Methods for using 1,2,4-oxadiazole benzoic acid compounds
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 nonsense mutation in a patient having a disease or disorder associated with a nonsense mutation, 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 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 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 nonsense mutation 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 1 , wherein the compound has the formula:
or a pharmaceutically acceptable salt 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 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 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.
4. The method of claim 3 , wherein X is halogen.
5. The method of claim 4 , wherein X is F.
6. The method of claim 3 , wherein R 1 is hydrogen.
7. The method of claim 3 , wherein R 2 , R 3 , R 4 and R 5 are hydrogen.
8. The method of claim 3 , wherein R 1 , R 2 , R 3 , R 4 and R 5 are hydrogen.
9. The method of claim 1 , wherein the compound is: 3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid or a pharmaceutically acceptable salt thereof.
10. The method of claim 9 , wherein the patient has undergone a screening process to determine the presence of a nonsense mutation.
11. The method of claim 9 , wherein the patient is a human.
12. The method of claim 9 , wherein the compound is administered parenterally, transdermally, mucosally, nasally, buccally, sublingually, or orally.
13. The method of claim 12 , wherein the compound is administered orally in a granule or powder form.
14. The method of claim 9 , wherein the therapeutically effective amount is from about 1 mg to about 2000 mg per day.
15. The method of claim 9 , wherein the disease or disorder is a muscular dystrophy.
16. The method of claim 15 , wherein the muscular dystrophy is Duchenne muscular dystrophy.
17. The method of claim 9 , wherein the disease or disorder is cystic fibrosis.
18. A method for increasing the expression of full-length dystrophin protein in a patient having a muscular dystrophy, comprising administering an effective amount of 3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid or a pharmaceutically acceptable salt thereof to said patient.
19. The method of claim 18 , wherein the muscular dystrophy is Duchenne muscular dystrophy.
20. A method for increasing the expression of full length CFTR protein in a patient having cystic fibrosis, comprising administering an effective amount of 3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid or a pharmaceutically acceptable salt thereof to said patient.