Example 4, 2 mL of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 2 hours. The mixture was transferred to a separating funnel, diluted by adding 50 OmL of ethyl acetate, washed successively twice with 30 OmL of water and 20 OmL of saturated saline, and dried using anhydrous magnesium sulfate. After filtration, the solvent was concentrated to give a yellow crystalline residue. This was subjected to silica gel column chromatography (silica gel BW—82 OMH, 300 g) using chloroform: methanol (100: 3) as a developing solvent, and the yellow portion was collected. To the obtained yellow crystals, 10 OmL of hexane: ethyl acetate (5: 1) was added and stirred, followed by suction filtration, washing with the same solvent, and air drying to give the target substance as yellow crystals. 12.80 g was obtained.

Melting point: 169-170. C

Ή-NMR: (Solvent for measurement: DMSO- d _6, δ ρηι)

9.0 to 9.8 (br), 7.50 (lH, d, J = 16.0Hz), 7.18 (1H, d, J = l 6.OHz),

7.09 to 7.13 (3H, m), 7.03 (lH, d, J = lHz), 6.63 (1H, d, J = ll.8Hz),

3.82 (3H, s), 3.75 (3H, s)

Example 2

2-Fluoro-4,5-dihydroxy-2 ', 4, dimethoxychalcone

In a 30 OmL eggplant-shaped flask, add methanol to 3.85 g of the product of Reference Example 5.

10 OmL was added, concentrated hydrochloric acid 2 mL was added, and the mixture was stirred at room temperature for 2 hours. The mixture was transferred to a separatory funnel, diluted by adding 50 OmL of ethyl acetate, washed successively twice with 30 OmL of water and 20 OmL of saturated saline, and dried using anhydrous magnesium sulfate. After filtration, the solvent was concentrated to give a yellow crystalline residue. This is the mouth form: methanol

Silica gel column chromatography using (100: 3) as the developing solvent (silica The mixture was applied to gel BW-82 OMH, 300 g) and the yellow part was collected. To the obtained yellow crystals, 10 OmL of hexane: ethyl acetate (5: 1) was added, and the mixture was stirred, suction filtered, washed with the same solvent, and air-dried to obtain the target compound as yellow crystals. 50 g were obtained.

Melting point: 177 ° C

Ή-NMR: (solvent: DMS0_d ₆ , 5 pm)

9.0 to 9.8 (br), 7.60 (1H, d, J = 8.6Hz), 7.52 (1H, d, J = 15.8Hz),

7.34 (lH, d, J = 15.8Hz), 7.09 (1H, d, J = 7.6Hz), 6.61 to 6.69 (3H, m),

3.91 (3H, s), 3.85 (3H, s)

Reference example 6

2-Fluoro-5-methoxy-41- (2-tetrahydrovilanyloxy) benzaldehyde

In a 1 L third-class flask, 2-fluoro-4-hydroxy-5-methoxybenzaldehyde 4.15 g, 3,4-dihydro-2H-pyran 6.168 and 13-10 monocamphorsulfonic acid 5 Omg ( ) And stirred at room temperature for 2 hours. The reaction solution was poured into a separating funnel, washed successively with 10 OmL of a saturated aqueous solution of sodium hydrogencarbonate, 30 OmL of water, and 20 OmL of saturated saline, and dried using anhydrous magnesium sulfate. After filtration, the solvent was concentrated to obtain a crystalline residue, which was subjected to silica gel column chromatography (silica gel BW—820MH, 100 g) using hexane: ethyl acetate (1: 1) as a developing solvent. As a result, 3.23 g of the target product was obtained as colorless crystals, and at the same time, the raw material 2-fluoro-hydroxy-5-methoxybenzaldehyde was recovered.

Also, 2-fluoro-5-methoxy-4_ (2-tetrahydropyranyloxy) benzaldehyde is 2-fluoro-5-hydroxy-14- (2-tetrahydroviranyloxy) benzaldehyde in methyl dimethylformamide in methyl iodide. And methylation. Reference Example 7

2-fluoro-4-methoxy-1-5- (2-methoxyethoxymethoxy) benzaldehyde

Add 2-OmL dichloromethane to 1.73 g of 2-fluoro-5-hydroxy-1- (2-tetrahydroviranyloxy) benzaldehyde and dissolve it. At room temperature, 2-methoxyethoxymethyl chloride 1.268 and 1, N 1.3 g of diisopropylethylamine were sequentially added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate (15 OmL), washed successively with water and saturated saline, and dried over anhydrous magnesium sulfate. The residue containing 2-fluoro-41- (2-tetrahydropyranyloxy) -15- (2-methoxyethoxymethoxy) benzaldehyde obtained by filtration under reduced pressure to remove the solvent is purified without purification. Was used for the reaction.

