Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-12-02
2004-02-03
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S061000, C568S632000, C568S633000, C568S634000, C568S719000, C514S721000, C514S732000
Reexamination Certificate
active
06686371
ABSTRACT:
FIELD OF THE INVENTION
The invention is in the field of non-steroidal compounds for estrogen-related treatments. Estrogenic and anti-estrogenic compounds have a generally recognised utility for estrogen-receptor related medical treatments, such as those for contraception and for treatment of menopausal complaints, osteoporosis, and estrogen dependent tumour control.
BACKGROUND OF THE INVENTION
More precisely, the invention pertains to non-steroidal estrogen receptor modulating compounds with an 11H-benzo[b]fluorene, an 11H-indeno-[1,2-b]quinoline, a benz[a]anthracene or analogous skeleton. Analogous compounds with claimed usefulness in estrogen related medical treatments are described in U.S. Pat. No. 5,688,808 (1H-indeno[1,2-g]quinolines) and Morreal et al., J.Med.Chem., 1982, Vol 25, pp 323-326 (benz[a]anthracenes). Related estrogen receptor modulating compounds are described in EP 524, 742, EP 832 881 and U.S. Pat. No. 5,147,880 (1H-benzo[a]fluorenes].
Whereas further improvements for treatment of estrogen-related diseases remains desirable and there is a keen interest in compounds with affinity for the estrogen receptor, new compounds with an 11H-benzo[b]fluorene, an 11H-indeno-[1,2-b]quinoline, a benz[a]anthracene or analogous skeleton and affinity for the estrogen receptor cannot be learnt from these documents. The interest in new compounds with affinity for the estrogen receptor stems from unsatisfactory results with known estrogenic compounds for osteoporose treatment and treatment of other postmenopausal complaints and from the discovery of two distinct types of receptors, denoted ER&agr; and ER&bgr; (see Mosselman et al.,
FEBS Letters
392 (1996) 49-53 as well as EP-A-0 798 378). Since these receptors have a different distribution in human tissue, the finding of compounds which possess a selective affinity for either of the two is an important technical progress, making it possible to provide an improved and/or more selective treatment in the field of estrogen-receptor related medical treatments, such as those for contraception and for treatment of menopausal complaints, osteoporosis, and estrogen dependent tumour control, with a lower burden of estrogen-related side-effects.
DETAILED DESCRIPTION OF THE INVENTION
This invention provides new tetracyclic non-steroidal compounds having the formula I
wherein,
one of R
a
or R
b
is 'R
e
;
R
e
and 'R
e
are OH, optionally independently etherified or esterified;
X is N or —(R
1
)—, wherein R
1
is H, halogen, CN, optionally substituted aryl, (1C-4C)alkyl, (2C-4C)alkenyl, (2C-4C)alkynyl or (3C-6C)cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl groups can optionally be substituted with one or more halogens;
Y is N or —C(R
2
)—, with the proviso that X and Y are not both N, wherein R
2
has the same meaning as defined for R
1
;
Z is —C(R
3
,'R
3
)— or —C(R
4
,'R
4
)—C(R
5
,'R
5
)—, wherein R
3
, 'R
3
, R
4
, 'R
4
, R
5
, and 'R
5
, independently are H, (1C-4C)alkyl, (2C-4C)alkenyl or (3C-6C) cycloalkyl, which alkyl, alkenyl and cycloalkyl groups can optionally be substituted with one or more halogens.
The compounds of this invention have surprising and often selective interactions with estrogen receptors.
The reference to the meanings of R
1
in the definition of R
2
does not imply that R
1
is the same as R
2
in a compound as defined above. In fact, a more specific embodiment of this invention is a compound wherein at least one of R
1
or R
2
is halogen or fluorine substituted methyl.
Depending on the selection of a meaning of R
3
, 'R
3
, R
4
, 'R
4
, R
5
and 'R
5
, compounds of the invention can have asymmetrically substituted atoms and can exist in enantiomeric pure forms or mixtures of enantimers differing from the usual 50/50 proportion.
Another specific embodiment of the invention is a compound according to formula I wherein X is —C(R
1
)
13
and Y is N, having the formula II:
wherein,
one of R
a
or R
b
is 'R
e
;
R
e
and 'R
e
are OH, optionally independently etherified or esterified;
Z is —C(R
3
,'R
3
)— or —C(R
4
,'R
4
)—C(R
5
,'R
5
)—, wherein R
3
, 'R
3
, R
4
, 'R
4
, R
5
, and 'R
5
, independently are H, (1C-4C)alkyl, (2C-4C)alkenyl or (3C-6C) cycloalkyl, which alkyl, alkenyl and cycloalkyl groups can optionally be substituted with one or more halogens.
