Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1999-12-02
2004-08-24
Qazi, Sabiha (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S170000, C514S176000, C514S172000, C514S267000, C540S047000, C540S113000, C540S107000, C540S114000, C540S117000, C540S120000, C552S626000
Reexamination Certificate
active
06780855
ABSTRACT:
This invention relates to 11&bgr;-halogen-7&agr;-substituted estratrienes of general formula I
in which
R
3
means a hydrogen atom, a hydrocarbon radical with up to 8 carbon atoms or a radical of partial formula R
3′
—C(O)—, in which R
3′
means a hydrogen atom or a hydrocarbon radical with up to 8 carbon atoms or a phenyl radical,
R
7
means a radical of formula —A—B—Z—R
20
,
in which
A stands for a direct bond or a benzylidene radical, whereby the methylene group is bonded to the 7-carbon atom of the steroid, or a phenylene radical,
B stands for a straight-chain or branched-chain alkylene, alkenylene or alkinylene group with 3 to 14 carbon atoms, and
Z stands for —NR
21
— and R
21
stands for a C
1
-C
3
alkyl group,
whereby then R
20
means
a hydrogen atom,
a straight-chain or branched-chain alkyl,
alkenyl or alkinyl group with up to 10 carbon atoms or one of groupings
—D—C
n
F
2n+1
, whereby D is a straight-chain or branched-chain alkylene, alkenylene or alkinylene group with up to 8 carbon atoms and n is an integer from 1 to 8,
—L—CH═CF—C
p
F
2p+1
, whereby L is a straight-chain or branched-chain alkylene, alkenylene or alkinylene group with 2 to 7 carbon atoms and p is an integer from 2 to 7,
—D—O—(CH
2
)
q
-aryl, whereby D has the already indicated meaning, q is 0, 1, 2 or 3, and aryl stands for a phenyl radical, 1- or 2-naphthyl radical or a heteroaryl radical that is optionally substituted in one or two places,
—D—O—(CH
2
)
r
—C
n
F
2n+1
, whereby D and n have the already indicated meanings and r stands for an integer from 1 to 5, or
R
20
and R
21
with the nitrogen atom to which they are bonded form a saturated or unsaturated heterocycle with 5 or 6 chain links, which optionally contains one or two additional heteroatoms, selected from nitrogen, oxygen and sulfur, and optionally is substituted, or
Z stands for —SO
x
and x stands for 0, 1 or 2,
whereby R
20
then means
a straight-chain or branched-chain alkyl, alkenyl or alkinyl group with up to 10 carbon atoms, or one of groupings
—D—C F
2n+1
, whereby D is a straight-chain or branched-chain alkylene, alkenylene or alkinylene group with up to 8 carbon atoms and n is an integer from 1 to 8,
—L—CH═CF—C
p
F
2p+1
, whereby L is a straight-chain or branched-chain alkylene, alkenylene or alkinylene group with 2 to 7 carbon atoms and p is an integer from 2 to 7,
—D—O—(CH
2
)
q
-aryl, whereby D has the already indicated meaning, q is 0, 1, 2 or 3, and aryl stands for a phenyl radical, 1- or 2-naphthyl radical or a heteroaryl radical that is optionally substituted in one or two places,
—D—O—(CH
2
)
r
—C
n
F
2n+1
, whereby D and n have the already indicated meanings and r stands for an integer from 1 to 5, or
Z stands for —NR
31
,
whereby then R
20
is a straight-chain or branched-chain, optionally partially fluorinated alkyl, alkenyl or alkinyl radical with up to 14 carbon atoms, which can be interrupted by one to three heteroatoms —O— and —S— and groupings —NR
32
—, in which R
32
is a hydrogen atom or a C
1
-C
3
alkyl radical, an aryl or heteroaryl radical that is optionally substituted in one or two places, a C
3
-C
10
cycloalkyl radical that is optionally substituted in one or two places, a C
4
-C
15
cycloalkylalkyl radical that is optionally substituted in one or two places, a C
7
-C
20
aralkyl radical that is optionally substituted in one or two places, a heteroaryl-C
1
-C
6
alkyl radical that is optionally substituted in one or two places or an optionally substituted aminoalkyl radical, and R
31
is a radical of formula —C(O)R
33
or —CH
2
—R
33
, whereby then R
33
is a straight-chain or branched-chain, optionally partially fluorinated alkyl, alkenyl or alkinyl radical with up to 14 carbon atoms, which can be interrupted by one to three heteroatoms —O— and —S— and groupings —NR
32
—, in which R
32
is a hydrogen atom or a C
1
-C
3
alkyl radical, an aryl or heteroaryl radical that is optionally substituted in one or two places, a C
3
-C
10
cycloalkyl radical that is optionally substituted in one or two places, a C
4
-C
15
cycloalkylalkyl radical that is optionally substituted in one or two places, a C
7
-C
20
aralkyl radical that is optionally substituted in one or two places, a heteroaryl-C
1
-C
6
alkyl radical that is optionally substituted in one or two places, an optionally substituted aminoalkyl radical or a biphenylene radical,
whereby side chain R
7
cannot have the meanings that are indicated there in PCT/EP97/04517 for SK,
R
11
means a fluorine or chlorine atom,
R
17
means a hydrogen atom or a radical of partial formula R
17′
—C(O)—, in which R
17′
is a hydrogen atom or a hydrocarbon radical with up to 8 carbon atoms.
