2-thio-substituted imidazole derivatives and the use thereof in the pharmaceutical industry
The invention relates to 2-thio-substituted imidazole derivatives of the formula I in which the radicals R 1 , R 2 , R 3 and R 4 are as defined in the description. The compounds according to the invention have immunomodulating and/or cytokine-release-inhibiting action and are therefore suitable for treating disorders associated with a disturbed immune system.
1. A 2-thio-substituted imidazole derivative of the formula I
wherein
R 1 is selected from the group consisting of:
C 1 -C 6 -alkyl which is unsubstituted or substituted by one or two hydroxyl or C 1 -C 4 -alkoxy groups or by a nonaromatic heterocyclic radical having 5 or 6 ring atoms and 1 or 2 heteroatoms independently of one another selected from the group consisting of N, O and S,
C 2 -C 6 -alkenyl,
C 3 -C 6 -cycloalkyl,
aryl which is unsubstituted or substituted by one or more halogen atoms or by a C 1 -C 4 -alkylsulfanyl group,
amino-C 1 -C 4 -alkyl, where the amino group is unsubstituted or substituted by one or two C 1 -C 4 -alkyl groups,
aminoaryl, where the amino group is unsubstituted or substituted by one or two C 1 -C 4 -alkyl groups,
aryl-C 1 -C 4 -alkyl and
an aromatic or nonaromatic heterocyclic radical having 5 or 6 ring atoms and 1 or 2 heteroatoms independently of one another selected from the group consisting of N, O and S, which heterocyclic radical is unsubstituted or substituted by 1, 2, 3 or 4 C 1 -C 4 -alkyl groups, an aryl or aryl-C 1 -C 4 -alkyl group,
R 2 is selected from the group consisting of:
C 1 -C 6 -alkyl,
phenyl-C 1 -C 4 -alkyl, where the phenyl group may have one or two substituents independently of one another selected from the group consisting of C 1 -C 4 -alkyl, halogen, C 1 -C 4 -alkylsulfanyl, C 1 -C 4 -alkylsulfinyl and C 1 -C 4 -alkylsulfonyl,
C 2 -C 6 -alkenyl,
C 2 -C 6 -alkenyl which is substituted by one or two halogen atoms and/or phenyl groups, where the phenyl group may independently be substituted by one or two C 1 -C 4 -alkyl or halogen atoms,
C 2 -C 6 -alkynyl,
C 2 -C 6 -alkynyl which is substituted by a phenyl group which may be unsubstituted or substituted by one or two C 1 -C 4 -alkyl or halogen atoms,
C 1 -C 6 -alkyl which is substituted by a nonaromatic heterocyclic radical having 5 or 6 ring atoms and 1 or 2 heteroatoms independently of one another selected from the group consisting of N, O and S, C 1 -C 4 -alkylsulfanyl, C 1 -C 4 -alkylsulfinyl or C 1 -C 4 -alkylsulfonyl,
phenyl and
phenyl which has one or two substituents independently of one another selected from the group consisting of C 1 -C 4 -alkyl, halogen, C 1 -C 4 -alkylsulfanyl, C 1 -C 4 -alkylsulfinyl and C 1 -C 4 -alkylsulfonyl, or
R 1 and R 2 together are —CH 2 CH 2 — or —CH 2 CH 2 CH 2 —,
R 3 is halogen substituted phenyl,
R 4 is 4-pyridyl which is substituted by amino, C 1 -C 4 -alkylamino, phenyl-C 1 -C 4 -alkylamino or R 5 CONR 6 —, where R 5 is C 1 -C 4 -alkyl, phenyl, which may have one or two substituents independently of one another selected from the group consisting of C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and halogen, or C 3 -C 6 -cycloalkyl and R 6 is H, C 1 -C 4 -alkyl or benzyl, and
with the proviso that, if R 1 represents aryl-C 1 -C 5 -alkyl or amino-C 1 -C 6 -alkyl, where the amino group is unsubstituted or substituted by one or two C 1 -C 4 -alkyl groups, R 2 represents alkylsulfonyl- or alkylsulfinylaryl-C 1 -C 5 -alkyl,
or an optical isomer or physiologically acceptable salt thereof.
