Riluzole prodrugs and their use

Patent metadata

Field	Value
Publication number	US-10905681-B2
Application number	US-201916449948-A
Country	US
Kind code	B2
Filing date	Jun 24, 2019
Priority date	Mar 3, 2015
Publication date	Feb 2, 2021
Grant date	Feb 2, 2021

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

What is claimed is:

1. A pharmaceutical composition comprising: (i) a compound having formula:

wherein:
R 23 is selected from the group consisting 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 a complex thereof; and (ii) a pharmaceutically acceptable carrier.

2. The pharmaceutical composition of 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.

3. The pharmaceutical composition of claim 1 wherein R 23 is H.

4. The pharmaceutical composition of claim 2 wherein the compound is 2-(2-aminoacetamido)-N-methyl-N-(2-oxo-2-((6-(trifluoromethoxy)benzo[d]thiazol-2-yl)amino)ethyl)acetamide.

5. The pharmaceutical composition of claim 1 in the form of a tablet.

6. The pharmaceutical composition of claim 5 in the form of an orally dissolving tablet.

7. The pharmaceutical composition of claim 6 wherein the orally dissolving tablet comprises gelatin.

8. The pharmaceutical composition of claim 7 wherein the orally dissolving tablet comprises mannitol.

9. The pharmaceutical composition of claim 1 in the form of a capsule.

10. The pharmaceutical composition of claim 9 wherein the capsule comprises at least one of a binder, a disintegrant, a glidant or a lubricant.

11. The pharmaceutical composition of claim 9 wherein the wherein the capsule comprises at least one of mannitol, microcrystalline cellulose, colloidal silicon dioxide, or magnesium stearate.

Assignees

• Biohaven Therapeutics Ltd

Inventors

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

Classifications

• A61K40/36

  Immune checkpoint inhibitors · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• C07K5/06026

  the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title