Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-11-24
2001-11-27
Cintins, Marianne M. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S470000
Reexamination Certificate
active
06323199
ABSTRACT:
This invention relates to the use of nonsteroidal compounds for the production of pharmaceutical agents that have an anti-inflammatory activity as well as the nonsteroidal compounds themselves.
In addition to a large number of steroid compounds, which bind well to the glucocorticoid receptor and have an anti-inflammatory action (glucocorticoids), nonsteroidal compounds are known that namely bind to the glucocorticoid receptor, for which to date no inflammatory suppression 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 anti-inflammatory action that is mediated by the receptor [J. Med. Chem. 36, 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 anti-inflammatory action from the metabolic effects, e.g., suppression of the suprarenal function.
Nonsteroidal compounds have now been found that bind well to the glucocorticoid receptor and, mediated by this bond, produce a suppression of inflammation. In the animal experiment, these compounds show a clear dissociation between anti-inflammatory and metabolic actions and are therefore superior both to the previously described steroidal glucocorticoids and the nonsteroidal glucocorticoids.
Compounds that are suitable according to this invention for the production of pharmaceutical agents that have an anti-inflammatory action are the nonsteroidal 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, 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 the group
(the dashed line means the interface site), in which R
4
means a hydrogen atom, a C
1
-C
5
alkyl group, a C
1
-C
10
acyl group, a C
3
-C
10
carbalkoxyalkyl group, a C
2
-C
5
cyanoalkyl 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,
R
5
to R
8
are the same or different from one another and are selected from hydrogen or halogen atoms or C
1
-C
5
alkoxy groups,
and R
4
and R
5
together mean a heterocyclic ring, which in addition to the oxygen atom optionally can contain at least one other heteroatom from the group of oxygen, nitrogen, sulfur, with a total of 5-7 links,
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 2-5,
in which
radicals X
3a
, X
3b
, X
4
, X
6
, X
7
(in partial formulas 2 and 3) and Y
4
, Y
5
, Y
7
, and Y
8
(in partial formulas 4 and 5) are the same or different and are selected from hydrogen atoms, C
1
-C
5
alkyl groups, partially or completely fluorinated C
1
-C
5
alkyl groups,
and, moreover, radicals X
4
, X
6
, X
7
(in partial formulas 2 and 3) or Y
5
, Y
7
, Y
8
(in partial formulas 4 and 5) are selected from the halogen atoms, hydroxy groups, C
1
-C
5
alkoxy groups or C
1
-C
5
alkanoyloxy groups, and if B stands for a CH
2
group, the physiologically compatible salts of the compounds of general formula I with acids.
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 of this invention.
The substituents that are defined as groups in the compounds of general formula I can have the meanings below in each case.
The C
1
-C
5
alkyl groups can readily be a methyl-, ethyl-, n-propyl-, iso-propyl-, n-, iso-, or tert-butyl group or an n-pentyl, 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. Fluorine, chlorine or bromine is preferred here.
If R
1
and R
2
together with the C-atom of the chain form a 3-to 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, above-mentioned alkyl groups and of the latter, mainly the trifluoromethyl group or pentafluoroethyl group, are considered, and 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 is considered.
For example, a carboxymethyl, tert-butoxymethyl or ethoxymethyl group can stand for the C
3
-C
10
carbalkoxyalkyl group; the first two mentioned groups are preferred. The information on the C-atoms relates to the C-atoms that are contained overall in the carbalkoxyalkyl group.
As representatives of the C
2
-C
5
cyanoalkyl group, cyanomethyl and 1- and 2-cyanoethyl can be mentioned; cyanomethyl is preferred.
The C
3
-C
10
allyl group is preferably an unsubstituted allyl group; in the case of a substituted allyl group, for example, 1-methylallyl, 1,1-dimethylallyl, 2-methylallyl, 3-methylallyl, 2,3-dimethylallyl, 3,3-dimethylallyl, cinnamyl and 3-cyclohexylallyl can be mentioned.
An unsubstituted propargyl, a methylpropargyl, 3-methylpropargyl, 3-phenylpropargyl or 3-cyclohexylpropargyl group are the typical representatives of a C
3
-C
10
propargyl group; the unsubstituted propargyl group is preferred.
For example, methoxymethyl, ethoxymethyl or 2-methoxyethyl can stand for C
2
-C
5
alkoxyalkyl.
Representatives of a C
1
-C
5
alkoxy group are selected from methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy 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.
As C
1
-C
5
alkyl groups for the 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 the esterification of hydroxy groups, a formyl, acetyl, propionyl, butyryl, iso-butyryl, valeryl or iso-valeryl or pivaloyl group is considered, preferably an acetyl group.
As a C
1
-C
10
acyl group for the esterification of hydroxy groups, for example, the above-mentioned alkanoyl groups, preferably in turn an acetyl group or a benzoyl, toluoyl, phenylacetyl, acryloyl, cinnamoyl or cyclohexylcarbonyl group can be mentioned.
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, propionyloxy, butyryloxy, iso-butyryloxy, valeryloxy or iso-valeryloxy group is considered, preferably an acetoxy group.
If the compounds of general formula I (B=—CH
2
—) are present as salts, this can be, for example, in the form of hydrochloride, sulfate, nitrate, maleate, fumarate, tartrate or benzoate.
If the compounds according to the invention are present as racemic mixtures, they can be separated into the pure, optically active forms according to the methods of racemate separation that are familiar to one skilled in the art. For example, the racemic mixtures can be separated into the pure isomers by chromatography on an even optically active carrier material (CHIRALPAK AD
(R)
). It is also possible to esterify the free hydroxy group in a racemic compound of general formula I with an optically active acid and to separate the diastereoisomer esters that are obtained by fractionated crystallization or by chromatography and to saponify the separated esters in each case to the optically pure isomers. As an optically active acid, for example, mandelic acid, camphorsulfonic acid or tartaric acid can be used.
Preferred according to this invention are those compounds of general
Ekerdt Roland
Giesen Claudia
Kalkbrenner Frank
Krolikiewicz Konrad
Lehmann Manfred
Cintins Marianne M.
Kim Vickie
Millen White Zelano & Branigan P.C.
Schering Aktiengesellschaft
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