Riluzole prodrugs and their use

Patent metadata

Field	Value
Publication number	US-12005047-B2
Application number	US-202318361837-A
Country	US
Kind code	B2
Filing date	Jul 29, 2023
Priority date	Mar 3, 2015
Publication date	Jun 11, 2024
Grant date	Jun 11, 2024

Abstract

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.

First claim

The invention claimed is:

1. A method for treating spinocerebellar ataxia, comprising administering to a subject in need of such treatment 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 R 23 is H.

3. 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;
2-(2-aminoacetamido)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide;
or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 3 , which is 2-(2-aminoacetamido)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide or a pharmaceutically acceptable salt thereof.

5. The method according to claim 1 , wherein the at least one compound is administered in a composition further comprising at least one excipient.

6. The method according to claim 1 , wherein the spinocerebellar ataxia is hereditary spinocerebellar ataxia.

Assignees

• Biohaven Therapeutics Ltd

Inventors

• Wrobel Jay Edward
• Reitz Allen B
• Pelletier Jeffery Claude
• Smith Garry Robert
• Bian Haiyan

Classifications

• A61K40/36

  Immune checkpoint inhibitors · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• A61K9/2004

  Excipients; Inactive ingredients · CPC title

• A61K9/1617

  Organic compounds, e.g. phospholipids, fats · CPC title

• A61K9/006 Primary

  Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays · CPC title