Transient protection of normal cells during chemotherapy

Patent metadata

Field	Value
Publication number	US-10660896-B2
Application number	US-201815943278-A
Country	US
Kind code	B2
Filing date	Apr 2, 2018
Priority date	Mar 15, 2013
Publication date	May 26, 2020
Grant date	May 26, 2020

Abstract

This invention is in the area of improved compounds, compositions and methods of transiently protecting healthy cells, and in particular hematopoietic stem and progenitor cells (HSPC) as well as renal cells, from damage associated with DNA damaging chemotherapeutic agents. In one aspect, improved protection of healthy cells is disclosed using disclosed compounds that act as highly selective and short, transiently-acting cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors when administered to subjects undergoing DNA damaging chemotherapeutic regimens for the treatment of proliferative disorders.

First claim

We claim:

1. A compound of Formula:

or a pharmaceutically acceptable salt thereof;
wherein:
R 10 is —C(O)-R 12 , or C(O)O—R 13 ;
R 12 is NHR A or R A ;
R 13 is R A ;
R A is C 1 -C 8 alkyl, cycloalkylalkyl, TT-RR, C 1 -C 8 cycloalkyl containing one or more heteroatoms selected from N, O, and S, or C 1 -C 8 cycloalkyl;
TT is C 1 -C 8 alkylene or C 3 -C 8 cycloalkylene linker; and
RR is hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 6 -C 10 aryl, heteroaryl having one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S, C 3 -C 10 carbocycle, or heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S.

2. The compound of claim 1 , wherein R 10 is —C(O)—R 12 .

3. The compound of claim 2 , wherein R 12 is R A .

4. The compound of claim 3 , wherein R A is C 1 -C 8 alkyl.

5. The compound of claim 2 , wherein R 12 is NHR A .

6. The compound of claim 5 , wherein R A is C 1 -C 8 alkyl.

7. The compound of claim 1 , wherein R 10 is —C(O)O—R 13 .

8. The compound of claim 1 , of Formula:

9. The compound of claim 1 , of Formula:

10. The compound of claim 9 , wherein R 10 is —C(O)—R 12 .

11. The compound of claim 10 , wherein R 12 is R A .

12. The compound of claim 11 , wherein R A is C 1 -C 8 alkyl.

13. The compound of claim 10 , wherein R 12 is NHR A .

14. The compound of claim 13 , wherein R A is C 1 -C 8 alkyl.

15. A pharmaceutical composition comprising an effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier.

16. A compound of Formula:

or a pharmaceutically acceptable salt thereof;
wherein:
each R 1 is independently aryl, alkyl, cycloalkyl, or haloalkyl;
or two R 1 's on adjacent ring atoms together with the ring atoms to which they are attached form a 3-8-membered cycle
R 10 is —C(O)—R 12 , or —C(O)O—R 13 ;
R 12 is NHR A or R A ;
R 13 is R A ;
R A is C 1 -C 8 alkyl, cycloalkylalkyl, -TT-RR, C 1 -C 8 cycloalkyl containing one or more heteroatoms selected from N, O, and S, or C 1 -C 8 cycloalkyl;
TT is C 1 -C 8 s alkylene or C 3 -C 8 cycloalkylene linker; and
RR is hydroxyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 6 -C 10 aryl, heteroaryl having one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S, C 3 -C 10 carbocycle, or heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S.

17. The compound of claim 16 , wherein R 10 is —C(O)—R 12 .

18. The compound of claim 17 , wherein R 12 is R A .

19. The compound of claim 18 , wherein R A is C 1 -C 8 alkyl.

20. The compound of claim 17 , wherein R 12 is NHR A .

21. The compound of claim 20 , wherein R A is C 1 -C 8 alkyl.

Assignees

• G1 Therapeutics Inc
• Gi Therapeutics Inc

Inventors

• Strum Jay Copeland
• Bisi John Emerson
• Roberts Patrick Joseph
• Tavares Francis X

Classifications

• A61K31/7048

  having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin {, digitoxin or digoxin} · CPC title

• A61K31/519

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

• A61K31/555

  containing heavy metals, e.g. hemin, hematin, melarsoprol · CPC title

• C07D487/14 Primary

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title