JP2523015B2 - 1,1,2-triaryl-1-butene derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel 1,1,2-triaryl-1-butene derivative and a pharmaceutically acceptable salt thereof.

Conventional technology and its problems 1,1,2-triphenyl-1-butene as a basic structure,
Certain compounds in which one substituted aminoalkoxy group is substituted at the 4-position of one 1-phenyl group are known to have non-steroidal anti-estrogen activity. For example, the following structural formula The compound represented by: Tamoxifen (Tamoxife
n) is its representative, and its strong anti-estrogen action makes it a useful therapeutic drug for hormone-dependent breast cancer (UK Patent No. 1013907).

In addition, the following structural formula, which is one of its metabolites as a related compound of tamoxifen, 4-hydroxy tamoxifen represented by
Its pharmacological properties were studied (UK published patent No. 2
003855).

4-hydroxy tamoxifen is in vitro (in vit)
Ro) showed a stronger antitumor effect than tamoxifen against hormone-dependent experimental tumors and was expected to be developed as a therapeutic agent for breast cancer.
It was confirmed that its efficacy was inferior to that of tamoxifen in the anti-tumor experiment of o) [Journal of Biological Chemistry (J. Biol. Chem.) 1981, 256 , 859; Cancer Res.) 1982, 42 , 317. European Journal of Cancer and Clinical Oncology (Eur.J.Cancer Clin.Oncology) 19
80, 16 , 239].

Means for Solving the Problems The present invention, for estrogen-dependent tumors, has a further superior antitumor effect than tamoxifen, useful as a therapeutic agent for breast cancer and anovulatory infertility 1,1, It is intended to provide a 2-triaryl-1-butene derivative and a pharmacologically acceptable salt thereof.

The present invention provides a 1,1,2-triaryl-1-butene derivative represented by the following general formula (I) and a pharmacologically acceptable salt thereof.

(In the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom or a lower alkyl group, and R ³ represents a lower alkenyl group or a lower alkyl group having a hydroxyl group or a lower alkoxy group.) The above general formula (I) In the 1,1,2-triaryl-1-butene derivative of, there are two kinds of geometrical isomers, E and Z isomers. Here, the expression E-form or Z-form relates to the relative positions of the substituents bonded to the two carbon atoms forming the double bond, and the two substituents bonded to one carbon atom according to the sequence rule. And the upper one of the two substituents bonded to the other carbon atom are on opposite sides of the double bond.
Body, and those on the same side are Z bodies. For example, referring to the compound of the present invention represented by the general formula (I), a phenyl group to which a substituted aminoethoxy group is bonded and an aryl group substituted to the other double bond The relative position of is in the Z configuration on the same side of the double bond and in the E configuration on the opposite side. The isomers can be distinguished by observing the signal of each proton in the substituent of the substituted amino group of the substituted aminoethoxy group and the methylene group adjacent to the oxygen atom in the ¹ H-nuclear magnetic resonance (NMR) spectrum. . The present invention includes all E-forms and Z-forms having the above-mentioned characteristics and mixtures thereof. In particular, the Z form has been recognized to have a remarkable therapeutic effect.

Examples of the lower alkyl group represented by R ¹ and R ² in the general formula (I) include a methyl group, an ethyl group, a propyl group,
Isopropyl group, n-butyl group, isobutyl group, sec-
C1-C1 such as butyl, tert-butyl, and pentyl groups
The alkyl group of 5 can be illustrated. As the lower alkyl group having a hydroxyl group represented by R ³ , a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 1-hydroxy-1-methylethyl group, a 2-hydroxy-1-methylethyl group, Carbon number 1 containing 1 or 2 hydroxyl groups such as 2-hydroxy-1-methylpropyl group, 1,2-dihydroxyethyl group, 1,2-dihydroxy-1-methylethyl group, 1,2-dihydroxypropyl group ~ 5
The lower alkyl group having a lower alkoxy group is a lower alkyl group having a lower alkoxy group having 1 to 4 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group and a butoxy group as a substituent. Include a methoxymethyl group, a 1-methoxyethyl group, a 1-methoxypropyl group, a 1-methoxy-1-methylethyl group, a 1-ethoxy-1-methylethyl group, a 1-propoxy-1-methylethyl group and the like. To be As the lower alkenyl group, a vinyl group, a 1-propenyl group, an isopropenyl group,
Examples thereof include alkenyl groups having 2 to 5 carbon atoms such as an isobutenyl group.

Examples of the salt of the compound of the present invention represented by the general formula (I) include inorganic acid salts such as hydrochloric acid, phosphoric acid and sulfuric acid, acetic acid, oxalic acid, tartaric acid, malic acid, citric acid, glutaric acid, Examples of pharmaceutically acceptable salts include organic acid salts such as methanesulfonic acid and p-toluenesulfonic acid.

The 1,1,2-triaryl-1-butene derivative of the present invention can be produced, for example, according to the following reaction process formulas (1) to (6).

(In the formula, R ¹ and R ² are the same as above. R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom or a lower alkyl group.) In the above reaction scheme, the compound represented by the general formula (II) is known. A compound or a known method,
For example, The Journal of Organic Chemistry, Volume 47,
The manufacturing method is described in 2387 (1982).

The lower alkyl group represented by R ⁴ and R ⁵ has a carbon number such as methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group and pentyl group. The alkyl group of 1-5 can be illustrated.

<Step A> The tetrahydropyranyl ether represented by the general formula (III) is obtained by reacting the compound represented by the general formula (II) with 2,3-dihydropyran in the presence of an acid catalyst in a suitable solvent. Get the body. The solvent is not particularly limited as long as it does not participate in the reaction, and aprotic solvents such as N, N-dimethylformamide, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, dioxane and the like can be used. As the acid catalyst, for example, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or the like can be used. With respect to the reaction rate, it is preferable that 2,3-dihydropyran is used in an equimolar amount to an excess amount and the acid catalyst is used in 1.1 to 3 times the molar equivalent with respect to the compound of the general formula (II). The reaction temperature is not particularly limited, but the reaction proceeds sufficiently quickly at room temperature.

<Step B> The obtained compound of the general formula (III) is reacted with an alkyllithium in a suitable solvent at 0 ° C. or lower to exchange the bromine group with a lithium group, and then the compound is represented by the general formula (IV). The compound represented by the general formula (V) is obtained by adding an aldehyde or ketone derivative and conducting a condensation reaction. The solvent is not particularly limited as long as it does not participate in the reaction, and tetrahydrofuran, dimethoxyethane or the like can be used. Examples of the alkyl lithium include methyl lithium, n-butyl lithium, sec-butyl lithium, tert.
-Butyl lithium and the like are used, and it is preferable to use 1 to 3 equivalents relative to the compound of the general formula (III). Further, the derivative represented by the general formula (IV) can be used in a large excess amount with respect to the compound of the general formula (III), and it is usually preferable to use 2 to 10 times equivalent amount thereof. The reaction temperature is preferably 0 ° C. or lower before the addition of the derivative represented by the general formula (IV), and after the addition, it is preferable to heat from room temperature to 50 ° C.

