JPH0539250A - Triarylalkene derivative and medicinal composition containing the same derivative, having inhibitory action on tumor - Google Patents

Abstract

PURPOSE:To obtain a triarylalkene derivative useful as a medicine or a pharmaceutically permissible salt thereof, showing more excellent antitumor effects on mammary tumor than tamoxifen. CONSTITUTION:A compound shown by formula I [R1 and R2 are H, lower alkyl, lower cycloalkyl, R1 and R2 are heterocyclic group with the proviso that R1=R2=H is excluded; R3 is H, OH, OCOR5, OCH2OR6 or OPO(OH)2(OH)2; R4 and R5 are lower alkyl, lower cycloalkyl and, further, R5 is substituted aryl; R6 is lower alkyl or lower alkylcarbonyl; Ar is 3,4-methylenedioxyphenyl] or a pharmaceutically permissible salt thereof such as (E/Z)-1-[4-(2- cyclohexylaminoethoxy)phenyl-1-(4-hydroxyphenyl)-2-(3,4-methylenedioxy phenyl)-1- butene. The compound is produced from a compound shown by formula II (R7 is H or OH) and a compound shown by formula III through compounds shown by formula IV and formula V (X is halogen).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a triarylalkene derivative and a pharmaceutical composition containing the same, which has a tumor suppressive action.

[0002]

2. Description of the Related Art It is known that a compound having a basic skeleton of 1,1,2-triphenyl-1-butene and a substituted aminoalkoxy group at the phenyl group at the 1-position has a nonsteroidal antiestrogenic activity. Has been. (Z) -2- [
4- (1,2-diphenyl-1-butenyl) phenoxy] -N, N-dimethylethylamine (tamoxifen) is its representative compound, and its strong anti-estrogen action makes it a useful therapeutic drug for hormone-dependent breast cancer. (British Patent No. 1013907).

[0003]

DISCLOSURE OF THE INVENTION It is an object of the present invention to provide a triarylalkene derivative which has a more excellent antitumor effect than tamoxifen against breast tumors and is useful as a medicine.

[0004]

The novel triarylalkene derivative of the present invention is a triarylalkene derivative represented by Chemical Formula 1 or a pharmaceutically acceptable acid addition salt thereof. In the triarylalkene derivative represented by the chemical formula 1, there are two kinds of geometrical isomers, E and Z, with respect to the carbon-carbon double bond. Both isomers can be clearly distinguished by the nuclear magnetic resonance signal of the proton of the methylene group adjacent to the ether bond. In the present invention, the above EZ
Also included are mixtures of isomers and each isolated E-form Z form. Examples of the triarylalkene derivative of the present invention include the following.

