JPH04330043A - Triarylethylene derivative and medicinal composition, containing the same and having tumor inhibitory action - Google Patents

Abstract

PURPOSE:To obtain a new triarylethylene derivative, having better antitumor effects on mammary tumor than those of tamoxifen and useful as a medicine. CONSTITUTION:A triarylethylene derivative expressed by formula I [R1 and R2 are lower alkyl or R1 and R2, together with the adjacent nitrogen atom, form heterocyclic group which may contain hetero-atom; R3 and R4 are lower alkyl or R3 and R4, together with the adjacent nitrogen atom, form heterocyclic group which may contain hetero-atom; R5 is H, OH, formula II (R7 is alkyl, cycloalkyl or aryl), R8OCH2O (R8 is lower alkyl, etc.), etc.; R5 is lower alkyl or lower cycloalkyl; Ar is phenyl or 3,4methylenedioxyphenyl], e.g. 1-[4-(1,3- bisdimethylamino-2-propoxy)phenyl]-1-(4-hydroxyphenyl)-2-(3,4- methylenedioxyphenyl)-1-butene. The compound expressed by formula I is obtained by reacting a compound expressed by formula III (R9 is H or OH) with a compound expressed by formula IV and then with a compound expressed by formula V.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to triarylethylene derivatives and pharmaceutical compositions containing the same which have tumor-suppressing activity.

0002

[Prior Art] Compounds with a basic skeleton of 1,1,2-triphenyl-1-butene and a substituted aminoalkoxy group in the phenyl group at the 1st position are known to have non-steroidal anti-estrogenic activity. It is being (Z)-2-[
4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethylamine (tamoxifen)
is a representative compound thereof, and its strong antiestrogenic action makes it a useful therapeutic agent for hormone-dependent breast cancer (British Patent No. 1013907).

0003

OBJECTS OF THE INVENTION An object of the present invention is to provide a triarylethylene derivative which has an even better antitumor effect than tamoxifen against breast tumors and is useful as a pharmaceutical.

0004

[Means for Solving the Problems] The novel triarylethylene derivative of the present invention is a triarylethylene derivative represented by formula 1 or a pharmaceutically acceptable acid addition salt thereof. The triarylethylene derivative of formula 1 has the following formula:
There are two types of geometric isomers, E-form and Z-form, 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. Although the present invention is a mixture of the above E and Z isomers, each of the isolated E and Z isomers is also included in the present invention.

Furthermore, in the triarylethylene derivative of formula 1, there are two types of optical isomers, R-form and S-form, with respect to the methine carbon that forms an ether bond with the phenyl group of the bisdialkylamino side chain. do. Both isomers can be clearly distinguished by liquid chromatography using a column for separating optical isomers. The present invention also includes mixtures of the R and S isomers and isolated R and S isomers.

