# US 11,440,893 B2 · Prodrugs of riluzole and their method of use

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- Number: US 11,440,893 B2
- Document ID: US11440893B2
- Status: Granted
- Kind: B2
- Application number: 17/101,239
- Filed: 2020-11-23
- Published: 2021-03-18
- Granted: 2022-09-13
- Earliest claimed: 2012-03-16
- Assignees: Biohaven Pharmaceutical Holding Company Ltd.; Rutgers, The State University of New Jersey
- Applicants: Biohaven Pharmaceutical Holding Company Ltd.; Rutgers, The State University of New Jersey
- Inventors: Garry Robert Smith; Allen B. Reitz; Mark McDonnell; Suzie Chen; Matthew D. Vera; Benjamin E. Blass; Jeffrey Claude Pelletier; Venkata N. Velvadapu; Jay Edward Wrobel
- Web page: https://patentgrep.com/patent/US11440893B2

## CPC

- C07D 277/82: Nitrogen atoms
- A61K 31/428: condensed with carbocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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)

## 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 cancer, said method comprising administering to a subject an effective amount of
at least one compound having formula (I) below:
including hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein:
R1 is OR2,
R2 is selected from the group consisting of optionally substituted C3-C6 alkyl and CH2(CH2)nNR8aR8b,
R8a is optionally substituted C1-C6 alkyl,
R8b is optionally substituted C2-C6 alkyl, and
n is 1 or 2;
or
at least one compound having formula (I) below:
including hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein:
R1 is CH2CH2CO2R4, and
R4 is selected from the group consisting of hydrogen and optionally substituted C1-C6 alkyl;
or
at least one compound having formula (I) below:
including hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein:
R1 is CH2CH2CONHR5,
R5 is selected from the group consisting of hydrogen, optionally substituted C1-C6 Alkyl, CH2CH2NR10aR10b, and CH2R11,
R10a and R10b are each independently selected from the group consisting of hydrogen and optionally substituted C1-C6 alkyl,
or
R10a and R10b are taken together with the atom to which they are bound to form an optionally substituted ring having 5 to 6 ring atoms,
or
R10a and R10b are taken together with the atom to which they are bound to form an optionally substituted ring having 5 to 6 ring atoms containing an oxygen,
or
R10a and R10b are taken together with the atom to which they are bound to form an optionally substituted ring having 5 to 6 ring atoms containing two nitrogen atoms, and
R11 is selected from the group consisting of optionally substituted phenyl and optionally substituted heteroaryl;
wherein the cancer is ovarian cancer, cervical cancer, breast cancer, prostate cancer, testicular cancer, lung cancer, renal cancer, colorectal cancer, skin cancer, brain cancer, or leukemia.

### Claim 2 (depends on 1)

The method of claim 1, wherein the at least one compound is administered in a composition further comprising at least one excipient and an anticancer agent.

### Claim 3

A method for treating melanoma, said method comprising administering to a subject an effective amount of
at least one compound having formula (I) below:
including hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein:
R1 is OR2,
R2 is selected from the group consisting of optionally substituted C3-C6 alkyl and CH2(CH2)nNR8aR8b,
R8a is optionally substituted C1-C6 alkyl,
R8b is optionally substituted C2-C6 alkyl, and
n is 1 or 2;
or
at least one compound having formula (I) below:
including hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein:
R1 is CH2CH2CO2R4, and
R4 is selected from the group consisting of hydrogen and optionally substituted C1-C6 alkyl;
or
at least one compound having formula (I) below:
including hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein:
R1 is CH2CH2CONHR5,
R5 is selected from the group consisting of hydrogen, optionally substituted C1-C6 Alkyl, CH2CH2NR10aR10b, and CH2R11,
R10a and R10b are each independently selected from the group consisting of hydrogen and optionally substituted C1-C6 alkyl,
or
R10a and R10b are taken together with the atom to which they are bound to form an optionally substituted ring having 5 to 6 ring atoms,
or
R10a and R10b are taken together with the atom to which they are bound to form an optionally substituted ring having 5 to 6 ring atoms containing an oxygen,
or
R10a and R10b are taken together with the atom to which they are bound to form an optionally substituted ring having 5 to 6 ring atoms containing two nitrogen atoms, and
R11 is selected from the group consisting of optionally substituted phenyl and optionally substituted heteroaryl.

### Claim 4 (depends on 3)

The method of claim 3, wherein the at least one compound is administered in a composition further comprising at least one excipient.

### Claim 5

A composition comprising an effective amount of
at least one compound having formula (I) below:
including hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein:
R1 is OR2,
R2 is selected from the group consisting of optionally substituted C3-C6 alkyl and CH2(CH2)nNR8aR8b,
R8a is optionally substituted C1-C6 alkyl,
R8b is optionally substituted C2-C6 alkyl, and
n is 1 or 2;
or
at least one compound having formula (I) below:
including hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein:
R1 is CH2CH2CO2R4, and
R4 is selected from the group consisting of hydrogen and optionally substituted C1-C6 alkyl;
or
at least one compound having formula (I) below:
including hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein:
R1 is CH2CH2CONHR5,
R5 is selected from the group consisting of hydrogen, optionally substituted C1-C6 Alkyl, CH2CH2NR10aR10b, and CH2R11,
R10a and R10b are each independently selected from the group consisting of hydrogen and optionally substituted C1-C6 alkyl,
or
R10a and R10b are taken together with the atom to which they are bound to form an optionally substituted ring having 5 to 6 ring atoms,
or
R10a and R10b are taken together with the atom to which they are bound to form an optionally substituted ring having 5 to 6 ring atoms containing an oxygen,
or
R10a and R10b are taken together with the atom to which they are bound to form an optionally substituted ring having 5 to 6 ring atoms containing two nitrogen atoms, and
R11 is selected from the group consisting of optionally
substituted phenyl and optionally substituted heteroaryl.