<Step C> The obtained compound represented by the general formula (V) is de-tetrahydropyranylated with an acid in a suitable solvent to obtain the desired 1,1,2-triaryl represented by the general formula (Ia). A -1-butene derivative is obtained. The solvent is not particularly limited as long as it does not participate in the reaction, and for example, an aprotic solvent such as N, N-dimethylformamide, tetrahydrofuran, dioxane, chloroform, or a mixed solvent of these and water can be used. As the acid, for example, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, acetic acid, propionic acid, trifluoroacetic acid and the like can be used, and they are usually easily deprotected at room temperature under ice cooling.

(In the formula, R ¹ , R ² and R ⁴ are the same as above. R ⁴ ′ and R ⁵ ′ are the same or different and each represents a hydrogen atom or a lower alkyl group.
At least one of R ⁴ ′ and R ⁵ ′ represents a lower alkyl group.
R ⁶ is the same as or different from R ⁴ and represents a hydrogen atom or a lower alkyl group. ) By reacting the compound (V ') obtained according to the reaction step formula (1) with a dehydrating agent in the presence or absence of a suitable solvent, 1,1 represented by the general formula (Ib) of interest can be obtained. A 2,2-triaryl-1-butene derivative is obtained. The solvent is not particularly limited as long as it does not participate in the reaction, for example N,
A solvent such as N-dimethylformamide, tetrahydrofuran, dioxane, chloroform, benzene or 1,2-dichloroethane can be used. As the dehydrating agent, a general reagent which can be usually used for producing a derivative of styrene or α-methylstyrene can be used. For example, acetic acid, propionic acid,
Organic acids such as oxalic acid, maleic acid, succinic acid, p-toluenesulfonic acid and mesylic acid, and inorganic acids such as hydrochloric acid and sulfuric acid can be used as they are or diluted with water. The dehydrating agent may be used in the same amount to an excess amount with respect to the compound of the general formula (V ′), and it is usually preferable to use 2 to 10 times equivalent amount.
The reaction temperature is preferably room temperature to 130 ° C., and the reaction time is preferably 2 to 10 hours. Alternatively, it is also effective to use thionyl chloride, phosphorus oxychloride, phosphorus tribromide or the like as a dehydrating agent in the above-mentioned solvent and to use it in 1 to 3 molar equivalents relative to the compound of the general formula (V ′).

(In the formula, R ¹ , R ² , R ⁴ and R ⁶ are the same as above.) The compound represented by the general formula (Ib) obtained by the reaction step formula (2) is treated with a hydroborane derivative in a suitable solvent. After the reaction, the desired 1,1,2-triaryl-1-butene derivative represented by the general formula (Ic) is obtained by hydrolyzing with a hydrogen peroxide solution in a suitable alkaline solution. The solvent is not particularly limited as long as it does not participate in the reaction, and for example, tetrahydrofuran, dioxane, benzene, toluene and the like can be used. Examples of the hydroborane derivative include diborane and 9-borabicyclo [3.3.1]
A commonly used borane derivative such as nonane (hereinafter abbreviated as 9-BBN) can be used, and it is preferably used in 2 to 10 times molar equivalent with respect to the compound represented by the general formula (Ib). The reaction temperature is preferably room temperature to 100 ° C. After the reaction, the solvent is distilled off, then dissolved in alcohols such as methanol, ethanol, isopropanol, etc.
It is preferable to add 10 times molar amount of sodium hydroxide, potassium hydroxide aqueous solution or sodium alkoxide to make it alkaline, and then use 30% hydrogen peroxide aqueous solution in 2 to 8 times molar amount. The reaction temperature is preferably room temperature to 80 ° C. for hydrolysis.

(In the formula, R ¹ , R ² , R ⁴ and R ⁶ are the same as the above.) The compound represented by the general formula (Ib) obtained in the reaction step formula (2) is 1 to 5 molar equivalents in pyridine. After reacting with osmium tetroxide at room temperature to 50 ° C., a water-pyridine mixed aqueous solution of sodium bisulfite is added to hydrolyze the osmium ester at room temperature to give the compound represented by the general formula (Id) of interest. A 1,1,2-triaryl-1-butene derivative is obtained.

(In the formula, R ¹ , R ² , R ⁴ and R ⁵ are the same as above. R ⁷ represents a lower alkyl group.) The compound represented by the general formula (V) obtained by the reaction formula (1) 2 in the lower alcohol represented by the general formula (VI)
By treatment with concentrated hydrochloric acid or hydrogen chloride gas in a molar ratio of up to 50 times, detetrahydropyranylation is performed, and an alcohol is added, which is represented by the general formula (Ie) of 1,1,2-
A triaryl-1-butene derivative is obtained. General formula (VI)
As the lower alcohol represented by, for example, methanol, ethanol, propanol, butanol and the like can be used. The reaction temperature is preferably room temperature to 50 ° C.

(In the formula, R ¹ and R ³ are the same as above. R ¹ ′ and R ² ′ are the same or different and each represents a lower alkyl group.) Of the compounds represented by the general formula (I), R ¹ and R ² When both of are lower alkyl groups, that is, in the case of the compound represented by the above general formula (I ′), ^{one of the} lower alkyl groups represented by R ¹ or R ² is de-N-alkylated, The target 1,1,2-triaryl-1-butene derivative represented by the general formula (If) is obtained.

Specifically, the compound represented by the general formula (I ') is refluxed or sealed with 2-5 times the molar equivalent of vinyloxycarbonyl chloride in a suitable solvent and sealed at a temperature of 140-170 ° C for 3-12.
After reacting for a period of time, the solvent is distilled off, and the resulting vinyloxycarbamoyl compound is immediately hydrolyzed in a lower alcohol solvent with an excess of concentrated hydrochloric acid or sodium ethoxide in excess of 5-fold molar equivalent at 50 to 90 ° C. As a result, a 1,1,2-triaryl-1-butene derivative represented by the general formula (If) that is de-N-alkylated is obtained. The solvent is not particularly limited as long as it does not participate in the reaction, for example, 1,2
-Apolar solvents such as dichloroethane, dioxane, toluene, xylene can be used.

