Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-06-13
2003-04-22
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S456000, C549S023000, C549S406000
Reexamination Certificate
active
06552069
ABSTRACT:
TECHNICAL FIELD
The present invention relates to chroman or thiochroman derivatives having anti-estrogenic activity.
BACKGROUND ART
In treating diseases caused by abnormal tissue growth that is dependent upon a certain sexual steroidal hormone such as estrogen, it is highly important to significantly inhibit, more preferably completely eliminate, the effect induced by the hormone. For this purpose, it is desirable to reduce the level of hormone capable of acting on the steroidal hormone receptor site. For instance, anti-estrogenic agents are commonly administered for alternative or combination therapy to limit the production of estrogen to the amount less than required to activate the receptor site. However, such conventional technique for blocking estrogen production could not sufficiently inhibit the effect induced through the estrogen receptor. Practically, even when estrogen is completely absent, some of the receptors may be activated. It was therefore considered that estrogen antagonists could provide better therapeutic effect in comparison to the technique for blocking only the production of sexual steroidal hormone. Thus, numerous estrogen antagonists have been developed. For example, many patent publications including U.S. Pat. Nos. 4,760,061, 4,732,912, 4,904,661, 5,395,842 and WO 96/22092 disclose various anti-estrogenic compounds. Sometimes, however, prior art antagonists may themselves act as agonists, and therefore activate rather than block the receptor. For example, Tamoxifen has been most widely used as an anti-estrogenic agent. However, this agent has a disadvantage that it exhibits estrogenic activity in some organs (see, M. Harper and A. Walpole, J. Reprod. Fertile., 1967, 13, 101).
As another non-steroidal anti-estrogenic compound, WO 93/10741 discloses a benzopyran derivative having an aminoethoxyphenyl substituent(s) (Endorecherche), the typical compound of which is EM-343 having the following structure:
Said compound also has the agonistic effect. It is therefore required to develop an anti-estrogenic compound which is substantially or completely free of agonistic effect and which can effectively block the estrogen receptor.
In addition, it has been known that 7&agr;-substituted derivatives of estradiol, for example, 7&agr;-(CH
2
)
10
CONMeBu derivatives, are steroidal anti-estrogenic agents without agonistic effect (see, EP-A 0138504, U.S. Pat. No. 4,659,516). Further, an estradiol derivative having a 7&agr;-(CH
2
)
9
SOC
5
H
6
F
5
substituent has also been disclosed (see, Wakeling et al., Cancer Res., 1991, 51, 3867).
Non-steroidal anti-estrogenic agents without agonistic effect have been first reported by Wakeling et al. in 1987 (see, A. Wakeling and Bowler, J. Endocrinol., 1987, 112, R7). Meanwhile, U.S. Pat. No. 4,904,661 discloses phenol derivatives having anti-estrogenic activity. These phenol derivatives generally have a naphthalene scaffold and include, typically, the following compounds:
Some chroman and thiochroman derivatives have been reported as anti-estrogenic compounds having no agonistic effect (WO 98/25916). Although the existing anti-estrogenic compounds having no agonistic effect show a substantial therapeutic effect when administered via intravenous or subcutaneous injection, they show a highly reduced therapeutic effect when administered orally, probably due to their low bioavailability by oral route, etc. Therefore, for convenience's sake in the case of administration, it is desired to develop anti-estrogenic compounds which show a sufficient effect when administered orally and at the same time have no agonistic effect.
DISCLOSURE OF THE INVENTION
The object of the present invention is to provide chroman or thiochroman derivatives which have anti-estrogenic activity and are advantageous in pharmaceutical use.
The present inventors researched anti-estrogenic activity of compounds having various structures. As a result, we have found that chroman or thiochroman derivatives of general formula (1) could show a good anti-estrogenic activity in substantial absence of agonistic effect and that they provided a sufficiently high activity even when administered orally. The present invention has been accomplished on the basis of this finding.
