1,1,2-triaryl-1-alkene derivatives

Details 1,1,2-triaryl-1-alkene derivatives 1,1,2-triaryl-1-alkene derivatives

1988-01-27

1990-01-30

Sutto, Anton H.

Organic compounds -- part of the class 532-570 series

Organic compounds

Phosphorus esters

558190, C07F 912

Patent

active

048975036

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to novel 1,1,2-triaryl-1-butene derivatives and pharmaceutically acceptable salts thereof, their preparation and a composition for treating breast cancer and a composition for treating anovulatory infertility.


BACKGROUND ART

It is known that certain compounds having a skeletal structure of 1,1,2-triphenyl-1-butene with one substituted aminoalkoxy group substituted at the 4-position of one of the phenyl groups at position 1 are known to have nonsteroidal antiestrogen activity. Tamoxifen, which is a compound of the formula ##STR3## is a typical example and is a useful therapeutic agent for hormone-dependent mammary cancer (breast cancer) owing to its potent antiestrogen activity (British Pat. No. 1,013,907).
Later, 4-hydroxytamoxifen, which is one of the metabolites of tamoxifen and has the formula ##STR4## was synthesized as a tamoxifen-related compound and its pharmacological properties were investigated (British Patent Application laid-open under No. 2003855).
In an in vitro study, 4-hydroxytamoxifen showed more potent antitumor activity than tamoxifen against experimental hormone-dependent tumor cells and was expected to be developed as a therapeutic agent for breast cancer. In an in vivo study, however, it was confirmed that it is inferior in effectiveness to tamoxifen (J. Biol. Chem. 1981, 256, 859; Cancer Res. 1982, 42, 317; Eur. J. Cancer Clin. Oncology 1980, 16, 239).


TECHNICAL PROBLEM

It is an object of the present invention to provide novel 1,1,2-triaryl-1-butene derivatives and pharmacologically acceptable salts thereof, which are superior to tamoxifen in antitumor effect against estrogen-dependent tumors and are useful as therapeutic agents for breast cancer and anovulatory infertility.


DISCLOSURE OF THE INVENTION

The present invention provides 1,1,2-triaryl-1-butene derivatives of the formula ##STR5## wherein R.sub.1 and R.sub.2 each represent a lower alkyl group, one of R.sub.3 and R.sub.4 is a lower alkyl group and the other is a group of the formula ##STR6## (in which R.sub.5 is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom or --OPO(OH).sub.2 group), and pharmacologically acceptable salts thereof.
The above 1,1,2-triaryl-1-butene derivatives of formula (I) each includes two geometrical isomers, namely the E and Z forms. The E and Z forms refer to relative orientations of substituents attached to the two carbon atoms constituting the double bond. An isomer wherein the senior substituent in the sense of the sequence rule which is attached to one carbon atom and the senior substituent attached to the other carbon atom are on the opposite sides of the double bond is referred to as the E form; an isomer wherein these two senior substituents are on the same side of the double bond is referred to as the Z form. For the compounds of the formula (I), the isomer in which phenyl group substituted with --OPO(OH).sub.2 and the group ##STR7## represented by R.sub.3 or R.sub.4 are on the same side of the double bond is the Z form while the isomer in which said two groups are on the opposite sides is the E form. These isomers can be distinguished from each other by observing those signals of the protons on the alkyl groups of the dialkylamino moiety and the methylene group adjacent to the oxygen atom in the dialkylaminoethoxy group which are found on the .sup.1 H-nuclear magnetic resonance (NMR) spectrum. For the E form, each signal appears at higher fields as compared with the corresponding signal for the Z form. It is to be noted that the present invention covers both the E and Z forms as featured above as well as mixtures thereof.
In this specification and in the appended claims, and particularly referring to the groups represented by R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 in the formula (I) have the meanings respectively given below.
As the lower alkyl group, there may be mentioned alkyl groups containing 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexy

REFERENCES:
patent: 3288806 (1967-04-01), De Wald
patent: 4198435 (1980-04-01), Richardson
patent: 4206234 (1980-06-01), Richardson

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