Prodrugs of riluzole and their method of use

Inventors: Garry Robert Smith (Royersford, PA); Allen B. Reitz (Lansdale, PA); Mark McDonnell (Lansdale, PA); Suzie Chen (Highland Park, NJ); Matthew D. Vera (Collegeville, PA); Benjamin E Blass (Eagleville, PA); Jeffrey Claude Pelletier (Lafayette Hill, PA); Venkata N. Velvadapu (Philadelphia, PA); Jay Edward Wrobel (Lawrenceville, NJ)

Assignees: Biohaven Pharmaceutical Holding Company Ltd.; Rutgers, The State University of New Jersey

C07D277/82 A61K31/428 A61K45/06 C07D417/12

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 12,172,974
App. No.: 17/940,287
Granted: Dec 24, 2024
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

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 (41)

1. A compound having the formula (II)

including hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein:

R 12a , R 12b , R 12c , R 12d , and R 12e are each independently selected from the group consisting of hydrogen, deuterium, halogen, trifluoromethyl, triflouromethoxy, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy.

2. A compound having the formula (IVa)

including hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof;

wherein R 3a is selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, CH 2 R 4a , optionally substituted phenyl, optionally substituted benzyl, optionally substituted CH 2 CH 2 Ar, Optionally substituted CH 2 heteroaryl, CH 2 OR 9 , CH(CH 3 )OR 9 ,CH 2 SR 9 ,CH 2 CH 2 SCH 3 , CH 2 CH 2 SO 2 CH 3 , CH 2 CH 2 CH 2 NR 10a R 10b ,CH 2 COR 9a , and CH 2 CH 2 COR 9a ; R 4a is selected from the group consisting of hydrogen, optionally substituted C1-C6 Alkyl, optionally substituted C3-C6 cycloalkyl, and optionally substituted four to six membered saturated heterocyclic ring comprising three to five carbon atoms and a member selected from the group consisting of O, NR 7a , S, and SO 2 ;

R 7a and R 7b are each independently selected from the group consisting of hydrogen, methyl, COR 12 , and CO 2 R 12 ;

R 8a and R 8b are each independently optionally substituted C1-C6 alkyl;

R 9 is selected from the group consisting of hydrogen, C1-C6 alkyl, optionally substituted phenyl, optionally substituted benzyl, and optionally substituted CH 2 CH 2 Ar;

R 9a is selected from the group consisting of OH, C1-C6 alkoxy, and NH 2 ;

R 10a and R 10b are each independently selected from the group consisting of hydrogen and optionally substituted C1-C6 alkyl;

or R 10a and R 10b are taken together with the atom to which they are bound to form an optionally substituted ring having 5 to 6 ring atoms;

or R 10a and R 10b 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 R 10a and R 10b 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;

R 12 is C1-C6 alkyl;

Ar is selected from the group consisting of optionally substituted phenyl and optionally substituted naphthyl ring; and

Ar is optionally substituted with 0-5 moieties selected from the group consisting of deuterium, halogen, trifluoromethyl, triflouromethoxy, cyano, NR 7a R 7b , CONR 8a R 8b , C1-C6 alkyl, and C1-C6 alkoxy.

3. A compound having the formula (Va)

including hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof;

wherein R 3b is selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, CH 2 R 4a , optionally substituted phenyl, optionally substituted benzyl, optionally substituted CH 2 CH 2 Ar, Optionally substituted CH 2 heteroaryl, CH 2 OR 9 , CH(CH 3 ) OR 9 ,CH 2 SR 9 ,CH 2 CH 2 SCH 3 , CH 2 CH 2 SO 2 CH 3 , CH 2 CH 2 CH 2 NR 10a R 10b , CH 2 COR 9a , and CH 2 CH 2 COR 9a ,

R 4a is selected from the group consisting of hydrogen, optionally substituted C1-C6 Alkyl, optionally substituted C3-C6 cycloalkyl, and optionally substituted four to six membered saturated heterocyclic ring comprising three to five carbon atoms and a member selected from the group consisting of O, NR 7a , S, and SO 2 ;