[0006] Examples of the triarylethylene derivatives of the present invention include the following. (1) 1-[4-(1,3-bisdimethylamino-2-
propoxy)phenyl]-1-(4-hydroxyphenyl)-2-(3,4-methylenedioxyphenyl)-1
-butene(2)1-[4-(1,3-bisdiethylamino-2-
propoxy)phenyl]-1-(4-hydroxyphenyl)-2-(3,4-methylenedioxyphenyl)-1
-butene(3)1-[4-(1,3-bisethylmethylamino-
2-propoxy)phenyl]-1-(4-hydroxyphenyl)-2-(3,4-methylenedioxyphenyl)
-1-Butene (4) 1-[4-(1,3-bispyrrolidino-2-propoxy)phenyl]-1-(4-hydroxyphenyl)
-2-(3,4-methylenedioxyphenyl)-1-butene (5) 1-[4-(1,3-bipiperidino-2-propoxy)phenyl]-1-(4-hydroxyphenyl)
-2-(3,4-methylenedioxyphenyl)-1-butene (6) 1-[4-(1,3-bisdimethylamino-2-
propoxy)phenyl]-1-phenyl-2-(3,4
-methylenedioxyphenyl)-1-butene (7) 1-
[4-(1,3-bisdiethylamino-2-propoxy)phenyl]-1-phenyl-2-(3,4-methylenedioxyphenyl)-1-butene (8) 1-[4-(1
,3-bisethylmethylamino-2-propoxy)phenyl]-1-phenyl-2-(3,4-methylenedioxyphenyl)-1-butene (9)1-[4-(1,3-
bispyrrolidino-2-propoxy)phenyl]-1-phenyl-2-(3,4-methylenedioxyphenyl)-
1-Butene (10) 1-[4-(1,3-bispiperidino-2-propoxy)phenyl]-1-phenyl-2-(3,4-
methylenedioxyphenyl)-1-butene (11) 1-[4-(1,3-bisdimethylamino-2
-propoxy)phenyl]-1-(4-methoxymethoxyphenyl)-2-(3,4-methylenedioxyphenyl)-1-butene (12) 1-[4-(1,3-bisdiethylamino-2
-propoxy)phenyl]-1-(4-methoxymethoxyphenyl)-2-(3,4-methylenedioxyphenyl)-1-butene (13) 1-[4-(1,3-bisethylmethylamino- 2-propoxy)phenyl]-1-(4-methoxymethoxyphenyl)-2-(3,4-methylenedioxyphenyl)-1-butene (14) 1-[4-(1,3-bispyrrolidino-2- propoxy)phenyl]-1-(4-methoxymethoxyphenyl)-2-(3,4-methylenedioxyphenyl)
-1-Butene (15) 1-[4-(1,3-bispiperidino-2-propoxy)phenyl]-1-(4-methoxymethoxyphenyl)-2-(3,4-methylenedioxyphenyl)
-1-butene (16) 1-[4-(1,3-bisdimethylamino-2
-propoxy)phenyl]-1-(4-acetoxyphenyl)-2-(3,4-methylenedioxyphenyl)-
1-Butene (17) 1-[4-(1,3-bisdiethylamino-2
-propoxy)phenyl]-1-(4-acetoxyphenyl)-2-(3,4-methylenedioxyphenyl)-
1-Butene (18) 1-[4-(1,3-bisethylmethylamino-2-propoxy)phenyl]-1-(4-acetoxyphenyl)-2-(3,4-methylenedioxyphenyl)- 1-Butene (19) 1-[4-(1,3-bispyrrolidino-2-propoxy)phenyl]-1-(4-acetoxyphenyl)-2-(3,4-methylenedioxyphenyl)-1-
Butene (20) 1-[4-(1,3-bispiperidino-2-propoxy)phenyl]-1-(4-acetoxyphenyl)-2-(3,4-methylenedioxyphenyl)-1-
Butene (21) 1-[4-(1,3-bisdimethylamino-2
-propoxy)phenyl]-1-(4-phosphonoxyphenyl)-2-(3,4-methylenedioxyphenyl)-1-butene (22) 1-[4-(1,3-bisdiethylamino-2
-propoxy)phenyl]-1-(4-phosphonoxyphenyl)-2-(3,4-methylenedioxyphenyl)-1-butene (23) 1-[4-(1,3-bisethylmethylamino) -2-propoxy)phenyl]-1-(4-phosphonoxyphenyl)-2-(3,4-methylenedioxyphenyl)-1-butene (24) 1-[4-(1,3-bispyrrolidino- 2-propoxy)phenyl]-1-(4-phosphonoxyphenyl)-2-(3,4-methylenedioxyphenyl)
-1-Butene (25) 1-[4-(1,3-bispiperidino-2-propoxy)phenyl]-1-(4-phosphonoxyphenyl)-2-(3,4-methylenedioxyphenyl)
-1-butene (26) 1-[4-(1,3-bisdimethylamino-2
-propoxy)phenyl]-1-(4-benzoyloxyphenyl)-2-(3,4-methylenedioxyphenyl)-1-butene (27) 1-[4-(1,3-bisdiethylamino-2
