Nitrogen-containing analogs of salinomycin, synthesis and use against cancer stem cells and malaria

1. A compound of formula (I), enantiomers, mixture of enantiomers, diastereoisomers and mixture of diasteroisomers thereof:

wherein:

W is selected from the group consisting of ═O; —NR 1 R 2 ; —NR 3 —(CH 2 ) n —NR 4 R 5 ; —O—(CH 2 ) n —NR 4 R 5 ; —NR 3 —(CH 2 ) n —N + R 6 R 7 R 8 and —O—(CH 2 ) n —N + R 6 R 7 R 8 ;

X is selected from the group consisting of ═O, —OH; —NR 1 R 2 ; —NR 3 —(CH 2 ) n —NR 4 R 5 ; —O—(CH 2 ) n —NR 4 R 5 ; —NR 3 —(CH 2 ) n —N + R 6 R 7 R 8 and —O—(CH 2 ) n —N + R 6 R 7 R 8 ,

Y is selected from the group consisting of —OH; ═N—OH; —NR 1 R 2 ; —NR 3 —(CH 2 ) n —NR 4 R 5 ; —O—(CH 2 ) n —NR 4 R 5 ; —NR 3 —(CH 2 ) n —N + R 6 R 7 R 8 and —O—(CH 2 ) n —N + R 6 R 7 R 8 ,

R 1 and R 2 , identical or different, are selected from the group consisting of H; (C 1 -C 16 )-alkyl; (C 3 -C 16 )-alkenyl; (C 3 -C 16 )-alkynyl; (C 3 -C 16 )-cycloalkyl; aryl; heteroaryl; (C 1 -C 6 )-alkyl-aryl; (C 1 -C 6 )-alkyl-heteroaryl; or R 1 represents H and R 2 represents OR 9 , where R 9 is H, (C 1 -C 6 )-alkyl, aryl and (C 1 -C 6 )-alkyl-aryl;

R 3 is selected from the group consisting of H; (C 1 -C 6 )-alkyl; (C 1 -C 6 )-alkyl-aryl;

R 4 and R 5 , identical or different, are selected from the group consisting of H; (C 1 -C 6 )-alkyl; aryl and (C 1 -C 6 )-alkyl-aryl;

R 6 , R 7 and R 8 , identical or different, are selected from the group consisting of (C 1 -C 6 )-alkyl; aryl and (C 1 -C 6 )-alkyl-aryl;

Z is selected from the group consisting of OH;

NHNR 9 R 10 ; NHOC(O)R 11 ; N(OH)—C(O)R 11 ; OOH, SR 12 ; 2-aminopyridine; 3-aminopyridine; —NR 3 —(CH 2 ) n —NR 4 R 5 ; and —NR 3 —(CH 2 ) n —OH; where:

R 9 and R 10 , identical or different, are selected from the group consisting of H, (C 1 -C 6 )-alkyl, aryl and (C 1 -C 6 )-alkyl-aryl;

R 11 is selected from the group consisting of H; (C 1 -C 16 )-alkyl; (C 3 -C 16 )-alkenyl; (C 3 -C 16 )-alkynyl; aryl; heteroaryl; (C 1 -C 6 )-alkyl-aryl; (C 1 -C 6 )-alkyl-heteroaryl;

R 12 is selected from the group consisting of H; (C 1 -C 16 )-alkyl; (C 3 -C 16 )-alkenyl; (C 3 -C 16 )-alkynyl; aryl; heteroaryl; (C 1 -C 6 )-alkyl-aryl; (C 1 -C 6 )-alkyl-heteroaryl

n=0, 2, 3, 4, 5 or 6,

with the proviso that at least one of W, X and Y is selected from the group consisting of —NR 1 R 2 ; —NR 3 —(CH 2 ) n —NR 4 R 5 ; —O—(CH 2 ) n —NR 4 R 5 ; —NR 3 —(CH 2 ) n —N + R 6 R 7 R 8 and —O—(CH 2 ) n —N + R 6 R 7 R 8 .

2. The compound according to claim 1 , wherein:

R 1 and R 2 , identical or different, are selected from the group consisting of H; (C 1 -C 16 )-alkyl; (C 3 -C 16 )-alkenyl; (C 3 -C 16 )-alkynyl; (C 3 -C 16 )-cycloalkyl; and

(C 1 -C 6 )-alkyl-heteroaryl,

R 3 is selected from the group consisting of H; and (C 1 -C 6 )-alkyl;

R 4 and R 5 , identical or different, are selected from the group consisting of H; (C 1 -C 6 )-alkyl; and (C 1 -C 6 )-alkyl-aryl.

3. The compound according to claim 1 or 2 , wherein R 1 is H and R 2 is selected from the group consisting of (C 1 -C 16 )-alkyl, —(C 3 -C 16 )-alkenyl, (C 3 -C 16 )-alkynyl, (C 3 -C 16 )-cycloalkyl, and (C 1 -C 6 )-alkyl-heteroaryl.

4. The compound of formula (I) according to claim 1 , wherein Z is OH or NHOH.

5. The compound according to claim 1 , wherein W, X and Y, identical or different, are selected from the group consisting of —NR 1 R 2 ; —NR 3 —(CH 2 ) n —NR 4 R 5 ; —O—(CH 2 ) n —NR 4 R 5 ; —NR 3 —(CH 2 ) n —N + R 6 R 7 R 8 ; and —O—(CH 2 ) n —N + R 6 R 7 R 8 ; R 1 to R 8 and n being as previously defined.

