Cancer treatment with (2,2-bishydroxymethyl) methylenecyclopropane nucleotides

Patent metadata

Field	Value
Publication number	US-12221459-B2
Application number	US-201916979152-A
Country	US
Kind code	B2
Filing date	Mar 8, 2019
Priority date	Mar 9, 2018
Publication date	Feb 11, 2025
Grant date	Feb 11, 2025

Abstract

The invention provides a compound of formula (I)whereinB is a nucleobase;U is O or S;Rx is —OC(═O)Ry, —OC(═O)CH(Ry)NH2, —OCH2OC(═O)Ry;Ry is optionally substituted alkyl or alkenyl or the side chain of a natural or unnatural amino acidR1 is H, or optionally substituted phenyl, benzyl, naphthyl, pyridyl or indolyl, orRx and R1 together define a bond thus forming a cyclic phosphate;R2 and R2′ together define the side chain of a natural or unnatural amino acid;R3 is optionally substituted alkyl, cycloalkyl, phenyl or benzyl;and pharmaceutically acceptable salts and compositions thereofwhich are useful in the treatment of cancer, especially leukemias.

First claim

The invention claimed is:

1. A compound represented by formula I:

wherein:
B is a nucleobase selected from the groups (a) to (d):

U is O or S;
R x is —OC(═O)R y , —OC(═O)CH(R y )NH 2 , or —OCH 2 OC(═O)R y ;
R y is C 1 -C 20 alkyl or C 2 -C 20 alkenyl any of which is optionally substituted with one, two or three substituents each independently selected from fluoro, hydroxy and amino; or
R y is the side chain of a natural amino acid, which may be in the D or L configuration;
R 1 is H, or a cyclic group selected from phenyl, benzyl, naphthyl, pyridyl or indolyl, each of which cyclic groups is optionally substituted with one, two or three R 22 ;
each R 22 is independently selected from halo, hydroxy, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, haloC 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl, C 1 -C 6 alkoxy, haloC 1 -C 6 alkoxy, C 1 -C 6 alkylcarbonyl, C 3 -C 6 cycloalkylcarbonyl, azido, cyano, amino, or any two R 22 groups attached to adjacent ring carbon atoms can combine to form —O—(CH 2 ) 1-2 —O—, wherein C 3 -C 6 cycloalkyl is optionally substituted with C 1 -C 3 alkyl; or
R 1 and R x together define a bond, thus forming a cyclic phosphate;
R 2 and R 2 ′ are each independently selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkylC 1 -C 3 alkyl, phenyl, benzyl and indolyl; or
R 2 and R 2 ′ together with the carbon atom to which they are attached form a C 3 -C 7 cycloalkylene group;
wherein each C 1 -C 6 alkyl is optionally substituted with halo or OR 12 , and each C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkylene, phenyl and benzyl is optionally substituted with one or two groups independently selected from C 1 -C 3 alkyl, halo and OR 12 ; or
one of R 2 and R 2 ′ is H, and the other is the side chain of a natural amino acid, wherein the carboxy terminus of an Asp or Glu is optionally esterified with C 1 -C 6 alkyl;
R 3 is C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 3 alkylC 3 -C 7 cycloalkyl, phenyl or benzyl; any of which is optionally substituted with 1, 2 or 3 substituents each independently selected from halo, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy and N(R 12 ) 2 ; R 4 , R 5 , R 7 and R 8 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, halo, —OR 12 or —N(R 12 ) 2 ;
R 6 , R 9 , R 10 and R 11 are each independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl,
C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, halo, OR 12 , —N(R 12 ) 2 , —NHC(O)OR 12 , cyano, —C(O)OR 12 , —C(O)N(R 12 ) 2 or —NHC(O)R 13 , wherein C 2 -C 6 alkenyl and C 2 -C 6 alkynyl is optionally substituted with halo or C 3 -C 5 cycloalkyl;
each R 12 is independently H, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or C 1 -C 6 alkylC 3 -C 7 cycloalkyl;
R 13 is R 12 or CH 2 CH(NH 2 )C(═O)OH;
or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein B is the group (d):

wherein
R 11 is NH 2 or NHCOC 1 -C 6 alkyl.

3. The compound according to claim 1 , wherein B is the group (c):

wherein R 9 is C 1 -C 6 alkoxy, C 3 -C 6 cycloalkoxy, C 1 -C 6 alkylamine or C 3 -C 6 cycloalkylamine, and R 10 is NH 2 or NHCOC 1 -C 6 alkyl.

4. The compound according to claim 1 , wherein B is the group (a):

wherein: R 4 is H,
R 5 is F or H, and
R 6 is NH 2 .

5. The compound according to claim 1 , wherein R 1 is H, or phenyl which is optionally substituted with one or two R 22 , and each R 22 is independently selected from halo, C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl, haloC 1 -C 3 alkyl, C 1 -C 3 alkoxy, haloC 1 -C 3 alkoxy, C 1 -C 3 alkylcarbonyl, C 3 -C 4 cycloalkylcarbonyl, wherein C 3 -C 4 cycloalkyl is optionally substituted with methyl.

6. The compound according to claim 5 , wherein phenyl is substituted in the 4-position with Br.

7. The compound according to claim 5 , wherein the phenyl is unsubstituted.

8. The compound according to claim 1 , wherein R 2 ′ is H and R 2 is C 1 -C 6 alkyl or haloC 1 -C 6 alkyl.

9. The compound according to claim 8 , wherein the stereochemistry is as indicated in the partial formula:

10. The compound according to claim 8 , wherein R 2 is methyl.

11. The compound according to claim 1 , wherein R 3 is C 4 -C 10 alkyl.

12. The compound according to claim 1 , wherein R 3 is benzyl or C 3 -C 7 cycloalkyl.

13. The compound according to claim 1 , wherein R x is —OC(═O)C 1 -C 6 alkyl.

14. The compound according to claim 1 , wherein R x is —OC(═O)C 16 -C 20 alkyl.

15. The compound according to claim 1 , wherein R x is —OC(═O)CH(R y )NH 2 and R y is the side chain of a natural amino acid and the configuration at the chiral center to which R y is attached is that of an L-amino acid.

16. The compound of claim 1 , wherein R x is —OCH 2 OC(═O)CH 3 or —OCH 2 OC(═O)C(CH 3 ) 3 .

17. The compound of claim 1 , wherein U is O.

18. The compound of claim 1 , selected from

or a pharmaceutically acceptable salt thereof.

19. A compound according to claim 1 , selected from

or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising a compound according to claim 1 , in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

21. A method for the treatment of cancer comprising the administration to a subject in need thereof an effective amount of a compound according to claim 1 , wherein the cancer is leukemia.

22. The compound according to claim 11 , wherein R 3 is 2-propylpentyl or 2-ethlybutyl.

23. The compound according to claim 13 , wherein the C 1 -C 6 alkyl moiety is methyl, isopropyl, isobutyl or t-butyl.

24. The compound according to claim 14 , wherein R x is —OC(═O)C 17 alkyl.

25. The compound according to claim 15 , wherein the natural amino acid is alanine.

26. The compound according to claim 16 , wherein R x is —OCH 2 OC(═O)C(CH 3 ) 3 .

Assignees

• Medivir Ab

Inventors

• Klasson Björn
• ÖBERG Fredrik

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61K31/513 Primary

  having oxo groups directly attached to the heterocyclic ring, e.g. cytosine · CPC title

• A61K31/522

  having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir · CPC title

• A61K31/675

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title

• C07D239/47

  One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine · CPC title