Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2002-05-07
2004-09-14
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S182000, C552S626000
Reexamination Certificate
active
06790842
ABSTRACT:
This invention relates to 11&bgr;-long-chain-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
11
means a radical of formula —A—B—Z—R
20
, in which
A stands for a direct bond, and
B stands for a straight-chain or branched-chain alkylene, alkenylene or alkinylene group with 4, 5 or 6 carbon atoms, or
A stands for a phenylene radical, and
B stands for a methylene, ethylene, propylene or trimethylene group, or
A stands for a phenylenoxy radical, whereby the latter is bonded via a carbon atom to the 11-carbon atom of the steroid, and
B stands for an ethylene group, and
Z stands for —NR
21
— and R
21
stands for a C
1
-C
3
alkyl group,
whereby R
20
means
a hydrogen atom,
a straight-chain or branched-chain alkyl, alkenyl or alkinyl group with up to 10 carbon atoms, whereby if A is a direct bond, R
20
and R
21
do not both simultaneously mean methyl, however, and, if A is a phenylenoxy radical, R
20
and R
21
do not both simultaneously mean methyl or ethyl in each case, and if A is a phenylenoxy radical and B means an ethylene group, OR
17b
should not be a hydroxy group and R
17a
should not be a C
1-4
alkyl group, and R
3
should not be a hydrogen atom,
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, D-aryl, whereby D has the already indicated meaning, and aryl stands for a phenyl, 1- or 2-naphthyl radical or a heteroaryl radical that is optionally substituted in one or two places,
—L—CH═CF—C
p
F
2p+1
, whereby L is a straight-chain or branched-chain alkylene, alkenylene or alkinylene group with up to 7 carbon atoms and p is an integer from 1 to 7,
whereby in the three cases above in D or L, a methylene group can be replaced by a sulfur atom, a sulfone group or a sulfoxide group,
—D—O—(CH
2
)
q
-aryl, whereby D and aryl have the already indicated meanings, and q is 0, 1, 2 or 3,
—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,
whereby in addition in all relevant cases above, R
21
together with D with the inclusion of the nitrogen atom can then form a pyrrolidine ring that is substituted in 2- or 3-position, or
if A is a direct bond or a phenylene radical, R
20
and R
21
with the nitrogen atom to which they are bonded form a saturated or unsaturated heterocyclic compound with 5 or 6 chain links, which optionally contains one or two additional heteroatoms, selected from nitrogen, oxygen and sulfur, and optionally is substituted,
whereby if A is a phenylene radical and B is a trimethylene radical, R
21
and R
20
do not form a methyl or ethyl group, or, together with the nitrogen atom to which they are bonded, do not form a pyrrolidine or and
R
17a&agr;
in &agr;- or &bgr;-position means a hydrogen atom, a C
1-5
alkyl, a C
2-5
alkenyl or a C
2-5
alkinyl group or a trifluoromethyl group, or together with the radical OR
17b
means a keto-oxygen atom, and
R
17b
means a hydrogen atom or a radical of partial formula R
17
′—C(O)—, in which R
17
′ means a hydrogen atom or a hydrocarbon radical with up to 8 carbon atoms.
As R
3
, the 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 hydrogen atom or a radical of partial formula R
17
′—C(O)— can stand for substituents R
17b
, 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
17b
. 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 addition, the substituent —OR
17b
can be in &agr;- or &bgr;-position. The &bgr;-position is preferred.
R
17b
can mean a hydrogen atom, a straight-chain or branched C
1-5
alkyl radical, such as, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl radical, a straight-chain or branched C
2-5
alkenyl radical, such as, for example, an ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-ethyl-ethenyl, 2-ethylethenyl, 1-methyl(1-propenyl), 1-methyl(2-propenyl) radical, or a straight-chain or branched C
2-5
alkinyl radical, such as, for example, an ethinyl, 1-propinyl, 2-propinyl, 1-butinyl, 2-butinyl, 3-butinyl, 3-methyl (1-butinyl)-, 1-methyl (3-butinyl) radical and a trifluoromethyl radical.
R
17b
preferably means a hydrogen atom, a C
2-3
alkenyl radical, a C
2-3
alkinyl radical or a trifluoromethyl group.
R
17a
especially preferably means a hydrogen atom, a methyl group, an ethenyl radical, an ethinyl radical or a trifluoromethyl group.
In addition, the radical R
17a
can be in &agr;- or &bgr;-position. The &agr;-position is preferred for R
17a
.
Another meaning for R
17b
together with OR
17a
is a keto-oxygen atom. This meaning is to be preferred before any other substitution in 17-position.
In the compounds of general formula I according to the invention, A stands for a direct bond, a phenylene or phenylenoxy radical, whereby the latter is connected via one of its carbon atoms to carbon atom 11 of the steroid skeleton.
An aryl radical that optionally can be substituted is a phenyl, 1- or 2-naphthyl radical in terms of this invention; 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, the 2- or 3-furyl, the 2- or 3-thienyl, the 2- or 3-pyrrolyl, the 2-, 4- or 5-imidazolyl, the pyrazinyl, the 2-, 4- or 5-pyrimidinyl or the 3- or 4-pyridazinyl radical.
If R
20
and R
21
with the nitrogen atom, to which they are bonded, contain 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 methyl-, ethyl-, propyl-, 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), as sulfone or sulfoxide.
As specific side chains,
—(CH
2
)
5
N(CH
3
)—(CH
2
)
3
—S—(CH
2
)
3
C
2
F
5
—(CH
2
)
5
NH—(CH
2
)
3
—S—(CH
2
)
3
C
2
F
5
—(CH
2
)
5
N(CH
3
)—(CH
2
)
3
—S—CH
2
-2-Pyridyl
—(CH
2
)
5
N(CH
3
)—(CH
2
)
3
—SO—CH
2
-2-Pyridyl
—(CH
2
)
5
N(CH
3
)—(CH
2
)
3
—S—CH
2
-p-CF
3
-Phenyl
—(CH
2
)
5
N(CH
3
)—(CH
2
)
3
—SO—CH
2
-p-CF
3
-Phenyl
—(CH
2
)
5
-[2-Pyrrolidin-1-yl]—CH
2
—S-p-CF
3
-Phenyl
—(CH
2
)
5
-[2-Pyrrolidin-1-yl]—CH
2
—SO-p-CF
3
-Phenyl
p-Phenylen-(CH
2
)
2
—N(CH
3
)—(CH
2
)
3
—S—(CH
2
)
3
C
2
F
5
p-Phenylen-(CH
2
)
2
—N(CH
3
)—(CH
2
)
3
—SO—(CH
2
)
3
C
2
F
5
p-Phenylen-(CH
2
)
2
—N(CH
3
)—(CH
2
)
3
—S—CH
2
-2-Pyridyl
p-Phenylen-(CH
2
)
2
—N(CH
Bohlmann Rolf
Fritzemeier Karl-Heinrich
Hegele-Hartung Christa
Heinrich Nikolaus
Hoffmann Jens
Badio Barbara P.
Millen White Zelano & Branigan P.C.
Schering Aktiengesellschaft
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