Sulfonamides with heterocycle and oxadiazolone headgroup, processes for their preparation and their use as pharmaceuticals
The invention relates to Sulfonamides with heterocycle and 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
A is a 5- or 6-membered mono- or a 9- or 10-membered bicyclic heterocycle, whereby R1, R2, SO2 and oxadiazolone groups are attached to a carbon atom;
R1 is H, (C1-C8) alkyl, halogen, (C0-C4) alkylene —(C3-C7) cycloalkyl, (C0-C4) alkylene —0—(C0-C8) alkyl, or (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 —(C3-C7) cycloalkyl, (C0-C4) alkylene —0—(C0-C8) alkyl, or (C0-C4) alkylene —(C6-C10) aryl, wherein alkyl and alkylene are unsubstituted or 1- to 3-fold substituted by F;
R3 is H, (C1-C8) alkyl, (C0-C4) alkylene —(C3-C7) cycloalkyl, or (C0-C4) alkylene —(C6-C 10) aryl, wherein alkyl and alkylene are unsubstituted or 1- to 3-fold substituted by F;
R4 is H, (Cl-C8) alkyl, (CO-C4) alkylene —(C3-C7) cycloalkyl, or (C0-C4) alkylene -(C6-C 10) aryl, wherein alkyl and alkylene are unsubstituted or 1- to 3-fold substituted by F;
R5 is H, (C1-C8) alkyl, (C0-C4) alkylene —(C3-C7) cycloalkyl, or (C0-C4) alkylene —(C6-C 10) aryl, wherein alkyl and alkylene are unsubstituted or 1- to 3-fold substituted by F;
R6 is H, (C1-C8) alkyl, (C0-C4) alkylene —(C3-C7) cycloalkyl, or (C0-C4) alkylene —(C6-C 10) aryl, wherein alkyl and alkylene are unsubstituted or 1- to 3-fold substituted by F or
R5 and R6 together with the carbon atom carrying them form a (C3-C7)cycloalkyl ring, wherein one carbon atom can be replaced by one heteroatom out of O, S, or N;
R7 is H, halogen, (C1-C8) alkyl, (C0-C4) alkylene—0—(C0-C4) alkylene-H, or (C3-C7) cycloalkyl, wherein alkyl and alkylene are unsubstituted or 1- to 3-fold substituted by F;
R8 is H, halogen, (Cl-C8) alkyl, (C0-C4) alkylene—0—(C0-C4) alkylene-H, or (C3-C7) cycloalkyl, wherein alkyl and alkylene are unsubstituted or 1- to 3-fold substituted by F;
R9 is H, halogen, (C1-C8) alkyl, (C0-C4) alkylene—0—(C0-C4) alkylene-H, or (C3-C7) cycloalkyl, wherein alkyl and alkylene are unsubstituted or 1- to 3-fold substituted by F; and
X1, X2, X3, X4, X5 are independently N or CH;
or stereoisomers, tautomers, and physiologically acceptable salts thereof.
2. The compound of the formula I, as claimed in claim 1 , wherein
A is a 5- or 6-membered mono- or a 9- or 10-membered bicyclic heterocycle, whereby R1, R2, SO2 and oxadiazolone groups are attached to a carbon atom;
R1 is H, (C1-C8) alkyl, halogen, or (C0-C4) alkylene-O—(C0-C8)alkyl;
R2 is H, (C1-C8) alkyl, halogen, or (C0-C4) alkylene-O—(C0-C8) alkyl;
R3 is H, or (C1-C8) alkyl;
R4 is H, or (C1-C8) alkyl;
R5 is H, or (C1-C8) alkyl;
R6 is H, or (C1-C8) alkyl; or
R5 and R6 together with the carbon atom carrying them form a (C3-C7)cycloalkyl ring;
R7 is H, halogen, or (C1-C8) alkyl;
R8 is H, halogen, or (C1-C8) alkyl;
R9 is H, halogen, (C1-C8) alkyl, or (C0-C4) alkylene-O—(C0-C4) alkylene-H, wherein alkyl and alkylene are unsubstituted or 1- to 3-fold substituted by F; and
X1, X2, X3, X4, X5 one or two are N, the others are CH.
3. The compound of the formula I, as claimed in claim 1 or 2 , wherein
A is thiopene, furan, pyridine, pyrazine, quinoline or dihydrobenzofuran.
4. The compound of the formula I, as claimed in claim 1 or 2 , wherein
R1 is H, (C1-C4) alkyl, F, or Cl.
5. The compound of the formula I, as claimed in claim 1 or 2 , wherein
R2 is H.
6. The compound of the formula I, as claimed in claim 1 or 2 , wherein
R3 is H.
7. The compound of the formula I, as claimed in claim 1 or 2 , wherein
R4 is H.
8. The compound of the formula I, as claimed in claim 1 or 2 , wherein
R5 and R6 are simultaneously H or (C1-C4) alkyl.
9. The compound of the formula I, as claimed in claim 1 or 2 , wherein
R5 and R6 together with the carbon atom carrying them form a (C3 -C6)cycloalkyl ring.
10. The compound of the formula I, as claimed in claim 1 or 2 , wherein
R7 is H, (C1-C4) alkyl, F, or Cl.
11. The compound of the formula I, as claimed in claim 1 or 2 , wherein
R8 is H, (C1-C4) alkyl, F, or Cl.
12. The compound of the formula I, as claimed in claim 1 or 2 , wherein
R9 is Cl, (C1-C4) alkyl, or O—(C0-C4) alkyl, wherein alkyl is unsubstituted or 1- to 3-fold substituted by F.
13. The compound of the formula I, as claimed in claim 1 or 2 , wherein
X1, X2, X3, X4, X5 are CH.
14. The compound of the formula I, as claimed in claim 1 , wherein
A is thiopene or pyridine;
R1 - R8 are H;
R9 is CF3; and
X1, X2, X3, X4, X5 are CH.
15. A pharmaceutical composition comprising one or more compounds of the formula I as claimed in claim 1 and a pharmaceutically suitable carrier.
16. A pharmaceutical composition comprising one or more compounds of the formula I as claimed in claim 1 and one or more antidiabetics.
17. A pharmaceutical composition comprising one or more compounds of the formula I as claimed in claim 1 and one or more lipid modulators.
18. A method of treating fatty acid metabolism or a glucose utilization comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 .
19. A method of treating insulin resistance comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 .
20. A method of treating diabetes mellitus comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 .
21. A method of treating dyslipidemia comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 .
22. A method of treating metabolic syndrome comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 .
23. A method of treating multiple sclerosis comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 .
24. A method of treating fatty acid metabolism or glucose utilization comprising administering to a patient in need thereof a therapeutically effective amount of an active compound of claim 1 in combination with at least one further active compound.
25. A method of treating insulin resistance comprising administering to a patient in need thereof a therapeutically effective amount of an active compound of claim 1 in combination with at least one further active compound.
26. A method of activating, in an agonistic manner, PPARalpha activity, PPARdelta, or PPARgamma activity in a patient in need thereof by administering an effective amount of a compound of claim 1 .
27. A process for preparing a pharmaceutical composition comprising one or more of the compounds as claimed in claim 1 , which comprises mixing the compound with a pharmaceutically suitable carrier and bringing this mixture into a form suitable for administration.