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
2003-04-29
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
06555571
ABSTRACT:
TECHNICAL FIELD
The present invention relates to 3-methyl-chromane or thiochromane derivatives having anti-estrogenic activity. More specifically, the present invention relates to 3-methyl-chromane or thiochromane derivatives represented by the following formula (1):
in which
X represents O or S,
R
1
represents hydrogen or metal, and
m represents an integer of 2 to 14, pharmaceutically acceptable salts, stereoisomers or hydrates thereof, and an anti-estrogenic pharmaceutical composition which comprises the compound of formula (1) as an active component.
BACKGROUND ART
In treating diseases that are dependent upon a certain sexual hormone such as estrogen, it is important to significantly reduce or inhibit the effect induced by the hormone. For this purpose, it is desirable to reduce the level of hormone capable of acting on the receptor site stimulated by sexual steroidal hormone. For instance, hysterectomy may be applied to limit the production of estrogen to the amount less than required to activate the receptor site. However, this method 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. 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 (see, WO 96/26201). 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, 5,395,842 and WO 96/22092, etc. disclose various anti-estrogenic compounds. Sometimes, however, prior antagonists may 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).
As another non-steroidal anti-estrogenic compound, WO 93/10741 discloses a benzopyran derivative having aminoethoxyphenyl substituent (Endorecherche), the typical compound of which is EM-343 having the following structure:
Said compound also has the agonistic effect. Therefore, it is required to develop an 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&agr;-substituted derivatives of estradiol, for example, 7&agr;-(CH
2
)
10
CONBuMe derivatives, are steroidal anti-estrogenic agent without agonistic effect (see, EP Appl. 0138504, U.S. Pat. No. 4,659,516). Further, estradiol derivative having 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 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 mainly has a tetrahydronaphthalene structure and includes, typically, the following compounds:
in which R
1
, R
2
, n, p and q are defined as described in the prior arts as mentioned above.
Some chromane and thiochromane 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 little therapeutic activity when administered orally, which is considered to be caused by several factors, one of which is the low bioavailability. Therefore, for convenience' 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
Under these technical backgrounds, the present inventors have screened the anti-estrogenic activity of the new compounds having various structures. As a result, we have identified that 3-methyl-chromane or thiochromane derivatives represented by the following formula (1) can exhibit a good anti-estrogenic activity with no substantial agonistic effect even when orally administered, whereby we completed the present invention.
Therefore, the present invention relates to 3-methyl-chromane or thiochromane derivatives represented by the following formula (1):
in which
X represents O or S,
R
1
represents hydrogen or metal, and
m represents an integer of 2 to 14, pharmaceutically acceptable salts, stereoisomers or hydrates thereof.
It is another object of the present invention to provide a medicine, more specifically an anti-estrogenic pharmaceutical composition which comprises the compound of formula (1) as an active component together with pharmaceutically acceptable carriers.
BEST MODE FOR CARRYING OUT THE INVENTION
In the compound of formula (1) according to the present invention, when R
1
is metal, R
1
may include alkali metals such as sodium, potassium, etc.; alkaline earth metals such as magnesium, calcium, etc.; rare earth metals such as cerium, samarium, etc.; and zinc, tin, etc. Among them, alkali metals and alkaline earth metals are more preferable, and alkali metals (particularly, sodium) are most preferable. When R
1
is a monovalent metal such as an alkali metal, the R
1
group combines with the residue of the compound of formula (1) in a ratio of 1:1. However, when R
1
is other than the monovalent metal, it combines in a ratio of more than 1:1 depending on the valency of the metal.
The compound of formula (1) according to the present invention can exist as a stereoisomer, and thus, the present invention also includes each of the stereoisomers and their mixtures including racemate. Among the stereoisomers, compounds wherein the configuration of 3- and 4-position chiral carbons in the chromane(or thiochromane) ring is (3R, 4R) or (3S, 4S) or mixtures thereof are preferable, and in this case, compounds wherein the chiral carbon in the 4-position side chain of chromane(or thiochromane) ring, to which R
1
OOC— group is attached, has the configuration of R or S or mixtures thereof are preferable.
As the pharmaceutically acceptable salts of the compound of formula (1), the metal salts as described above, for example, sodium, potassium, calcium salt, etc. can be mentioned. These salts may be prepared according to the conventional conversion methods.
Among the compound of formula (1), the preferred compounds include those wherein R
1
is hydrogen, X is oxygen or sulfur, and m is an integer of 6 to 10, particularly preferably an integer of 8 or 9.
As typical examples of the compound of formula (1), the following compounds can be mentioned:
(3′RS,4′RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)decanoic acid;
(3′RS,4′RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)undecanoic acid;
(3′RS,4′RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)undecanoic acid; and
(3′RS,4′RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)decanoic acid.
The compound of formula (1) according to the present invention can be prepared by the following Processes I to V, and thus, the present invention also provides these processes.
(Process I)
The compound of formula (1) can be prepared by a process characterized in that
(a) a compound of the following formula (2):
in which
X is defined as previously described, and
R
11
represents hydroxy- or carboxy-protecting group, preferably t-butyldimethylsilyl, triisopropylsilyl, triethylsilyl, t-butyldiphenylsilyl, methoxymethyl, tetrahydropyranyl, methyl, ethyl, etc., is reacted
Ahn KooHyeon
Ho Pil-Su
Jo JaeChon
Kanbe Yoshitake
Kim JuSu
Browdy and Neimark
Chugai Seiyaku Kabushiki Kaisha
Lambkin Deborah C.
LandOfFree
3-methyl -chromane or thiochromane derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 3-methyl -chromane or thiochromane derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 3-methyl -chromane or thiochromane derivatives will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3105369