Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-05-11
2002-08-13
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S274100
Reexamination Certificate
active
06432988
ABSTRACT:
The present invention relates to 2-arylaklylthioimidazole, 2-arylalkenylthioimidazole and 2-arylalkynylthioimidazole derivatives, a process for their preparation and medicaments which contain these imidazole derivatives.
It is known that various imidazole derivatives have an antiinflammatory activity. Inter alia, compounds having 4,5-di(hetero)arylimidazole structural elements have been investigated in detail.
Thus U.S. Pat. No. 5,656,644 and WO 93/14081 disclose 4-aryl-5-heteroarylimidazole derivatives which are substituted in the 2-position by an optionally substituted aryl or heteroaryl group and which have an inhibitory activity on the release of cytokines such as IL-1, IL-6, IL-8 and TNF.
U.S. Pat. No. 3,940,486 discloses 4(5)-phenyl-5(4)-heteroarylimidazole derivatives which are substituted in the 2-position by an alkyl, cycloalkyl or phenyl radical. Various pharmaceutical actions of these compounds, such as an antiinflammatory activity, are mentioned.
U.S. Pat. No. 4,585,771 discloses 4,5-diphenylimidazole derivatives which are substituted in the 2-position by a pyrrolyl, indolyl, imidazolyl or thiazolyl radical.
These compounds have an antiinflammatory and antiallergic activity.
U.S. Pat. Nos. 4,528,298 and 4,402,960 disclose 4,5-di(hetero)arylimidazole derivatives which are substituted in the 2-position by a thio, sulfinyl or sulfonyl group having a phenyl, pyridyl, N-oxypyridyl, pyrimidinyl, thiazolyl or thienyl radical. These compounds have an antiinflammatory and antiallergic activity.
U.S. Pat. Nos. 4,461,770 and 4,584,310 disclose 4(5)-aryl-5(4)-heteroarylimidazole derivatives which are substituted in the 2-position by a thio, sulfinyl or sulfonyl group having a substituted or unsubstituted aliphatic hydrocarbon radical. The substituted or unsubstituted aliphatic hydrocarbon radical is, for example, a phenyl-C
1-4
-alkyl group in which the phenyl radical can be substituted by C
1-4
-alkyl, C
1-4
-alkoxy, halogen having an atomic weight of not more than 35, nitro, amino or N,N-di-C
1-4
-alkylamino. These compounds have, inter alia, an antiinflammatory activity.
4,5-Diaryl-substituted imidazoles as cyclooxygenase-2-inhibitors are disclosed in WO 95/00501.
The molecular target of the 4-(4-fluorophenyl)-5-(4-pyridyl)imidazole derivatives is described by Wilson K. P. et al. (Chemistry & Biology (1997), 4, 423-431) and Young P. R. et al. (J. Biol. Chem. (1997), 272, 12116-12121) as the p38 MAP kinase (mitogen-activatable kinase) activated in the signal transduction of inflammatory stimuli in a phosphorylation cascade, and a serine threonine kinase (Cobb, M. H., Goldsmith, E. J., J. Biol. Chem. (1995), 270, 14843-14846). According to Wilson K. P. et al. and Young P. R. et al., the structural element competes with ATP for binding to the ATP binding site of the kinase center (for this cf. Tong et al. & Pargellis, C. A. Nat.Struct. Biol. 4, (1997) 311-316).
Other 1,2-diaryl-substituted heteroaromatic systems additionally show a high affinity for enzyme systems of the arachidonic acid cascade, whose metabolic products exert decisive influence on the inflammatory process. It is seen that with suitable choice of the substituents, of the aromatics flanking the heterocycle, a favorable combination effect takes place on targets such as 5-lipoxygenase, cyclooxygenase-1 and -2 and p38 MAP kinase (TNF-&agr;, IL-1&bgr; release).
Despite numerous known compounds, a need furthermore exists for substances having antiinflammatory activity, which inhibit the release of various cytokines and serve as inhibitors of the mediators of the arachidonic acid cascade. In particular, a need exists for compounds which do not only act on the parameters which are decisive in the acute course of inflammatory diseases (mediators of inflammation), but which can also intervene in the immunological processes crucial to the chronic course (cytokine release, expression of cell-surface antigens).
One object of the present invention consists in making such compounds available.
It has now surprisingly been found that 4-heteroaryl-5-phenylimidazole derivatives which are substituted in the 2-position by a phenylalkylthio group whose phenyl radical is in turn substituted by an alkylthio, alkylsulfinyl, alkylsulfonyl, sulfonamido or aklycarbonyl group achieve this object.