R
7
can have the meanings that are described in EP 138 504 B1 for the 7&agr;-side chain of the steroid, with the restriction of the above-indicated disclaimer.
As R
3
, the 7&agr;-substituted estratrienes according to the invention preferably have a hydrogen atom. The hydroxy group, however, can also be etherified with a straight-chain or branched-chain, saturated or unsaturated hydrocarbon radical with up to 8 carbon atoms, such as, e.g., a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl or octyl radical or esterified with an acyl radical R
3′
—C(O)—, in which R
3′
is a hydrogen atom or a hydrocarbon radical with up to 8 carbon atoms or a phenyl radical.
A fluorine atom is preferred for substituents R
11
.
A hydrogen atom or a radical of partial formula R
17′
—C(O)— can stand for substituents R
17
, in which R
17′
is a hydrogen atom or a hydrocarbon radical with up to 8 carbon atoms. A hydrogen atom is preferred for R
17
. The hydrocarbon radical can have the meaning of, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl or octyl radical.
In the compounds of general formula I according to the invention, A stands for a direct bond, a phenylene or benzylidene radical, whereby in the last case, the methylene group is bonded to carbon atom 7 of the steroid skeleton.
An aryl radical within the terms of this invention is preferably a phenyl radical, 1- or 2-naphthyl radical; the phenyl radical is preferred. Unless expressly indicated otherwise, aryl also always includes a heteroaryl radical. Examples of a heteroaryl radical are the 2-, 3- or 4-pyridinyl radical, the 2-or 3-furyl radical, the 2- or 3-thienyl radical, the 2- or 3-pyrrolyl radical, the 2-, 4- or 5-imidazolyl radical, the pyrazinyl radical, the 2-, 4- or 5-pyrimidinyl radical or 3- or 4-pyridazinyl radical.
In the ring, aralkyl groups in R20 and R
31
can contain up to 14 C atoms, preferably 6 to 10 C atoms, and in the alkyl chain, they can contain 1 to 8, preferably 1 to 4 C atoms. As aralkyl radicals, for example, benzyl, phenylethyl, phenylpropyl, naphthylmethyl, and naphthylethyl are suitable.
As heteroalkylalkyl radicals, for example, furylmethyl, thienylethyl, and pyridylpropyl can be mentioned.
The aralkyl or heteroarylalkyl radical can be substituted.
If R
20
and R
21
with the nitrogen atom, to which they are bonded, a saturated or unsaturated heterocycle with 5 or 6 chain links, which optionally contains one or two additional heteroatoms that are selected from nitrogen, oxygen and sulfur, this is especially a pyrrolidine, piperidine, morpholine or piperazine ring.
As substituents for the aryl, heteroaryl, aralkyl and heteroarylalkyl radicals, for example, a trifluoromethyl-, pentafluoroethyl-, trifluoromethylthio-, methoxy-, ethoxy-, nitro-, cyano-, halogen- (fluorine, chlorine, bromine, iodine), hydroxy-, amino-, mono(C
1-8
alkyl)- or di(C
1-8
alkyl)amino, whereby both alkyl groups are identical or different, di(aralkyl)amino, whereby both aralkyl groups are identical or different (for aralkyl, see above at R
20
and R
31
) or the 1-methoxyacetylamino radical can be mentioned.
The sulfur atom in the side chain can be present as a single sulfur bridge (sulfide),
Bohlmann Rolf
Fritzemeier Karl-Heinrich
Heinrich Nikolaus
Hofmeister Helmut
Kroll Jorg
Millen White Zelano & Branigan P.C.
Qazi Sabiha
Schering Aktiengesellschaft
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