The compounds represented by the general formula (I) obtained by the above reaction process formulas (1) to (6) are all a mixture of geometrical isomers of E isomer and Z isomer, and can be directly used for therapeutic use. is there. However, if each of E-form and Z-form is desired separately, they may be recrystallized or silica gel modified with octyl group, silica gel modified with octadecyl group, etc. According to the method, the E body and the Z body can be easily separated from each other.

Further, the pharmacologically acceptable salt of the compound represented by the general formula (I) is a mixture of E isomers and Z isomers or a compound obtained by separating E isomer and Z isomer from each other, and a known conventional method for producing a salt, for example, It can be obtained by reacting the acid with 1 molar equivalent or a slight excess in a suitable solvent. The solvent is not particularly limited as long as it does not participate in the reaction, and for example, ether, dioxane, dichloromethane, chloroform, methanol, ethanol, hexane and the like can be used alone or as a mixed solvent. The salts thus obtained can be used in the therapeutic applications of the invention.

The compounds of the present invention represented by the general formula (I) and their pharmacologically acceptable salts are more effective than conventional 1,1,2-triaryl-1-butene anti-estrogens represented by tamoxifen. It has an excellent anti-estrogen action without increasing toxicity, and is particularly effective for treating breast tumors and anovulatory infertility.

EXAMPLES Next, the present invention will be described in more detail by showing Reference Examples and Examples.

Reference Example 1 (E, Z) -2- (4-bromophenyl) -1- {4-
[2-Dimethylamino) ethoxy] phenyl} -1-
[4- (2-tetrahydropyranyloxy) phenyl]
-1-Manufacturing Butene The Journal of Organic Chemistry, 1982, 47th
Vol., Page 2387. (E, Z) -2- (4-bromophenyl) -1- {4-
[2-Dimethylamino) ethoxy] phenyl} -1-
159 g of (4-hydroxyphenyl) -1-butene (0.316
Mol) and 66.1 g (0.347 mol) of p-toluenesulfonic acid
To the N, N-dimethylformamide (0.9) solution, 615 g (7.31 mol) of 2,3-dihydropyran was added, and the mixture was stirred at room temperature overnight. 70 g of triethylamine was added dropwise to the reaction solution at 20 ° C or lower to neutralize and then concentrated. Add 500 ml of water to the residue and add 2N.
-Adjust the pH to 12-13 with aqueous sodium hydroxide, extract with ethyl ether 1, and wash the organic layer with water (250 ml x 3).
After that, it was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography using a mixed solvent of ethanol: chloroform (1:10) as a light brown oil (E, Z) -2- (4-bromophenyl).
-1- {4- [2-dimethylamino) ethoxy] phenyl} -1- [4- (2-tetrahydropyranyloxy)
132 g (yield 76%) of phenyl] -1-butene was obtained.

The obtained compound is a mixture of the E-form and the Z-form in a ratio of about 1: 1 as described above, but it can be used as it is in the reaction of the next step. Since it was necessary to confirm the structure, a part of this mixture was used and E form and Z form were separated as follows.

Take 1 g of E, Z mixture, subject to silica gel column chromatography (200 g of silica gel) again, and elute with a mixed solvent of ethanol: chloroform (1:10),
The above fraction was recrystallized from methanol to obtain (E) -2- (4
0.3 g of -bromophenyl) -1- {4- [2- (dimethylamino) ethoxy] phenyl} -1- [4- (2-tetrahydropyranyloxy) phenyl] -1-butene was obtained, and the subsequent fractionation Is recrystallized from ethanol (Z) -2-
(4-Bromophenyl) -1- {4- [2- (dimethylamino) ethoxy] phenyl} -1- [4- (2-tetrahydropyranyloxy) phenyl] -1-butene 0.35
got g.

Mp 111 to 113 ° C. Fast Atomic Bombardment Mass spectrum (hereinafter, abbreviated as FABMS) m / e: 550,552 (hereinafter referred EIMS) (M ⁺ H) + electron impact mass spectra m / e: 549,551 (M) + 1 H- nuclear magnetic resonance spectrum _{δppm (CDCl 3): 0.91 (} 3H, t, J = 7.3Hz, -CH 2 CH 3), 1.4-2.0 (6H, m, 2.29 (6H, s, -N ( CH 3) 2), 2.45 (2H, q, J = 7.3Hz, -CH 2 CH 3), 2.65 (2H, t, J = 5.9Hz, -OCH 2 CH 2 N =), 3.45-4.1 (2H, m, 3.94 (2H, t, J = 5.9Hz, -OCH ₂ CH ₂ N =), 5.41 (1H, brs, 6.5−7.4 (12H, m, ArH) Melting point 120-121 ° C Elemental analysis value (%) (as C ₃₁ H ₃₆ BrNO ₃ ) Calculated value: C 67.63, H 6.59, N 2.54 Actual value: C 67.87, H 6.38, N 2.59 EIMS m / e: 549 (M ) ^{+ 1} H- nuclear magnetic resonance spectrum _{δppm (CDCl 3): 0.91 (} 3H, t, J = 7.3Hz, -CH 2 CH 3), 1.4-2.0 (6H, m, 2.34 (6H, s, -N ( CH 3) 2), 2.45 (2H, q, J = 7.3Hz, -CH 2 CH 3), 2.73 (2H, t, J = 5.9Hz, -OCH 2 CH 2 N =), 3.4-4.0 (2H, m, 4.07 (2H, t, J = 5.9Hz, -OCH ₂ CH ₂ N =), 5.27 (1H, brs, 6.6-7.4 (12H, m, ArH) Reference Example 2 (E, Z) -2- [4- (1-hydroxy-1-methylethyl) phenyl] -1- {4- [2- (dimethylamino) ethoxy ] Phenyl} -1- [4- (2-tetrahydropyranyloxy) phenyl] -1-butene (E, Z) -2- (4-bromophenyl) -1- {4 produced in Reference Example 1 -[2- (Dimethylamino) ethoxy] phenyl} -1- [4- (2-tetrahydropyranyloxy) phenyl] -1-butene 93.8 g (0.17 mol)
Was dissolved in 0.45 dry tetrahydrofuran, and 212 ml of a 1.6 M n-butyllithium-hexane solution was added dropwise at a temperature of -50 ° C or lower under a nitrogen gas atmosphere. After completion of dropping, the mixture was further stirred at −50 ° C. for 30 minutes, and then 25.3 ml of acetone (0.343
Mol) was added dropwise at the same temperature and then stirred for 1 hour. After adding 50 g of dry ice powder to the reaction solution, the temperature was gradually returned to room temperature, and then the solvent was distilled off under reduced pressure. Water 0.4 on the residue
Was added, the pH was adjusted to 13 with a 2N sodium hydroxide aqueous solution, and the mixture was extracted with ethyl ether, and the organic layer was washed with water (250 ml x
After 3), it was dried over anhydrous magnesium sulfate and concentrated. (E, Z) -2- [4- (1-hydroxy-1-methylethyl) phenyl] -1- {4- [2- as a light brown oil
(Dimethylamino) ethoxy] phenyl} -1- [4-
(2-Tetrahydropyranyloxy) phenyl] -1-
Butene 91.2 g (yield 90%) was obtained.