6. The compound according to claim 1 , wherein two of X, Y or Z, identical or different, are selected from the group consisting of —NR 1 R 2 ; —NR 3 —(CH 2 ) n —NR 4 R 5 ; —O—(CH 2 ) n —NR 4 R 5 ; —NR 1 —(CH 2 ) n —N + R 6 R 7 R 8 ; and —O—(CH 2 ) n —N + R 6 R 7 R 8 ; R 1 to R 8 and n being as previously defined.

7. The compound of formula (I) according to claim 1 , wherein one of X, Y or Z is selected from the group consisting of —NR 1 R 2 ; —NR 3 —(CH 2 ) n —NR 4 R 5 ; —O—(CH 2 ) n —NR 4 R 5 ; —NR 1 —(CH 2 ) n —N + R 6 R 7 R 8 ; and —O—(CH 2 ) n —N + R 6 R 7 R 8 ; R 1 to R 8 and n being as previously defined.

8. The compound of formula (I) according to claim 7 , wherein X is selected from the group consisting of —NR 1 R 2 , —NR 3 —(CH 2 ) n —NR 4 R 5 ; —O—(CH 2 ) n —NR 4 R 5 ; —NR 1 —(CH 2 ) n —N + R 6 R 7 R 8 ; and —O—(CH 2 ) n —N + R 6 R 7 R 8 and Y is OH; R 1 to R 8 and n being as previously defined.

9. The compound of formula (I) according to claim 7 , wherein X is selected from the group consisting of ═O and OH and Y is selected from the group consisting of —NR 1 R 2 ; —NR 3 —(CH 2 ) n —NR 4 R 5 ; —O—(CH 2 ) n —NR 4 R 5 ; —NR 1 —(CH 2 ) n —N + R 6 R 7 R 8 ; and —O—(CH 2 ) n —N + R 6 R 7 R 8 ; R 1 to R 8 and n being as previously defined.

10. The compound according to claim 9 , wherein X is OH, Z is OH and Y is NR 1 R 2 where R 1 is H and R 2 is selected from the group consisting of (C 1 -C 16 )-alkyl, (C 3 -C 16 )-alkenyl, (C 3 -C 16 )-alkynyl, and (C 3 -C 16 )-cycloalkyl.

11. The compound according to claim 1 , selected from the group consisting of:

12. The compound according to claim 1 or 2 , wherein R 1 is H and R 2 is selected from the group consisting of (C 3 -C 14 )-alkyl; (C 3 -C 5 )-alkenyl; (C 3 -C 5 )-alkynyl; (C 3 -C 6 )-cycloalkyl; and CH 2 -pyridinyl.

13. The compound of formula (I) according to claim 1 , wherein Z is OH.

14. The compound of formula (I) according to claim 7 , wherein X is selected from the group consisting of —NR 1 R 2 ; —NR 3 —(CH 2 ) n —NR 4 R 5 and —O—(CH 2 ) n —NR 4 R 5 and Y is OH; R 1 to R 8 and n being as previously defined.

15. The compound of formula (I) according to claim 7 , wherein X is OH and Y is selected from the group consisting of —NR 1 R 2 , —NR 3 —(CH 2 ) n —NR 4 R 5 , and —O—(CH 2 ) n —NR 4 R 5 ; R 1 to R 8 and n being as previously defined.

16. The compound according to claim 9 , wherein X is OH, Z is OH and Y is NR 1 R 2 where R 1 is H and R 2 is selected from the group consisting of (C 8 -C 14 )-alkyl, (C 3 -C 5 )-alkenyl, (C 3 -C 5 )-alkynyl, and (C 3 -C 6 )-cycloalkyl.

17. A drug containing the compound according to claim 1 .

18. A pharmaceutical composition comprising at least a compound of formula (I) according to claim 1 , a pharmaceutically acceptable salt, solvate, or hydrate thereof, and at least one pharmaceutically acceptable excipient.

19. The pharmaceutical composition according to claim 18 , further comprising another anticancer drug.

20. The pharmaceutical composition according to claim 19 , wherein said other anticancer drug is Adriamycin and Cyclophosphamide or Docetaxel.

21. A combination medicament comprising:

a) the compound of formula (I) according to claim 1 , and

b) another chemotherapy compound,

for simultaneous, separate, or staggered use.

22. The medicament according to claim 21 , wherein said another chemotherapy compound is Adriamycin, Cyclophosphamide, or Docetaxel, and wherein said medicament is used in the treatment of cancer.

23. A method for the treatment of cancer in a subject in need thereof, comprising administering to the subject an effective amount of at least one compound according to claim 1 .

24. The method according to claim 23 for reducing the risk of cancer relapse and/or metastases.

25. The method according to claim 23 for the treatment of malaria.

26. The method according to claim 23 for the treatment of breast cancer.

27. A method for the treatment of cancer in a subject in need thereof, comprising administering to the subject an effective amount of at least one pharmaceutical composition according to claim 18 .

28. The method according to claim 27 for the treatment of breast cancer.