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
2003-08-26
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...
C514S458000, C549S023000, C549S406000
Reexamination Certificate
active
06610733
ABSTRACT:
TECHNICAL FIELD
The present invention relates to optically active 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 optically active chroman or thiochroman derivatives with asymmetric center(s), which have an excellent anti-estrogenic activity and are advantageous in pharmaceutical use.
The present inventors have researched anti-estrogenic activity of compounds having various structures. As a result, we have found that optically active chroman or thiochroman derivatives represented by general formulae (1) to (4) could be more advantageous in pharmaceutical use because of, for example, their far superior anti-estrogenic activity over the corresponding diastereomer mixture. 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
x represents an oxygen atom or a sulfur atom,
m represents an integer of 2 to 14, and
n represents an integer of 2 to 7,
or the following general formula (2):
in which
x represents an oxygen atom or a sulfur atom,
m represents an integer of 2 to 14, and
n represents an integer of 2 to 7,
or the following general formula (3):
in which
x represents an oxygen atom or a sulfur atom,
m represents an integer of 2 to 14, and
n represents an integer of 2 to 7,
or the following general formula (4):
in which
x represents an oxygen atom or a sulfur atom,
m represents an integer of 2 to 14, and
n represents an integer of 2 to 7,
or hydrates thereof.
In addition, the present invention provides an optically single isomer of a compound having general formula (1) or (2) where the carbon which is on the side chain bonded to the 4-position of the parent scaffold (i.e., chroman or thiochroman ring) and to which the carboxylic acid in said side chain is bonded has R- or S-configuration, and mixtures thereof.
Further, the present invention provides a pharmaceutical composition comprising an optically active compound of general formula (1), (2), (3) or (4) as an active ingredient. Furthermore, 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.
In the definition of a compound having general formula (1), (2), (3) or (4), m may preferably be an integer of 6 to 10, particularly 8 or 9, and n may preferably be an integer of 2 to 7, particularly 3 or 4.
Compounds of general formula (1) or (2) have chiral carbons at positions 3 and 4 of the parent scaffold (i.e., chroman or thiochroman ring) in either the (3S,4S) or (3R,4R) configuration. Any of these compounds is preferred per se. In particular, the compounds having R- or S-configuration at the carbon to which the carboxylic acid is bonded are more preferable, wherein said carbon is the carbon on the side chain which is bonded to the 4-position of the parent scaffold. Also preferred are compounds of general formula (2), particularly those compounds in which X is a sulfur atom.
Another aspect of the present invention includes compounds of general formula (1) or (2) in which X is an oxygen atom.
Among compounds of general formula (1) or (2), preferred are those compounds in which X is an oxygen atom or a sulfur atom; m is an integer of 8 or 9; and n is an integer of 3 or 4. In particular, the compound having R- or S-configuration at the carbon to which the carboxylic acid is bonded are more preferable, wherein said carbon is the carbon on the side chain which is bonded to the 4-position of the parent scaffold.
As typical examples of these compounds, the following compounds can be mentioned:
10-[(3R,4R)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-(2R)-2-(4,4,5,5,5-pentafluoropentyl)decanoic acid;
10-[(3R,4R)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-(2S)-2-(4,4,5,5,5-pentafluoropentyl)decanoic acid;
10-[(3S,4S)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-(2R)-2-(4,4,5,5,5-pentafluoropentyl)decanoic acid;
10-[(3S,4S)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-(2S)-2-(4,4,5,5,5-pentafluoropentyl)decanoic acid;
10-[(3R,4R)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoic acid;
10-[(3S,4S)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoic acid;
10-[(3RS,4RS)
Ho Pil-Su
Kanbe Yoshitake
Kim Hong-Ki
Kim Myung-Hwa
Kwon Hee-An
Browdy and Neimark , P.L.L.C.
Chugai Seiyaku Kabushiki Kaisha
Lambkin Deborah C.
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