FABMS m / e: 530 (M + H) ^{+ The} obtained compound is a mixture of E-form and Z-form in a ratio of about 1: 1 and can be used as it is for the next step reaction. Since it was necessary to confirm the structure, a part of this mixture was used, and E form and Z form were separated as follows.

1 g of the E and Z mixture was taken and subjected to silica gel column chromatography (200 g of silica gel), and chloroform:
Elution with a mixed solvent of methanol (1:10), recrystallization of the above fraction from acetonitrile, and (Z) -2- [4-
(1-Hydroxy-1-methylethyl) phenyl] -1
-{4- [2- (dimethylamino) ethoxy] phenyl} -1- [4- (2-tetrahydropyranyloxy)
0.32 g of phenyl] -1-butene was obtained, and the subsequent fraction was recrystallized from acetonitrile to give (E) -2- [4- (1-hydroxy-1-methylethyl) phenyl] -1- {4-
[2- (dimethylamino) ethoxy] phenyl} -1-
[4- (2-tetrahydropyranyloxy) phenyl]
There was obtained 0.28 g of -1-butene.

Melting point 133 to 134.5 ° C Elemental analysis value (%) (as C ₃₄ H ₄₃ NO ₄ ) Calculated value: C 77.09, H 8.18, N 2.64 Measured value: C 77.30, H 8.37, N 2.81 EIMS m / e: 529 (M ) ^{+ 1} H- nuclear magnetic resonance spectrum _{δppm (DMSO-d 6):} 0.84 (3H, t, J = 6.8Hz, -CH 2 CH 3), 1.38 (6H, s, -C (CH 3) 2 O) , 1.3-1.9 (6H, m, 2.22 (6H, s, -N ( CH 3) 2), 2.63 (2H, t, -OCH 2 CH 2 N =), 3.3-3.9 (2H, m, 4.05 (2H, t, J = 5.6Hz, -OCH ₂ CH ₂ N =), 4.92 (1H, s, OH), 5.28 (1H, brs, 6.5−7.4 (12H, m, ArH) Melting point 120 to 122 ° C Elemental analysis value (%) (as C ₃₄ H ₄₃ NO ₄ ) Calculated value: C 77.09, H 8.18, N 2.64 Measured value: C 76.98, H 7.89, N 2.81 EIMS m / e: 529 (M ) ^{+ 1} H- Nuclear magnetic resonance spectrum δppm (DMSO-d ₆ ): 0.84 (3H, t, J = 6.8Hz-CH ₂ CH ₃ ), 1.37 (6H, s, -C (CH ₃ ) ₂ O), 1.4-1.9 (6H, m, 2.15 (6H, s, -N ( CH 3) 2), 3.4-4.0 (2H, m, 3.89 (2H, t, J = 5.6Hz, -OCH ₂ CH ₂ N =), 4.90 (1H, s, OH), 5.45 (1H, brs, 6.5-7.4 (12H, m, ArH) Example 1 (E, Z) -2- [4- (1-hydroxy-1-methylethyl) phenyl] -1- {4- [2- (dimethylamino) ethoxy ] Production of phenyl} -1- (4-hydroxyphenyl) -1-butene (E, Z) -2- [4- (1-hydroxy-1-methylethyl) phenyl] -1- produced in Reference Example 2 {4-
[2- (dimethylamino) ethoxy] phenyl} -1-
[4- (2-tetrahydropyranyloxy) phenyl]
4.46 g (8.42 mmol) of -1-butene was dissolved in 40 ml of tetrahydrofuran, 4 ml of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was neutralized with a saturated aqueous solution of sodium hydrogen hydrogen and extracted with chloroform, and the organic layer was subjected to silica gel column chromatography (silica gel 0.4 kg, chloroform:
(E, Z) -2- [4- (1-hydroxy-1-methylethyl) phenyl] -1- {4- [2- (dimethylamino) as a light brown solid. ) Ethoxy] phenyl} -1- (4-hydroxyphenyl) -1-butene (1.64 g, yield 44%) was obtained.

Melting point 75-85 ° C EIMS m / e: 445 (M) ⁺ 1.60 g of E and Z mixture obtained above was packed with octadecylation-modified (ODS) silica gel (particle size 15-30 μm) (30 × 500 mm) Thus, the E form and the Z form were separated from each other. The injection amount is E, Z mixture 0.4g methanol 3ml
As a solution, methanol / phosphate buffer (pH 6.8 / 10mM) (75:25) was used as the elution solvent, eluted at a flow rate of 16.6 ml / min, and the eluate was detected with an ultraviolet absorption detector (275 nm). The first-eluted fraction (first fraction) and the second-eluted fraction (second fraction) are separated, and the respective fractions are subjected to solvent distillation under reduced pressure at low temperature, and then a 10% aqueous sodium hydrogencarbonate solution is added. In addition, the mixture was extracted with ether, the ether layer was washed with water and then dried over anhydrous potassium carbonate. The solvent was distilled off under reduced pressure and vacuum dried at room temperature,
A colorless solid was obtained in each case. Repeat this operation 4 times E, Z
1.6 g of the mixture was processed.

From the first fraction (Z) -2- [4- (1-hydroxy-
0.355 g of 1-methylethyl) phenyl] -1- {4- [2- (dimethylamino) ethoxy] phenyl} -1- (4-hydroxyphenyl) -1-butene was obtained.

Melting point 133-136 ° C Elemental analysis value (%) (as C ₂₉ H ₃₅ NO ₃ · H ₂ O) Calculated value: C 75.13, H 8.04, N 3.02 Measured value: C 75.27, H 8.05, N 3.05 EIMS m / e : 445 ^{(M) + 1} H- nuclear magnetic resonance spectrum _{δppm (DMSO-d 6):} 0.84 (3H, t, J = 7.1Hz, -CH 2 CH 3), 1.37 (6H, s, -CCH 3) 2 O), 2.16 (6H, s , -NCH 3) 2), 3.89 (2H, t, J = 6.7Hz, -OCH 2 CH 2 N =), 4.90 (1H, s, OH), 6.5-7.4 (12H , m, ArH), 9.40 (1H, brs, ArOH) From the second fraction, (E) -2- [4- (1-hydroxy-1-methylethyl) phenyl] -1- {4- [2-
(Dimethylamino) ethoxy] phenyl} -1- (4-
0.428 g of hydroxyphenyl) -1-butene was obtained.

