Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-27
2004-08-17
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S470000, C544S063000, C549S307000
Reexamination Certificate
active
06777409
ABSTRACT:
This invention relates to the use of nonsteroidal compounds for the production of pharmaceutical agents for treatment of inflammations, selected compounds and production processes thereof.
In addition to a large number of steroid compounds, which bind well to the glucocorticoid receptor and have an antiinflammatory action (glucocorticoids), nonsteroidal compounds are known that namely bind to the glucocorticoid receptor, for which to date no antiinflammatory action has been shown, however [cf. Nature Medicin 4 (1998) 92, Mol. Pharmacol. 52 (1997) 571]. In addition, nonsteroidal compounds were described that are derived from steroidal compounds, have an affinity to the glucocorticoid receptor and probably have an antiinflammatory action that is mediated by the receptor [J. Med. Chem. 36, (1993), 3278-3285]. In animal experiments, however, these compounds did not show any advantages relative to steroidal glucocorticoids, i.e., it was not possible to separate the antiinflammatory action from the metabolic effects, e.g., suppression of the suprarenal function.
From WO 98/54159, nonsteroidal compounds are known that have a high gestagenic activity. In the document, there is the observation that the claimed compounds partially also have action on the glucocorticoid and/or mineral corticoid receptor. In this connection, however, there is neither actual mention of compounds nor disclosure of test results. That is to say that from the pool of generically claimed compounds of WO 98/54159, compounds that are not specified in more detail are known that have both high gestagenic activity and action on the glucocorticoid receptor. In terms of industrial applicability, however, compounds that have a selectivity with respect to the above-mentioned actions are advantageous.
In turn, from WO 00/32584, phenol derivatives that have a dissociation of action between antiinflammatory action and undesirable metabolic side effects are known as nonsteroidal antiinflammatory agents.
The compounds that are disclosed in the prior art are still in need of improvement with respect to their dissociation of action between antiinflammatory action and the undesirable side effects.
The object was therefore to make available new nonsteroidal antiinflammatory agents that show a dissociation of action that is at least as good or better than the compounds of the prior art.
Nonsteroidal compounds have now been found that bind well to the glucocorticoid receptor and, mediated by this bond, produce an antiinflammatory action. In the experiment, these compounds show a significantly better or at least equally good dissociation of action between antiinflammatory and undesirable actions and are superior to the previously described nonsteroidal glucocorticoids or have at least just as good an action.
According to this invention, the following compounds of general formula I that have an antiinflammatory action are suitable for use for the production of pharmaceutical agents:
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, together with the C-atom of the chain, stand for a ring with a total of 3-7 links,
R
3
stands for a straight-chain or branched C
1
-C
5
alkyl group or a straight-chain or branched, partially or completely fluorinated C
1
-C
5
alkyl group,
A stands for the group
(the dashed line means the interface site), in which
R
4
to R
8
are the same or different from one another and mean a hydrogen atom, a halogen atom, a cyano group, a nitro group, a COOR
9
group
whereby R
9
stands for a hydrogen atom, a straight-chain or branched C
1
-C
5
alkyl group or a benzyl group,
a CONR
10
group,
whereby R
10
stands for a hydrogen atom or a straight-chain or branched C
1
-C
5
alkyl group,
an NHR
11
group,
whereby R
11
stands for a hydrogen atom, a straight-chain or branched C
1
-C
5
alkyl group, a straight-chain or branched, partially or completely fluorinated C
1
-C
5
alkyl group, a C
1
-C
5
acyl group, an —SO
2
—(C
1
-C
5
) alkyl group or an —SO
2
-phenyl group that is optionally substituted by halogen or a C
1
-C
5
alkyl group,
a straight-chain or branched C
1
-C
5
alkyl group, a straight-chain or branched C
2
-C
5
alkenyl group, a straight-chain or branched C
2
-C
5
alkinyl group, a straight-chain or branched C
1
-C
5
alkyl group that is partially or completely substituted by fluorine atoms, a C
1
-C
5
acyl group, an aryl radical or a heteroaryl radical,
R
4
and R
5
together with the two carbon atoms of ring A mean a saturated or unsaturated carbocyclic ring with a total of 5-7 links,
Ar stands for a ring system, selected from the group of general partial formula 1 or 2,
in which
radicals X
3a
, X
3b
, X
4
, X
6
, X
7
(in partial formula 1) and Y
4
, Y
5
, Y
7
, and Y
8
(in partial formula 2) are the same or different and mean a hydrogen atom, a straight-chain or branched C
1
-C
5
alkyl group, or a straight-chain or branched, partially or completely fluorinated C
1
-C
5
alkyl group,
radicals X
4
, X
6
, X
7
(in partial formula 1) or Y
5
, Y
7
, Y
8
(in partial formula 2) in addition are the same or different and mean a hydrogen atom, a halogen atom, a hydroxy group, a C
1
-C
5
alkoxy group or a C
1
-C
5
alkanoyloxy group,
as well as their racemates or separately present stereoisomers, and optionally their physiologically compatible salts.
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 separately present stereoisomers are part of the subject matter of this invention.
A special subject of this invention are the isomers that turn the plane of polarized light in the way that they are referred to as (+)-compounds.
The substituents that are defined as groups or radicals in the compounds of general formula I can have the meanings below in each case.
The C
1
-C
5
alkyl groups R
1
, R
2
, R
3
, R
4
, R
5
, R
12
, X
n
, and Y
o
can be straight-chain or branched and can stand for a methyl-, ethyl-, n-propyl-, iso-propyl-, n-butyl, iso-butyl, tert-butyl or n-pentyl, 2,2-dimethylpropyl-, 2-methylbutyl- or 3-methylbutyl group. A methyl group or ethyl group is preferred.
If R
1
and R
2
together with the C-atom of the chain form a 3- to 7-membered ring, the latter optionally can be substituted by 1-2 oxygen atoms and can be, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl ring.
For a partially or completely fluorinated C
1
-C
5
alkyl group, the partially or completely fluorinated alkyl groups that appear above are considered. Of the latter, 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 preferred. The trifluoromethyl group and the pentafluoroethyl group are preferred.
The substituents of phenyl ring A, independently of one another, can have the meanings that are defined in the claims, such as a hydrogen atom, a halogen atom, a cyano group, a nitro group, an NHR
11
group, whereby R
11
stands for a hydrogen atom, a straight-chain or branched C
1
-C
5
alkyl group, a straight-chain or branched, partially or completely fluorinated C
1
-C
5
alkyl group, a C
1
-C
5
acyl group, an —SO
2
—(C
1
-C
5
)alkyl group or an —SO
2
-phenyl group that is optionally substituted by halogen or a C
1
-C
5
alkyl group, a straight-chain or branched C
1
-C
5
alkyl group, a straight-chain or branched C
2
-C
5
alkenyl group, a straight-chain or branched C
2
-C
5
alkinyl group, a straight-chain or branched C
1
-C
5
alkyl group that is partially or completely substituted by fluorine atoms, a C
1
-C
5
acyl group, an aryl radical or a heteroaryl radical.
Preferred are phenyl rings A, which carry 1-3 non-hydrogen substituents.
In addition, R
4
and R
5
together with the two carbon atoms of ring A can mean a saturated or unsaturated carbocyclic ring with a total of 5 to 7 links, such as, for example, indane, naphthalene, tetrah
Buchmann Bernd
Droescher Peter
Hennekes Hartwig
Jaroch Stefan
Krolikiewicz Konrad
Millen White Zelano & Branigan P.C.
Raymond Richard L.
Schering Aktiengesellschaft Patents
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