Namely, the present invention provides a compound having the following general formula (1):
in which
R
1
represents a hydrogen atom or a salt-forming metal;
R
2
represents a linear or branched C
3
-C
5 perhalogenoalkyl group or a group of the following general formula (
2):
in which
each of R
5
and R
6
represents a linear or branched C
1
-C
3
perhalogenoalkyl group;
each of R
3
and R
4
independently represents a hydrogen atom, an optionally substituted linear or branched C
1
-C
3
alkyl group, an acyl group or a salt-forming metal;
X represents an oxygen atom or a sulfur atom;
m represents an integer of 2 to 14; and
n represents an integer of 0 to 8;
or enantiomers of the compound, or hydrates or pharmaceutically acceptable salts of the compound or its enantiomers.
In addition, the present invention provides a pharmaceutical composition comprising a compound of general formula (1) as an active ingredient. Further, the present invention provides an anti-estrogenic pharmaceutical composition comprising the above compound as an active ingredient. The present invention also provides a therapeutic agent for breast cancer comprising the above compound as an active ingredient.
Salt-forming metals as R
1
include, but are not limited to, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium and calcium, rare earth metals such as cerium and samarium, as well as zinc and tin. Among these, preferred are alkali metals and alkaline earth metals, particularly sodium, potassium and calcium.
R
1
may preferably be a hydrogen atom, an alkali metal or an alkaline earth metal.
Halogens in the linear or branched C
3
-C
5
perhalogenoalkyl groups as R
2
include fluorine, chlorine, bromine and iodine, with fluorine being preferred. Alkyls in the linear or branched C
3
-C
5
perhalogenoalkyl groups under consideration include, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and 1-ethylpropyl. Preferred are linear or branched C
3
-C
4
alkyls, e.g., n-propyl and n-butyl.
Examples of the linear or branched C
3
-C
5
perhalogenoalkyl group as R
2
include the above-listed linear or branched C
3
-C
5
alkyl groups, provided that they are perhalogenated, preferably perfluorinated, for example, perfluoro-n-propyl, perfluoro-n-butyl and perfluoro-n-pentyl. More specifically, a perfluoro-n-butyl group is preferred.
In the case where R
2
is a group of general formula (2), halogens in the linear or branched C
1
-C
3
perhalogenoalkyl groups as R
5
and R
6
include fluorine, chlorine, bromine and iodine, with fluorine being preferred. Alkyls in the linear or branched C
1
-C
3
perhalogenoalkyl groups under consideration include, methyl, ethyl, n-propyl and i-propyl, with methyl being preferred.
In the case where R
2
is a group of general formula (2), examples of the linear or branched C
1
-C
3
perhalogenoalkyl group as R
5
and R
6
include the above-listed linear or branched C
1
-C
3
alkyl groups, provided that they are perhalogenated, preferably perfluorinated. Further, perhalogenated C
1
alkyl groups are preferred and a perfluorinated group is particularly preferred. More specifically, a perfluoromethyl group is preferred.
A group of general formula (2) as R
2
is preferably a 1,1,1,3,3,3-hexafluoroisopropyl group.
Having the definition given above, R
2
is preferably a perfluoro-n-butyl group.
Alkyls in the optionally substituted linear or branched C
1
-C
3
alkyl groups as R
3
and R
4
include, but are not limited to, methyl, ethyl, n-propyl and i-propyl.
Substituents on the optionally substituted linear or branched C
1
-C
3
alkyl groups as R
3
and R
4
include, an alkoxy group having a linear or branched C
1
-C
5
alkyl as its alkyl moiety and a hydr
Heo HongIl
Jo JaeChon
Kanbe Yoshitake
Kim Jong-Min
Kim Myung-Hwa
Browdy and Neimark , P.L.L.C.
Chugai Seiyaku Kabushiki Kaisha
Lambkin Deborah C.
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