Melting point 150-152 ° C Elemental analysis value (%) (as C ₂₉ H ₃₅ NO ₃ ) Measured value: C 78.17, H 7.92, N 3.14 Measured value: C 77.92, H 8.04, N 3.12 EIMS m / e: 445 (M ) ^{+ 1} H- nuclear magnetic resonance spectrum _{δppm (DMSO-d 6):} 0.84 (3H, t, J = 7.1Hz, -CH 2 CH 3), 1.38 (6H, s, -C (CH 3) 2 O) , 2.23 (6H, s, -N (CH 3) 2), 2.63 (2H, t, J = 6.7Hz, = -OCH 2 CH 2 N), 4.05 (2H, t, J = 6.7Hz, -OCH 2 _{CH 2 N =), 4.93 (} 1H, s, OH), 6.3-7.4 (12H, m, ArH), 9.16 (1H, brs, ArOH) example 2 (E, Z) -2- ( 4- isopropenyl Phenyl) -1
Preparation of-{4- [2- (dimethylamino) ethoxy] phenyl} -1- (4-hydroxyphenyl) -1-butene (E, Z) -2- [4- (1- Hydroxy-1-methylethyl) phenyl] -1- {4-
[2- (dimethylamino) ethoxy] phenyl} -1-
[4- (2-tetrahydropyranyloxy) phenyl]
5.76 g (10.9 mmol) of -1-butene was dissolved in 25 ml of acetic acid and the mixture was stirred at 90 ° C for 5 hours, and then saturated potassium carbonate aqueous solution
After pouring into 350 ml and stirring at room temperature for 30 minutes, the precipitated colorless precipitate was collected and washed with water. The obtained solid was purified by silica gel column chromatography (silica gel 300 g, solvent chloroform: methanol (6: 1)) to give (E, Z) -2- (4-isopropenylphenyl) -1- {4 as a colorless solid. -[2- (dimethylamino) ethoxy]
Phenyl} -1- (4-hydroxyphenyl) -1-butene (3.90 g, yield 84%) was obtained.

0.90 g of the E and Z mixture obtained here is injected once at 0.3 g
Was dissolved in methanol (3 ml) and the elution solvent was changed to methanol / phosphate buffer (pH 6.8 / 10 mM) (80:20), and fractionation was performed by the same ODS column chromatography separation operation as in Example 1. . The obtained solid of each fraction was dissolved in tetrahydrofuran, an excess hydrogen chloride-dioxane solution was added, and then ether was added for crystallization. These were collected, washed with ether, and dried in vacuum to give each hydrochloride.

From the first fraction, hydrochloric acid (Z) -2- (4-isopropenylphenyl) -1- {4- [2- (dimethylamino) ethoxy] phenyl} -1- (4-hydroxyphenyl)-
0.126 g of 1-butene was obtained.

Melting point 212-215 ° C Elemental analysis value (%) (as C ₂₉ H ₃₃ NO ₂ · HCl) Calculated value: C 75.06, H 7.38, N 3.02 Measured value: C 74.60, H 7.34, N 2.96 EIMS m / e: 427 ^{(M) + 1} H- nuclear magnetic resonance spectrum _{δppm (DMSO-d 6):} 0.85 (3H, t, J = 6.8Hz, -CH 2 CH 3), 2.05 (3H, s, -C (= CH 2) _{CH 3), 2.42 (2H,} q, -CH 2 CH 3), 2.79 (6H, s, -N (CH 3) 2, 4.20 (2H, brt, J = 5.6Hz, -OCH 2 CH 2 N =) , 5.05,5.41 (each 1H, s, -C (= CH 2) CH 3), 6.6-6.85 (6H, m, ArH), 6.98 (2H, d, J = 9.0Hz, ArH meta to OH), 7.08 , 7.34 (each 2H, d, J = 8.4Hz, ArH ortho and meta to
_{-C (= CH 2) CH 3} ), 9.47 (1H, s, ArOH), 10.01 (1H, brs, -NH + (CH 3) 2 · Cl -) from the second fraction hydrochloric acid (E) -2 -(4-isopropenylphenyl) -1- {4- [2- (dimethylamino) ethoxy] phenyl} -1- (4-hydroxyphenyl)
0.13 g of -1-butene was obtained.

Melting point 126-130 ° C Elemental analysis value (%) (as C ₂₉ H ₃₃ NO ₂ · HCl) Calculated value: C 75.06, H 7.38, N 3.02 Measured value: C 74.61, H 7.34, N 2.96 EIMS m / e: 427 ^{(M) + 1} H- nuclear magnetic resonance spectrum _{δppm (DMSO-d 6):} 0.85 (3H, t, J = 6.8Hz, -CH 2 CH 3), 2.06 (3H, s, -C (= CH 2) _{CH 3), 2.40 (2H,} q, -CH 2 CH 3), 2.86 (6H, s, -H (CH 3) 2), 3.52 (2H, brt, J = 5.6Hz, -OCH 2 CH 2 N = ), 4.36 (2H, brt, J = 5.6Hz, -OCH 2 CH 2 N =), 5.05,5.41 ( each 1H, s, -C (= CH 2) CH 3), 6.43 (2H, d, J = 8.5Hz, ArH ortho to OCH ₂ CH ₂ N (CH ₃ )
₂ ), 6.63 (2H, d, J = 8.5Hz, ArH meta to OCH ₂ CH ₂ N (CH ₃ )
₂ ), 6.99 (2H, d, J = 9.2Hz, ArH ortho to OH), 7.15 (2H, d, J = 9.2Hz, ArH meta to OH), 7.07,7.34 (each 2H, d, J = 8.2Hz) , ArH ortho and meta to
_{-C (= CH 2) CH 3} ), 9.23 (1H, s, ArOH), 10.25 (1H, brs, -NH + (CH 3) 2 · Cl -) Example 3 (E, Z) -2- [ Preparation of 4- (2-hydroxy-1-methylethyl) phenyl] -1- {4- [2- (dimethylamino) ethoxy] phenyl} -1- (4-hydroxyphenyl) -1-butene In Example 2 Prepared (E, Z) -2- (4-isopropenylphenyl) -1- {4- [2- (dimethylamino)
2.43 g (5.69 mmol) of ethoxy] phenyl} -1- (4-hydroxyphenyl) -1-butene and 2.68 g (21 mmol) of 9-borabicyclo [3.3.1] nonane (9-BBN) under an argon gas atmosphere. It was stirred in 80 ml of benzene for 10 hours. After distilling off benzene, the residue was dissolved in 60 ml of methanol and 28% sodium methoxide-methanol solution 1
4.2 ml (70 mmol), then 30% hydrogen peroxide water 7.9 ml
(70 mmol) was carefully added dropwise. After the dropwise addition was completed, the mixture was stirred at 50 ° C. in water for 2.5 hours and then concentrated to about 1/3 volume. 5%
Aqueous potassium carbonate solution (100 ml) was added to this solution and extracted with chloroform (70 ml × 3). The chloroform layer was washed with saturated brine and the solvent was evaporated to give a brown oil. Purification by silica gel column chromatography (200 g of silica gel, solvent chloroform: methanol (5: 1)) gave (E, Z) -2- [4- (2-hydroxy-1) as pale yellow crystals.
-Methylethyl) phenyl] -1- {4- [2- (dimethylamino) ethoxy] phenyl} -1- (4-hydroxyphenyl) -1-butene (1.12 g, yield 44%) was obtained.

