Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-14
2002-02-05
Raymond, Richard L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S248000, C514S259500, C514S361000, C514S362000, C544S063000, C544S237000, C548S126000, C548S260000, C548S261000
Reexamination Certificate
active
06344454
ABSTRACT:
This invention relates to nonsteroidal compounds, which have a high gestagenic activity.
In addition to a large number of steroid compounds with gestagenic action, gestagens that are not steroids are also known (for example from EP 0 253 500 B1 and WO 94/01412, cf. J. Med. Chem. 38 (1995) 4878).
This invention describes the compounds of general formula I
in which
R
1
and R
2
are the same or different and stand for a hydrogen atom, a C
1
-C
5
alkyl group or a halogen atom, and also together with the C-atom of the chain stand for a ring with a total of 3-7 links,
R
3
stands for a C
1
-C
5
alkyl group or a partially or completely fluorinated C
1
-C
5
alkyl group,
A stands for a monocyclic or bicyclic aromatic ring that is optionally substituted by one or more radicals, selected from halogen atoms, C
1
-C
5
alkyl groups, C
2
-C
5
alkenyl groups —CR
5
═CR
6
R
7
, whereby R
5
, R
6
and R
7
are the same or different and, independently of one another, mean hydrogen atoms or C
1
-C
5
alkyl groups; hydroxy groups, hydroxy groups that carry a C
1
-C
10
acyl group, a C
3
-C
10
carbalkoxyalkyl group, a C
2
-C
5
cyanalkyl group, a C
3
-C
10
unsubstituted or substituted allyl group, a C
3
-C
10
unsubstituted or substituted propargyl group, a C
2
-C
5
alkoxyalkyl group, a C
1
-C
5
alkyl group that is partially or completely substituted by fluorine atoms, the cyano or nitro group, C
1
-C
5
alkoxy groups, C
1
-C
5
alkylthio groups, mono- or disubstituted C
1
-C
10
amino groups or partially or completely fluorinated C
1
-C
5
alkyl groups,
for an ester group —COOR
4
1
, whereby R
4
means a C
1
-C
5
alkyl group,
for a C
2
-C
5
alkenyl group —CR
5
═CR
6
R
7
, whereby R
5
, R
6
and R
7
are the same or different, and, independently of one another, mean hydrogen atoms, halogen atoms, aryl radicals or C
1
-C
5
alkyl groups, for an alkenyl group —C═CR
5
, whereby R
5
means a hydrogen atom or a C
5
-C
5
alkyl group,
for a partially or completely fluorinated C
1
-C
5
alkyl group,
B stands for a carbonyl group or a CH
2
group,
and
Ar stands for a ring system, selected from the group of general partial formulas 2-11,
in which
radicals x
3a
, X
4
, X
6
, X
7
(in partial formula 2), X
4
, X
6
, X
7
(in partial formulas 3 and 4), X
3a
, X
3b
, X
4
, X
6
, X
7
(in partial formulas 5, 6 and 7) or Y
4
, Y
5
, Y
7
, Y
8
(in partial formulas 8, 9, 10 and 11) are the same or different and are selected from hydrogen atoms, C
1
-C
5
alkyl groups, which in addition can contain a hydroxy group that is optionally etherified with a C
1
-C
5
alkyl group or esterified with a C
1
-C
5
alkanoyl group, partially or completely fluorinated C
1
-C
5
alkyl groups, C
2
-C
5
alkenyl groups
—CR
5
═CR
6
R
7
, whereby R
5
, R
6
, and R
7
have the above-mentioned meaning, alkenyl groups —C═CR
5
, whereby R
5
has the above-mentioned meaning,
radicals X
3a
and X
3b
also together with the C-atom of benzocondensed ring system 5, 6 or 7 can form a ring with a total of 3-7 links,
and moreover, radicals X
4
, X
6
, X
7
(in partial formulas 2, 3, 4, 5, 6 and 7) or Y
4
, Y
5
, Y
7
, Y
8
(in partial formulas 8, 9, 10 and 11) are selected from halogen atoms, hydroxy groups, C
1
-C
5
alkoxy groups or C
1
-C
5
alkanoyloxy groups,
also if B in general formula I stands for a CH
2
group, Ar in addition stands for a phenyl radical of general partial formula 12,
in which R
9
and R
10
are the same or different and mean a cyano group, a nitro group, a halogen atom, a C
1
-C
5
alkyl group, a C
1
-C
5
alkoxy group, a partially or completely fluorinated C
1
-C
5
alkyl group, a C
1
-C
5
alkylthio group, a C
1
-C
5
alkylsulfinyl group or a C
1
-C
5
alkylsulfonyl group, and if B stands for a CH
2
group, the physiologically compatible salts of the compounds of general formula I with acids.