-propoxy)phenyl]-1-(4-benzoyloxyphenyl)-2-(3,4-methylenedioxyphenyl)-1-butene (28) 1-[4-(1,3-bisethylmethylamino- 2-propoxy)phenyl]-1-(4-benzoyloxyphenyl)-2-(3,4-methylenedioxyphenyl)-1-butene (29) 1-[4-(1,3-bispyrrolidino-2- propoxy)phenyl]-1-(4-benzoyloxyphenyl)-2-(3,4-methylenedioxyphenyl)
-1-Butene (30) 1-[4-(1,3-bispiperidino-2-propoxy)phenyl]-1-(4-benzoyloxyphenyl)-2-(3,4-methylenedioxyphenyl)
-1-butene (31) 1-[4-(1,3-bisdimethylamino-2
-propoxy)phenyl]-1-(4-pivaloyloxymethoxyphenyl)-2-(3,4-methylenedioxyphenyl)-1-butene (32) 1-[4-(1,3-bisdiethylamino -2
-propoxy)phenyl]-1-(4-pivaloyloxymethoxyphenyl)-2-(3,4-methylenedioxyphenyl)-1-butene (33) 1-[4-(1,3-bisethyl) Methylamino-2-propoxy)phenyl]-1-(4-pivaloyloxymethoxyphenyl)-2-(3,4-methylenedioxyphenyl)-1-butene (34) 1-[4-(1, 3-bispyrrolidino-2-propoxy)phenyl]-1-(4-pivaloyloxymethoxyphenyl)-2-(3,4-methylenedioxyphenyl)-1-butene (35) 1-[4-(1 ,3-bispiperidino-2-propoxy)phenyl]-1-(4-pivaloyloxymethoxyphenyl)-2-(3,4-methylenedioxyphenyl)-1-butene (36)1-[4-( 1,3-bisdimethylamino-2
-propoxy)phenyl]-1-(4-hydroxyphenyl)-2-(3,4-methylenedioxyphenyl)-
2-cyclopropylethene (37) 1-[4-(1,3-bisdiethylamino-2
-propoxy)phenyl]-1-(4-hydroxyphenyl)-2-(3,4-methylenedioxyphenyl)-
2-Cyclopropylethene (38) 1-[4-(1,3-bisethylmethylamino-2-propoxy)phenyl]-1-(4-hydroxyphenyl)-2-(3,4-methylenedioxyphenyl )-2-cyclopropylethene (39) 1-[4-(1,3-bispyrrolidino-2-propoxy)phenyl]-1-(4-hydroxyphenyl)-2-(3,4-methylenedioxyphenyl) -2-
Cyclopropylethene (40) 1-[4-(1,3-bispiperidino-2-propoxy)phenyl]-1-(4-hydroxyphenyl)-2-(3,4-methylenedioxyphenyl)-2-
Cyclopropylethene (41) 1-[4-(1,3-bisdimethylamino-2
-propoxy)phenyl]-1-(4-cyclopropanecarbonyloxyphenyl)-2-(3,4-methylenedioxyphenyl)-1-butene (42)1-[4-(1,3-bisdiethylamino- 2
-propoxy)phenyl]-1-(4-cyclopropanecarbonyloxyphenyl)-2-(3,4-methylenedioxyphenyl)-1-butene (43) 1-[4-(1,3-bisethylmethyl Amino-2-propoxy)phenyl]-1-(4-cyclopropanecarbonyloxyphenyl)-2-(3,4-methylenedioxyphenyl)-1-butene (44) 1-[4-(1,3- bispyrrolidino-2-propoxy)phenyl]-1-(4-cyclopropanecarbonyloxyphenyl)-2-(3,4-methylenedioxyphenyl)-1-butene (45) 1-[4-(1,3- bispiperidino-2-propoxy)phenyl]-1-(4-cyclopropanecarbonyloxyphenyl)-2-(3,4-methylenedioxyphenyl)-1-butene (46) 1-[4-(1,3- Bisdimethylamino-2
-propoxy)phenyl]1,2-diphenyl-1-butene (47)1-[4-(1,3-bisdiethylamino-2-propoxy)phenyl]1,2-diphenyl-1
-Butene (48) 1-[4-(1,3-bisethylmethylamino-2-propoxy)phenyl] 1,2-diphenyl-1-butene (49) 1-[4-(1,3-bispyrrolidino- 2-propoxy)phenyl]1,2-diphenyl-1-butene (50)1-[4-(1,3-bispiperidino-2-propoxy)phenyl]1,2-diphenyl-1-butene (51)1- [4-(1,3-bisdimethylamino-2
-propoxy)phenyl]-1-(4-hydroxyphenyl)-2-phenyl-1-butene (52) 1-[4-(1,3-bisdiethylamino-2
-propoxy)phenyl]-1-(4-hydroxyphenyl)-2-phenyl-1-butene (53) 1-[4-(1,3-bisethylmethylamino-2-propoxy)phenyl]-1-( 4-hydroxyphenyl)-2-phenyl-1-butene (54) 1-[4-(1,3-bispyrrolidino-2-propoxy)phenyl]-1-(4-hydroxyphenyl)-2-phenyl-1- Butene (55) 1-[4-(1,3-bispiperidino-2-propoxy)phenyl]-1-(4-hydroxyphenyl)-2-phenyl-1-butene

