1,2,4-Oxadiazole benzoic acid compounds and their use for nonsense suppression and the treatment of disease
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 method for treating a disease or disorder associated with a premature stop codon in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound having the formula:
or a pharmaceutically acceptable salt thereof, wherein:
Z is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted arylalkyl;
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 ; and
n is an integer from 1 to 7,
wherein the disease or disorder associated with a premature stop codon is cystic fibrosis, a muscular dystrophy, retinitis pigmentosa, hemophilia, ataxia-telangiectasia, tuberous sclerosis, neurofibromatosis, Marfan syndrome, Parkinson's disease, mucopolysaccharidosis type III A, mucopolysaccharidosis type VI or mucopolysaccharidosis type VII.
2. The method of claim 1 , wherein the compound has the formula:
or a pharmaceutically acceptable salt thereof, wherein:
Z is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocycle, substituted or unsubstituted arylalkyl; and R is hydrogen or halogen.
3. The method of claim 2 , wherein the compound is: 3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid or a pharmaceutically acceptable salt thereof.
4. The method of claim 3 , wherein the premature stop codon is caused by a mutation comprising a point mutation, a missense mutation, a frameshift mutation, an insertion mutation, a deletion mutation, a transition mutation or a transversion mutation.
5. The method of claim 3 , wherein the patient has undergone a screening process to determine the presence of a premature stop codon.
6. The method of claim 3 , wherein the patient is a human.
7. The method of claim 3 , wherein the compound is administered parenterally, transdermally, mucosally, nasally, buccally, sublingually, or orally.
8. The method of claim 7 , wherein the compound is administered orally in a tablet, liquid or capsule form.
9. The method of claim 3 , wherein the therapeutically effective amount is from about 1 mg to about 2000 mg per day.
10. The method of claim 3 , wherein the disease or disorder is a muscular dystrophy.
11. The method of claim 3 , wherein the disease or disorder is tuberous sclerosis.
12. The method of claim 3 , wherein the disease or disorder is hemophilia.
13. The method of claim 12 , wherein hemophilia is hemophilia A or hemophilia B.
14. The method of claim 3 , wherein the disease or disorder is Marfan syndrome.
15. The method of claim 3 , wherein the disease or disorder is Parkinson's disease.
16. The method of claim 3 , wherein the disease or disorder is cystic fibrosis.
17. The method of claim 10 , wherein the muscular dystrophy is Duchenne muscular dystrophy.
18. A method for treating cystic fibrosis, comprising administering to a patient having cystic fibrosis a therapeutically effective amount of 3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid or a pharmaceutically acceptable salt thereof.
19. A method for treating a muscular dystrophy, comprising administering to a patient having a muscular dystrophy a therapeutically effective amount of 3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid or a pharmaceutically acceptable salt thereof.
20. The method of claim 19 , wherein the muscular dystrophy is Duchenne muscular dystrophy.
21. The method of claim 18 or 19 , wherein the patient is a human.
22. The method of claim 18 or 19 , wherein the compound is administered parenterally, transdermally, mucosally, nasally, buccally, sublingually, or orally.
23. The method of claim 22 , wherein the compound is administered orally in a tablet, liquid or capsule form.
24. The method of claim 18 or 19 wherein the therapeutically effective amount is from about 1 mg to about 2000 mg per day.
25. The method of claim 1 , wherein the compound has the formula:
or a pharmaceutically acceptable salt thereof, wherein:
Z is substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted arylalkyl;
R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or —(CH 2 CH 2 O) n R 6 ;
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 aryl, alkoxy, aryloxy, 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 aryl, alkoxy, aryloxy, halogen or CF 3 ; and
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 methyl, 2-carboxy ethyl, phenyl or 4-cyanophenyl.
26. The method of claim 1 , wherein the compound has the formula:
or a pharmaceutically acceptable salt thereof, wherein:
Z is substituted aryl, substituted or unsubstituted cycloalkyl, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted arylalkyl;
R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, —(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 aryl, alkoxy, aryloxy, 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 aryl, alkoxy, aryloxy, halogen or CF 3 ; and
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, then Z is not 2-carboxy ethyl or 4-cyanophenyl.
27. The method of claim 1 , wherein the compound has the formula:
or a pharmaceutically acceptable salt, solvate or stereoisomer thereof wherein:
X is halogen, substituted alkyl, alkoxy or hydroxy;
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 ; and
n is an integer from 1 to 7.
28. The method of claim 3 , wherein said disease associated with a premature stop codon is retinitis pigmentosa.
29. The method of claim 3 , wherein said disease associated with a premature stop codon is neurofibromatosis.
30. The method of claim 3 , wherein said disease associated with a premature stop codon is ataxia-telangiectasia.
31. The method of claim 3 , wherein said disease associated with a premature stop codon is mucopolysaccharidosis type III A.
32. The method of claim 3 , wherein said disease associated with a premature stop codon is mucopolysaccharidosis type VI.
33. The method of claim 3 , wherein said disease associated with a premature stop codon is mucopolysaccharidosis type VII.