The compounds according to the invention are distinguished from the known nonsteroidal compounds with gestagenic action by the substitution pattern on the aryl radical that is on the right in general formula I. In the compounds that are present here, Ar is a benzocondensed, bicyclic ring system, while in the structures that are known from EP 0 253 500 B
1
and that can be considered as the closest compounds, a phenyl radical that is substituted in one, two or three places is at this point.
The compounds of general formula I according to the invention can be present as different stereoisomers because of the presence of asymmetry centers. Both the racemates and the stereoisomers that are detached are part of the subject of this invention.
The substituents that are defined as groups in the compounds of general formula I can have the following meanings in each case.
C
1
-C
5
Alkyl groups can readily be a methyl, ethyl, n-propyl, isopropyl, n-, iso-, tert-butyl group or an n-pentyl, 2,2-dimethylpropyl or 3-methylbutyl group. A methyl or ethyl group is preferred.
A fluorine, chlorine, bromine or iodine atom can stand for a halogen atom. Here, fluorine, chlorine or bromine is preferred.
If R
1
and R
2
together with the C-atom of the chain form a 3-7-membered ring, this is, for example, a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring. The cyclopropyl ring is preferred.
For a partially or completely fluorinated C
1
-C
5
alkyl group, the perfluorinated alkyl groups that appear above and of the latter mainly the trifluoromethyl group or pentafluoroethyl group as well as partially fluorinated alkyl groups, for example, the 5,5,5,4,4-pentafluoropentyl group or 5,5,5,4,4,3,3-heptafluoropentyl group are considered.
As a C
2
-C
5
alkenyl group, for example, a vinyl-, allyl- or 2,3-dimethyl-2-propenyl group can appear; if aromatic compound A is substituted with an alkenyl group, preferably it is a vinyl group.
Representatives of a C
1
-C
5
alkoxy group are selected from methoxy, ethoxy, n-propoxy, iso-propoxy, n-, iso-, tert-butoxy groups or n-pentoxy, 2,2-dimethylpropoxy or 3-methylbutoxy groups. A methoxy or ethoxy group is preferred.
C
1
-C
5
Perfluoroalkoxy groups are the corresponding perfluorinated radicals of the C
1
-C
5
alkoxy groups above.
Monocyclic or bicyclic aromatic ring A, which can be substituted, is a carbocyclic or heterocyclic aryl radical.
In the first case, this is, for example, a phenyl or naphthyl radical, preferably a phenyl radical.
As a heterocyclic radical, for example, a monocyclic heterocyclic radical can be, for example, the thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazanyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl, tetrazolyl radical, specifically all possible isomers relative to the positions of the heteroatoms. The thienyl radical is preferred as heteroaryl radical A.
For R
4
, a methyl, ethyl, n- or iso-propyl group is preferred as a C
1
-C
5
alkyl group in ester group —COOR
4
.
As a C
1
-C
5
alkyl group for etherification of hydroxy groups, the above-mentioned alkyl groups are suitable; primarily a methyl or ethyl group.
As a C
1
-C
5
alkanoyl group for esterification of hydroxy groups, a formyl, acetyl, propionyl, butyryl, isobutyl, valeryl or isovaleryl group is suitable, preferably an acetyl group.
If X
3a
and X
3b
together with the C-atom of the benzocondensed ring system form a 3-7-membered ring, this is, for example, a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring. The cyclopropyl ring is preferred.
As a C
1
-C
5
alkanoyloxy group for X
4
, X
6
, X
7
, Y
4
, Y
5
, Y
7
or Y
8
, a formyloxy, acetoxy, propinoyloxy, butyryloxy, iso-butyryloxy, valeryloxy or isovaleryloxy group is suitable, preferably an acetoxy group.
The above-mentioned C
1
-C
5
alkyl groups can stand for C
1
-C
5
alkyl within the C
1
-C
5
alkylthio, C
1
-C
5
alkylsulfinyl or C
1
-C
5
alkylsulfonyl group.
If the compounds of general formula I (B=—CH
2
) are present as salts, this can be in the form of, for example, hydrochloride, sulfate, nitrate, tartrate or benzoate.
If the compounds according to the invention are present as racemic mixtur
Fritzemeier Karl-Heinrich
Heinrich Nikolaus
Krattenmacher Rolf
Lehmann Manfred
Muhn Hans-Peter
Millen White Zelano & Branigan P.C.
Raymond Richard L.
Schering Aktiengesellschaft
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