4-oxy-N-[1,3,4]-thiadiazol-2-yl-benzene sulfonamides, pharmaceutical compositions and methods for their therapeutic use
View Patent ↗The present invention comprises 4-Oxy-N-[1,3,4]-thiadiazol-2-yl-benzene sulfonamides, the derivatives thereof and salts thereof as well as processes for their preparation and methods for their use as pharmaceutical compositions. More specifically, the invention relates to 4-oxy-N-[1,3,4]-thiadiazol-2-yl-benzene sulfonamides and to their physiologically acceptable salts and physiologically functional derivatives that exhibit peroxisome proliferator activator receptor (PPAR) PPARalpha, PPARdelta and PPARgamma agonist activity. The compounds themselves are defined by the structure of the formula I, wherein the various unnamed substituents are defined herein. The compounds are suitable for the treatment of disorders of fatty acid metabolism and glucose utilization disorders as well as of disorders in which insulin resistance is 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 alkyl, alkylene, aryl and cycloalkyl are unsubstituted or mono-, di- or tri-substituted by F, Cl, Br, (C1-C6) alkyl, O-(C1-C6) alkyl, CF 3 , OCF 3 , CN, CO-(C1-C6) alkyl, COO-(C1-C6) alkyl, CON((C0-C6) alkylene-H) (C0-C6) alkylene-H), and S(O) m (C1-C6) alkyl;
R2 and R3 are independently selected from the group consisting of H, halogen, (C1-C6) alkyl, (C0-C4) alkylene-O-(C0-C4) alkylene-H, SCH3 and CN, wherein alkyl and alkylene is unsubstituted or mono-, di- or trisubstituted by F;
R4, R5, R6 and R7 are independently selected from the group consisting of H, (C1-C6) alkyl, (C0-C4) alkylene-(C3-C6) cycloalkyl, (C0-C6) alkylene-(C6-C14) aryl, (C0-C6) alkylene-(C5-C15) heteroaryl, (C0-C6) alkylene-(C3-C15) heterocycloalkyl and (C0-C6) alkylene-(C3-C15) heterocycloalkenyl, wherein alkyl, cycloalkyl, aryl, heterocycloalkyl, heterocycloalkenyl and heteroaryl are unsubstituted or mono-, di- or trisubstituted by F, Cl, Br, CF3, (C1-C4) alkyl and (C0-C4)-alkylene-O-(C0-C4) alkylene-H;
m is 0 or 1;
A is (C6-C14) aryl or (C5-C15) heteroaryl;
B is selected from the group consisting of (C6-C14) aryl, (C3-C12) cycloalkyl, and (C5-C15) heteroaryl;
Z is a bond, O or
Ring A and Ring B together form an annealed (C5-C15) heterocyclic or (C8-C14) aromatic ring system; and Z is absent;
R8 and R9 are independently selected from the group consisting of H, halogen, (C1-C6) alkyl, (C0-C4) alkylene-O-(C0-C4) alkylene-H, SCF3, SF5, S(O)2CF3, O—(C6-C14) aryl, (C6-C14) aryl, and NO2, wherein alkyl and alkylene is unsubstituted or mono, bi- or tri-substituted by F and wherein aryl is unsubstituted or mono-, di- or tri-substituted by F, Cl, Br, CF3, (C1-C4) alkyl and (C0-C4)-alkylene-O-(C0-C4) alkylene-H;
p is 0, 1, 2 or 3;
q is 0, 1 or 2;
its' stereoisomers, enantiomers, tautomers their salts and mixtures thereof.
2. The compounds of the formula I as recited in claim 1 , wherein
R1 is selected from the group consisting of (C1-C6) alkyl, (C0-C6) alkylene-O-(C1-C6) alkyl and (C0-C6) alkylene-(C6-C14) aryl, wherein alkyl, alkylene and aryl are unsubstituted or mono- or disubstituted by F;
R2 and R3 are independently selected from the group consisting of H, halogen, (C1-C6) alkyl, (C0-C4) alkylene-O-(C0-C4) alkylene-H, wherein alkyl and alkylene is unsubstituted or mono-, di- or trisubstituted by F;
0ne of R4, R5, R6 and R7 is selected from the group consisting of H, (C1-C6) alkyl, (C0-C2) alkylene-(C3-C6) cycloalkyl, (C0-C2) alkylene-(C6-C10) aryl, (C0-C2) alkylene-(C5-C10) heteroaryl, (C0-C2) alkylene-(C3-C10) heterocycloalkyl, and (C0-C2) alkylene-(C3-C10) heterocycloalkenyl, wherein alkyl, cycloalkyl, aryl, heterocycloalkyl, heterocycloalkenyl and heteroaryl are unsubstituted or mono-, di- or trisubstituted by F, Cl, CF3, (C1-C4) alkyl and (C0-C4)-alkylene-O-(C0-C4) alkylene-H; and the other three of the substituents is H
m is 0 or 1;
A is (C6-C10) aryl, (C5-C10) heteroaryl;
B is selected from the group consisting of (C6-C10) aryl, (C6-C8) cycloalkyl, (C5-C10) heteroaryl;
Z is a bond or O;
A and B together form an annealed (C8-C10) heterocyclic ring and Z is absent;
R8 is H or (C1-C6) alkyl;
R9 is H, (C1-C6) alkyl, (C0-C4) alkylene-O-(C0-C4) alkylene-H, O-(C6-C10) aryl, wherein alkyl and alkylene is unsubstituted or mono, bi- or trisubstituted by F;
p is 0, 1, 2;
q is 0, 1.
3. The compound of formula I as claimed in claim 1 , wherein
R1 is selected from the group consisting of (C1-C6) alkyl, phenyl, and (C3-C6) cycloalkyl.
4. The compounds of formula I as recited in claim 2 , wherein
R1 is isopropyl.
5. The compounds of formula I as recited in claim 4 , wherein
R2 and, R3 are H.
6. The compounds of formula I as recited in claim 5 , wherein
R4, R5, R6 and R7 are H.
7. The compounds of formula I as recited in claim 6 , wherein
m is 0.
8. The compounds of formula I as recited in claim 7 , wherein
A is selected from the group consisting of oxazole, thiazole, phenyl and, 1,2,4-oxadiazole.
9. The compounds of formula I as recited in claim 8 wherein
B is phenyl or cyclohexyl.
10. The compounds of formula I as recited in claim 9 , wherein
z is a bond.
11. The compounds of formula I as recited in claim 9 , wherein
A and B together form a benzofuran ring and z is absent.
12. The compounds of the formula I as recited in claim 10 , wherein
R8 is H, (C1-C4) alkyl and
p is 0 or 1.
13. The compounds of the formula I as recited in claim 11 , wherein
R9 is H, CF3, O-(C1-C4) alkyl, phenoxy and
q is 1.
14. A pharmaceutical composition comprising one or more compounds of the formula I as recited in claim 1 .
15. A process for preparing a pharmaceutical composition comprising one or more of the compounds as claimed in claim 1 , which comprises mixing the active compound with a pharmaceutically suitable carrier and bringing this mixture into a form suitable for administration.