The present invention thus relates to a compound of the general formula I:
in which
Ar is a phenyl radical which can optionally be substituted by one or more substituents, selected from halogen, C
1-4
-alkyl, C
1-4
-alkoxy and C
1-4
-alkylthio;
Het is a pyridyl, pyrimidinyl or pyrazinyl radical which can optionally be substituted by one or more substituents selected from halogen, amino, C
1-4
-alkylamino, C
1-4
-alkyl, hydroxyl, C
1-4
-alkoxy or C
1-4
-alkylthio;
A is a straight-chain or branched, saturated or unsaturated alkylene chain having up to 6 carbon atoms;
R
1
is C
1-4
-alkylthio, C
1-4
-alkylsulfinyl, C
1-4
-alkylsulfonyl, sulfonamido or C
1-4
-alkylcarbonyl;
R
2
is halogen, C
1-4
-alkyl, hydroxyl, C
1-4
-alkoxy, C
1-4
-alkoxycarbonyl, sulfonamido, carboxyl, nitro or aminocarbonyl;
n is 1 or 2 and
m is 0 to 2
or a pharmaceutically tolerable salt thereof.
“Alkyl” is presently understood as meaning a lower alkyl group having up to 4 C atoms, which can be straight-chain or branched. This includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.
“Alkoxy”, “alkylthio”, “alkylamino”, “alkylsulfinyl”, “alkylsulfonyl”, “alkylcarbonyl” and “alkoxycarbonyl” are presently in each case understood as meaning a group which contains an alkyl group defined above.
“Halogen” is presently understood as meaning fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine and in particular fluorine.
A “straight-chain or branched, saturated or unsaturated alkylene chain having up to 6 carbon atoms” is presently understood as meaning a C
1-6
-alkylene chain, such as methylene, ethylene, 1,3-propylene, 1-methylethylene, 2-methylethylene, 1,4-butylene, 1-methyl-1,3-propylene, 2-methyl-1,3-propylene, 3-methyl-1,3-propylene, 1-ethylethylene, 2-ethylethylene, 2,3-dimethylethylene and 2,2-dimethyl-1,3-propylene, a C
3-6
-alkenylene chain having one or more double bonds, such as propenylene and allenylene, and a C
3-6
-alkynylene chain having one or more triple bonds, such as propynylene and butynylene. The straight-chain or branched, saturated or unsaturated alkylene chain A is preferably a straight-chain, saturated alkylene chain having 1 to 4 carbon atoms, preferably 1 or 2 carbon atoms, namely methylene or ethylene.
The heteroaromatic radical Het in the compound of the general formula I is pyridyl, pyrimidinyl or pyrazinyl, where these heteroaromatic radicals can optionally be substituted. The substituent is preferably a halogen, or an amino group. Particularly preferably, the heteroaromatic radical Het is 4-pyridyl, 3-aminopyridyl, 2,4-pyrimidinyl or 3-amino-2,4-pyrimidinyl.
The substituents by which the phenyl radical Ar in the compound of the general formula I can each be substituted are preferably fluorine, chlorine, bromine, C
1-4
-alkyl, C
1-4
-alkoxy or C
1-4
-alkylthio. Particularly advantageously, the phenyl radical Ar is substituted in the para-position by fluorine, methoxy or methylthio.
The phenyl radical Ar is particularly preferably a 4-fluorophenyl group.
The phenyl group of the phenylalkylthio radical which substitutes the imidazole base unit in the compound of the general formula I in the 2-position, is substituted according to the invention by at least one group R
1
, but at most by two groups R
1
. The substituent R
1
is a C
1-4
-alkylthio, C
1-4
-alkylsulfinyl, C
1-4
-alkylsulfonyl, sulfonamido or C
1-4
-alkylcarbonyl group, where R
1
is advantageously a methylthio, methylsulfinyl, methylsulfonyl, sulfonamido or acetyl group.
The phenyl group of the phenylalkylthio radical which substitutes the imidazole base unit in the compound of the general formula I in the 2-position can include further substituents R
2
. These substituents R
2
are C
1-4
-alkyl, C
1-4
-alkoxy, C
1-4
-alkoxycarbon
Laufer Stefan
Neher Karola
Striegel Hans-Günter
Heller Ehrman White and McAuliffe
Merckle GmbH
Robinson Binta
Rotman Alan L.
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