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

A benzophenone derivative represented by the formula 3 (wherein R9 represents a hydrogen atom or a hydroxyl group) and the following formula 4

[0008]

embedded image (wherein, R6 represents a lower alkyl group or a lower cycloalkyl group; Ar represents a 3,4-methylenedioxyphenyl group or a phenyl group) and the ketone body represented by the formula is substantially dried. The reaction was carried out in a medium containing a reducible titanium compound and a reducing agent effective to generate titanium in a substantially zero valence state under an inert atmosphere, and from the resulting mixture, the following formula 5 was obtained.

[0009]

After purifying the phenol derivative represented by the formula (wherein R6, R9, and Ar are the same as above) using column chromatography,
For example, in the presence of a dehydration condensation agent such as dicyclohexylcarbodiimide and copper iodide, the following formula 6 is prepared.

0010

It can be obtained by reaction with an alcohol derivative represented by the following formula (wherein R1, R2, R3, and R4 are the same as above). The triarylethylene derivative shown by the formula 1 obtained here is a mixture of E and Z isomers with respect to the carbon-carbon double bond, but it can be separated into two peaks on a high performance liquid chromatograph. , each can be separated individually by adding a preparative separation operation. As another method of separation, it is also possible to separate by recrystallization of a mineral acid salt. Furthermore, the triarylethylene derivative represented by the formula 1 is a mixture of optical isomers, R form and S form, with respect to the methine carbon forming an ether bond with the phenyl group of the bisdialkylamino side chain.
Both isomers can be separated individually by high performance liquid chromatography using a column for separating optical isomers. Furthermore, the compound of the present invention represented by Formula 1 can be converted into a pharmacologically acceptable acid addition salt by treatment with an inorganic or organic acid. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; examples of organic acids include citric acid, maleic acid, malic acid, fumaric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, and sulfuric acid. Examples include acids.

The compound of the present invention represented by formula 1 and its pharmacologically acceptable acid addition salts have excellent anti-estrogenic effects and are particularly effective in treating breast tumors. The dosage form for administering the compound of the present invention may be, for example, oral preparations such as tablets, capsules, granules, powders, and solutions, injections, suppositories, etc., but oral preparations are generally preferred. Examples of forms used in producing tablets, capsules, granules, and powders include lactose, sucrose, starch, talc, magnesium stearate, crystalline cellulose, methylcellulose, glycerin, sodium alginate, gum arabic, cornstarch, Glucose, sorbitol, silicon dioxide, etc. are used as binders, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, gum arabic, Sierrac, white sugar, tragacanth, gelatin, hydroxypropylcellulose, hydroxypropyl starch, polyvinylpyrrolidone, etc. are used as lubricants. , magnesium stearate, talc, etc., and other commonly known additives such as colorants and disintegrants can be optionally used. In addition, the tablet may be coated by a well-known method. The liquid preparation may also be an aqueous or oily suspension, solution, syrup, or elixir, and is prepared in a conventional manner using conventional additives.

The dose when orally administering the compound of the present invention to a patient varies depending on the patient's symptoms, weight, age, etc., and cannot be unconditionally prescribed, but is usually about 1 dose per adult.
~500 mg, which is preferably administered in 1 to 4 divided doses. Further, the content of the active ingredient compound per unit preparation is preferably about 0.5 to 50 mg.

[0013]

EFFECTS OF THE INVENTION The triarylethylene derivatives of the present invention have even better antitumor effects than tamoxifen against breast tumors, and are extremely useful compounds as pharmaceuticals.

[0014]

[Examples] Next, the present invention will be explained in more detail with reference to Examples and formulation examples, but the present invention is not limited to these Examples. In addition, in the following examples,
1H-NMR spectrum is PM manufactured by JEOL Ltd.
Measurements were made using X-60SI or GX-400 using TMS as an internal standard, and chemical shifts were expressed as δ values (ppm).