The obtained reaction product was dissolved in 1 OmL of methanol, 30 mg (catalytic amount) of D-10 monocamphorsulfonic acid was added, and the mixture was stirred at room temperature for 5 minutes. The reaction solution was diluted with 15 OmL of ethyl acetate, washed successively with a saturated aqueous solution of sodium hydrogen carbonate, water and saturated saline, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue obtained was directly used for the next reaction without purification.

Further, the obtained reaction product was dissolved in 3 OmL of dimethylformamide, 2 mL of methyl iodide and 3,000 g of anhydrous potassium carbonate were added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate (15 OmL), washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (silica gel BW-82 OMH, 100 g) using hexane: ethyl acetate (4: 1) as a developing solvent. —Fluoro-1

—Dimethyloxymethyl-1-methoxy-5- (2-methoxyethoxymethoxy) benzene was obtained as a colorless syrup.

Ή-NMR: (Solvent for measurement: CDC1 _3, (5 pm)

7.04 (1H, d, J = 6.6Hz), 6.98 (1H, d, J = l 1.2Hz), 5.53 (lH, s), 5.31 (2H, s), 3.87 (3H, s), 3.85 (2H, m), 3.55 (2H, m),

3.39 (6H, s), 3.38 (3H, s)

The obtained colorless syrup was dissolved in ethyl acetate (3 OmL), tetrahydrofuran (2 OmL) and 2N-hydrochloric acid aqueous solution (5 mL) were sequentially added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was diluted with 15 OmL of ethyl acetate, washed sequentially with water, a saturated aqueous solution of sodium hydrogencarbonate, water and saturated saline, and dried over anhydrous magnesium sulfate. After filtration, the residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (silica gel BW—820 MH, 100 g) using hexane: ethyl acetate (3: 1) as a developing solvent, to obtain the desired compound. Was obtained as a colorless syrup.

Ή-NMR: (Solvent for measurement: CDC1 _3, δ ριη)

10.25 (lH, s), 7.30 (1H, d, J = 6.3Hz), 7.03 (lH, d, J = 12Hz),

5.40 (2H, s), 3.90 (3H, s), 3.86 (2H, m), 3.56 (2H, m),

3.38 (3H, s)

Reference Example 8

4-methoxy-2_ (2-methoxyethoxymethoxy) acetophenone

4-methoxy-2-hydroxyacetophenone in 2.00 g of dichloromethane

Add 2 OmL to dissolve and add 2-methoxyethoxymethyl chloride at room temperature

1.50 g and 1.386 g of N, N-diisopropylethylamine were sequentially added, followed by stirring at room temperature for 2 hours. The reaction solution was diluted with 15 OmL of ethyl acetate, washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (silica gel BW—820MH, 100 g) using hexane: ethyl acetate (3: 1) as a developing solvent. 3.05 g of the desired product was obtained as a colorless syrup.

Ή-NMR: (Solvent for measurement: CDC1 _3, δ legs)

7.80 (1H, d, J = 8.5Hz), 6.75 (1H, d, J = 2.3Hz),

6.57 (lH.dd, J = 8.5, 2.3Hz), 5.37 (2H, s), 3.86 (2H, m), 3.84 (3H, s), 3.58 (2H, m), 3.39 (3H, s), 2.59 (3H, s)

Reference Example 9

2-Methoxy-1-41- (2-tetrahydropyranyloxy) acetophenone 2,4-dihydroxyacetophenone 5.97 g, 3,4-dihydro-2H-pyran 9 mL and D_10-camphorsulfonic acid 0.1 lg (catalytic amount) Was added and stirred at room temperature for 2 hours. The reaction solution was poured into a separating funnel, washed successively with 100 mL of a saturated aqueous solution of sodium hydrogencarbonate, 30 OmL of water and 20 OmL of a saturated saline solution, and dried using anhydrous magnesium sulfate. After filtration, the solvent was concentrated to obtain 9.27 g of a colorless syrup.

