Compositions of 1,2,4-oxadiazole benzoic acid compounds and methods for their use

Patent metadata

Field	Value
Publication number	US-9861617-B2
Application number	US-201514940345-A
Country	US
Kind code	B2
Filing date	Nov 13, 2015
Priority date	Apr 11, 2003
Publication date	Jan 9, 2018
Grant date	Jan 9, 2018

Abstract

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.

First claim

What is claimed is:

1. A method for treating a lysosomal storage disorder associated with a premature stop codon in a patient having a lysosomal storage disorder associated with a premature stop codon, 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.

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:
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.

4. 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.

5. 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, —(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.

6. The method of claim 1 , wherein the lysosomal storage disorder associated with a premature stop codon is mucopolysaccharidosis type VII, mucopolysaccharidosis type III A, or mucopolysaccharidosis type VI.

7. 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.

8. The method of claim 7 , 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.

9. The method of claim 7 , wherein the patient has undergone a screening process to determine the presence of a premature stop codon.

10. The method of claim 7 , wherein the patient is a human.

11. The method of claim 7 , wherein the compound is administered parenterally, transdermally, mucosally, nasally, buccally, sublingually, or orally.

12. The method of claim 7 , wherein the therapeutically effective amount is from about 1 mg to about 2000 mg per day.

13. The method of claim 7 , wherein the lysosomal storage disorder associated with a premature stop codon is mucopolysaccharidosis type VII, mucopolysaccharidosis type III A, or mucopolysaccharidosis ty

Assignees

• Ptc Therapeutics Inc
• Ptc Therapeutics Inc

Inventors

• Karp Gary Mitchell
• Hwang Seongwoo
• Chen Guangming
• Almstead Neil Gregory
• Moon Young-Choon

Classifications

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• C07D271/06 Primary

  1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles · CPC title

• A61K31/4245 Primary

  Oxadiazoles · CPC title