(1) 1- [4- (2-methylaminoethoxy) phenyl] -1- (4-hydroxyphenyl)-
2- (3,4-methylenedioxyphenyl) -1-butene (2) 1- [4- (2-ethylaminoethoxy) phenyl] -1- (4-hydroxyphenyl) -2- (3,4
-Methylenedioxyphenyl) -1-butene (3) 1- [4- (2-isopropylaminoethoxy)
Phenyl] -1- (4-hydroxyphenyl) -2-
(3,4-Methylenedioxyphenyl) -1-butene (4) 1- [4- (2-cyclohexylaminoethoxy) phenyl] -1- (4-hydroxyphenyl) -2
-(3,4-Methylenedioxyphenyl) -1-butene (5) 1- [4- (2-dimethylaminoethoxy) phenyl] -1- (4-hydroxyphenyl) -2- (3,
4-Methylenedioxyphenyl) -1-butene (6) 1- [4- (2-diethylaminoethoxy) phenyl] -1- (4-hydroxyphenyl) -2- (3,
4-Methylenedioxyphenyl) -1-butene (7) 1- [4- (2-methylethylaminoethoxy)
Phenyl] -1- (4-hydroxyphenyl) -2-
(3,4-Methylenedioxyphenyl) -1-butene (8) 1- [4- (2-cyclohexylmethylaminoethoxy) phenyl] -1- (4-hydroxyphenyl)
-2- (3,4-Methylenedioxyphenyl) -1-butene (9) 1- [4- (2-pyrrolidinoethoxy) phenyl] -1- (4-hydroxyphenyl) -2- (3,4
-Methylenedioxyphenyl) -1-butene (10) 1- [4- (2-methylaminoethoxy) phenyl] -1-phenyl-2- (3,4-methylenedioxyphenyl) -1-butene (11 ) 1- [4- (2-Ethylaminoethoxy) phenyl] -1-phenyl-2- (3,4-methylenedioxyphenyl) -1-butene (12) 1- [4- (2-isopropylaminoethoxy) ) Phenyl] -1-phenyl-2- (3,4-methylenedioxyphenyl) -1-butene (13) 1- [4- (2-cyclohexylaminoethoxy) phenyl] -1-phenyl-2- (3 , 4-Methylenedioxyphenyl) -1-butene (14) 1- [4- (2-dimethylaminoethoxy) phenyl] -1-phenyl-2- (3,4-methylenedioxyphenyl)- -Butene (15) 1- [4- (2-diethylaminoethoxy) phenyl] -1-phenyl-2- (3,4-methylenedioxyphenyl) -1-butene (16) 1- [4- (2- Methylethylaminoethoxy) phenyl] -1-phenyl-2- (3,4-methylenedioxyphenyl) -1-butene (17) 1- [4- (2-cyclohexylmethylaminoethoxy) phenyl] -1-phenyl -2- (3, 4-
Methylenedioxyphenyl) -1-butene (18) 1- [4- (2-Pyrrolidinoethoxy) phenyl] -1-phenyl-2- (3,4-methylenedioxyphenyl) -1-butene (19) 1- [4- (2-methylaminoethoxy) phenyl] -1- (4-methoxymethoxyphenyl) -2-
(3,4-Methylenedioxyphenyl) -1-butene (20) 1- [4- (2-ethylaminoethoxy) phenyl] -1- (4-methoxymethoxyphenyl) -2-
(3,4-Methylenedioxyphenyl) -1-butene (21) 1- [4- (2-isopropylaminoethoxy) phenyl] -1- (4-methoxymethoxyphenyl) -2- (3,4-methylene Dioxyphenyl) -1
-Butene (22) 1- [4- (2-cyclohexylaminoethoxy) phenyl] -1- (4-methoxymethoxyphenyl) -2- (3,4-methylenedioxyphenyl) -1
-Butene (23) 1- [4- (2-dimethylaminoethoxy) phenyl] -1- (4-methoxymethoxyphenyl) -2
-(3,4-Methylenedioxyphenyl) -1-butene (24) 1- [4- (2-diethylaminoethoxy) phenyl] -1- (4-methoxymethoxyphenyl) -2
-(3,4-Methylenedioxyphenyl) -1-butene (25) 1- [4- (2-methylethylaminoethoxy) phenyl] -1- (4-methoxymethoxyphenyl) -2- (3,4 -Methylenedioxyphenyl) -1
-Butene (26) 1- [4- (2-cyclohexylmethylaminoethoxy) phenyl] -1- (4-methoxymethoxyphenyl) -2- (3,4-methylenedioxyphenyl)
-1-Butene (27) 1- [4- (2-Pyrrolidinoethoxy) phenyl] -1- (4-methoxymethoxyphenyl) -2-
(3,4-Methylenedioxyphenyl) -1-butene (28) 1- [4- (2-methylaminoethoxy) phenyl] -1- (4-acetoxyphenyl) -2- (3,
4-Methylenedioxyphenyl) -1-butene (29) 1- [4- (2-ethylaminoethoxy) phenyl] -1- (4-acetoxyphenyl) -2- (3,
