Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2001-07-16
2003-11-11
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S254110, C514S320000, C514S337000, C514S456000, C514S432000, C544S376000, C546S207000, C546S208000, C546S280100, C546S282700, C548S127000, C548S235000, C549S023000, C549S220000, C549S403000, C549S406000
Reexamination Certificate
active
06645951
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel benzopyran or thiobenzopyran derivative having anti-estrogenic activity. More specifically, the present invention relates to a novel benzopyran or thiobenzopyran derivative represented by the following formula (1):
pharmaceutically acceptable salt or stereoisomer thereof, in which
X represents O or S,
R
1
represents hydrogen, hydroxy, or —OR
6
(wherein R
6
represents acyl or alkyl),
R
2
represents phenyl which is optionally substituted by one or more substituents selected from a group consisting of hydroxy, lower alkyl, halogen, nitro, hydroxymethyl, carboxy, alkoxycarbonyl, —OR
6
(wherein R
6
represents acyl or alkyl) and amino which is optionally substituted by one or two lower alkyl or represents 5- or 6-membered unsaturated heterocycle containing nitrogen, oxygen or sulfur as the hetero atom,
R
3
represents hydrogen or lower alkyl, provided that R
3
does not exist when
is a double bond(wherein
represents a single bond or a double bond),
R
4
represents hydrogen or lower alkyl,
A represents hydrogen, hydroxyalkyl, carboxyalkyl, carboxyvinylphenyl; pyrrole substituted by carboxyvinylbenzyl; or represents a group selected from the following formulae (a) to (l);
in the above formulae (a) to (l)
m
1
to m
3
independently of one another represent an integer of 0 to 15,
n
1
to n
2
independently of one another represent an integer of 0, 1 or 2,
R
5
represents cyano, alkyl; halogenoalkyl; alkoxy; hydroxy; carboxy; alkoxycarbonyl; carbamoyl; monoalkylamino; phenyl which is optionally substituted by one or more substituents selected from a group consisting of straight-chain or branched alkyl, carboxy and cyano; piperidinyl which is optionally substituted by one or more substituents selected from a group consisting of carboxy, alkyl and alkoxycarbonyl; cyclohexyl which is optionally substituted by carboxy; imidazolyl; dialkylamino; or piperidinyl oxide,
D
1
and D
2
independently of one another represent a direct bond, or a group selected from the following:
wherein
m, m
1
and m
2
independently of one another represent an integer of 0 to 15, and
R
5
is defined as previously described,
and to a process for preparation thereof and a pharmaceutical composition having anti-estrogenic activity which contains the compound (1) 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, 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&agr;-substituted derivatives of estradiol, for example, 7&agr;-(CH
2
)
10
CONMeBu derivative, exhibit anti-estrogenic activity (see, EP Appl. 0138504, U.S. Pat. No. 4,659,516). Further, estradiol derivative having —(CH
2
)
9
SOC
5
H
6
F
5
substituent has also been disclosed (see, Wakeling et al., Cancer Res., 1991, 51, 3867) as steroidal anti-estrogenic agent 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 tetrahydronaphthalene structure and includes, typically, the following compounds:
As other non-steroidal anti-estrogenic compounds, WO 93/10741 discloses a benzopyran derivative having aminoethoxyphenyl substituent (Endorecherche), of which the typical compound is EM-343 having the following structure:
Accordingly, the present inventors have researched the anti-estrogenic activity of compounds having, various structures. As a result, we have identified that the benzopyran or thiobenzopyran derivatives represented by formula: (1), as defined above, can exhibit a good anti-estrogenic activity without agonistic activity, to be expected no undesirable side effect and thus, completed the present invention.
DISCLOSURE OF THE INVENTION
Therefore, the present invention relates to a novel benzopyran or thiobenzopyran derivative represented by the following formula (1):
pharmaceutically acceptable salt or stereoisomer thereof, in which
X represents O or S,
R
1
represents hydrogen, hydroxy, or —OR
6
(wherein R
6
represents acyl or alkyl),
R
2
represents phenyl which is optionally substituted by one or more substituents selected from a group consisting of hydroxy, lower alkyl, halogen, nitro, hydroxymethyl, carboxy, alkoxycarbonyl, —OR
6
(wherein R
6
represents acyl or alkyl) and amino which is optionally substituted by one or two lower alkyl; or represents 5- or 6-membered unsaturated heterocycle containing nitrogen, oxygen or sulfur as the hetero atom,
R
3
represents hydrogen or lower alkyl, provided that R
3
does not exist when
is a double bond(wherein
represents a single bond or a double bond),
R
4
represents hydrogen or lower alkyl,
A represents hydrogen; hydroxyalkyl; carboxyalkyl; carboxyvinylphenyl; pyrrole substituted by carboxyvinylbenzyl; or represents a group selected from the following formulae (a) to (l);
in the above formulae (a) to (l)
m
1
to m
3
independently of one another represent an integer of 0 to 15,
n
1
to n
2
independently of one another represent an integer of 0, 1 or 2,
R
5
represents cyano; alkyl; halogenoalkyl; alkoxy; hydroxy; carboxy; alkoxycarbonyl; carbamoyl; monoalkylamino; phenyl which is optionally substituted by one or more substituents selected from a group consisting of straight-chain or branched alkyl, carboxy and cyano; piperidinyl which is optionally substituted by one or more substituents selected from a group consisting of carboxy, alkyl and alkoxycarbonyl; cyclohexyl which is optionally substituted by carboxy; imidazolyl; dialkylamino; or piperidinyl oxide,
D
1
and D
2
independently of one another represent a direct bond, or a group selected from the following:
wherein
m, m
1
and m
2
independently of one another represent an integer of 0 to 15, and
R
5
is defined as previously described.
In addition, the present invention also relates to processes for preparing the benzopyran or thiobenzopyran derivative of formula (1).
Further, the present invention relates to a pharmaceutical composi
Jo Jae Chon
Kanbe Yoshitake
Kim Jong Min
Kim Ju Su
Kim Myung Hwa
Alexander John B.
Berch Mark L.
Chugai Seiyaku Kabushiki Kaisha
Corless Peter F.
Edwards & Angell LLP
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