Bicyclic aryl-sulfonic acid [1,3,4]-thiadiazol-2-yl-amides, processes for their preparation, pharmaceutical compositions and methods for their use
View Patent ↗The present invention comprises bicyclic aryl-sulfonic acid [1,3,4]-thiadiazol-2-yl-amides, their functional derivatives thereof as well as their physiologically acceptable salts and pharmaceutical compositions thereof that exhibit peroxisome proliferator activated receptor (PPAR) PPARdelta and PPARgamma agonist activity. The structure of the compounds of the invention are defined by Formula I below, wherein the various substituents are defined herein, including their physiologically acceptable salts. Processes for the preparation of compounds are also disclosed. The compounds are suitable for the treatment of fatty acid metabolism and glucose utilization disorders, disorders relating to insulin resistance are involved as well as demyelinating and other neurodegenerative disorders of the central and peripheral nervous system.
1. A compound of formula I:
wherein
R1 is selected from the group consisting of (C1-C6) alkyl, (C0-C6) alkylene (C3-C6) cycloalkyl, (C0-C6) alkylene-O—(C1-C6) alkyl, (C0-C6) alkylene-O—(C3-C6) cycloalkyl (C0-C6) alkylene-(C6-C14) aryl and (C0-C6) alkylene-(C5-C15) heteroaryl, wherein the alkyl, alkylene, aryl, heteroaryl and cycloalkyl can be unsubstituted or mono-, di- or tri-substituted by F, Cl, Br, OCF 3 , CN, CO—(C1-C6) alkyl, COO(C1-C6) alkyl, CON((C0-C6) alkylene-H)((C0-C6) alkylene-H), or S(O) m (C1-C6) alkyl;
R2, R3, R4 and R5 are independently selected from the group consisting of H, halogen, (C1-C6) alkyl, (C0-C4) alkylene-O—(C0-C4) alkylene-H, CN, COO(C1-C6) alkyl, CON((C0-C6)alkylene-H)((C0-C6)alkylene-H) and S(O) m (C1-C6) alkyl, wherein the alkyl and alkylene are unsubstituted or mono-, di- or tri-substituted by F;
A is (C4-C10) heteroaryl;
n is 1, 2, or 3;
m and z are independently 0, 1, or 2; and
R6, R7 and R8 are independently selected from the group consisting of H, (C1-C6) alkyl, CN, CO—(C1-C6) alkyl, COO—(C1-C6) alkyl, CON((C0-C6) alkylene-H((C0-C6) alkylene-H), S(O) m (C1-C6) alkyl, N((C0-C6) alkylene-H)((C0-C6) alkylene-H), N((C0-C6) alkylene-H)—CO—(C1-C6) alkyl, N((C0-C6) alkylene-H)—CO—(C1-C6) alkyl, halogen, (C0-C6) alkylene-(C6-C14) aryl (C0-C6) alkylene-O—(C0-C6) alkylene-H, (C0-C6) alkylene-O—(C6-C14) aryl, SCF3, S(O)2CF3 and NO2, wherein the alkyl, aryl and alkylene are unsubstituted or mono-, di- or tri-substituted by F, and the aryl can also be unsubstituted or monosubstituted by CF3;
or a stereoisomer, enantiomer, tautomer, or physiologically acceptable salt thereof.
2. The compound according to claim 1 , wherein
R1 is selected from the group consisting of (C1-C6) alkyl, (C0-C6) alkylene-(C3-C6) cycloalkyl, (C0-C6) alkylene-O—(C1-C6) alkyl, (C0-C6) alkylene-O—(C3-C6) cycloalkyl and (C0-C6) alkylene-(C6-C14) aryl, wherein the alkyl, alkylene, aryl, and cycloalkyl can be unsubstituted or mono-, di- or tri-substituted by F, Cl, or Br;
R2, R3, R4, R5 are independently selected from the group consisting of H, halogen, (C1-C6) alkyl, and (C0-C4) alkylene-O—(C0-C4) alkylene-H, wherein the alkyl and alkylene are unsubstituted or mono-, di- or tri-substituted by F;
n is 1, or 2;
z is 1, or 2; and
R6, R7 and R8 are independently selected from the group consisting of H, (C1-C6) alkyl, CN, halogen, (C0-C6) alkylene-O—(C0-C6) alkylene-H, (C0-C6) alkylene-(C6-C14) aryl, (C0-C6) alkylene-O—(C6-C14) aryl, SCF3, and S(O)2CF3, wherein the alkyl, aryl and alkylene are unsubstituted or mono-, di- or tri-substituted by F, or the aryl can be unsubstituted or monosubstituted by CF3;
or a stereoisomer, enantiomer, tautomer, or physiologically acceptable salt thereof.
3. The compound according to claim 1 , wherein
R1 is selected from the group consisting of (C1-C6) alkyl, (C0-C6) alkylene (C3-C6) cycloalkyl and (C0-C6) alkylene-(C6-C14) aryl, wherein the alkyl, alkylene, aryl, and cycloalkyl can be unsubstituted or mono, di- or tri substituted by F;
R2, R3, R4 and R5 are independently selected from the group consisting of H, halogen, (C1-C6) alkyl and (C0-C4) alkylene-O—(C0-C4) alkylene-H, wherein the alkyl and alkylene are unsubstituted or mono-, di- or tri-substituted by F;
A is pyridine or thiophene;
n is 1;
z is 1;
R6 is F, Cl, Br, or O(C1-C4)-alkyl, and is in the ortho position;
R7 is F, Cl, Br, CH3 or CF3, and is in the para position; and
R8 is H;
or a stereoisomer, enantiomer, tautomer, or physiologically acceptable salt thereof.