4-Methylenedioxyphenyl) -1-butene (30) 1- [4- (2-isopropylaminoethoxy) phenyl] -1- (4-acetoxyphenyl) -2
-(3,4-Methylenedioxyphenyl) -1-butene (31) 1- [4- (2-cyclohexylaminoethoxy) phenyl] -1- (4-acetoxyphenyl) -2
-(3,4-Methylenedioxyphenyl) -1-butene (32) 1- [4- (2-dimethylaminoethoxy) phenyl] -1- (4-acetoxyphenyl) -2-
(3,4-Methylenedioxyphenyl) -1-butene (33) 1- [4- (2-diethylaminoethoxy) phenyl] -1- (4-acetoxyphenyl) -2-
(3,4-Methylenedioxyphenyl) -1-butene (34) 1- [4- (2-methylethylaminoethoxy) phenyl] -1- (4-acetoxyphenyl) -2
-(3,4-Methylenedioxyphenyl) -1-butene (35) 1- [4- (2-cyclohexylmethylaminoethoxy) phenyl] -1- (4-acetoxyphenyl) -2- (3,4- Methylenedioxyphenyl) -1
-Butene (36) 1- [4- (2-pyrrolidinoethoxy) phenyl] -1- (4-acetoxyphenyl) -2- (3,4)
-Methylenedioxyphenyl) -1-butene (37) 1- [4- (2-methylaminoethoxy) phenyl] -1- (4- (dihydroxyphosphinooxyphenyl) -2- (3,4-methylenedi) Oxyphenyl) -1-butene (38) 1- [4- (2-ethylaminoethoxy) phenyl] -1- (4-dihydroxyphosphinooxyphenyl) -2- (3,4-methylenedioxyphenyl)
-1-Butene (39) 1- [4- (2-isopropylamineaminoethoxy) phenyl] -1- (4-dihydroxyphosphinooxyphenyl) -2- (3,4-methylenedioxyphenyl) -1- Butene (40) 1- [4- (2-Cyclohexylaminoethoxy) phenyl] -1- (4-dihydroxyphosphinooxyphenyl) -2- (3,4-methylenedioxyphenyl) -1-butene (41) 1- [4- (2-Dimethylaminoethoxy) phenyl] -1- (4- (dihydroxyphosphinooxyphenyl) -2- (3,4-methylenedioxyphenyl) -1-butene (42) 1- [ 4- (2-diethylaminoethoxy) phenyl] -1- (4-dihydroxyphosphinooxyphenyl) -2- (3,4-methylenedioxyfuran Nil) -1-butene (43) 1- [4- (2-methylethylaminoethoxy) phenyl] -1- (4-dihydroxyphosphinooxyphenyl) -2- (3,4-methylenedioxyphenyl)- 1-butene (44) 1- [4- (2-cyclohexylmethylaminoethoxy) phenyl] -1- (4-dihydroxyphosphinooxyphenyl) -2- (3,4-methylenedioxyphenyl) -1-butene (45) 1- [4- (2-Pyrrolidinoethoxy) phenyl] -1- (4-dihydroxyphosphinooxyphenyl) -2- (3,4-methylenedioxyphenyl)-
1-butene (46) 1- [4- (2-methylaminoethoxy) phenyl] -1- (4-benzoyloxyphenyl) -2-
(3,4-Methylenedioxyphenyl) -1-butene (47) 1- [4- (2-ethylaminoethoxy) phenyl] -1- (4-benzoyloxyphenyl) -2-
(3,4-Methylenedioxyphenyl) -1-butene (48) 1- [4- (2-isopropylaminoethoxy) phenyl] -1- (4-benzoyloxyphenyl) -2- (3,4-methylene Dioxyphenyl) -1
-Butene (49) 1- [4- (2-cyclohexylaminoethoxy) phenyl] -1- (4-benzoyloxyphenyl) -2- (3,4-methylenedioxyphenyl) -1
-Butene (50) 1- [4- (2-dimethylaminoethoxy) phenyl] -1- (4-benzoyloxyphenyl) -2
-(3,4-Methylenedioxyphenyl) -1-butene (51) 1- [4- (2-diethylaminoethoxy) phenyl] -1- (4-benzoyloxyphenyl) -2
-(3,4-Methylenedioxyphenyl) -1-butene (52) 1- [4- (2-methylethylaminoethoxy) phenyl] -1- (4-benzoyloxyphenyl) -2- (3,4 -Methylenedioxyphenyl) -1
-Butene (53) 1- [4- (2-cyclohexylmethylaminoethoxy) phenyl] -1- (4-benzoyloxyphenyl) -2- (3,4-methylenedioxyphenyl)
-1-Butene (54) 1- [4- (2-Pyrrolidinoethoxy) phenyl] -1- (4-benzoyloxyphenyl) -2-
(3,4-Methylenedioxyphenyl) -1-butene (55) 1- [4- (2-methylaminoethoxy) phenyl] -1- (4-pivaloyloxymethoxyphenyl) -2- (3, 4-methylenedioxyphenyl) -1
-Butene (56) 1- [4- (2-ethylaminoethoxy) phenyl] -1- (4-pivaloyloxymethoxyphenyl) -2- (3,4-methylenedioxyphenyl) -1
