Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-07-24
2004-06-29
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S730000, C514S765000, C544S154000, C544S294000, C544S357000, C546S195000, C546S285000, C548S528000, C548S160000, C568S812000, C568S817000, C568S719000, C568S633000, C549S365000, C564S280000
Reexamination Certificate
active
06756375
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a non-steroidal compound with affinity for estrogen receptors and to a method for selective estrogen receptor modulation (SERM) with such a compound and to the use of such a compound for the manufacture of a medicine for estrogen-receptor-related treatments.
BACKGROUND OF THE INVENTION
Compounds with affinity for estrogen receptors have found long-standing utility in the treatment of a variety of medical indications and in regimes for contraceptive purposes. Despite the long history of the field there still is a need for more effective, safer and more economical compounds than the existing ones. This need is the more pressing in view of advancement in health care in other areas, which has led to an increasingly longer life span. This is in particular a problem for women for whom the decline in estrogenic hormones at menopause is drastic and has negative consequences for bone strength and cardiovascular functions. For the control or prevention of estrogen sensitive tumor growth, compounds are needed which are antagonists, partial antagonists or tissue selective agonists for estrogen receptors.
The discovery of subtypes of estrogen receptors, there being an &agr;-subtype (ER&agr;) and a &bgr;-subtype (ER&bgr;) of such receptors (Mosselman et al.,
FEBS Letters
vol. 392 (1996) pp. 49-53 as well as EP-A-0 798 378), offers the possibility to influence one particular subtype of those two receptors more selectively, immanently resulting in more effective treatments or treatments with less side effects. Since these receptors have a different distribution in human tissue, the finding of compounds which possess a selective afinity for either of the two is an important technical progress, making it possible to provide a more selective treatment in 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.
This invention pertains to non-steroidal estrogenic compounds with a 10-aryl-11H-benzo[b]fluorene or a 7-aryl-5,6-dihydrobenz[a]anthracene skeleton. Compounds with a 10-phenyl-11H-benzo[b]fluorene skeleton are described as products from enediyne thermocyclisation [Schittel, M., Z.
Naturforsch, B: Chem. Sci
. (1998), 53, 1015-1020] and from [4+2] cycloaddition reactions of diarylacetylenes [Rodriguez, D.,
Org. Lett
. (2000), 2, 1497-1500], but no medicinal activity of these compounds is known. Indeno[1,2-g]quinolines with interactions with nuclear receptors are disclosed in WO 96 19458. Despite the keen interest in compounds with affinity for the estrogen receptor, new compounds with a 10-aryl-11H-benzo[b]fluorene or 7-aryl-5,6-dihydrobenz[a]anthracene skeleton and affinity for the estrogen receptor cannot be learnt from these documents.
SUMMARY OF THE INVENTION
The present invention resides in the finding that compounds with an unsaturated or partially unsaturated four-ring skeleton with hydroxyl substitutions at specific locations, i.e. 2,8-dihydroxy-10-aryl-11H-benzo[b]fluorene and 3,9-dihydroxy-7-aryl-5,6-dihydro-benz[a]anthracene, possess surprisingly high antagonism for ER&bgr;. Some of these compounds also show ER&agr; antagonism or ER&agr; agonism.
DETAILED DESCRIPTION OF THE INVENTION
Specifically, the invention provides non-steroidal compounds having the formula 1
wherein:
R
e
and ′R
e
are OH, optionally independently etherified or esterified;
Z is —CH
2
— or —CH
2
CH
2
—;
R
1
is H, halogen, CF
3
, or (1C-4C)alkyl;
R
2
, R
3
and R
4
are independently H, halogen, —CF
3
, —OCF
3
, (1C-8C)Alkyl, hydroxy, (1C-8C)alkyloxy, aryloxy, aryl(1C-8C)alkyl, halo(1C-8C)alkyl, —O(CH
2
)
m
X, wherein X is halogen or phenyl and m=2-4; —O(CH
2
)
m
NR
a
R
b
, —S(CH
2
)
m
N
a
R
b
or —(CH
2
)
m
NR
a
R
b
, wherein m=2-4 and wherein R
a
, R
b
are independently (1C-8C)alkyl, (2C-8C)alkenyl, (2C-8C)alkynyl, or aryl, optionally substituted with halogen, —CF3, —OCF3, —CN, —NO
2
, —OH, (1C-8C)alkoxy, aryloxy, carboxyl, (1C-8C)alkylthio, carboxylate, (1C-8C)alkyl, aryl, aryl(1C-8C)alkyl, halo(1C-8C)alkyl or R
a
and R
b
form a 3-8 membered ring structure, optionally substituted with halogen, —CF3, —OCF
3
, —CN, —NO
2
, hydroxy, hydroxy(1C-4C)alkyl, (1C-8C)alkoxy, aryloxy, (1C-8C)alkylthio, carboxyl, carboxylate, (1C-8C)alkyl, aryl, aryl(1C-10 8C)alkyl, halo(1C-8C)alkyl.
