Rationally improved isoniazid and ethionamide derivatives and activity through selective isotopic substitution
View Patent ↗The present invention relates to the use of isotopically labeled derivatives of isoniazid, ethionamide and related compounds as effective therapy for the treatment of mycobacterial diseases, including Mycobacterium tuberculosis.
1. A compound having the chemical structure:
or a pharmaceutically acceptable salt thereof wherein the compound contains at least one isotopically labeled atom selected from the group consisting of carbon-13, oxygen-17 and oxygen-18 in the exocyclic acyl hydrazide moiety of the compound and said NH 2 NH 2 group is optionally isotopically labeled with at least one 15 N atom.
2. A compound according to claim 1 having the chemical structure:
or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 2 having an isotopically labeled oxygen-17 or oxygen-18 atom.
4. The compound according to claim 2 having an isotopically labeled carbon-13 atom.
5. The compound according to claim 2 having an isotopically labeled oxygen-17 atom.
6. The compound according to claim 2 having an isotopically labeled oxygen-18 atom.
7. The compound according to claim 2 having an isotopically labeled carbon-13 atom and an isotopically labeled oxygen-18 atom.
8. The compound according to claim 1 having an isotopically labeled nitrogen-15 atom.
9. A pharmaceutical composition in dosage form comprising a therapeutically effective amount of a compound according to claim 1 in an amount of at least 25 mg.
10. A pharmaceutical composition in dosage form comprising a therapeutically effective amount of a compound according to claim 1 in an amount of at least 50 mg.
11. A pharmaceutical composition in dosage form comprising a therapeutically effective amount of a compound according to claim 1 in an amount of at least 100 mg.
12. A pharmaceutical composition in dosage form comprising a therapeutically effective amount of a compound according to claim 1 in an amount of at least 150 mg.
13. A pharmaceutical composition in dosage form comprising a therapeutically effective amount of a compound according to claim 1 in an amount of at least 250 mg.
14. A pharmaceutical composition in dosage form comprising a therapeutically effective amount of a compound according to claim 1 in an amount of at least 300 mg.
15. The pharmaceutical composition according to claim 9 in oral dosage form.
16. The pharmaceutical composition according to claim 9 in parenteral dosage form.
17. The pharmaceutical composition according to claim 9 in pulmonary dosage form,
18. The pharmaceutical composition according to claim 10 in pulmonary dosage form.
19. The pharmaceutical composition according to claim 9 further comprising a therapeutically effective amount of at least one additional, anti-tuberculosis agent.
20. The pharmaceutical composition according to claim 19 wherein said anti-tuberculosis agent is selected from the group consisting of rifampin, pyrazinamide, ethambutol/ethambutol hydrochloride, aminosalicyclic acid/aminosalicylate sodium, capreomycin sulfate, clofazimine, cycloserine, kanamycin sulfate, rifabutin, rifapentine, streptomycin sulfate, gatifloxacin and mixtures thereof.
21. The pharmaceutical composition according to claim 19 wherein said composition is a mixture of therapeutically effective amounts of isoniazid, rifampin, pyrazinamide and optionally, ethambutol/ethambutol hydrochloride.
22. The pharmaceutical composition according to claim 19 wherein said composition is a mixture of ethionamide and gatifloxacin, and optionally pyrazinamide all in therapeutically effective amounts.
23. The pharmaceutical composition according to claim 20 wherein said composition is a mixture of therapeutically effective amounts of isoniazid, rifampin, pyrazinamide and optionally, ethambutol/ethambutol hydrochloride.
24. The pharmaceutical composition according to claim 20 wherein said composition is a mixture of ethionamide and gatifloxacin, and optionally pyrazinamide all in therapeutically effective amounts.
25. A pharmaceutical composition in dosage form comprising a therapeutically effective amount of a compound according to claim 2 in an amount of at least 25 mg.
26. A pharmaceutical composition in dosage form comprising a therapeutically effective amount of a compound according to claim 2 in an amount of at least 100 mg.