Benzothiophene derivative

Details Benzothiophene derivative Benzothiophene derivative

1994-05-13

1995-12-05

Ivy, C. Warren

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

514253, 514307, 514324, 514422, 514443, 514444, 544146, 544376, 546148, 546202, 546237, 548525, 548527, 549 51, A61K 3138, A61K 31445, C07D40910, C07D33364

Patent

active

054729629

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to novel benzothiophene derivatives having an antiestrogenic activity, and relates more detailedly to benzothiophene derivatives represented by the formula ##STR2## wherein,
R.sup.1 denotes a hydrogen atom, a hydroxyl group, a lower alkoxy group, an acyloxy group or an N,N-di-lower alkyl-substituted or unsubstituted carbamoyloxy group,
R.sup.2 denotes a halogen atom; a lower alkyl group; or a cycloalkyl or cycloalkenyl group optionally substituted by a lower alkyl group, a hydroxyl group, an acyloxy group or an oxo group,
R.sup.3 and R.sup.4 each denote a hydrogen atom or a lower alkyl group, or R.sup.3 and R.sup.4 combine with the nitrogen atom to which they bind, to denote a heterocyclic ring which may further contain a hetero atom selected from O, S and N,
A denotes O or CH.sub.2,
B denotes C.dbd.O or CH.sub.2, and
n denotes 1 or 2.


BACKGROUND ART

In gynecologic cancers such as breast cancer and endometrial cancer, the activities of the estrogen receptor and the estrogen-biosynthesizing enzyme in the tumor tissue are higher than those in the normal mammary gland tissue and the endometrial tissue, and the proliferation of these tumors have close relation to endogenous or local increase of estrogenic activity. Thus as one means for therapy of gynecologic cancers, it is put into practice to make competition against the estrogenic effect in the estrogenic target tissue, namely to administer antiestrogenic agents.
Among these antiestrogenic agents, a compound of the following formula called tamoxifen was, first, proposed (see, UK Patent No. 1,013,907). ##STR3## Tamoxifen is now widely used for treatment of breast cancer, etc. as a representative antiestrogenic agent. Thereafter, several kinds of compounds having the same characteristic as tamoxifen is chemical structure, namely three benzene rings were proposed as antiestrogenic agents (see, for example, Proc. Soc. Exp. Biol. Med., 112, 439-442 (1963), J. Med. Chem. 8, 725-726 (1965), J. Med. Chem., 22, 962-966 (1979)).
Further, several benzothiophene derivatives having an antiestrogenic activity have been known (see, Japanese Laid-Open Patent Publication No. 181081/1982, Life Sci., 26, 1453-1458, 1980). Among them, a compound of the following formula called raloxifene has a very strong antiestrogenic activity, and is now under clinical tests. ##STR4##
However, all of these antiestrogenic agents also have an estrogenic activity too strong to be neglected, simultaneously with the antiestrogenic activity, and they were yet unsatisfactory in this point.
The present inventors have intensely researched for benzothiophene derivatives having an antiestrogenic activity, and as a result have found that a series of compounds wherein a specific substituent such as a cycloalkyl group or a lower alkyl group was introduced in place of a substituted phenyl group so far known as the substituent as the 2-position of the benzothiophene nucleus have a strong antiestrogenic activity but have only a very weak estrogenic activity.


DISCLOSURE OF INVENTION

The term "lower" in this description means that the carbon atom number of a group or compound to which this term was attached is 6 or less, preferably 4 or less.
In the above formula (I), the "lower alkyl group" can be straight-chain or branched chain, and there can, for example, be mentioned a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl group or the like, and as the "lower alkoxy group", there can, for example, be mentioned a methoxy, ethoxy, n-propoxy, isopropoxy or n-butoxy group or the like. Further, as the "cycloalkyl group", those having 3 to 12 preferably 3 to 8 carbon atoms are preferable, and there can, for example, be mentioned a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group or the like, and as the "cycloalkenyl group", those having 4 to 12, preferably 5 to 8 carbon atoms are preferable, and there can, for example, be mentioned a 1-cyclopentenyl, 1-cyclohexenyl, 1-cycloheptenyl or 1-cyclooctenyl

REFERENCES:
patent: 4007204 (1977-02-01), Descamps et al.
patent: 4156732 (1979-05-01), Lang et al.
Gubin et al., European Journal of Medicinal Chemistry--Chimica Therapeurica, 10(4), pp. 418-424 (1975).
Duncan et al., Proc. Soc. Exp. Biol. Med. 112, 439-442 (1963).
Lednicer et al., J. Med. Chem. 8, 725-726 (1965).
Jones et al., J. Med. Chem. 22, 962-966 (1979).
Black et al., Life Sci. 26, 1453-1458 (1980).
E. Campaigne et al., Journal of Organic Chemistry, vol. 26, No. 1, pp. 363-365 (1961).

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