3.50 g of this was dissolved in 3 OmL of dimethylformamide, 5 mL of methyl iodide and 6.00 g of anhydrous potassium carbonate were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with 15 OmL of ethyl acetate, washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. After filtration, the residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (silica gel BW—82 OMH, 100 g) using hexane: ethyl acetate (4: 1) as a developing solvent. The product was obtained as colorless syrupy substance (3.63 g).

Example 3

2-Fluoro-1-hydroxy-4-methoxy-2'-hydroxy-4'-methoxychalcone

4-methoxy-1- 2- (2-methoxyethoxymethoxy) acetophenone

0.60 g and 2-fluoro-4-methoxy-5- (2-methoxyethoxymethoxy) benzaldehyde (0.60 g) were dissolved in ethanol (2 OmL), and 2 mL of 50% hydroxylated water solution was added at room temperature. Stirred for hours. Ethyl acetate

The mixture was diluted to 15 OmL, washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. After filtration, the solvent is distilled off under reduced pressure, and the colorless syrup-like residue obtained is dissolved in 2 OmL of methanol without purification, 2 mL of concentrated hydrochloric acid is added and the mixture is stirred at room temperature for 2 hours did. The reaction mixture was diluted with 15 mL of ethyl acetate, washed sequentially with water and saturated saline, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain a yellow crystalline residue. Form: Silica gel column chromatography (silica gel BW-820MH, 100 g) using methanol (100: 3) as a developing solvent, and the yellow portion was collected. To the obtained yellow crystals, 3 OmL of hexane: ethyl acetate (5: 1) was added, and the mixture was stirred. Then, the mixture was filtered by suction, washed with the same solvent, and air-dried to obtain the desired product, 2-fluoro-. 0.63 g of 5-hydroxy-4-methoxy-2′-hydroxy-4′-methoxychalcone was obtained as yellow crystals.

Ή-NMR: (Measurement solvent: DMSO—d _fi , δρρπι)

13.56 (lH, s), 10.36 (1H, s), 8.26 (1H, d, J = 8.5Hz),

7.90 (lH, d, J = 15.5Hz), 7.88 (1H, d, J = 15.5Hz),

7.61 (lH, d, J = 7.3Hz), 6.72 (1H, d, J = 12.9Hz),

6.58 (lH, dd, J = 8.5,2Hz), 6.53 (lH, d, J = 2Hz), 3.89 (3H, s),

3.86 (3H, s)

Hereinafter, the compounds of Examples 4 to 8 were produced in the same manner.

Example 4

2-Fluoro-4-hydroxy-5-methoxy-1 4'-hydroxy-2'-methoxychalcone

Yellow crystals

Ή-NMR: (Measurement solvent: DMS0_d ₆ , (5ppm)

10.32 (lH, br), 9.24 (lH, br), 7.55 (lH, d, J = 8.5Hz),

7.53 (1H, d, J = 15.8Hz), 7.43 (1H, d, J = 15.8Hz), 7.12 (1H, d, J = 7.6Hz), 6.95 (1H, d, J = 12.3Hz), 6.51 ( 1H, d, J = 2Hz), 6.46 (1H, dd, J = 8.5, 2Hz), 3.86 (3H, s), 3.83 (3H, s)

Example 5

2-fluoro-4-hydroxy-5-methoxy-1'-hydroxy-1'-meth Toxiccone

Yellow crystals

Ή-NMR: (Measurement solvent: DMSO— d δ ppm)

13.47 (lH, s), 9.12 (lH, s), 8.23 (1H, d, J = 8.5Hz),

7.86 (lH, d, J = 15.5Hz), 7.80 (lH, d, J = 15.5Hz),

7.49 (lH, d, J = 7.6Hz), 6.98 (IH, d, J = 12.3Hz),

6.46 (IH, dd, J = 8.5,2Hz), 6.51 (lH, d, J = 2Hz), 3.87 (3H, s),

3.85 (3H, s)

Example 6

2-fluoro-5-hydroxy-4-methoxy-1 4'-hydroxy-1 2'-me yellow crystal

Ή-NMR: (Solvent for _{measurement: DMS0 - d 6, <5} pm)

10.23 (2H, br), 7.52 (1H, d, J = 8.5Hz), 7.51 (IH, d, J = 15.5Hz),

7.48 (lH, d, J = 15.5Hz), 7.29 (IH, d, J = 7.3Hz), 6.68 (IH, d, J = 12Hz),

6.51 (lH, d, J = 2Hz), 6.46 (IH, dd, J = 8.5, 2Hz), 3.84 (3H, s),

3.83 (3H, s)

