Substituted 1,2,4-oxadiazoles, compositions and methods of use
View Patent ↗Novel 1,2,4-oxadiazole benzoic acid compounds, methods of using and pharmaceutical compositions comprising an 1,2,4-oxadiazole benzoic acid derivative are disclosed. The methods include methods of treating or preventing a disease ameliorated by modulation of premature translation termination or nonsense-mediated mRNA decay, or ameliorating one or more symptoms associated therewith.
1. A compound of the formula:
or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein:
Z is substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle;
R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH 2 CH 2 O) n R 6 or any biohydrolyzable group;
R 2 , R 3 , R 4 , R 5 and R 6 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, alkoxy, aryloxy, heteroaryloxy, halogen, CF 3 , OCF 3 , OCHF 2 , CN, COOH, COOR 7 , SO 2 R 7 , NO 2 , NH 2 , or N(R 7 ) 2 ;
each occurrence of R 7 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, alkoxy, aryloxy, heteroaryloxy, halogen or CF 3 ;
n is an integer from 1 to 7;
with the proviso that when R 1 , R 2 , R 3 , R 4 , and R 5 are each hydrogen, Z is not 3-(4-pyridinyl)propyl, or 2-(4-piperidinyl) ethyl.
2. The compound of claim 1 having the formula:
or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein:
Z is substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle; and R is hydrogen or halogen.
3. The compound of claim 1 wherein R 1 is a biohydrolyzable ester.
4. The compound of claim 1 wherein Z is (2-Chloro-pyridin-3-yl); Benzo[1,3]dioxol-yl; (3-Methyl-thiophen-2-yl); Benzo[b]thiophen-2-yl; Thiophen-2-yl; (2,5-Dimethyl-furan-3-yl); (4-Pyrrol-1-yl-phenyl); Benzo[1,2,5]oxadiazol-yl; (6-Chloro-pyridin-3-yl); Furan-2-yl; Pyridin-3-yl; Pyridin-4-yl; 5-(1-Acetyl-piperidin-4-yl); 5-Isoxazol-5-yl; [3-(2-Chloro-6-fluoro-phenyl)-5-methyl-isoxazol-4-yl] or [3-(2-Chloro-phenyl)-5-methyl-isoxazol-4-yl].
5. A compound selected from the group consisting of:
3-[5-(2-Chloro-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acid;
3-(5-Benzo[1,3]dioxol-5-yl-[1,2,4]oxadiazol-3-yl)-benzoic acid;
3-[5-(3-Methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acid;
3-(5-Benzo[b]thiophen-2-yl-[1,2,4]oxadiazol-3-yl)-benzoic acid;
3-(5-Thiophen-2-yl-[1,2,4]oxadiazol-3-yl)-benzoic acid;
3-[5-(2,5-Dimethyl-furan-3-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acid;
3-[5-(4-Pyrrol-1-yl-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid;
3-(5-Benzo[1,2,5]oxadiazol-5-yl-[1,2,4]oxadiazol-3-yl)-benzoic acid;
3-[5-(6-Chloro-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acid;
3-(5-Furan-2-yl-[1,2,4]oxadiazol-3-yl)-benzoic acid;
3-(5-Pyridin-3-yl-[1,2,4]oxadiazol-3-yl)-benzoic acid;
3-(5-Pyridin-4-yl-[1,2,4]oxadiazol-3-yl)-benzoic acid;
3-[5-(1-Acetyl-piperidin-4-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acid;
3-(5-Isoxazol-5-yl-[1,2,4]oxadiazol-3-yl)-benzoic acid;
3-{5-[3-(2-Chloro-6-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-[1,2,4]oxadiazol-3-yl}-benzoic acid;
3-[5-(6-Chloro-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acid;
3-[5-(2-Methylsulfanyl-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acid;
3-[5-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acid;
3-{5-[3-(2-Chloro-phenyl)-5-methyl-isoxazol-4-yl]-[1,2,4]oxadiazol-3-yl}-benzoic acid;
3-[5-(6-Pyrrolidin-1-yl-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acid;
3-[5-(6-Morpholin-4-yl-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acid;
3-[5-(3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-[1,2,4]oxadiazol-3-yl]-benzoic acid;
or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.
6. A pharmaceutical composition comprising a compound according to claim 1 , 2 or 5 and a pharmaceutically acceptable carrier, excipient or diluent.
7. A pharmaceutical composition of claim 6 suitable for oral, parenteral, mucosal, transdermal or topical administration.
8. A pharmaceutical composition of claim 7 suitable for oral administration.
9. A pharmaceutical composition of claim 8 in solid form.
10. A pharmaceutical composition of claim 9 , wherein the composition is a powder.
11. A pharmaceutical composition of claim 9 , wherein the composition is a tablet.
12. A pharmaceutical composition of claim 9 , wherein the composition is a capsule.
13. A pharmaceutical composition of claim 8 in liquid form.
14. A pharmaceutical composition of claim 13 , wherein the composition is a suspension.
15. A pharmaceutical composition of claim 14 , wherein the composition is aqueous.
16. A single unit dosage form comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, excipient or diluent.
17. A single unit dosage form comprising a compound according to claim 2 and a pharmaceutically acceptable carrier, excipient or diluent.
18. A single unit dosage form comprising a compound according to claim 5 and a pharmaceutically acceptable carrier, excipient or diluent.
19. The pharmaceutical composition according to claim 6 , wherein the composition is sterile.