# US 12,005,047 B2 · Riluzole prodrugs and their use

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- Number: US 12,005,047 B2
- Document ID: US12005047B2
- Status: Granted
- Kind: B2
- Application number: 18/361,837
- Filed: 2023-07-29
- Published: 2023-11-30
- Granted: 2024-06-11
- Earliest claimed: 2015-03-03
- Assignees: Biohaven Therapeutics Ltd.
- Applicants: Biohaven Therapeutics Ltd.
- Inventors: Jay Edward Wrobel; Allen B. Reitz; Jeffery Claude Pelletier; Garry Robert Smith; Haiyan Bian
- Web page: https://patentgrep.com/patent/US12005047B2

## CPC

- A61K 31/428: condensed with carbocyclic rings
- A61K 9/006: {Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays}
- A61K 9/1617: {Organic compounds, e.g. phospholipids, fats}
- A61K 9/2004: {Excipients; Inactive ingredients}
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/541: Non-condensed thiazines containing further heterocyclic rings
- A61K 38/05: Dipeptides
- A61K 38/06: Tripeptides
- A61K 40/36: Immune checkpoint inhibitors
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: 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
- A61P 35/00: Antineoplastic agents
- C07D 277/82: Nitrogen atoms
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07K 5/06026: {the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala}
- C07K 5/0806: {the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala}
- C07K 5/0808: {the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu}
- C07K 5/0812: {and aromatic or cycloaliphatic}
- A61K 9/0056: {Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals}
- A61K 9/2018: {Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates}
- A61K 9/2063: {Proteins, e.g. gelatin}
- A61K 9/485: {Inorganic compounds}
- A61K 9/4858: {Organic compounds}
- A61K 9/4866: {Organic macromolecular compounds}
- A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## 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.

## Claims

### Claim 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 R23 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH2CCH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2OH, CH2OCH2Ph, CH2CH2OCH2Ph, CH(OH)CH3, CH2Ph, CH2(cyclohexyl), CH2(4-OH-Ph), (CH2)4NH2, (CH2)3NHC(NH2)NH, CH2(3-indole), CH2(5-imidazole), CH2CO2H, CH2CH2CO2H, CH2CONH2, and CH2CH2CONH2; or an enantiomer, diastereomer, hydrate, solvate, pharmaceutically acceptable salt, or complex thereof.

### Claim 2 (depends on 1)

The method according to claim 1, wherein R23 is H.

### Claim 3 (depends on 1)

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.

### Claim 4 (depends on 3)

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.

### Claim 5 (depends on 1)

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

### Claim 6 (depends on 1)

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