Example 7

2-fluoro-4,5-dihydroxy-2,1-hydroxy-4'-methoxychalcone

Yellow crystals

Ή-NMR: (Solvent for measurement: DMS0 - d _6, δρριη)

13.46 (lH, s), 10.2 (lH, br), 9.2 (lH, br), 8.20 (IH, d, J = 8.5Hz),

7.90 (IH, d, J = 15.5Hz), 7.73 (IH, d, J = 15.5Hz), 7.42 (IH, d, J = 7.5Hz), 6.66 (IH, d, J = 12.1Hz), 6.56 ( IH, dd, J = 8.5, 2Hz), 6.51 (IH, d, J = 2Hz), 3.85 (3H, s) Example 8

2-fluoro-4,5-dihydroxy-1 4'-hydroxy-2'-methoxycalcon

Yellow crystals

Ή-NR: (Measurement solvent: DMSO— d ₆ , δ ριη)

10.3 (m, br), 10.1 (lH, br), 9.3 (lH, br),

7.56 (lH, d, J = 8.5Hz), 7.52 (lH, d, J = 15.5Hz), 7.38 (1H, d, J = 15.5Hz),

7.09 (lH, d, J = 7.6Hz), 6.65 (1H, d, J = 12.1Hz), 6.52 (lH, d, J = 2Hz),

6.47 (lH, dd, J = 8.5, 2Hz), 3.86 (3H, s)

[Effectiveness test]

The compound of Example 2 was evaluated for its cancer cell growth inhibitory effect in vitro by a cancer cell inhibition test (cancer and chemotherapy, 24 (2): 129-135, 1997). That is, as cancer cells, 5 breast cancer (Br), 6 brain tumor (CNS), colon cancer

(Co) 5 strains, Lung cancer strain (Lu) 7 strain, Melanoma (Me) 1 strain, Ovarian cancer strain

(Ov) 5 strains, Kidney cancer (Re) 2 strains, Gastric cancer (St) 6 strains, Prostate cancer strains

(x P g) using a total of 39 strains of two strains, these cell 1 ines diary, GI _5. Values (inhibiting proliferation as compared to controls at 50% strength), TGI values (inhibiting the proliferation to the same number of cells as the time zero concentration), LC _5. The values (concentration that reduces the number of cells to 50% of time zero) were determined, the average of 39 values was determined for each value, and the relative sensitivity of each cell from the average was plotted and analyzed.

Table 1 shows the parameters of effective concentration and specific efficacy. TG

G C--!

o o

MG-MID: Average value of Log GI 50 for all tested strains

De l ta: i between the most sensitive and the average

Range: Log Gl ₅₀ of the most sensitive and least sensitive strain

Concentration that suppresses proliferation to 50% compared to control

Concentration that suppresses proliferation to the same number of cells as at time zero

Concentration that reduces cell number to 50% of time zero

The relative sensitivity of each cell is shown in FIGS.

According to the present cancer cell inhibition test, specific growth inhibition was observed at a sufficiently low effective concentration of the fluorochalcone derivative of the present invention.

Industrial applicability

INDUSTRIAL APPLICABILITY The fluorinated chalcone derivative of the present invention provides an anticancer agent having a new action, has excellent anticancer activity, and has low toxicity, and thus can be administered alone or in combination with other agents. .

Claims

The scope of the claims

1. The following general formula (1)

[Wherein, R ′, R ⁴ and R ⁵ represent a hydrogen atom or a lower alkyl group which may be the same or different, and R ² and R ³ represent a hydrogen atom which may be the same or different, a hydroxyl group or a lower alkoxy group. A fluorinated chalcone derivative or a salt thereof.

2. A medicament comprising the fluorinated chalcone derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

3. The medicament according to claim 2, which is an anticancer agent.

4. A pharmaceutical composition comprising the fluorinated chalcone derivative according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

5. Use of the fluorinated chalcone derivative according to claim 1 or a pharmaceutically acceptable salt thereof as a medicament.

6. Use according to claim 5, wherein the medicament is an anticancer agent.

7. A method for treating cancer, which comprises administering the fluorinated chalcone derivative according to claim 1 or a pharmaceutically acceptable salt thereof.