-Butene (57) 1- [4- (2-isopropylaminoethoxy) phenyl] -1- (4-pivaloyloxymethoxyphenyl) -2- (3,4-methylenedioxyphenyl) -1-butene (butene) 58) 1- [4- (2-Cyclohexylaminoethoxy) phenyl] -1- (4-pivaloyloxymethoxyphenyl) -2- (3,4-methylenedioxyphenyl) -1-butene (59) 1 -[4- (2-Dimethylaminoethoxy) phenyl] -1- (4-pivaloyloxymethoxyphenyl) -2- (3,4-methylenedioxyphenyl) -1
-Butene (60) 1- [4- (2-diethylaminoethoxy) phenyl] -1- (4-pivaloyloxymethoxyphenyl) -2- (3,4-methylenedioxyphenyl) -1
-Butene (61) 1- [4- (2-methylethylaminoethoxy) phenyl] -1- (4-pivaloyloxymethoxyphenyl) -2- (3,4-methylenedioxyphenyl) -1-butene (62) 1- [4- (2-Cyclohexylmethylaminoethoxy) phenyl] -1- (4-pivaloyloxymethoxyphenyl) -2- (3,4-methylenedioxyphenyl) -1-butene (63 ) 1- [4- (2-Pyrrolidinoethoxy) phenyl] -1- (4-pivaloyloxymethoxyphenyl)
-2- (3,4-Methylenedioxyphenyl) -1-butene (64) 1- [4- (2-methylaminoethoxy) phenyl] -1- (4-hydroxyphenyl) -2- (3,
4-Methylenedioxyphenyl) -2-cyclopropylethene (65) 1- [4- (2-ethylaminoethoxy) phenyl] -1- (4-hydroxyphenyl) -2- (3,
4-Methylenedioxyphenyl) -2-cyclopropylethene (66) 1- [4- (2-isopropylaminoethoxy) phenyl] -1- (4-hydroxyphenyl) -2
-(3,4-Methylenedioxyphenyl) -2-cyclopropylethene (67) 1- [4- (2-cyclohexylaminoethoxy) phenyl] -1- (4-hydroxyphenyl) -2
-(3,4-Methylenedioxyphenyl) -2-cyclopropylethene (68) 1- [4- (2-dimethylaminoethoxy) phenyl] -1- (4-hydroxyphenyl) -2-
(3,4-Methylenedioxyphenyl) -2-cyclopropylethene (69) 1- [4- (2-diethylaminoethoxy) phenyl] -1- (4-hydroxyphenyl) -2-
(3,4-Methylenedioxyphenyl) -2-cyclopropylethene (70) 1- [4- (2-methylethylaminoethoxy) phenyl] -1- (4-hydroxyphenyl) -2
-(3,4-Methylenedioxyphenyl) -2-cyclopropylethene (71) 1- [4- (2-cyclohexylmethylaminoethoxy) phenyl] -1- (4-hydroxyphenyl) -2- (3, 4-methylenedioxyphenyl) -2
-Cyclopropylethene (72) 1- [4- (2-pyrrolidinoethoxy) phenyl] -1- (4-hydroxyphenyl) -2- (3,4
-Methylenedioxyphenyl) -2-cyclopropylethene (73) 1- [4- (2-methylaminoethoxy) phenyl] -1- (4-cyclopropanecarbonyloxyphenyl) -2- (3,4-methylene Dioxyphenyl)
-1-butene (74) 1- [4- (2-ethylaminoethoxy) phenyl] -1- (4-cyclopropanecarbonyloxyphenyl) -2- (3,4-methylenedioxyphenyl)
-1-Butene (75) 1- [4- (2-Isopropylaminoethoxy) phenyl] -1- (4-cyclopropanecarbonyloxyphenyl) -2- (3,4-methylenedioxyphenyl) -1-butene (76) 1- [4- (2-Cyclohexylaminoethoxy) phenyl] -1- (4-cyclopropanecarbonyloxyphenyl) -2- (3,4-methylenedioxyphenyl) -1-butene (77) 1 -[4- (2-Dimethylaminoethoxy) phenyl] -1- (4-cyclopropanecarbonyloxyphenyl) -2- (3,4-methylenedioxyphenyl) -1-butene (78) 1- [4- (2-Diethylaminoethoxy) phenyl] -1- (4-cyclopropanecarbonyloxyphenyl) -2- (3,4-methylenedioxyphenyl) 1-butene (79) 1- [4- (2-methylethylaminoethoxy) phenyl] -1- (4-cyclopropanecarbonyloxyphenyl) -2- (3,4-methylenedioxyphenyl) -1-butene (80) 1- [4- (2-Cyclohexylmethylaminoethoxy) phenyl] -1- (4-cyclopropanecarbonyloxyphenyl) -2- (3,4-methylenedioxyphenyl) -1-butene (81) 1- [4- (2-pyrrolidinoethoxy) phenyl] -1- (4-cyclopropanecarbonyloxyphenyl) -2- (3,4-methylenedioxyphenyl)-
1-butene