Example 1 (E.Z)-1-[4-(1,3-bisdimethylamino-2-propoxy)phenyl]-1-(4-hydroxyphenyl)-2-(3,4-methylene Synthesis of dioxyphenyl)-1-butene (compound 1) Under an argon atmosphere, 12.6 ml of titanium tetrachloride was added dropwise to 240 ml of anhydrous tetrahydrofuran under ice cooling. After returning to room temperature and stirring for about 15 minutes, 12 g of zinc powder was added.
The mixture was heated under reflux for 5 hours. After cooling this solution to room temperature, 4
, 3.84 g of 4'-dihydroxybenzophenone and 3,
3.22 g of 4-methylenedioxypropiophenone was added, and the mixture was heated under reflux for 2 hours. This reaction solution was cooled and heated to 200
ml of water followed by ether extraction. After washing the organic layer with water and drying over sodium sulfate, the solvent was removed under vacuum. The oily residue was applied to a silica gel column (developing solvent: chloroform/methanol), and 1.
1-bis(4-hydroxyphenyl)-2-(3,4-
Crystals of methylenedioxyphenyl)-1-butene 3.7
3g was obtained. Take 0.949 g of this crystal, add it to a mixture of 0.658 g of 1,3-bisdimethylamino-2-propanol, 1.05 g of dicyclohexylcarbodiimide and 40 mg of copper iodide (stirred at 60°C for 2 hours), The mixture was stirred at ℃ for 2 hours. After adding 50 ml of ether to this reaction solution and filtering off the resulting solid, the filtrate was concentrated. The oily residue after concentration was purified by thin layer chromatography (developing solvent: toluene/methanol) to obtain the target product (E・Z)-1-[4-(1,3-bisdimethylamino-2-propoxy). ) phenyl]-1-(4-
0.402 g of hydroxyphenyl)-2-(3,4-methylenedioxyphenyl)-1-butene was obtained.

1H-NMR spectrum, δ(CDC
l3):0.90-0.93(3H,t,CH2C
H3)2.11-2.66(18H,m,N(CH3
)2 , (CH3 )2 N, NCH2 CH(OA
r) CH2N,CH2CH3) 3.95-4.09(1H,m,NCH2CH(OA
r) CH2 N) 5.87 (2H, s, OCH2 O) 6.49-6.81 (10H, m, aromatic proton, H
O-ph) 7.01-7.10 (2H, m, aromatic proton)

0
The anti-estrogenic activity of the triarylethylene derivative of the present invention was evaluated by the effect of the compound on the uterine weight of rats. A predetermined amount of the triarylethylene derivative of the present invention and 0.01 m
100 μl of each g/ml estradiol solution in olive oil was injected subcutaneously for 3 consecutive days. On the fourth day, the uterus was removed and its dry weight was measured. E is the weight of the uterus when only estradiol is administered, V is the weight of the uterus when only olive oil is administered, and W is the weight of the uterus when estradiol and the triarylethylene derivative of the present invention are administered. Estrogen effect (uterine weight increase suppression effect) was determined using the following formula.

[0018] Table 1 summarizes the anti-estrogen activity values of each derivative. Values obtained using tamoxifen are shown as a comparative example.

[0019]

[Table 1]

[0020]

[Preparation example] 0.2 g of 1-[4-(1,
3-bisdimethylamino-2-propoxy)phenyl]
-1-(4-Hydroxyphenyl)-2-(3,4-methylenedioxyphenyl)-1-butene was mixed with 1.11 g mannitol, 0.15 g starch and 6 g alginic acid and granulated. The granules were dried and then 7.5
mg of methylcellulose and 15 mg of magnesium stearate and compressed to obtain 10 tablets, each tablet containing 20 mg of active ingredient.

Claims (2)

[Claims] 1. A triarylethylene derivative represented by the following formula 1 or a pharmaceutically acceptable acid addition salt thereof. [Formula 1] [In the formula, R1 and R2 may be the same or different and represent a lower alkyl group, or R1 and R2 together with adjacent nitrogen atoms form a heterocyclic group which may contain a heteroatom. represent something. R3 and R4 may be the same or different and represent a lower alkyl group, or R3
and R4 represents a heterocyclic group which together with the adjacent nitrogen atom may contain a heteroatom. R5 represents a hydrogen atom, a hydroxyl group, [Formula 2] R8 OCH2 O- group or -OPO(OH)2 group, R7 represents a lower alkyl group which may contain a branch,
Represents a lower cycloalkyl group or substituted aryl group, R
8 represents a lower alkyl group or a lower alkylcarbonyl group. R6 represents a lower alkyl group or a lower cycloalkyl group. Ar represents a phenyl group or a 3,4-methylenedioxyphenyl group. ] 2. A tumor comprising a triarylethylene derivative represented by Formula 1 or a pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically acceptable diluent or carrier substance. A pharmaceutical composition having an inhibitory effect.