Riluzole prodrugs and their use
Pharmaceutical compositions of the invention include substituted riluzole prodrugs useful for the treatment of cancers including melanoma, breast cancer, brain cancer, and prostate cancer through the release of riluzole. Prodrugs of riluzole have enhanced stability to hepatic metabolism and are delivered into systemic circulation by oral administration, and then cleaved to release riluzole in the plasma via either an enzymatic or general biophysical release process.
1. A method of attenuating presynaptic glutamate release, the method comprising administering to a subject an effective amount of at least one compound having formula:
wherein R 23 is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 CCH, CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 ) CH 2 CH 3 , CH 2 OH, CH 2 OCH 2 Ph, CH 2 CH 2 OCH 2 Ph, CH(OH) CH 3 , CH 2 Ph, CH 2 (cyclohexyl), CH 2 (4-OH-Ph), (CH 2 ) 4 NH 2 , (CH 2 ) 3 NHC(NH 2 ) NH, CH 2 (3-indole), CH 2 (5-imidazole), CH 2 CO 2 H, CH 2 CH 2 CO 2 H, CH 2 CONH 2 , and CH 2 CH 2 CONH 2 ;
or an enantiomer, diastereomer, hydrate, solvate, pharmaceutically acceptable salt, or complex thereof.
2. The method according to claim 1 , wherein the compound is selected from the group consisting of:
(S)-2-amino-N-(2-(methyl (2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino) ethyl)amino)-2-oxoethyl) propanamide;
(R)-2-amino-N-(2-(methyl (2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino) ethyl)amino)-2-oxoethyl) propanamide;
(S)-2-amino-3-methyl-N-(2-(methyl (2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino) ethyl)amino)-2-oxoethyl) butanamide;
(R)-2-amino-3-methyl-N-(2-(methyl (2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino) ethyl)amino)-2-oxoethyl) butanamide;
(S)-2-amino-N-(2-(methyl (2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino) ethyl)amino)-2-oxoethyl)-3-phenylpropanamide;
(R)-2-amino-N-(2-(methyl (2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino) ethyl)amino)-2-oxoethyl)-3-phenylpropanamide;
(S)-2-amino-4-methyl-N-(2-(methyl (2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino) ethyl)amino)-2-oxoethyl) pentanamide;
(R)-2-amino-4-methyl-N-(2-(methyl (2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino) ethyl)amino)-2-oxoethyl) pentanamide;
(S)-2-amino-3-hydroxy-N-(2-(methyl (2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino) ethyl)amino)-2-oxoethyl) propanamide;
(R)-2-amino-3-hydroxy-N-(2-(methyl (2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino) ethyl)amino)-2-oxoethyl) propanamide; and
2-(2-aminoacetamido)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino) ethyl) acetamide;
or a pharmaceutically acceptable form thereof.
3. The method of claim 1 , wherein the effective amount of at least one compound is administered in a composition further comprising at least one excipient.
4. The method of claim 1 , wherein the attenuating presynaptic glutamate release comprises an inhibitory effect on glutamate release, inactivation of voltage-dependent sodium channels, ability to interfere with intracellular events that follow transmitter binding at excitatory amino acid receptors, or a combination thereof.
5. The method of claim 1 , wherein R 23 is H.