The triarylalkene derivative represented by the chemical formula 1 of the present invention is represented by the following chemical formula 3.

[Chemical 3] (Wherein R ₇ represents a hydrogen atom or a hydroxyl group) and a benzophenone derivative represented by the following chemical formula 4

[0007]

[Chemical 4] (Wherein R ₄ represents a lower alkyl group or a lower cycloalkyl group and Ar represents a 3,4-methylenedioxyphenyl group) under a substantially dry and inert atmosphere. The reaction is carried out in a medium containing a reducing titanium compound and a reducing agent effective for generating titanium having a valence of substantially zero, and the resulting mixture is represented by the following chemical formula 5.

[0008]

[Chemical 5] (In the formula, R ₄ represents a lower alkyl group or a lower cycloalkyl group, R ₇ represents a hydrogen atom or a hydroxyl group,
Ar represents a 3,4-methylenedioxyphenyl group. After purifying the phenol derivative represented by) by column chromatography or the like, the phenol derivative is converted to phenoxide, and dihaloethane is allowed to act on the phenol derivative.

[0009]

[Chemical 6] (In the formula, R ₄ represents a lower alkyl group or a lower cycloalkyl group, R ₇ represents a hydrogen atom or a hydroxyl group,
Ar represents a 3,4-methylenedioxyphenyl group,
X represents a halogen atom. )

It can be obtained by obtaining a halogen derivative represented by and reacting it with a suitable amine.
The triarylalkene derivative represented by the chemical formula 1 obtained here is a mixture of E / Z isomers with respect to a carbon-carbon double bond, but it is separated into two peaks on a high performance liquid chromatograph. Each can be separated individually by adding a preparative operation. As another separation method, a salt of a mineral acid may be used for separation by a recrystallization method. Further, the compound of the present invention represented by the chemical formula 1 can be treated with an inorganic acid or an organic acid to induce a pharmaceutically acceptable acid addition salt. As the inorganic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc., and as the organic acid, citric acid, maleic acid, malic acid, fumaric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, oxalic acid, etc. Acid etc. are mentioned.

The compound of the present invention represented by the chemical formula 1 and the pharmaceutically acceptable acid addition salts have an excellent anti-estrogen action and are particularly effective for the treatment of breast tumors. Examples of dosage forms for administering the compound of the present invention include:
Oral agents such as tablets, capsules, granules, powders, and liquids,
Injections, suppositories and the like may be taken, but oral preparations are generally preferred. Tablets, capsules, granules, as a form used when producing powders, for example, lactose, sucrose, starch, talc, magnesium stearate, crystalline cellulose, methyl cellulose, glycerin, sodium alginate, acacia, corn starch, Glucose, sorbit, silicon dioxide, etc., as the binder, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, gum arabic, sierra tuk, sucrose, tragacanth, gelatin, hydroxypropyl cellulose, hydroxypropyl starch, polyvinylpyrrolidone, etc. as the lubricant. , Magnesium stearate, talc and the like, and other commonly known additives such as colorants and disintegrants can be optionally used. The tablets may be coated by a known method. The liquid preparation may be an aqueous or oily suspension, solution, syrup, or elixir, and is prepared according to a conventional method using usual additives.