A preferred variant of this embodiment is R
a
is 'R
e
and consequently R
b
is H and further meanings are as defined for Formula II above. More preferred is R
1
is halogen or fluorine substituted methyl.
Compounds according to formula II in which Z is —C(R
3
,'R
3
)—, R
a
is 'R
e
and R
b
is H have the formula III
whereby the symbols have the meaning as defined for Formula II. Such compounds are named 11H-indeno[1,2-b]quinolines according to the convention of the chemical abstracts.
An embodiment of the invention is a compound according to Formula II, in which Z is —C(R
4
,'R
4
)—C(R
5
,'R
5
)—; R
a
is 'R
e
; R
b
, R
4
, 'R
4
, R
5
and 'R
5
are H, having the formula IV
wherein,
R
1
is H, halogen, CN, optionally substituted aryl, (1C-4C)allyl, (2C-4C)alkenyl, (2C-4C)alkynyl or (3C-6C)cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl groups can optionally be substituted with one or more halogens. Such compounds are named 3,9-dihydroxy-5,6-dihydro-benz[c]acridines. In this embodiment of the invention it is preferred that R
1
is halogen or fluorine substituted methyl.
Another embodiment of the invention is a compound having Formula I, wherein X is N, Y is —C(R
2
)—, R
a
is H and R
b
is 'R
e
, having Formula V
wherein,
Re and 'R
e
are OH, optionally independently etherified or esterified;
Z is —C(R
3
,'R
3
)— or —C(R
4
,'R
4
)—C(R
5
,'R
5
)—, wherein R
3
, 'R
3
, R
4
, 'R
4
, R
5
, and 'R
5
, independently are H, (1C-4C)alkyl, (2C-4C)alkenyl or (3C-6C) cycloalkyl, which alkyl, alkenyl and cycloalkyl groups can optionally be substituted with one or more halogens;
R
2
is H, halogen, CN, optionally substituted aryl, (1C-4C)alkyl, (2C-4C)alkenyl, (2C-4C)alkynyl, (3C-6C)cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl groups can optionally be substituted with one or more halogens.
In this embodiment it is preferred that R
2
is halogen or fluorine substituted methyl and R
3
, 'R
3
, R
4
, 'R
4
, R
5
, and 'R
5
, independently are H or methyl. More preferred is that Z is —C(R
4
,'R
4
)—C(R
5
,'R
5
)—, wherein R
4
, 'R
4
, R
5
, and 'R
5
, are H.
Another embodiment of this invention is a compound according to formula I, wherein X is —C(R
1
)—, Y is —C(R
2
)—, having Formula VI
wherein,
one of R
a
or R
b
is 'R
e
;
R
e
and 'R
e
are OH, optionally independently etherified or esterified;
R
1
and R
2
independently are H, halogen, CN, optionally substituted aryl, (1C-4C)alkyl, (2C-4C)alkenyl, (2C-4C)alkynyl or (3C-6C)cycloalkyl, which alkyl, alkenyl, alkynyl and cycloalkyl groups can optionally be substituted with one or more halogens;
Z is —C(R
3
,—R
3
)— or —C(R
4
,'R
4
)—C(R
5
,'R
5
)—, wherein R
3
, 'R
3
, R
4
, 'R
4
, R
5
, and 'R
5
, independently are H, (1C-4C)alkyl, (2C-4C)alkenyl or (3C-6C) cycloalkyl, which alkyl, alkenyl and cycloalkyl groups can optionally be substituted with one or more halogens. In this embodiment it is preferred that R
1
or R
2
is halogen or fluorine substituted methyl.
Also preferred in this embodiment are those compounds according to Formula VI whereby R
a
is 'R
e
; R
b
is H; Z is —C(R
4
,'R
4
)—C(R
5
,'R
5
)—, wherein R
4
, 'R
4
, R
5
, and 'R
5
are H, which compounds are having Formula VII
wherein,
R
e
and 'R
e
are OH, optionally independently etherified or esterified;
R
1
and R
2
independently are H, halogen, CN, optionally substituted aryl, (1C-4C)alkyl, (2C-4C)alkenyl, (2C-4C)alkynyl or (3C-6
De Zwart Eduard Willem
Loozen Hubert Jan Jozef
Mestres Jordi
Veeneman Gerrit Herman
Akzo Nobel N.V.
Aulakh Charanjit S.
Minstead Mark W.
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