2. A compound as claimed in claim 1 , wherein the pyridyl is substituted in 2-position.
3. A compound as claimed in claim 1 , wherein R 4 is 4-pyridyl which is substituted by phenyl-C 1 -C 4 -alkylamino.
4. A compound as claimed in claim 1 , wherein R 3 is 4-fluorophenyl.
5. A compound of the formula I as claimed in claim 1 , wherein R 1 is C 1 -C 3 -alkyl, C 3 -C 6 -cycloalkyl or 2,2,6,6-tetramethylpiperidinyl.
6. A compound as claimed in claim 5 , wherein R 1 is C 1 -C 3 -alkyl or 2,2,6,6-tetramethylpiperidinyl.
7. A compound of the formula I as claimed in claim 1 , wherein R 2 is C 1 -C 6 -alkyl or phenyl-C 1 -C 4 -alkyl, where the phenyl group is substituted by C 1 -C 4 -alkylsulfanyl, C 1 -C 4 -alkylsulfinyl or C 1 -C 4 -alkylsulfonyl.
8. A compound of the formula I as claimed in claim 1 , wherein
R 1 is C 1 -C 6 -alkyl which is unsubstituted or substituted by one or two hydroxyl or C 1 -C 4 -alkoxy groups, or a nonaromatic heterocyclic radical having 5 or 6 ring atoms and 1 or 2 heteroatoms independently of one another selected from the group consisting of N, O and S, C 3 -C 6 -cycloalkyl or an aromatic or nonaromatic heterocyclic radical having 5 or 6 ring atoms and 1 or 2 heteroatoms independently of one another selected from the group consisting of N, O and S, which heterocyclic radical is unsubstituted or substituted by 1, 2, 3 or 4 C 1 -C 4 -alkyl groups, an aryl or aryl-C 1 -C 4 -alkyl group,
R 2 is, C 1 -C 6 -alkyl, phenyl-C 1 -C 4 -alkyl, where the phenyl group may have one or two substituents independently of one another selected from the group consisting of C 1 -C 4 -alkyl, halogen, C 1 -C 4 -alkylsulfanyl, C 1 -C 4 -alkylsulfinyl and C 1 -C 4 -alkylsulfonyl, phenyl, C 1 -C 6 -alkyl substituted by a nonaromatic heterocyclic radical having 5 or 6 ring atoms and 1 or 2 heteroatoms independently of one another selected from the group consisting of N, O and S, C 1 -C 4 -alkylsulfanyl, C 1 -C 4 -alkylsulfinyl or C 1 -C 4 -alkylsulfonyl, or is phenyl which has one or two substituents independently of one another selected from the group consisting of C 1 -C 4 -alkyl, halogen, C 1 -C 4 -alkylsulfanyl, C 1 -C 4 -alkylsulfinyl and C 1 -C 4 -alkylsulfonyl,
R 1 and R 2 together are —CH 2 CH 2 — or —CH 2 CH 2 CH 2 —,
R 3 is halogen substituted phenyl, and
R 4 is 4-pyridyl which is substituted by amino, C 1 -C 4 -alkylamino, phenyl-C 1 -C 4 -alkylamino or R 5 CONR 6 —, where R 5 is C 1 -C 4 -alkyl, phenyl which may have one or two substituents independently of one another selected from the group consisting of C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and halogen, or C 3 -C 6 -cycloalkyl and R 6 is H, C 1 -C 4 -alkyl or benzyl,
or an optical isomer or physiologically acceptable salt thereof.
9. A compound as claimed in claim 8 , wherein R 1 is C 1 -C 3 -alkyl, C 3 -C 6 -cycloalkyl or 2,2,6,6-tetramethylpiperidinyl.
10. A compound as claimed in claim 8 , wherein R 2 is C 1 -C 6 -alkyl or phenyl-C 1 -C 4 -alkyl, where the phenyl group is substituted by C 1 -C 4 -alkylsulfanyl, C 1 -C 4 -alkylsulfinyl or C 1 -C 4 -alkylsulfonyl.
11. A compound as claimed in claim 8 , wherein R 4 is 4-pyridyl which is substituted by phenyl-C 1 -C 4 -alkylamino.
12. A pharmaceutical composition, comprising at least one compound as claimed in claim 1 , together with one or more pharmaceutically acceptable carriers and/or additives.