The dose of the compound of the present invention to be orally administered to a patient varies depending on the patient's symptoms, body weight, age and the like and cannot be specified unconditionally, but it is usually about 1 to 5 per adult.
The dose may be 00 mg, which is preferably administered in 1 to 4 divided doses. In addition, the content of the active ingredient compound per unit preparation is preferably about 0.5 to 50 mg.

[0013]

INDUSTRIAL APPLICABILITY The triarylalkene derivative of the present invention shows a further superior antitumor effect than tamoxifen against breast tumors, and is a very useful compound as a drug.

[0014]

The present invention will be described in more detail with reference to Examples and Formulation Examples, but the present invention is not limited to these Examples. In the examples below, ¹ H
-NMR spectrum is PMX-60S manufactured by JEOL Ltd.
Using I or GX-400, TMS was measured as an internal standard, and chemical shifts are shown by δ values (ppm).

Example 1 (E · Z) -1- [4- (2-cyclohexylaminoe
Toxy) phenyl] -1- (4-hydroxyphenyl)
-2- (3,4-methylenedioxyphenyl) -1-bu
Synthesis of Ten (Compound 1) 16 ml of titanium tetrachloride was added dropwise to 240 ml of anhydrous tetrahydrofuran under ice cooling under an argon stream. After returning to room temperature and stirring for about 20 minutes, 14.3 g of zinc powder was added and the mixture was heated under reflux for 2 hours. After cooling the solution to room temperature, 4,
5.46 g of 4'-dihydroxybenzophenone and 3.42 g of propiophenone were added, and the mixture was heated under reflux for 4 hours. The reaction was cooled, added to 200 ml of water and then extracted with ether. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was removed under vacuum. The oily residue was applied to a silica gel column (developing solvent: hexane / ethyl acetate) to obtain about 8 g of crystals, which was recrystallized using a toluene solvent to give 1,1-bis (4-hydroxyphenyl) -2-. Phenyl-1-butene 6.15
White crystals of g were obtained. 3.0 g of this crystal is 14.3 ml
Was dissolved in 1,2-dibromoethane, and 0.513 g of powdery potassium hydroxide was added, and the mixture was heated under reflux for 2 days. Since the reaction proceeded about 20% and then stopped, the following treatment was performed at this stage. That is, the reaction system is set to 200
After diluting with ml methylene chloride and washing with a 2N aqueous hydrochloric acid solution, the organic layer was dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel chromatography (chloroform / methanol) to obtain 0.680 g of a brom body as a pale yellow viscous liquid. 2 g of the raw material diphenol body was recovered. The brominated body was positive in the Beilstein reaction. 0.2 g of this bromine product was dissolved in 0.5 ml of ethanol, and cyclohexylamine of 0.2.
5 ml was added, and the mixture was stirred at about 60 ° C. overnight. The reaction proceeded about 50% and then stopped, so that the following treatment was carried out at this stage. That is, the reaction system was concentrated under reduced pressure, and the obtained residue was separated and purified by preparative thin layer chromatography (chloroform: methanol = 8: 1) to obtain the desired product, 1- [4
-(2-Cyclohexylaminoethoxy) phenyl]-
45 mg of 1- (4-hydroxyphenyl) -2- (3,4-methylenedioxyphenyl) -1-butene was obtained as white crystals.

[0016] IH-NMR _{spectrum, δ (CDCl 3): 0.92} (3H, t, CH 2 C H 3) 1.13-2.05 (11H, m, cyclohexane ring methylene hydrogen, N H) 2 .38-2.43 (2H, m, C H 2 CH 3) 2.44-2.60 (1H, m, cyclohexane ring methine hydrogen) 2.99-3.09 (2H, m, OCH 2 C _{H 2 N) 3.90-4.52 (3H,} m, OC H 2 CH 2 N, O
H) 5.88-5.89 (2H, s, OC H 2 O) 6.44-7.18 (11H, m, aromatic protons)

