Methods and compositions for inhibition of dihydroorotate dehydrogenase

Patent metadata

Field	Value
Publication number	US-11312686-B2
Application number	US-201917253342-A
Country	US
Kind code	B2
Filing date	Jun 22, 2019
Priority date	Jun 22, 2018
Publication date	Apr 26, 2022
Grant date	Apr 26, 2022

Abstract

Disclosed herein are compounds, 3,4,6,8-substituted-2-([1′-biphenyl]-4-yl)quinoline analogs, that are inhibitors of dihydroorotate dehydrogenase (DHODH) with improved pharmacokinetic properties. The disclosed compounds can be used in the treatment of a variety of disorders and diseases in which inhibition of DHODH can be clinically useful, including cancer, such as a hematological cancer, including acute myeloid leukemia (AML); graft-versus-host-diseases; autoimmune disorders; and disorders associated with T-cell proliferation. The disclosed compounds can demonstrate flip-flop kinetics when administered orally, i.e., pharmacokinetics in which the rate of absorption, rather than the rate of elimination, dominates the pharmacokinetics. The disclosed compounds can demonstrate a sustained pharmacokinetic profile instead of an immediate release profile. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present disclosure.

First claim

What is claimed:

1. A compound having a formula represented by a structure:

wherein R 1 is selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CF 3 , and —CF 2 CF 3 ;
wherein each of R 5b and R 5c is independently selected from —R 20 , hydrogen, halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CF 3 , and —CF 2 CF 3 ; wherein R 20 is selected from —C1-C10 alkylamino and —C1-C10 alkoxy;

provided that one of R 5b and R 5c is —R 20 ; and
wherein each R 5a , R 5d , and R 5e is independently selected from hydrogen, halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CF 3 , and —CF 2 CF 3 ;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R 5b is —R 20 ; and wherein each of R 5a , R 5c , R 5d , and R 5e is independently selected from hydrogen, halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CF 3 , and —CF 2 CF 3 .

3. The compound of claim 2 , wherein R 20 is —C2-C7 alkylamino.

4. The compound of claim 2 , wherein R 20 is —C2-C7 alkoxy.

5. The compound of claim 2 , wherein each of R 5a , R 5c , R 5d , and R 5e is selected from halogen and hydrogen.

6. The compound of claim 2 , wherein each of R 5a , R 5c , R 5d , and R 5e is hydrogen.

7. The compound of claim 2 , wherein R 1 is halogen.

8. The compound of claim 7 , wherein R 1 is fluoro.

9. The compound of claim 1 , wherein R 5c is —R 20 ; and wherein each of R 5a , R 5b , R 5d , and R 5e is independently selected from hydrogen, halogen, —SF 5 , —CN, —OH, —NH 2 , —CF 3 , and —CF 2 CF 3 .

10. The compound of claim 9 , wherein R 20 is —C2-C7 alkylamino.

11. The compound of claim 9 , wherein R 20 is —C2-C7 alkoxy.

12. The compound of claim 9 , wherein each of R 5a , R 5b , R 5d , and R 5e is selected from halogen and hydrogen.

13. The compound of claim 9 , wherein each of R 5a , R 5b , R 5d , and R 5e is hydrogen.

14. The compound of claim 9 , wherein R 1 is halogen.

15. The compound of claim 14 , wherein R 1 is fluoro.

16. The compound of claim 1 , present as:

or a subgroup thereof.

17. The compound of claim 1 , wherein the compound is a pharmaceutically acceptable salt thereof comprising the conjugate base form of the compound, and a counter ion selected from Li + , K + , Na + , ammonium, tetramethylammonium, tetraethylammonium, Fe +2 , Cu +2 , Zn +2 , Mg +2 , Ca +2 , Al +3 , Fe +3 , and combinations thereof.

18. The compound of claim 17 , wherein the counter ion is Na + .

19. A pharmaceutical composition comprising a therapeutically effective amount of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Assignees

• Ohio State Innovation Foundation
• Hendrix College

Inventors

• Byrd John C
• Goodwin Thomas E
• Elgamal Ola
• Hertlein Erin
• Abdulrahim Mouad
• Bennett Chad E
• Vibhute Sandip Madhukar

Classifications

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61P17/06

  Antipsoriatics · CPC title

• A61K31/573

  substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone · CPC title

• A61K45/06

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

• A61P35/00

  Antineoplastic agents · CPC title