4. The compound according to claim 1 , wherein:
R1 is selected from the group consisting of (C1-C4) alkyl, (C0-C2) alkylene (C3-C6) cycloalkyl and (C0-C2) alkylene-(C6-C10) aryl, wherein the alkyl, aryl, and cycloalkyl can be unsubstituted or mono-, di- or tri-substituted by F;
R2 is selected from the group consisting of H, halogen, (C1-C6) alkyl and O—(C0-C4) alkylene-H, wherein the alkyl and alkylene are unsubstituted or mono-, di- or tri-substituted by F;
R3 is H;
R4 is H;
R5 is H, or (C1-C4) alkyl;
A is (C5-C6) heteroaryl;
n is 1, or 2;
z is 1;
R6 is selected from the group consisting of (C1-C4) alkyl, halogen, (C0-C2) alkylene-O—(C0-C6) alkylene-H and (C0-C2) alkylene-(C6-C10) aryl, wherein the alkyl, aryl and alkylene are unsubstituted or mono-, di- or tri-substituted by F, and the aryl also can be unsubstituted or monosubstituted by CF3;
R7 is selected from the group consisting of H, (C1-C4) alkyl and halogen, wherein the alkyl is unsubstituted or mono-, di- or tri-substituted by F; and
R8 is H or F;
or a stereoisomer, enantiomer, tautomer, or physiologically acceptable salt thereof.
5. The compound according to claim 1 , wherein
R1 is selected from the group consisting of (C1-C4) alkyl, (C3-C6) cycloalkyl, and phenyl, wherein the alkyl can be unsubstituted or mono-, di- or tri-substituted by F;
R2 is selected from the group consisting of H, F, Cl and O—(C1-C4) alkylene-H, wherein the alkylene is unsubstituted or mono-, di- or tri-substituted by F;
R3 is H;
R4 is H;
R5 is H or (C1-C4) alkyl;
A is thiophene, thiazole, or pyridine;
n is 1, or 2;
z is 1;
R6 is selected from the group consisting of (C1-C4) alkyl, F, C 1-10 —(C0-C6) alkylene-H, and phenyl, wherein the phenyl can be unsubstituted or monosubstituted by CF3;
R7 is selected from the group consisting of H, (C1-C4) alkyl, and Cl, wherein the alkyl is unsubstituted or mono-, di- or tri-substituted by F; and
R8 is H or F,
or a stereoisomer, enantiomer, tautomer, or physiologically acceptable salt thereof.
6. The compound according to claim 1 , wherein
R1 is isopropyl;
R2, R3, R4 and R5 are H;
A is thiophene;
n is 1;
z is 1;
R6 is O-ethyl, and is in ortho position;
R7 is C1 or CF3, and is in the in para position; and
R8 is H;
or a stereoisomer, enantiomer, tautomer, or physiologically acceptable salt thereof.
7. A pharmaceutical composition comprising at least one compound according to claim 1 , or a stereoisomer, enantiomer, tautomer, or physiologically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or excipient.
8. The pharmaceutical composition according to claim 7 , further comprising at least one additional active pharmaceutical compound, wherein the additional active pharmaceutical compound is effective in the treatment of metabolic disturbance or a physiological disorder associated therewith.
9. The pharmaceutical composition according to claim 8 wherein the additional active pharmaceutical compound is an anti-diabetic compound effective in the treatment of diabetes.
10. The pharmaceutical composition according to claim 8 wherein the additional active pharmaceutical compound is a lipid modulator compound.
11. The pharmaceutical composition according to claim 8 wherein the additional active pharmaceutical compound is a compound effective in the treatment of metabolic syndrome or a physical manifestation thereof.
12. A pharmaceutical composition comprising at least one compound according to claim 2 , or a stereoisomer, enantiomer, tautomer, or physiologically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or excipient.
13. A pharmaceutical composition comprising at least one compound according to claim 3 , or a stereoisomer, enantiomer, tautomer, or physiologically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or excipient.
14. A pharmaceutical composition comprising at least one compound according to claim 4 , or a stereoisomer, enantiomer, tautomer, or physiologically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or excipient.
15. A pharmaceutical composition comprising at least one compound according to claim 5 , or a stereoisomer, enantiomer, tautomer, or physiologically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or excipient.
16. A pharmaceutical composition comprising at least one compound according to claim 6 , or a stereoisomer, enantiomer, tautomer, or physiologically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or excipient.
17. A method for treating type-2 diabetes or diabetes mellitus or a physical manifestation in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of the compound according to claim 1 , or a stereoisomer, enantiomer, tautomer, or physiologically acceptable salt thereof.
18. A process for preparing a pharmaceutical composition comprising at least one compound according to claim 1 , or a stereoisomer, enantiomer, tautomer, or physiologically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or excipient, which comprises mixing the compound according to claim 1 or the stereoisomer, enantiomer, tautomer, or physiologically acceptable salt thereof, with the pharmaceutically acceptable carrier or excipient, and bringing this mixture into a form suitable for administration.