Salts of diphosphate phosphoramidate of nucleosides as anticancer compounds

Patent metadata

Field	Value
Publication number	US-11560400-B2
Application number	US-201816769635-A
Country	US
Kind code	B2
Filing date	Dec 5, 2018
Priority date	Dec 5, 2017
Publication date	Jan 24, 2023
Grant date	Jan 24, 2023

Abstract

The present invention relates to compounds comprising a salt of a diphosphate phosphoramidate of a nucleoside drug, e.g. clofarabine. The compounds are useful in the treatment of cancer, e.g. leukemia.

First claim

The invention claimed is:

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:

wherein
R 1 is selected from: C 1 -C 24 -alkyl, C 3 -C 24 -alkenyl, C 3 -C 24 -alkynyl, C 0 -C 4 -alkylene-C 3 -C 8 -cycloalkyl and C 0 -C 4 -alkylene-aryl;
R 2 and R 3 are independently selected from H, C 1 -C 6 -alkyl and C 1 -C 3 -alkylene-R 7 ; or R 2 and R 3 together with the atom to which they are attached form a 3- to 6-membered cycloalkyl or heterocycloalkyl group;
R 4 is selected from H or C 1 -C 4 -alkyl;
or R 4 is joined with a group selected from R 2 and R 3 to form a 3- to 6-membered heterocycloalkyl group;
R 5 is selected from aryl, 5-, 6-, 9- or 10-membered heteroaryl, C 3 -C 8 -cycloalkyl, 3- to 7-membered heterocycloalkyl, C 1 -C 3 -alkylene-R 5a and C 1 -C 8 -alkyl, and wherein the aryl may be optionally fused to C 6 -C 8 -cycloalkyl;
R 5a is selected from aryl, 5-, 6-, 9- or 10-membered heteroaryl, C 3 -C 8 -cycloalkyl, and 3- to 7-membered heterocycloalkyl, wherein the aryl may be optionally fused to C 6 -C 8 -cycloalkyl;
R 6 is selected from:

R 7 is selected from aryl, imidazole, indole, SR a , OR a , CO 2 R a , CO 2 NR a R a , NR a R b and NH(═NH)NH 2 ;
R 8 is selected from H and

Z 1 and Z 2 are each independently selected from O and S;
Y is selected from H, F, Cl and OMe;
X is at each occurrence a pharmaceutically acceptable cation;
wherein any aryl group is either phenyl or naphthyl;
wherein where any of R 1 , R 2 , R 3 , R 4 , R 5 or R 7 is an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, that alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally substituted with from 1 to 4 substituents selected from: halo, nitro, cyano, NR a R a , NR a S(O) 2 R a , NR a C(O)R a , NR a CONR a R a , NR a CO 2 R a , OR a , SR a , SOR a , SO 3 R a , SO 2 R a , SO 2 NR a R a , CO 2 R a , C(O)R a , CONR a R a , CR a R a NR a R a , C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl and C 1 -C 4 -haloalkyl;
wherein R a is independently at each occurrence selected from: H and C 1 -C 4 -alkyl; and R b is independently at each occurrence selected from: H, and C 1 -C 4 -alkyl and C(O)—C 1 -C 4 -alkyl.

2. The compound of claim 1 , wherein R 4 is H.

3. The compound of claim 1 , wherein R 6 is

4. The compound of claim 1 , wherein R 6 is

5. The compound of claim 1 , wherein R 6 is

6. The compound of claim 5 , wherein Y is H.

7. The compound of claim 5 , wherein Y is F.

8. The compound of claim 5 , wherein R 8 is H.

9. The compound of claim 5 , wherein R 8 is

10. The compound of claim 9 , wherein Z 2 is O.

11. The compound of claim 9 , wherein Z 2 is S.

12. The compound of claim 1 , wherein R 6 is

13. The compound of claim 1 , wherein R 6 is

14. The compound of claim 1 , wherein R 6 is

15. The compound of claim 1 , wherein R 1 is selected from C 5 -C 7 -cycloalkyl, C 1 -C 8 -alkyl and benzyl.

16. The compound of claim 15 , wherein R 1 is benzyl.

17. The compound of claim 15 , wherein R 1 is C 1 -C 8 -alkyl.

18. The compound of claim 1 , wherein R 3 is H.

19. The compound of claim 1 , wherein R 2 is C 1 -C 4 -alkyl.

20. The compound of claim 1 , wherein R 2 is H.

21. The compound of claim 1 , wherein R 5 is phenyl.

22. The compound of claim 1 , wherein R 5 is naphthyl.

23. The compound of claim 1 , wherein the compound is selected from:

24. A method for treating cancer, comprising administering to a patient in need thereof a compound of claim 1 , wherein the cancer is a leukaemia or a lymphoma.

25. The method of claim 24 , wherein the cancer is a leukaemia selected from the group consisting of acute myeloid leukaemia (AML), acute lymphoid leukaemia (ALL), chronic myeloid leukaemia (CML), chronic lymphoid leukaemia (CLL) and biphenotypic acute leukaemia (BAL).

26. The method of claim 24 , wherein the cancer is a lymphoma selected from the group consisting of Hodgkin's lymphoma and non-Hodgkin's lymphoma.

27. A pharmaceutical composition comprising the compound of claim 1 ; and at least one pharmaceutically acceptable excipient.

Assignees

• NuCana plc

Inventors

• Griffith Hugh
• Serpi Michaela
• Pertusati Fabrizio
• Slusarczyk Magdalena

Classifications

• A61P35/02

  specific for leukemia · CPC title

• C07H19/10 Primary

  with the saccharide radical esterified by phosphoric or polyphosphoric acids · CPC title

• C07H19/207 Primary

  the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide · CPC title

• A61K31/7076

  containing purines, e.g. adenosine, adenylic acid · CPC title

• A61P35/00

  Antineoplastic agents · CPC title