Preferred compounds of the invention can be obtained by selecting —CH
2
— for Z and hydrogen for R
4
in formula 1. For R
1
it is preferred to select compounds having H, halogen or CF
3
. Compounds with R
1
in formula 1 is halogen, whereby chlorine is most preferred, are particularly potent and selective for the ER&bgr;.
Another embodiment of the invention is a non-steroidal compound with a 10-Aryl-11H-benzo[b]fluorene skeleton having the formula 2
wherein:
R
e
and ′R
e
are OH, optionally independently etherified or esterified;
R
1
is H, halogen or CF
3
;
R
2
and R
3
are independently H, halogen, —CF
3
, —OCF
3
, (1C-8C)Alkyl, hydroxy, (1C-8C)alkyloxy, aryloxy, aryl(1C-8C)alkyl, halo(1C-8C)alkyl, —O(CH
2
)
m
NR
a
R
b
, —S(CH
2
)
m
NR
a
R
b
or —(CH
2
)
m
NR
a
R
b
, wherein m=2-4 and R
a
, R
b
are independently (1C-8C)allyl, (2C-8C)alkenyl, (2C-8C)alkynyl, or aryl, optionally substituted with halogen, —CF
3
, —OCF
3
, —CN, —NO
2
, —OH, (1C-8C)alkoxy, aryloxy, carboxyl, (1C-8C)alkylthio, carboxylate, (1C-8C)alkyl, aryl, aryl(1C-8C)alkyl, halo(1C-8C)alkyl or R
a
and R
b
form a 3-8 membered ring structure, optionally substituted with halogen, —CF
3
, —OCF
3
, —CN, —NO
2
, hydroxy, (1C-8C)alkoxy, aryloxy, (1C-8C)alkylthio, carboxyl, carboxylate, (1C-8C)alkyl, aryl, aryl(1C-8C)alkyl, halo(1C-8C)alkyl.
For compounds, having formula 3,
it is preferred to select those in which
R
e
and ′R
e
are OH, optionally independently etherified or esterified;
R
1
is H, halogen, CF
3
;
R
2
is —O(CH
2
)
m
NR
a
R
b
, wherein m=2-3 and R
a
, R
b
are independently (1C-5C)alkyl or (3C-5C)alkenyl, optionally substituted with OH or methoxy, or R
a
and R
b
form a 4-7 membered ring structure selected from the list: azetidine, pyrrolidine, 3-pyrroline, piperidine, piperazine, tetrahydropyridine, morpholine, thiomorpholine, thiazolidine, homopiperidine, tetrahydroquinoline and 6-azabicyclo[3.2.1]octane, which 4-7 membered ring structure can optionally be substituted with OH, methoxy, acetyl, carboxylate, (1C-3C)alkyl, phenyl, benzyl, and phenylethyl.
In particular, a very effective compound is made available by this invention by selecting a compound having formula 4:
wherein:
R
e
and ′R
e
are OH, optionally independently etherified or esterified;
R
2
is (3C-6C)alkyloxy, —O(CH
2
)
m
X (wherein X is halogen or phenyl and m=2-3), or —O(CH
2
)
m
NR
a
R
b
, (wherein m=2-3), whereby R
a
, R
b
are independently (1C-5C)alkyl or (3C-5C)alkenyl, optionally substituted with OH or methoxy, or R
a
and R
b
form a 4-7 membered ring structure selected from the list: azetidine, pyrrolidine, 3-pyrroline, piperidine, piperazine, tetrahydropyridine, morpholine, thiomorpholine, thiazolidine, homopiperidine, tetrahydroquinoline and 6azabicyclo[3.2.1]octane, which 4-7 membered ring structure can optionally be substituted with OH, hydroxy(1C-2C)alkyl, methoxy, acetyl, carboxylate, (1C-3C)alkyl, phenyl, benzyl, and phenylethyl.
In those cases that the compound in formulas 1-4 contain a basic amine function, the compound may be used as a free base or as a pharmaceutically acceptable salt such as hydrochloride, acetate, oxalate, tartrate, citrate, phosphate, maleate or fumarate.
The ester and ether compounds in the collection of compounds according to the invention often have activity as prodrug. A prodrug is defined as being a compound which converts in the body of a recipient to a compound as defined by the formulas 1 to 4 and to the free
De Zwart Eduard Willem
Loozen Hubert JanJozef
Mestres Jordi
Veeneman Gerrit Herman
Akzo Nobel N.V.
Milstead Mark W.
Ramsuer Robert W.
Small Andrea D.
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