0.92 g of the E and Z mixture obtained here is injected once at 0.46 g
Was dissolved in methanol in 3 ml and the elution solvent was changed to methanol / phosphate buffer (pH 6.8 / 10 mM) (75:25) by the same procedure as in Example 1 for separation by ODS column chromatography. Painted. When the obtained eluate of each fraction is concentrated under reduced pressure, colorless crystals are precipitated.
A 5% aqueous sodium hydrogencarbonate solution was added to this, which was crushed well, then collected, washed with water, and vacuum dried.

From the first fraction (Z) -2- [4- (2-hydroxy-
0.28 g of 1-methylethyl) phenyl] -1- {4- [2- (dimethylamino) ethoxy] phenyl} -1- (4-hydroxyphenyl) -1-butene was obtained.

Melting point 126-128 ° C Elemental analysis value (%) (as C ₂₉ H ₃₅ NO ₃ ) Calculated value: C 78.17, H 7.92, N 3.14 Measured value: C 78.11, H 7.75, N 3.09 EIMS m / e: 445 (M ) ^{+ 1} H- nuclear magnetic resonance spectrum _{δppm (DMSO-d 6):} 0.84 (3H, t, J = 7.0Hz, -CH 2 CH 3), 1.14 (3H, d, J = 6.8Hz, -CH (CH ₂ OH) CH ₃ ), 2.15 (6H, s, -N (CH ₃ ) ₂ ), 2.74 (2H, t, J = 5.7Hz, -OCH ₂ CH ₂ N =), 3.1-3.6 (2H, m, _{-CH (CH 2 OH) CH 3} ), 3.89 (2H, t, J = 5.7Hz, -OCH 2 CH 2 N =), 4.59 (1H, t, J = 5.6Hz, -CH 2 OH), 6.56, 6.71 (2H, d, J = 8.9Hz, ArH ortho and meta to
-OCH ₂ CH ₂ N (CH ₃ ) ₂ ), 6.73,6.96 (2H, d, J = 8.6Hz, ArH ortho and meta to
−OH), 7.01 (4H, s, ArH ortho and meta to −CH (CH ₂ OH) CH
₃ ), 9.38 (1H, s, ArOH), from the second fraction (E) -2- [4- (2-hydroxy-
0.29 g of 1-methylethyl) phenyl] -1- {4- [2- (dimethylamino) ethoxy] phenyl} -1- (4-hydroxyphenyl) -1-butene was obtained.

Melting point 155 to 157 ° C Elemental analysis value (%) (as C ₂₉ H ₃₅ NO ₃ ) Calculated value: C 78.17, H 7.92, N 3.14 Measured value: C 78.09, H 8.10, N 3.06 EIMS m / e: 445 (M ) ^{+ 1} H- nuclear magnetic resonance spectrum _{δppm (DMSO-d 6):} 0.83 (3H, t, J = 7.0Hz, -CH 2 CH 3), 1.14 (3H, d, J = 6.8Hz, -CH (CH ₂ OH) CH ₃ ), 2.22 (6H, s, -N (CH ₃ ) ₂ ), 2.82 (2H, t, J = 5.6Hz, -OCH ₂ CH ₂ N =), 3.1-3.6 (2H, m, _{-CH (CH 2 OH) CH 3} ), 4.04 (2H, t, J = 5.6Hz, -OCH 2 CH 2 N =), 4.60 (1H, brt, -CH 2 OH), 6.39,6.60 ( each 2H, d, J ＝ 8.6Hz, ArH ortho and meta to
-OCH ₂ CH ₂ N (CH ₃ ) ₂ ), 6.90, 7.06 (2H, d, J = 8.8Hz, ArH ortho and meta to
−OH), 7.01 (4H, s, ArH ortho and meta to −CH (CH ₂ OH) CH
₃ ), 9.16 (1H, s, ArOH) Example 4 (E, Z) -2- [4- (1,2-dihydroxy-1-methylethyl) phenyl] -1- {4- [2- (dimethyl Production of (amino) ethoxy] phenyl} -1- (4-hydroxyphenyl) -1-butene (E, Z) -2- (4-isopropenylphenyl) -1- {4- [2 produced in Example 2 -(Dimethylamino)
Ethoxy] phenyl} -1- (4-hydroxyphenyl] -1-butene 2.0 g (4.68 mmol) pyridine 15 ml
1.0 g of osmium tetroxide was added to and the mixture was stirred at room temperature for 5 hours. Add 1.8 g of sodium bisulfite and 20 ml of pyridine to this solution.
30 ml of water solution was added and stirred for 30 minutes. The reaction solution was extracted with chloroform (100 ml × 2), and the organic layer was concentrated to give a brown oil. Purify by silica gel column chromatography (solvent chloroform: ethanol (5: 1)),
(E, Z) -2- [4- (1,2-dihydroxy-1-methylethyl) phenyl] -1- {4- [2- (dimethylamino) ethoxy] phenyl} -1- (4-hydroxyphenyl ) -1-Butene (1.3 g, yield 59%) was obtained as a colorless solid.

1.2 g of the E and Z mixture obtained here was made into a 3 ml solution of methanol with a single injection amount of 0.4 g, and the elution solvent was changed to methanol / phosphate buffer (pH 6.8 / 10 mM) (70:30). Fractionation was carried out by the separation operation by ODS column chromatography in the same manner as in Example 1. When the eluate of each of the obtained fractions was concentrated under reduced pressure, crystals were precipitated, so 5% aqueous sodium hydrogencarbonate solution was added thereto, and the crystals were collected, washed with water, and dried in vacuum.

