Annelated pyrrolidin sulfonamides with oxadiazolone headgroup, processes for their preparation and their use as pharmaceuticals
The invention relates to annelated pyrrolidin sulfonamides with oxadiazolone headgroup and to their physiologically acceptable salts and physiologically functional derivatives showing PPARdelta or PPARdelta and PPARalpha agonist activity. What is described are compounds of the formula (I), in which the radicals are as defined, and their physiologically acceptable salts and processes for their preparations. The compounds are suitable for the treatment and/or prevention of disorders of fatty acid metabolism and glucose utilization disorders as well as of disorders in which insulin resistance is involved and demyelinating and other neurodegenerative disorders of the central and peripheral nervous system.
1. Compound of the formula I
wherein
R1 is H, halogen, (C1-C8) alkyl, (C0-C4) alkylene —(C3-C7) cycloalkyl, (C0-C4) alkylene —(C5-C10) heteroaryl, (C0-C4) alkylene —O—(C0-C8) alkyl, (C0-C4) alkylene —(C6-C10) aryl, wherein alkyl and alkylene are unsubstituted or 1- to 3-fold substituted by F;
R2 is H, (C1-C8) alkyl, halogen, (C0-C4) alkylene —O—(C0-C8) alkyl, wherein alkyl and alkylene are unsubstituted or 1- to 3-fold substituted by F;
R3, R4 are independently H, (C1-C8) alkyl, halogen, (C0-C4) alkylene —O—(C0-C8) alkyl, wherein alkyl and alkylene are unsubstituted or 1- to 3-fold substituted by F;
R5, R6 are independently H, (C1-C8) alkyl, (C0-C4) alkylene —(C3-C7) cycloalkyl, (C0-C4) alkylene —(C5-C10) heteroaryl, (C0-C4) alkylene —O—(C0-C8) alkyl, (C0-C4) alkylene —(C6-C10) aryl, wherein alkyl and alkylene are unsubstituted or 1- to 3-fold substituted by F;
R5 and R6 together with the carbon atom carrying them form a (C3-C7) cycloalkylring, wherein one carbon atom can be replaced by one heteroatom selected from the group consisting of O, S or N;
R7 is H, halogen, (C1-C8) alkyl, (C0-C4) alkylene-O—(C0-C4) alkylene-H, wherein alkyl and alkylene are unsubstituted or 1- to 3-fold substituted by F;
R8 is H, halogen, (C1-C8) alkyl, (C0-C4) alkylene-O—(C0-C4) alkylene-H, wherein alkyl and alkylene are unsubstituted or 1- to 3-fold substituted by F, whereby R8 is only attached to carbon;
R9 is H, halogen, (C1-C8) alkyl, (C0-C4) alkylene —(C3-C7) cycloalkyl, (C0-C4) alkylene —O—(C0-C8) alkyl, (C0-C4) alkylene —(C6-C10) aryl, (C0-C4) alkylene —(C5-C10) heteroaryl, wherein alkyl and alkylene are unsubstituted or 1- to 3-fold substituted by F;
at least one of X1, X2, X3, X4, X5 is N, the others are CH;
in all its stereoisomeric forms and mixtures in any ratio, and its physiologically acceptable salts and tautomeric forms.
2. Compound of the formula I, as claimed in claim 1 , wherein
R1 is H, halogen, (C0-C4) alkylene —O—(C0-C8) alkyl, wherein alkyl and alkylene are unsubstituted or 1- to 3-fold substituted by F;
R2 is H or halogen;
R3, R4 are independently H, (C1-C8) alkyl;
R5, R6 are independently H, (C1-C8) alkyl;
R5 and R6 together with the carbon atom carrying them form a (C3-C6) cycloalkylring;
R7 is H or halogen;
R8 is H, halogen, or (C0-C4) alkylene-O—(C0-C4) alkylene-H;
R9 is H, (C1-C8) alkyl, (C0-C4) alkylene —O—(C0-C8) alkyl, wherein alkyl and alkylene are unsubstituted or 1- to 3-fold substituted by F;
at least one of X1, X2, X3 is N and the other are CH and X4 and X5 are CH, or
at least one of X1, X2, X3 is CH and at least one of X4 and X5 is N and the other is CH.
3. Compound of the formula I, as claimed in claim 1 or 2 , wherein
R1 is Cl, F or O—(C1-C4)-alkyl.
4. Compound of the formula I, as claimed in claim 1 or 2 , wherein
R2 is in the para position to R1.
5. Compound of the formula I, as claimed in claim 1 or 2 , wherein
R2 is H or F.
6. Compound of the formula I, as claimed in claim 1 or 2 , wherein
R3, R4 are H or (C1-C4)-alkyl.
7. Compound of the formula I, as claimed in claim 1 or 2 , wherein
R5, R6 are H or (C1-C4)-alkyl.
8. Compound of the formula I, as claimed in claim 1 or 2 , wherein
R7 is F or Cl.
9. Compound of the formula I, as claimed in claim 1 or 2 , wherein
R8 is H, F, or O—(C1-C4)-alkyl.
10. Compound of the formula I, as claimed in claim 1 or 2 , wherein
R9 is (C1-C4)-alkyl or O—(C1-C4)-alkyl.
11. Compound of the formula I, as claimed in claim 1 or 2 , wherein
One X1, X2, X3, X4, X5 is N, the others are CH.
12. Compound of the formula I, as claimed in claim 1 or 2 , wherein
X1, X2, X3 is CH and X4 or X5 is N and the other of X4 and X5 is CH.
13. Compound of the formula I, as in one of claims 1 - 12 , wherein
R1 is H or Cl;
R2 is H;
R3 is H;
R4 is H;
R5 is H or methyl;
R6 is H or methyl;
R7 is H;
R8 is H or methoxy;
R9 is H, methyl, methoxy or CF3;
one or two of X1, X2, X3, X4, X5 is N, the others are CH.
14. A pharmaceutical comprising one or more compounds of the formula I as claimed in one or more of claims 1 to 13 .
15. A pharmaceutical comprising one or more compounds of the formula I as claimed in one or more of claims 1 to 13 and one or more antidiabetics.
16. A pharmaceutical comprising one or more compounds of the formula I as claimed in one or more of claims 1 to 13 and one or more lipid modulators.
17. A process for preparing a pharmaceutical comprising one or more of the compounds as claimed in one or more of claims 1 to 13 , which comprises mixing the active compound with a pharmaceutically suitable carrier and bringing this mixture into a form suitable for administration.
18. A method of treating disorders of insulin resistance comprising administering to a patient in need thereof the pharmaceutical compound as in one of claims 1 - 13 .
19. A method of treating diabetes mellitus comprising administering to a patient in need thereof the pharmaceutical compound as in one of claims 1 - 13 .
20. A method of treating glucose utilization disorders comprising administering to a patient in need thereof the pharmaceutical compound as in one of claims 1 - 13 .
21. A method of treating dyslipidaemia comprising administering to a patient in need thereof the pharmaceutical compound as in one of claims 1 - 13 .