Prodrugs of riluzole and their method of use

Patent metadata

Field	Value
Publication number	US-11440893-B2
Application number	US-202017101239-A
Country	US
Kind code	B2
Filing date	Nov 23, 2020
Priority date	Mar 16, 2012
Publication date	Sep 13, 2022
Grant date	Sep 13, 2022

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 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:
R 1 is OR 2 ,
R 2 is selected from the group consisting of optionally substituted C3-C6 alkyl and CH 2 (CH 2 ) n NR 8a R 8b ,
R 8a is optionally substituted C1-C6 alkyl,
R 8b 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:
R 1 is CH 2 CH 2 CO 2 R 4 , and
R 4 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:
R 1 is CH 2 CH 2 CONHR 5 ,
R 5 is selected from the group consisting of hydrogen, optionally substituted C1-C6 Alkyl, CH 2 CH 2 NR 10a R 10b , and CH 2 R 11 ,
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, and

R 11 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.

2. 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.

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:
R 1 is OR 2 ,
R 2 is selected from the group consisting of optionally substituted C3-C6 alkyl and CH 2 (CH 2 ) n NR 8a R 8b ,
R 8a is optionally substituted C1-C6 alkyl,
R 8b 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:
R 1 is CH 2 CH 2 CO 2 R 4 , and
R 4 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:
R 1 is CH 2 CH 2 CONHR 5 ,
R 5 is selected from the group consisting of hydrogen, optionally substituted C1-C6 Alkyl, CH 2 CH 2 NR 10a R 10b , and CH 2 R 11 ,
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, and

R 11 is selected from the group consisting of optionally substituted phenyl and optionally substituted heteroaryl.

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

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:
R 1 is OR 2 ,
R 2 is selected from the group consisting of optionally substituted C3-C6 alkyl and CH 2 (CH 2 ) n NR 8a R 8b ,
R 8a is optionally substituted C1-C6 alkyl,
R 8b 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:
R 1 is CH 2 CH 2 CO 2 R 4 , and
R 4 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:
R 1 is CH 2 CH 2 CONHR 5 ,
R 5 is selected from the group consisting of hydrogen, optionally substituted C1-C6 Alkyl, CH 2 CH 2 NR 10a R 10b , and CH 2 R 11 ,
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, and
R 11 is selected from the group consisting of optionally
substituted phenyl and optionally substituted heteroaryl.

Assignees

• Biohaven Pharm Holding Co Ltd
• Univ Rutgers

Inventors

• Smith Garry Robert
• Reitz Allen B
• Mcdonnell Mark
• Chen Suzie
• Vera Matthew D
• Blass Benjamin E
• Pelletier Jeffrey Claude
• Velvadapu Venkata N
• Wrobel Jay Edward

Classifications

• C07D277/82 Primary

  Nitrogen atoms · CPC title

• A61K31/428

  condensed with carbocyclic rings · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title