Benzopyran derivatives

Details Benzopyran derivatives Benzopyran derivatives

1999-06-08

2000-11-28

Owens, Amelia

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

514336, 514422, 514456, 548525, 5462821, C07D31104

Patent

active

061537683

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to a novel benzopyran derivative having anti-estrogenic activity. More specifically, the present invention relates to a novel benzopyran derivative represented by formula (I): ##STR1## and pharmaceutically acceptable salt thereof, in which ----- represents a single bond or a double bond; hydroxy or OR group, wherein R represents acyl or alkyl; that when ----- represents a double bond, R.sub.3 is not present; ##STR2## R.sub.5, R.sub.6 and R.sub.7 independently of one another represent hydrogen, alkyl, halogenoalkyl, alkenyl or halogenoalkenyl, or form a 4- to 8-membered heterocyclic ring which can be substituted with R.sub.5 ; alkyl; having anti-estrogenic activity which contains the compound (I) as an active component.


BACKGROUND ART

In treating diseases caused by the abnormal tissue growth depending on a certain sexual steroidal hormone such as estrogen, it is very important to significantly inhibit, if possible, to completely remove the effect induced by said sexual steroidal hormone. For this purpose, it is desirable to block the receptor site which can be stimulated by sexual steroidal hormone and further, to reduce the level of sexual steroidal hormone capable of acting on said receptor site. For instance, as a substitution or combined therapy, administration of anti-estrogenic agents to limit the production of estrogen to the amount less than required to activate the receptor site may be used. However, prior methods for blocking the estrogen production could not sufficiently inhibit the effect induced through estrogen receptor. Practically, even when estrogen is completely absent, some of the receptors may be activated. Accordingly, it was considered that antagonists for estrogen can provide better therapeutic effect in comparison to the method for blocking only the production of sexual steroidal hormone. Thus, numerous anti-estrogenic compounds have been developed. For example, many patent publications including U.S. Pat. Nos. 4,760,061, 4,732,912, 4,904,661 and 5,395,842 and WO 96/22092, etc. disclose various anti-estrogenic compounds. However, prior antagonists have sometimes insufficient affinity to the receptors. In some cases, moreover, they can combine to the receptor but act themselves as agonists, and therefore, activate rather than block the receptor. For example, Tamoxifen has been most widely used as an anti-estrogenic agent. However, it has a disadvantage that it exhibits estrogenic activity in some organs (see, M. Harper and A. Walpole, J. Reprod. Fertil., 1967, 13, 101). Therefore, it is required to develop the anti-estrogenic compound which has substantially or completely no agonistic effect and can effectively block the estrogenic receptor.
In addition, it has been known that 7 .alpha.-substituted derivatives of estradiol, for example, 7 .alpha.--(CH.sub.2).sub.10 CONMeBu derivative, exhibit anti-estrogenic activity (see, EP Appl. 0138504, U.S. Pat. No. 4,659,516). Further, estradiol derivative having --(CH.sub.2).sub.9 SOC.sub.5 H.sub.6 F.sub.5 substituent has also been disclosed (see, Wakeling et al., Cancer Res., 1991, 51, 3867) as steroidal anti-estrogen without agonistic effect.
Non-steroidal anti-estrogenic drug without agonistic effect has been first reported by Wakeling et al. in 1987 (see, A. Wakeling and J. Bowler, J. Endocrinol., 1987, 112, R7). Meanwhile, U.S. Pat. No. 4,904,661 (ICI, Great Britain) discloses a phenol derivative having anti-estrogenic activity. This phenol derivative generally has a naphthalene structure and includes, typically, the following compounds: ##STR3##
As other non-steroidal anti-estrogenic compounds, WO 93/10741 discloses benzopyran derivatives having aminoethoxyphenyl substituent (Endore-cherche), of which the typical compound is EM-343 having the following structure: ##STR4##
Accordingly, the present inventors have researched the anti-estrogenic activity of compounds having various structures. As a result, we have identified that the benzopyran derivatives represented by formula (I), as define

REFERENCES:
patent: 4904661 (1990-02-01), Pilgrim et al.
Chemical Abstracts, vol. 110, p. 718, (1989).
Jacobsen, P. et al. "Preparation of Novel Cis-3,4-Chroman Derivatives Useful in the Prevention or Treatment of Estrogen Related Diseases or Syndromes" CA 129:4579 (1998).
Jacobsen, P. et al. "Novel (-)-Enatomers of Cis-3,4-Chroman Derivaties Useful in the Prevention or Treatment of Estrogen Related Diseases or Syndromes" CA 129:4522 (1998).

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