From the first fraction (Z) -2- [4- (1,2-dihydroxy-1-methylethyl) phenyl] -1- {4- [2-
(Dimethylamino) ethoxy] phenyl} -1- (4-
0.30 g of hydroxyphenyl) -1-butene was obtained.

Melting point 147-149 ° C Elemental analysis value (%) (as C ₂₉ H ₃₅ NO ₄・ 1 / 2H ₂ O) Calculated value: C 74.01, H 7.71, N 2.98 Measured value: C 73.69, H 7.67, N 3.01 EIMS m ^{/ e: 461 (M) +} 1 H- nuclear magnetic resonance spectrum _{δppm (DMSO-d 6):} 0.84 (3H, t, J = 6.8Hz, -CH 2 CH 3), 1.33 (3H, s, -C ( _{CH 3) (OH) -)} , 2.15 (6H, s, -N (CH 3) 2), 3.35 (2H, brs, -CH 2 OH), 3.89 (2H, t, J = 5.8Hz, -OCH 2 _{CH 2 N =), 4.60 (} 1H, t, J = 5.8Hz, -CH 2 OH), 4.76 (1H, s, -C (CH 3) (OH) -), 6.56,6.72 ( each 2H, d, J ＝ 9.3Hz, ArH ortho and meta to
-OCH ₂ CH ₂ N (CH ₃ ) ₂ ), 6.74,6.99 (2H, d, J = 8.6Hz, ArH ortho and meta to
-OH), 7.01,7.25 (each 2H, d, J = 8.3Hz, ArH ortho and meta to
_{-CH (CH 3) (OH)} CH 2 OH), 9.39 (1H, s, ArOH) from the second fraction (E)-2-[4- (1,2-dihydroxy-1-methylethyl) phenyl ] -1- {4- [2
-(Dimethylamino) ethoxy] phenyl} -1- (4
0.50 g of -hydroxyphenyl) -1-butene was obtained.

Melting point 164 to 167 ° C Elemental analysis value (%) (as C ₂₉ H ₃₅ NO ₄・ 1 / 2H ₂ O) Calculated value: C 74.01, H 7.71, N 2.98 Measured value: C 74.13, H 7.93, N 2.90 EIMS m ^{/ e: 461 (M) +} 1 H- nuclear magnetic resonance spectrum _{δppm (DMSO-d 6):} 0.84 (3H, t, J = 6.8Hz, -CH 2 CH 3), 1.34 (3H, s, -C ( _{CH 3) (OH) -)} , 2.23 (6H, s, -N (CH 3) 2), 2.64 (2H, t, J = 5.7Hz, -OCH 2 CH 2 N =), 3.35 (2H, brs, _{-CH 2 OH), 4.05 (2H} , t, J = 5.7Hz, -OCH 2 CH 2 N =), 4.62 (1H, brt, -CH 2 OH), 4.76 (1H, s, -C (CH 3) (OH)-), 6.39, 6.61 (each 2H, d, J = 8.5Hz, ArH ortho and meta to
-OCH ₂ CH ₂ N (CH ₃ ) ₂ ), 6.91, 7.08 (each 2H, d, J = 8.5Hz, ArH ortho and meta to
-OH), 7.00,7.26 (2H, d, J = 8.3Hz, ArH ortho and meta to
_{-CH (CH 3) (OH)} CH 2 OH), 9.15 (1H, s, ArOH) Example 5 (E, Z) -2- [4- (2-hydroxy-1-methylethyl) phenyl] -1 Preparation of-{4- [2- (methylamino) ethoxy] phenyl} -1- (4-hydroxyphenyl) -1-butene (E, Z) -2- [4- (2- Hydroxy-1-methylethyl) phenyl] -1- {4-
[2- (dimethylamino) ethoxy] phenyl} -1-
1.78 g (4.0 mmol) of (4-hydroxyphenyl) -1-butene was dissolved in 40 ml of 1,2-dichloroethane, added with 1.70 g (16 mmol) of vinyloxycarbonyl chloride, and then sealed in a glass sealed tube container. Then, the mixture was reacted at 170 ° C for 6 hours. After returning to room temperature, the tube was opened and the solvent was distilled off. Dissolve the residue in 50 ml of ethanol and use 4N-sodium hydroxide aqueous solution 10
After adding ml, the mixture was refluxed for 5 hours. The solvent was distilled off to obtain a brown residual solid. Purified by silica gel column chromatography (silica gel 100 g, solvent chloroform: methanol: triethylamine (10: 1: 1)) to obtain (E, Z) -2- [4- (2-hydroxy-1-methylethyl) as a light brown solid. ) Phenyl] -1- {4- [2- (methylamino) ethoxy] phenyl} -1- (4-hydroxyphenyl) -1-butene (1.06 g, yield 61%) was obtained.

1.0 g of E and Z mixture obtained here is injected once 0.33 g
Was dissolved in methanol in 3 ml and the elution solvent was changed to methanol / phosphate buffer (pH 6.8 / 10 mM) (70:30) in the same manner as in Example 1 to perform separation by ODS column chromatography. Painted. When the eluate of each of the obtained fractions was concentrated under reduced pressure, crystals were precipitated, so a 5% aqueous sodium hydrogen carbonate solution was added, and the crystals were collected and washed with water. The obtained crystals were recrystallized from a mixed solvent of methanol / isopropyl ether / n-hexane, and the Z- and E-isomers could each be isolated as pure products.

From the first fraction (Z) -2- [4- (2-hydroxy-
0.26 g of 1-methylethyl) phenyl] -1- {4- [2- (methylamino) ethoxy] phenyl} -1- (4-hydroxyphenyl) -1-butene was obtained.

