Compounds with hydroxycarbonyl-halogenoalkyl side chain

Details Compounds with hydroxycarbonyl-halogenoalkyl side chain Compounds with hydroxycarbonyl-halogenoalkyl side chain

2002-06-13

2004-05-18

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C552S630000, C552S526000, C552S500000, C552S504000, C552S536000, C514S182000

Reexamination Certificate

active

06737417

ABSTRACT:

TECHNICAL FIELD
The present invention relates to hydroxycarbonyl-halogenoalkyl derivatives designed to significantly increase oral activity of compounds having low activity following oral administration, compounds having anti-tumor activity, compounds having estrogenic activity or compounds 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 as a 7&agr;-substituted derivative of estradiol (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, due to their low bioavailability by oral route. 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. Also, it is generally desired to develop agents which show a sufficient effect when administered orally.
DISCLOSURE OF THE INVENTION
The object of the present invention is to provide hydroxycarbonyl-halogenoalkyl derivatives designed to significantly increase oral activity of compounds having low activity following oral administration, compounds having anti-tumor activity, compounds having estrogenic activity or compounds having anti-estrogenic activity by enhancing their absorption from the intestinal tract and/or improving their stability against metabolism.
Our research efforts were directed to achieving the above object, and we have found that a side chain of general formula (1) allowed estrogenic compounds to show a significantly increased activity by oral route when attached to the parent scaffolds of the compounds. The present invention has been accomplished on the basis of this finding.
Namely, the present invention provides a compound consisting-of a moiety and a group chemically bonded to said moiety, wherein said moiety contains a compound having low activity following oral administration or its parent scaffold and said group has 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
1
-C
7
halogenoalkyl group,
m represents an integer of 2 to 14, and
n represents an integer of 2 to 7,
or enantiomers of the first-mentioned compound, or hydrates or pharmaceutically acceptable salts of the compound or enantiomers thereof.
The present invention also provides a compound consisting of a moiety and a group chemically bonded to said moiety, wherein said moiety contains a compound having anti-tumor activity or its parent scaffold and said group has 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
1
-C
7
halogenoalkyl group,
m represents an integer of 2 to 14, and
n represents an integer of 2 to 7,
or enantiomers of the first-mentioned compound, or hydrates or pharmaceutically acceptable salts of the first-mentioned compound or enantiomers thereof.
The present invention further provides a compound consisting of a moiety and a group chemically bonded to a moiety, wherein said moiety contains a compound having estrogenic activity or its parent scaffold or a compound having anti-estrogenic activity or its parent scaffold and said group has 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
1
-C
7
halogenoalkyl group,
m represents an integer of 2 to 14, and
n represents an integer of 2 to 7,
or enantiomers of the first-mentioned compound, or hydrates or pharmaceutically acceptable salts of the first-mentioned compound or enantiomers.
The present invention even further provides a compound having the following general formula (2):
in which
R
1
represents a hydrogen atom or a salt-forming metal,
R
2
represents a linear or branched C
1
-C
7
halogenoalkyl group,
m represents an integer of 2 to 14,
n represents an integer of 2 to 7, and
A represents a group selected from the following formulae (3) to (8) and (10) to (26):
in which
in formulae (6), (7), (14) and (24), each of R
3
and R
6
represents a linear or branched C
1
-C
5
alkyl group,
in formulae (10), (11) and (12), Z
10
represents a hydrogen atom or an acyl group,
in formulae (13), (21) and (22), each of Z
1
, Z
2
, Z
3
, Z
4
, Z
5
and Z
6
independently represents a hydrogen atom, a hydroxyl group or a linear or branched C
1
-C
5
alkyl group,
in formula (15), R
7
represents a hydrogen atom or a linear or branched C
1
-C
5
alkyl group,
in formula (16), each of Z
7
, Z
8
, and Z
9
independently represents a hydrogen atom or a hydroxyl group,
in formulae (18) and (20), R
8
represents a linear or branched C
1
-C
5
alkyl group, a linear or branched C
2
-C
5
alkenyl group or a linear or branched C
2
-C
5
alkynyl group,
in formula (23), each of R
21
, R
22
, R
23
and R
24
independently represents a hydrogen atom, a linear or branched C
1
-C
5
alkyl group, a linear or branched C
1
-C
7
halogenoalkyl group, a halogen atom or an acyl group, an

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