Example 2 (E · Z) -1- [4- (2-dimethylaminoethoxy)
Si) phenyl] -1- (4-hydroxyphenyl) -2
-(3,4-Methylenedioxyphenyl) -1-butene
Synthesis of (Compound 1) 1.62 g of the bromine product of Example 1 was dissolved in 24 ml of ethanol, 1.00 ml of 50% aqueous dimethylamine solution was added, and the mixture was stirred at about 45 ° C. for 6 hours, and again 50% aqueous dimethylamine solution 1. 00 ml was added and the mixture was stirred at about 45 ° C. for 6 hours. The reaction proceeded for about 80% and then stopped, so the following treatment was carried out. That is, the reaction system was concentrated under reduced pressure, and the resulting residue was subjected to silica gel chromatography (ethanol /
Separated and purified with toluene) and then the desired product, 1- [4- (2
0.818 mg of -dimethylaminoethoxy) phenyl] -1- (4-hydroxyphenyl) -2- (3,4-methylenedioxyphenyl) -1-butene was obtained as white crystals.

[0018] IH-NMR _{spectrum, δ (CDCl 3): 0.82} (3H, t, CH 2 C H 3) 2.20-2.45 (8H, m, C H 2 CH 3, N (C
_{H 3) 2) 2.78-2.87 (2H} , m, OCH 2 C H 2 N) 3.85-4.00 (2H, m, OC H 2 CH 2 N) 5.77,5.80 _{(2H, s, OC H 2} O) 6.22-7.02 (11H, m, aromatic protons) 8.00-8.06 (1H, m, O H)

Example 3 The antiestrogenic activity of the triphenylethylene derivative of the present invention was evaluated by the effect of the compound on the uterine weight of rats. To a 3-week-old female SD rat, 100 μl of a predetermined amount of the triphenylethylene derivative of the present invention and 0.01 mg / ml of estradiol in olive oil were each added.
I was subcutaneously injected continuously for 3 days. On day 4, the uterus was taken out and the dry weight was measured. The uterine weight when Estradiol alone was administered was E, the uterine weight when olive oil alone was administered was V, and the uterine weight when Estradiol and the triphenylethylene derivative of the present invention were administered was W. The estrogen effect (the effect of suppressing the increase in uterine weight) was determined by the following formula 1.

[0020]

[Equation 1] The anti-estrogen action values of each derivative are summarized in Table 1. The value when tamoxifen was used is shown as a comparative example.

[0021]

[Table 1]

[0022]

[Preparation example] 0.2 g of 1- [4- (3-
Dimethylamino-2-hydroxypropoxy) phenyl] -1- (4-hydroxyphenyl) -2- (3,4
1-methylenedioxyphenyl) -1-butene
g mannitol, 0.15 g starch and 6 g alginic acid were mixed and granulated. The granules are dried, then 7.
It was mixed well with 5 mg of methylcellulose and 15 mg of magnesium stearate and compressed to give 10 tablets, each tablet containing 20 mg of active ingredient.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display area A61K 31/36 7252-4C 31/40 7252-4C 31/66 8314-4C 31/675 8314-4C C07D 295/08 Z 6701-4C C07F 9/09 K 7106-4H

Claims (2)

[Claims] 1. A triarylalkene derivative represented by the following chemical formula 1 or a pharmaceutically acceptable acid addition salt thereof. [Chemical 1] [Wherein R ₁ and R ₂ may be the same or different and each represents a hydrogen atom, a lower alkyl group or a lower cycloalkyl group, or R ₁ and R ₂ may contain a hetero atom together with an adjacent nitrogen atom. It represents a heterocyclic group, but R ₁ and R ₂ are not hydrogen atoms at the same time.
R ₃ is a hydrogen atom, a hydroxyl group, or R ₆ OCH ₂ O— or —OPO (OH) ₂ group, R ₅ represents a lower alkyl group, a lower cycloalkyl group or a substituted aryl group, and R ₆ represents a lower alkyl group or a lower alkylcarbonyl group. R ₄ represents a lower alkyl group or a lower cycloalkyl group. Ar represents a 3,4-methylenedioxyphenyl group. ] 2. A triarylalkene derivative represented by the chemical formula 1 or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable diluent or carrier. A pharmaceutical composition having a tumor suppressor effect.