Melting point 155 to 157 ° C Elemental analysis value (%) (as C ₂₈ H ₃₃ NO ₃ ) Calculated value: C 77.93, H 7.71, N 3.25 Measured value: C 77.88, H 7.68, N 3.13 EIMS m / e: 431 (M ) ^{+ 1} H- nuclear magnetic resonance spectrum _{δppm (DMSO-d 6):} 0.83 (3H, t, J = 7.0Hz, -CH 2 CH 3), 1.14 (3H, d, J = 6.8Hz, -CH (CH ₂ OH) CH ₃ ), 2.28 (3H, s, -NHCH ₃ ), 2.73 (2H, t, J = 5.6Hz, -OCH ₂ CH ₂ N =), 3.1-3.5 (2H, m, -CH (CH ₃ ) CH ₂ OH), 3.85 (2H, t, J = 5.6Hz, -OCH ₂ CH ₂ N =), 4.55 (1H, brs, -CH ₂ OH), 6.56,6.71 (each 2H, d, J = 9.1Hz, ArH ortho and meta to
−OCH ₂ CH ₂ NHCH ₃ ), 6.73,6.97 (2H, d, J = 8.6Hz, ArH ortho and meta to
−OH), 7.00 (4H, s, ArH ortho and meta to −CH (CH ₃ ) CH ₂ O
H), from the second fraction (E) -2- [4- (2-hydroxy-1-methylethyl) phenyl] -1- {4- [2-
0.24 g of (methylamino) ethoxy] phenyl} -1- (4-hydroxyphenyl) -1-butene was obtained.

Melting point 180-187 ° C Elemental analysis value (%) (as C ₂₈ H ₃₃ NO ₃ ) Calculated value: C 77.93, H 7.71, N 3.25 Measured value: C 77.97, H 7.61, N 3.18 EIMS m / e: 431 (M ) ^{+ 1} H- nuclear magnetic resonance spectrum _{δppm (DMSO-d 6):} 0.84 (3H, t, J = 6.8Hz, -CH 2 CH 3), 1.14 (3H, d, J = 6.8Hz, -CH (CH ₂ OH) CH ₃ ), 2.34 (3H, s, -NHCH ₃ ), 2.70 (1H, m, -CH (CH ₃ ) CH ₂ OH), 2.82 (2H, t, J = 5.6Hz, -OCH ₂ CH ₂ N =), 3.0−3.5 (2H, m, −CH (CH ₃ ) CH ₂ OH), 4.01 (2H, t, J = 5.6Hz, −OCH ₂ CH ₂ N =), 4.55 (1H, brs, -CH ₂ OH), 6.39, 6.61 (each 2H, d, J = 8.5Hz, ArH ortho and meta to
−OCH ₂ CH ₂ NHCH ₃ ), 6.91, 7.05 (2H, d, J = 8.7Hz each, ArH ortho and meta to
−OH), 7.01 (4H, s, ArH ortho and meta to −CH (CH ₃ ) CH ₂ O
H) Example 6 (E, Z) -2- [4- (1-methoxy-1-methylethyl) phenyl] -1- {4- [2- (dimethylamino) ethoxy] phenyl} -1- (4 Preparation of -hydroxyphenyl) -1-butene (E, Z) -2- [4- (1-hydroxy-1-methylethyl) phenyl] -1- {4-prepared in Reference Example 2.
[2- (dimethylamino) ethoxy] phenyl} -1-
[4- (2-tetrahydropyranyloxy) phenyl]
0.3 g (0.57 mmol) of -1-butene was dissolved in 10 ml of methanol, 0.5 ml of concentrated hydrochloric acid was added, and after stirring at room temperature for 1 hour, 2 ml of triethylamine was added to neutralize. The residue obtained after concentration was purified by silica gel column chromatography (solvent chloroform: methanol (5: 1)) to give (E, Z) -2- [4- (1-methoxy-1-methylethyl) as a light brown solid. ) Phenyl] -1- {4- [2- (dimethylamino) ethoxy] phenyl} -1- (4-hydroxyphenyl) -1-butene (0.28 g) was obtained.

EIMS m / e: 459 (M ) + 1 H- nuclear magnetic resonance spectrum _{δppm (DMSO-d 6):} 0.86 (3H, t, J = 7.3Hz, -CH 2 CH 3), 1.41 (6H, s, - _{C (CH 3) 2 -OCH 3} ), 2.64,2.73 (6H, s, -N (CH 3) 2), 2.89 (3H, s, OCH 3), 4.11,4.32 (2H, t, J = 5.8Hz _{, -OCH 2 CH 2 N =)} , affinity 6.3-7.3 (12H, m, ArH) pharmacological test (1) binding affinity estrogen receptor for estradiol receptors, Alan.
E. Walkling (ALAN, E, WAKELING) method (Steroid holmons, B. Green (B.Gr
een), RE leak (RELeake) IRL Press page 219 (198
It was examined according to 7)). That is, the uterus of a 4-week-old SD rat stored at −80 ° C. was buffered at pH 7.4 (20 mM
Tris-hydrochloric acid, 1.5 mM EDTA, 5% glycerol, 12 mM thioglycerol) and homogenized in 100,000 × G,
After centrifugation for 1 hour at 4 ° C, the supernatant was collected and used as an estrogen receptor. Estrogen receptor from 10 ^-5 M in the presence of 5 × 10 ^-9 M ³ H-estradiol
The compound of the present invention having a concentration of up to 10 ^-11 M was allowed to stand for 16 hours under ice-cooling and reacted, and then dextran-coa powder (dextran-coa
The unbound ³ H-estradiol was removed by the ted charcoal) adsorption method (sequel to the biochemical experiment course, page 7, page 207, edited by the Japanese Biochemical Society), and the radioactivity of the supernatant was measured with a liquid scintillation counter to determine whether there was no drug. The binding ability of ³ H-estradiol at the estrogen receptor was calculated assuming that the addition was 100% and the addition of a large excess of unlabeled estradiol was 0%, and the concentration that inhibits the binding of ³ H-estradiol by 50% (IC ₅₀ ) Was used to determine the relative binding capacity (RBA) for estradiol.

 The results are shown in Table 1.

(2) Anti-uterotrophic action VC Jordan (VCJORDAN) and other methods (Journal of Endocrinolo
gy) 75, pp. 305-316 (1977)), and examined the anti-uterotrophic effect in vivo.

That is, the ovaries of 4-week-old SD rats were removed, and 2 weeks later, 0.1 ml of estradiol dissolved in sesame oil to a concentration of 3.0 μg / ml was subcutaneously administered. The test compound was dissolved in ethanol, diluted with physiological saline, and intraperitoneally administered at 40 μg / kg for 3 consecutive days 2 weeks after ovariectomy.
On the day after the final administration, the animals were dissected and the uterine weight was measured.

 The results are shown in Table 2.

The compound of the present invention showed a stronger anti-uterotrophic action than tamoxifen. Since the above-mentioned action is based on the anti-estrogen action, it means that the compound of the present invention has a stronger anti-estrogen action than tamoxifen.

Claims (1)

(57) [Claims] 1. A general formula (In the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom or a lower alkyl group, and R ³ represents a lower alkenyl group or a lower alkyl group having a hydroxyl group or a lower alkoxy group.) 1, 1,2-triaryl-1-butene derivatives and pharmaceutically acceptable salts thereof.